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Intellectual disability - microarray and sequencing v5.518 TBC1D2B Sarah Leigh reviewed gene: TBC1D2B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v5.506 ZFX Tracy Lester reviewed gene: ZFX: Rating: GREEN; Mode of pathogenicity: None; Publications: 38325380; Phenotypes: Intellectual disability, developmental delay, behavioural abnormalities, hypotonia, dysmorphic facies; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability - microarray and sequencing v5.506 GLI3 Tracy Lester reviewed gene: GLI3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v5.499 ZFHX3 Sarah Leigh reviewed gene: ZFHX3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v5.497 SOX9 Tracy Lester reviewed gene: SOX9: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Skeletal dysplasia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.487 SMARCAL1 Arina Puzriakova reviewed gene: SMARCAL1: Rating: ; Mode of pathogenicity: None; Publications: 28796785, 20301550; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v5.485 ZFX Sarah Leigh reviewed gene: ZFX: Rating: GREEN; Mode of pathogenicity: None; Publications: 38325380; Phenotypes: X-linked neurodevelopmental disorder with recurrent facial gestalt; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability - microarray and sequencing v5.480 NXF5 Arina Puzriakova reviewed gene: NXF5: Rating: ; Mode of pathogenicity: None; Publications: 11566096, 20096387, 22030050, 23675524; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v5.475 INTS8 Arina Puzriakova Phenotypes for gene: INTS8 were changed from to ?Neurodevelopmental disorder with cerebellar hypoplasia and spasticity, OMIM:618572
Intellectual disability - microarray and sequencing v5.474 EFNB1 Arina Puzriakova Added comment: Comment on list classification: Upgrading from Red to Amber as a literature search did reveal evidence to suggest that some individuals may develop intellectual deficits. However, in most affected cases this was a mild presentation and there are more prominent and recognisable features observed in the general group of EFNB1-related cases which are more likely to inform diagnostic testing (e.g. craniosynostosis and clefting).
Intellectual disability - microarray and sequencing v5.472 EFNB1 Arina Puzriakova reviewed gene: EFNB1: Rating: AMBER; Mode of pathogenicity: None; Publications: 23335590, 25679214, 27650623, 31088393, 24520368; Phenotypes: Craniofrontonasal dysplasia, OMIM:304110; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability - microarray and sequencing v5.465 KCNA1 Achchuthan Shanmugasundram reviewed gene: KCNA1: Rating: AMBER; Mode of pathogenicity: None; Publications: 30055040, 34778950; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.453 BAZ2B Achchuthan Shanmugasundram reviewed gene: BAZ2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 37872713; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.453 KCNA1 Tracy Lester reviewed gene: KCNA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30055040, 34778950; Phenotypes: epileptic encephalopathy, ataxia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.451 LRRC32 Achchuthan Shanmugasundram reviewed gene: LRRC32: Rating: AMBER; Mode of pathogenicity: None; Publications: 30976112, 35656379; Phenotypes: Cleft palate, proliferative retinopathy, and developmental delay, OMIM:619074; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.451 ACBD6 Jana Jezkova reviewed gene: ACBD6: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 37951597; Phenotypes: HP:0001263, HP:0001249; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.450 ABCC9 Sarah Leigh Mode of pathogenicity for gene: ABCC9 was changed from None to None
Intellectual disability - microarray and sequencing v5.450 ABCC9 Sarah Leigh Mode of pathogenicity for gene: ABCC9 was changed from Other to None
Intellectual disability - microarray and sequencing v5.448 ABCC9 Sarah Leigh Added comment: Comment on mode of pathogenicity: Loss of function variants do cause the phenotype of Intellectual disability and myopathy syndrome (OMIM:619719) , which is relevant to this panel.
Intellectual disability - microarray and sequencing v5.448 ABCC9 Sarah Leigh Mode of pathogenicity for gene: ABCC9 was changed from to Other
Intellectual disability - microarray and sequencing v5.445 ABCC9 Sarah Leigh reviewed gene: ABCC9: Rating: GREEN; Mode of pathogenicity: None; Publications: 38217872; Phenotypes: Intellectual disability and myopathy syndrome, OMIM:619719, intellectual disability and myopathy syndrome, MONDO:0859224; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.440 KIRREL3 Sarah Leigh reviewed gene: KIRREL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 29271092; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v5.429 LRRC32 Hannah Knight reviewed gene: LRRC32: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 35656379; Phenotypes: Cleft palate, proliferative retinopathy, and developmental delay; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.414 GAN Tracy Lester reviewed gene: GAN: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301315; Phenotypes: Intellectual disability, developmental delay, neuropathy, hypotonia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.411 KCNA3 Achchuthan Shanmugasundram reviewed gene: KCNA3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.411 LGI3 Achchuthan Shanmugasundram changed review comment from: PMID:35948005 reported sixteen individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3. All of them exhibited a potentially clinically recognizable peripheral nerve hyperexcitability syndrome (PNHS) trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability. All sixteen patients had global developmental delay and all thirteen tested patients had mild or moderate intellectual disability. Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons.

This gene has been associated with relevant phenotype in OMIM (MIM #620007), but not yet in Gene2Phenotype.
Sources: Literature; to: PMID:35948005 reported sixteen individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3. All of them exhibited a potentially clinically recognizable peripheral nerve hyperexcitability syndrome (PNHS) trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability. All sixteen patients had global developmental delay and all thirteen tested patients had mild or moderate intellectual disability.

Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons.

This gene has been associated with relevant phenotypes in OMIM (MIM #620007), but not yet in Gene2Phenotype.
Sources: Literature
Intellectual disability - microarray and sequencing v5.410 LGI3 Achchuthan Shanmugasundram gene: LGI3 was added
gene: LGI3 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: LGI3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LGI3 were set to 35948005
Phenotypes for gene: LGI3 were set to Intellectual developmental disorder with muscle tone abnormalities and distal skeletal defects, OMIM:620007
Review for gene: LGI3 was set to GREEN
Added comment: PMID:35948005 reported sixteen individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3. All of them exhibited a potentially clinically recognizable peripheral nerve hyperexcitability syndrome (PNHS) trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability. All sixteen patients had global developmental delay and all thirteen tested patients had mild or moderate intellectual disability. Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons.

This gene has been associated with relevant phenotype in OMIM (MIM #620007), but not yet in Gene2Phenotype.
Sources: Literature
Intellectual disability - microarray and sequencing v5.409 ABCC9 Tracy Lester reviewed gene: ABCC9: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v5.405 DHX37 Tracy Lester reviewed gene: DHX37: Rating: GREEN; Mode of pathogenicity: None; Publications: 26539891, 31256877, 35982159; Phenotypes: Intellectual disability, developmental delay; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v5.402 ACBD6 Arina Puzriakova edited their review of gene: ACBD6: Added comment: - PMID: 21937992 (2011) - single individuals with a p.G22fs variant in the ACBD6 gene, presenting with mild ID, microcephaly, facial dysmorphism, spasticity. Limited additional information.

- PMID: 32108178 (2020) - two unrelated individuals with neurodevelopmental disorder (moderate ID is noted but otherwise limited clinical information) and carrying homozygous LoF variants in the ACBD6 gene (1 frameshift, 1 canonical splice). One individual also carried an allelic homozygous variant in the PRDX6 gene (unlikely but unknown disease consequence). Skin-derived patient fibroblasts showed reduced ACBD6 expression and N-myristoylation deficiency.

- PMID: 36457943 (2023) - two Thai siblings presenting with profound ID, morbid obesity, pancytopenia with severe recurrent infections, diabetes mellitus, cirrhosis, and renal failure, leading to deaths in their early 30s. Sequencing showed a novel homozygous single bp duplication (c.360dup; p.Leu121Thrfs*27) in the ACBD6 gene. Parents were heterozygous carriers.

- PMID: 37951597 (2023) - 45 previously undiagnosed individuals from 28 families with a neurodevelopmental syndrome including a complex and progressive movement disorder phenotype. Cardinal clinical features include moderate-to-severe GDD/ID (45/45), facial dysmorphism (38/40), HC <2nd percentile (21/31), weight >50th percentile (20/34), mild cerebellar ataxia (35/41), limb spasticity/hypertonia (31/41), gait abnormalities (33/35), dystonia (30/32) and variable epilepsy (13/29).

Homozygous ACBD6 variants were identified by WES in all cases, including 18 predicted LoF, 1 missense and 1 inframe insertion. Knockout studies in zebrafish recapitulate clinical features reported in patients such as movement disorders, seizures, and facial dysmorphology, while inactivation of acbd6 in X. tropicalis predominantly caused embryo death while surviving tadpoles demonstrated microcephaly, reduced movement, eye abnormalities, and brain structure differences.; Changed rating: GREEN; Changed publications to: 21937992, 32108178, 36457943, 37951597; Changed phenotypes to: Neurodevelopmental disorder, MONDO:0700092; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.401 KIRREL3 Dmitrijs Rots reviewed gene: KIRREL3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37605258; Phenotypes: NDD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.395 RPL10 Achchuthan Shanmugasundram reviewed gene: RPL10: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, X-linked syndromic 35, OMIM:300998; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability - microarray and sequencing v5.391 RELN Achchuthan Shanmugasundram reviewed gene: RELN: Rating: GREEN; Mode of pathogenicity: None; Publications: 35769015; Phenotypes: Lissencephaly 2 (Norman-Roberts type), OMIM:257320, neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.388 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from None to None
Intellectual disability - microarray and sequencing v5.388 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from None to None
Intellectual disability - microarray and sequencing v5.387 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from None to None
Intellectual disability - microarray and sequencing v5.388 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from None to None
Intellectual disability - microarray and sequencing v5.388 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from None to None
Intellectual disability - microarray and sequencing v5.388 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from None to None
Intellectual disability - microarray and sequencing v5.387 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from None to None
Intellectual disability - microarray and sequencing v5.387 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to None
Intellectual disability - microarray and sequencing v5.381 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability - microarray and sequencing v5.380 YARS Achchuthan Shanmugasundram reviewed gene: YARS: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Infantile-onset multisystem neurologic, endocrine, and pancreatic disease 2, OMIM:619418; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.379 CLCN6 Sarah Leigh Added comment: Comment on mode of pathogenicity: PMID 33217309 reports gain of function associated with CLCN6 variants.
Intellectual disability - microarray and sequencing v5.379 CLCN6 Sarah Leigh Mode of pathogenicity for gene: CLCN6 was changed from None to None
Intellectual disability - microarray and sequencing v5.377 CLCN6 Sarah Leigh edited their review of gene: CLCN6: Added comment: Review copied from Neuronal ceroid lipofuscinosis panel: PMID 33217309: Three unrelated families reported with recurrent GOF de novo c.1658A>G (p.Tyr553Cys) and severe developmental delay with pronounced generalized hypotonia, respiratory insufficiency, and variable neurodegeneration and diffusion restriction in cerebral peduncles, midbrain, and/or brainstem in MRI scans. Previously, monoallelic variants reported in 3 families with BPEI, but functional data/segregation not compelling. Mouse knockout model has features of NCL (Zornitza Stark (Australian Genomics), 9 Dec 2020).; Changed rating: GREEN; Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability - microarray and sequencing v5.371 SGSM3 Achchuthan Shanmugasundram reviewed gene: SGSM3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.363 AGPAT3 Achchuthan Shanmugasundram reviewed gene: AGPAT3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.354 CDK16 Sarah Leigh edited their review of gene: CDK16: Added comment: To date, CDK16 variants have not been associated with a phenotype in OMIM, but have a limited association with intellectual disability (ID) in Gen2Phen. Four CDK16 variants have been associated with a spectrum of phenotypic features, including ID (n= 3), autism spectrum disorder (n= 3), seizures (n= 2) and spacity (n= 2)(PMID:36323681, 31981491, 25644381).; Changed rating: GREEN
Intellectual disability - microarray and sequencing v5.347 MYH10 Achchuthan Shanmugasundram reviewed gene: MYH10: Rating: GREEN; Mode of pathogenicity: None; Publications: 35980381; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.346 TEFM Achchuthan Shanmugasundram reviewed gene: TEFM: Rating: GREEN; Mode of pathogenicity: None; Publications: 36823193; Phenotypes: Combined oxidative phosphorylation deficiency 58, OMIM:620451; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.342 KMT2B Arina Puzriakova reviewed gene: KMT2B: Rating: ; Mode of pathogenicity: None; Publications: 33150406; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v5.338 CASP2 Achchuthan Shanmugasundram reviewed gene: CASP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 37880421; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.337 CASP2 Dmitrijs Rots reviewed gene: CASP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 37880421; Phenotypes: neurodevelopmental disorder with lissencephaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.335 VCP Achchuthan Shanmugasundram reviewed gene: VCP: Rating: GREEN; Mode of pathogenicity: None; Publications: 37883978; Phenotypes: Intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.332 RAP1B Achchuthan Shanmugasundram reviewed gene: RAP1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 35451551; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.332 DPP6 Gavin Ryan reviewed gene: DPP6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.332 ZBTB47 Sarah Leigh reviewed gene: ZBTB47: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v5.330 MYCN Sarah Leigh Added comment: Comment on mode of pathogenicity: Gain-of-function MYCN variants have been reported (PMID: 30573562; 37710961) where the phenotypic features are to an extent opposite the phenotype of Feingold syndrome 1 (OMIM:164280) caused by loss-of-function MYCN variants.
Intellectual disability - microarray and sequencing v5.330 MYCN Sarah Leigh Mode of pathogenicity for gene: MYCN was changed from to None
Intellectual disability - microarray and sequencing v5.321 FAM111A Sarah Leigh reviewed gene: FAM111A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v5.318 ARF3 Achchuthan Shanmugasundram reviewed gene: ARF3: Rating: GREEN; Mode of pathogenicity: None; Publications: 36369169; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v5.318 RBL2 Mike Spiller reviewed gene: RBL2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32105419, PMID: 33980986; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.315 DOCK8 Dmitrijs Rots reviewed gene: DOCK8: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.310 RFX7 Arina Puzriakova Phenotypes for gene: RFX7 were changed from Intellectual disability, MONDO:0001071; Autism spectrum disorder, MONDO:0005258; Attention deficit-hyperactivity disorder, MONDO:0007743 to Intellectual developmental disorder, autosomal dominant 71, with behavioral abnormalities, OMIM:620330
Intellectual disability - microarray and sequencing v5.307 SRSF1 Achchuthan Shanmugasundram gene: SRSF1 was added
gene: SRSF1 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: SRSF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SRSF1 were set to 37071997
Phenotypes for gene: SRSF1 were set to Neurodevelopmental disorder with dysmorphic facies and behavioral abnormalities, OMIM:620489
Review for gene: SRSF1 was set to GREEN
Added comment: There are 17 individuals from 16 different families were reported with 15 different monoallelic variants (mostly de novo) in SRSF1 gene. They were reported with a neurodevelopmental disorder mainly comprising neurological abnormalities such as intellectual disability/ developmental delay, motor delay, speech delay, and behavioural disorders and facial dysmorphisms. Intellectual disability was present in 16 of 17 individuals (3 severe, 2 moderate, 3 mild to moderate, 3 mild, 1 borderline and 4 unknown severity), while the remaining one had learning disability.

Functional testing of a subset of variants in Drosophila supported pathogenicity in most, but 2 missense variants showed no functional effect and were classified VUS.

This gene has already been associated with neurodevelopmental disorder in both OMIM (MIM #620489) and Gene2Phenotype ('limited' rating in the DD panel).
Sources: Literature
Intellectual disability - microarray and sequencing v5.300 PRKAR1B Arina Puzriakova Phenotypes for gene: PRKAR1B were changed from Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Aggressive behavior; Abnormality of movement; Upslanted palpebral fissure to Marbach-Schaaf neurodevelopmental syndrome, OMIM:619680
Intellectual disability - microarray and sequencing v5.286 ZNF292 Arina Puzriakova reviewed gene: ZNF292: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v5.286 ZMYND8 Arina Puzriakova reviewed gene: ZMYND8: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.286 ZMYM3 Arina Puzriakova reviewed gene: ZMYM3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability - microarray and sequencing v5.286 WIPI2 Arina Puzriakova reviewed gene: WIPI2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.286 UBAP2L Arina Puzriakova reviewed gene: UBAP2L: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v5.286 TRA2B Arina Puzriakova reviewed gene: TRA2B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.286 TMEM147 Arina Puzriakova reviewed gene: TMEM147: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.286 TCEAL1 Arina Puzriakova reviewed gene: TCEAL1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability - microarray and sequencing v5.286 TAF4 Arina Puzriakova reviewed gene: TAF4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.286 TAF2 Arina Puzriakova reviewed gene: TAF2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.286 STXBP1 Arina Puzriakova reviewed gene: STXBP1: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.286 SLC32A1 Arina Puzriakova reviewed gene: SLC32A1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.286 SHANK1 Arina Puzriakova reviewed gene: SHANK1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.286 SEMA6B Arina Puzriakova reviewed gene: SEMA6B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.286 ROBO1 Arina Puzriakova reviewed gene: ROBO1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.286 RBSN Arina Puzriakova reviewed gene: RBSN: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.286 PRKAR1B Arina Puzriakova reviewed gene: PRKAR1B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.286 PPFIBP1 Arina Puzriakova reviewed gene: PPFIBP1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.286 POU3F2 Arina Puzriakova reviewed gene: POU3F2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v5.286 PLXNA1 Arina Puzriakova reviewed gene: PLXNA1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.286 PLK1 Arina Puzriakova reviewed gene: PLK1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.286 PAX6 Arina Puzriakova reviewed gene: PAX6: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v5.286 PAN2 Arina Puzriakova reviewed gene: PAN2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.286 OTUD7A Arina Puzriakova reviewed gene: OTUD7A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.286 NUP214 Arina Puzriakova reviewed gene: NUP214: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.286 MED11 Arina Puzriakova reviewed gene: MED11: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.286 MAN2C1 Arina Puzriakova reviewed gene: MAN2C1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.286 LHX2 Arina Puzriakova reviewed gene: LHX2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v5.286 KIF4A Arina Puzriakova reviewed gene: KIF4A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability - microarray and sequencing v5.286 KDM5A Arina Puzriakova reviewed gene: KDM5A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.286 KDM2B Arina Puzriakova reviewed gene: KDM2B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.286 IQSEC2 Arina Puzriakova reviewed gene: IQSEC2: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability - microarray and sequencing v5.286 HUWE1 Arina Puzriakova reviewed gene: HUWE1: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability - microarray and sequencing v5.286 HIST1H4E Arina Puzriakova reviewed gene: HIST1H4E: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v5.286 HECTD4 Arina Puzriakova reviewed gene: HECTD4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.286 GRM7 Arina Puzriakova reviewed gene: GRM7: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.286 GCSH Arina Puzriakova reviewed gene: GCSH: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.286 FLNA Arina Puzriakova reviewed gene: FLNA: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v5.286 FILIP1 Arina Puzriakova reviewed gene: FILIP1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.286 DPH5 Arina Puzriakova reviewed gene: DPH5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.286 DOHH Arina Puzriakova reviewed gene: DOHH: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.286 DDX23 Arina Puzriakova reviewed gene: DDX23: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.286 CTR9 Arina Puzriakova reviewed gene: CTR9: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.286 CPLX1 Arina Puzriakova reviewed gene: CPLX1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.286 CLDN5 Arina Puzriakova reviewed gene: CLDN5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.286 CCDC82 Arina Puzriakova reviewed gene: CCDC82: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.286 CAPRIN1 Arina Puzriakova reviewed gene: CAPRIN1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.286 BAP1 Arina Puzriakova reviewed gene: BAP1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v5.284 ESAM Achchuthan Shanmugasundram changed review comment from: As reviewed by Julia Baptista, PMID:36996813 reported the identification of biallelic ESAM variants in 13 individuals from eight unrelated families, which included four foetuses. All nine born individuals had profound global developmental delay/ unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/ cerebral calcifications, the latter being also observed in the foetuses.

This gene has been associated with relevant phenotypes in OMIM (MIM #620371), but not yet in Gene2Phenotype.; to: As reviewed by Julia Baptista, PMID:36996813 reported the identification of biallelic ESAM variants in 13 individuals from eight unrelated families, which included four foetuses. All nine live-born individuals had profound global developmental delay/ unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/ cerebral calcifications, the latter being also observed in the foetuses.

This gene has been associated with relevant phenotypes in OMIM (MIM #620371), but not yet in Gene2Phenotype.
Intellectual disability - microarray and sequencing v5.283 ESAM Achchuthan Shanmugasundram Phenotypes for gene: ESAM were changed from severe ID; seizures, spasticity to Neurodevelopmental disorder with intracranial hemorrhage, seizures, and spasticity, OMIM:620371
Intellectual disability - microarray and sequencing v5.281 ESAM Achchuthan Shanmugasundram reviewed gene: ESAM: Rating: GREEN; Mode of pathogenicity: None; Publications: 36996813; Phenotypes: Neurodevelopmental disorder with intracranial hemorrhage, seizures, and spasticity, OMIM:620371; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.277 PPP1R3F Achchuthan Shanmugasundram reviewed gene: PPP1R3F: Rating: GREEN; Mode of pathogenicity: None; Publications: 37531237; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability - microarray and sequencing v5.274 NR2F2 Achchuthan Shanmugasundram reviewed gene: NR2F2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29663647, 37500725; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.271 U2AF2 Achchuthan Shanmugasundram reviewed gene: U2AF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28135719, 31785789, 34112922, 36747105, 37092751, 37134193; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.271 NR2F2 Katherine Lachlan reviewed gene: NR2F2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37500725; Phenotypes: intrauterine growth restriction (IUGR), CHD, CDH, genital anomalies, DSD, developmental delays, hypotonia, feeding difficulties, failure to thrive, congenital and acquired microcephaly, dysmorphic facial features, renal failure, hearing loss, strabismus, asplenia, vascular malformations; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.271 ATM Zornitza Stark reviewed gene: ATM: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Ataxia-telangiectasia, MIM#208900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.271 ESAM Julia Baptista gene: ESAM was added
gene: ESAM was added to Intellectual disability - microarray and sequencing. Sources: Literature,Expert Review
Mode of inheritance for gene: ESAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ESAM were set to PMID: 36996813
Phenotypes for gene: ESAM were set to severe ID; seizures, spasticity
Review for gene: ESAM was set to GREEN
Added comment: Lecca et al 2023 reported thirteen patients from eight unrelated families with biallelic loss of function variants (nonsense, frameshift, canonical splice site, all predicted to result in a transcript targeted for nonsense-mediated decay). Protein staining assays in one of the brain fetal samples confirmed loss the loss of protein.
The phenotype reported in this cohort is of a severe neurodevelopmental disorder with brain anomalies (calcifications, hydrocephalus, enlarged ventricles, cerebral atrophy, etc), and dysmorphic features.
Sources: Literature, Expert Review
Intellectual disability - microarray and sequencing v5.268 U2AF2 celia duff reviewed gene: U2AF2: Rating: GREEN; Mode of pathogenicity: None; Publications: (PMID: 28135719):(PMID: 31785789):(PMID: 34112922):(PMID: 36747105):(PMID: 37092751):(PMID 37134193); Phenotypes: intellectual disability, global developmental delay, dysmorphism, epilepsy, brain malformation, microcephaly, possible emerging phenotype of hypomyelinating leukodystrophy.; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v5.264 NEUROG1 Achchuthan Shanmugasundram reviewed gene: NEUROG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23419067, 26077850, 33439489, 36647078; Phenotypes: Cranial dysinnervation disorder, congenital, with absent corneal reflex and developmental delay, OMIM:620469; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.264 CMIP Sarah Leigh reviewed gene: CMIP: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v5.257 ATP6V0C Achchuthan Shanmugasundram reviewed gene: ATP6V0C: Rating: GREEN; Mode of pathogenicity: None; Publications: 33190975, 35600075, 36074901, 37161035; Phenotypes: Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.256 NEUROG1 Julia Baptista gene: NEUROG1 was added
gene: NEUROG1 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: NEUROG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NEUROG1 were set to 36647078; 33439489; 23419067; 26077850
Phenotypes for gene: NEUROG1 were set to developmental delay; behavioural problems; cranial dysinnervation; absent corneal reflex
Review for gene: NEUROG1 was set to GREEN
Added comment: Five affected individuals from four independently reported families (Middle Eastern, Portuguese, Indian and Turkish backgrounds) with biallelic microdeletion, missense, nonsense or frameshift variants.

Affected individuals present at birth or in early infancy with corneal opacities due to absent blinking, sensorineural deafness associated with hypoplastic or malformed cochlea and hypoplasia or agenesis of CN VIII was reported. Developmental delay, poor speech, autistic behavior and dysmorphic facial features were also present.
Sources: Literature
Intellectual disability - microarray and sequencing v5.256 ATP6V0C Julia Baptista reviewed gene: ATP6V0C: Rating: GREEN; Mode of pathogenicity: None; Publications: 36074901; Phenotypes: Epilepsy, Intellectual Disability, Microcephaly; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.255 DNAH14 Sarah Leigh reviewed gene: DNAH14: Rating: RED; Mode of pathogenicity: None; Publications: 26036949, 30125339, 26636390, 32848021; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.255 FAM111A Tracy Lester reviewed gene: FAM111A: Rating: RED; Mode of pathogenicity: None; Publications: 23684011, 37023242; Phenotypes: Skeletal dysplasia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.255 CMIP Tord Jonson edited their review of gene: CMIP: Changed phenotypes to: HP:0012759 Neurodevelopmental abnormality, HP:0000717 Autism, HP:0007018 Attention deficit hyperactivity disorder, HP:0001250 Seizure, HP:0011471 Gastrostomy tube feeding in infancy
Intellectual disability - microarray and sequencing v5.247 MKL2 Achchuthan Shanmugasundram reviewed gene: MKL2: Rating: AMBER; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 37013900; Phenotypes: neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.239 PSMC3 Achchuthan Shanmugasundram reviewed gene: PSMC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 32500975, 37256937; Phenotypes: ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354, neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.238 KCNH5 Achchuthan Shanmugasundram Mode of pathogenicity for gene: KCNH5 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability - microarray and sequencing v5.238 KCNH5 Achchuthan Shanmugasundram Mode of pathogenicity for gene: KCNH5 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability - microarray and sequencing v5.238 KCNH5 Achchuthan Shanmugasundram Mode of pathogenicity for gene: KCNH5 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability - microarray and sequencing v5.237 KCNH5 Achchuthan Shanmugasundram Mode of pathogenicity for gene: KCNH5 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability - microarray and sequencing v5.235 KCNH5 Achchuthan Shanmugasundram reviewed gene: KCNH5: Rating: GREEN; Mode of pathogenicity: None; Publications: 23647072, 35874597, 36307226, 24133262; Phenotypes: developmental and epileptic encephalopathy, MONDO:0100062, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.230 KCNH5 Dmitrijs Rots reviewed gene: KCNH5: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: PMID: 36307226, 35874597; Phenotypes: Neurodevelopmental disorder and Epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.223 ZNF292 Achchuthan Shanmugasundram reviewed gene: ZNF292: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal dominant 64, OMIM:619188; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.211 SLC30A9 Achchuthan Shanmugasundram reviewed gene: SLC30A9: Rating: GREEN; Mode of pathogenicity: None; Publications: 28334855, 34716203, 37041080; Phenotypes: Birk-Landau-Perez syndrome, OMIM:617595; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.211 DAGLA Achchuthan Shanmugasundram Mode of pathogenicity for gene: DAGLA was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability - microarray and sequencing v5.211 DAGLA Achchuthan Shanmugasundram Mode of pathogenicity for gene: DAGLA was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability - microarray and sequencing v5.211 DAGLA Achchuthan Shanmugasundram Mode of pathogenicity for gene: DAGLA was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability - microarray and sequencing v5.211 DAGLA Achchuthan Shanmugasundram Mode of pathogenicity for gene: DAGLA was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability - microarray and sequencing v5.211 DAGLA Achchuthan Shanmugasundram Mode of pathogenicity for gene: DAGLA was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability - microarray and sequencing v5.210 DAGLA Achchuthan Shanmugasundram Mode of pathogenicity for gene: DAGLA was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability - microarray and sequencing v5.210 DAGLA Achchuthan Shanmugasundram Mode of pathogenicity for gene: DAGLA was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability - microarray and sequencing v5.210 DAGLA Achchuthan Shanmugasundram Mode of pathogenicity for gene: DAGLA was changed from Other to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability - microarray and sequencing v5.209 DAGLA Achchuthan Shanmugasundram edited their review of gene: DAGLA: Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability - microarray and sequencing v5.205 DAGLA Achchuthan Shanmugasundram reviewed gene: DAGLA: Rating: GREEN; Mode of pathogenicity: None; Publications: 35737950; Phenotypes: intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.204 DAGLA Irina Ziravecka gene: DAGLA was added
gene: DAGLA was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: DAGLA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DAGLA were set to PMID: 35737950
Phenotypes for gene: DAGLA were set to developmental delay; ataxia; complex oculomotor abnormality
Mode of pathogenicity for gene: DAGLA was set to Other
Review for gene: DAGLA was set to GREEN
Added comment: PMID: 35737950 - nine children from eight families with heterozygous, de novo truncating variants in the last exon of DAGLA with a neuro-ocular phenotype.
Sources: Literature
Intellectual disability - microarray and sequencing v5.200 PTPA Achchuthan Shanmugasundram reviewed gene: PTPA: Rating: AMBER; Mode of pathogenicity: None; Publications: 36073231; Phenotypes: Intellectual disability, MONDO:0001071; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.196 FOXR1 Achchuthan Shanmugasundram reviewed gene: FOXR1: Rating: AMBER; Mode of pathogenicity: None; Publications: 34723967; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.191 PSMC3 Dmitrijs Rots gene: PSMC3 was added
gene: PSMC3 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: PSMC3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PSMC3 were set to PMID: 37256937
Phenotypes for gene: PSMC3 were set to neurodevelopmental delay
Mode of pathogenicity for gene: PSMC3 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: PSMC3 was set to GREEN
Added comment: 23 individuals with NDD due to 15 different de novo missense variants in PMID: 37256937.
Sources: Literature
Intellectual disability - microarray and sequencing v5.191 MKL2 Dmitrijs Rots gene: MKL2 was added
gene: MKL2 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: MKL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MKL2 were set to PMID:37013900
Phenotypes for gene: MKL2 were set to neurodevelopmental phenotype with dysmorphic features
Mode of pathogenicity for gene: MKL2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: MKL2 was set to GREEN
Added comment: 2 cases with de novo missense GoF variants in MRTFB (previously known as MKL2) + functional evidence
Sources: Literature
Intellectual disability - microarray and sequencing v5.180 CCDC82 Achchuthan Shanmugasundram reviewed gene: CCDC82: Rating: GREEN; Mode of pathogenicity: None; Publications: 27457812, 28397838, 35118659, 35373332; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.180 FLNA Sarah Leigh reviewed gene: FLNA: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v5.175 HECTD4 Achchuthan Shanmugasundram gene: HECTD4 was added
gene: HECTD4 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: HECTD4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HECTD4 were set to 36401616
Phenotypes for gene: HECTD4 were set to Neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum, OMIM:620250
Review for gene: HECTD4 was set to GREEN
Added comment: PMID:36401616 reported seven patients from five unrelated families with either homozygous (3 families) or compound heterozygous variants (2 families) in HECTD4 gene and presenting with syndromic neurodevelopmental, seizure, and movement disorders and neurobehavioral phenotypes. All seven patients had severe (4 cases) or moderate (3 cases) intellectual disability.
Sources: Literature
Intellectual disability - microarray and sequencing v5.152 FLNA Tracy Lester reviewed gene: FLNA: Rating: RED; Mode of pathogenicity: None; Publications: 20301392; Phenotypes: Skeletal dysplasia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.145 TAF4 Achchuthan Shanmugasundram reviewed gene: TAF4: Rating: GREEN; Mode of pathogenicity: None; Publications: 28191890, 33875846, 35904126; Phenotypes: intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.143 ZMYND8 Achchuthan Shanmugasundram reviewed gene: ZMYND8: Rating: GREEN; Mode of pathogenicity: None; Publications: 32530565, 35916866; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.137 PRSS12 Achchuthan Shanmugasundram reviewed gene: PRSS12: Rating: GREEN; Mode of pathogenicity: None; Publications: 12459588, 25529582; Phenotypes: Intellectual developmental disorder, autosomal recessive 1, OMIM:249500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.135 MAN2C1 Achchuthan Shanmugasundram reviewed gene: MAN2C1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35045343; Phenotypes: Congenital disorder of deglycosylation 2, OMIM:619775; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.131 FAAH2 Achchuthan Shanmugasundram reviewed gene: FAAH2: Rating: AMBER; Mode of pathogenicity: None; Publications: 25885783, 34645488; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability - microarray and sequencing v5.130 ITPR1 Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from 'biallelic' to 'both mono- and biallelic' at the next GMS panel update inline with the review by Tracy Lester. Although not observed in all, some patients do exhibit cognitive deficits which may be an early and severe feature. There are sufficient unrelated cases with heterozygous variants and ID (associated with either Gillespie or SCA) to warrant including this MOI on this panel.
Intellectual disability - microarray and sequencing v5.127 BLM Arina Puzriakova reviewed gene: BLM: Rating: ; Mode of pathogenicity: None; Publications: 22514588, 23552953, 36646944; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v5.125 NSF Achchuthan Shanmugasundram reviewed gene: NSF: Rating: RED; Mode of pathogenicity: None; Publications: 36645181; Phenotypes: Developmental and epileptic encephalopathy 96, OMIM:619340; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.118 ENTPD1 Achchuthan Shanmugasundram reviewed gene: ENTPD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35471564; Phenotypes: Spastic paraplegia 64, autosomal recessive, OMIM:615683; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.107 ITPR1 Tracy Lester edited their review of gene: ITPR1: Added comment: PMID:29925855 - All 7 EOA patients with ITPR1 de novo variants (3 from cohort #1; 4 from cohort #2) presented with infantile onset cerebellar ataxia starting before the age of 2 years, including delayed motor milestones (Table 2). Cognitive deficits of variable degree were observed in 3 out of 4 patients where this information was available, reaching from only mild dyscalculia (P2) to severe intellectual disability with a speech vocabulary of only a few words (P7 at age 12 years). In contrast, patient P1 showed normal intelligence with an IQ of 97.

PMID:27108797 - Here, we report that both recessive and dominant ITPR1 mutations cause Gillespie syndrome. ITPR1 is a predominant isoform in the brain among the three types of ITPRs and is strongly expressed in cerebellar Purkinje cells.31 Mice with complete homozygosity for Itpr1 ablation suffer from severe epilepsy and ataxia and die either in utero or before weaning.32 Consistently, ITPR1 mutations have been reported to cause cerebellar diseases including late-onset spinocerebellar ataxia type 15 (SCA15 [MIM: 606658]),33 congenital nonprogressive spinocerebellar ataxia and mild cognitive impairment (SCA29 [MIM: 117360]),34 infantile-onset cerebellar ataxia with mild cognitive deficit,35 and childhood-onset ataxic cerebellar palsy with moderate intellectual disability36 (see ITPR1 schematic diagram in Figure 3A).
Affected individuals had similar iris anomalies and neonatal ataxia with progressive cerebellar atrophy (Figure 2). Moderate to severe intellectual disabilities were noted in the three individuals with recessive mutations (F1:II1, F2:II1, and F3:II1; Table 1). In contrast, the affected individual F4:II1 aged 18 years and harboring the de novo c.7687_7689del mutation was reported to have normal intelligence (Table 1).

As de novo variants are associated with ID/DD the inheritance should be updated to be BOTH AD and AR.; Set current diagnostic: yes
Intellectual disability - microarray and sequencing v5.107 ITPR1 Tracy Lester reviewed gene: ITPR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29925855, 27108797; Phenotypes: developmental delay, intellectual disability, hypotonia, ataxia, cerebellar malformatons; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.105 SLC32A1 Achchuthan Shanmugasundram changed review comment from: PMID:36073542 reported four unrelated patients with four different de novo missense variants in SLC32A1 gene reported with global developmental delay, moderate-to-severe intellectual disability, infantile-onset epilepsy within the first 18 months of life, and a choreiform, dystonic, or dyskinetic movement disorder.

In silico modeling and functional analyses showed that these variants can impair GABAergic neurotransmission through at least two mechanisms, by affecting synaptic vesicle filling and by altering synaptic short-term plasticity.
Sources: Literature; to: PMID:36073542 reported four unrelated patients with four different de novo missense variants in SLC32A1 gene reported with global developmental delay, moderate-to-severe intellectual disability, infantile-onset epilepsy within the first 18 months of life, and a choreiform, dystonic, or dyskinetic movement disorder.

In silico modeling and functional analyses showed that these variants can impair GABAergic neurotransmission through at least two mechanisms, by affecting synaptic vesicle filling and by altering synaptic short-term plasticity.

Although this gene has not yet been associated with phenotypes in OMIM, it has been added to Gene2Phenotype with 'moderate' rating in the DD panel.

Sources: Literature
Intellectual disability - microarray and sequencing v5.105 SLC32A1 Achchuthan Shanmugasundram gene: SLC32A1 was added
gene: SLC32A1 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: SLC32A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC32A1 were set to 36073542
Phenotypes for gene: SLC32A1 were set to developmental and epileptic encephalopathy, MONDO:0100062
Review for gene: SLC32A1 was set to GREEN
Added comment: PMID:36073542 reported four unrelated patients with four different de novo missense variants in SLC32A1 gene reported with global developmental delay, moderate-to-severe intellectual disability, infantile-onset epilepsy within the first 18 months of life, and a choreiform, dystonic, or dyskinetic movement disorder.

In silico modeling and functional analyses showed that these variants can impair GABAergic neurotransmission through at least two mechanisms, by affecting synaptic vesicle filling and by altering synaptic short-term plasticity.
Sources: Literature
Intellectual disability - microarray and sequencing v5.98 CSTF2 Achchuthan Shanmugasundram reviewed gene: CSTF2: Rating: AMBER; Mode of pathogenicity: None; Publications: 32816001; Phenotypes: Intellectual disability, MONDO:0001071; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability - microarray and sequencing v5.98 HIST1H4E Ronnie Wright reviewed gene: HIST1H4E: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v5.98 SRRM2 Alistair Pagnamenta reviewed gene: SRRM2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35567594, 33057194; Phenotypes: Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.96 PRKAR1B Achchuthan Shanmugasundram Phenotypes for gene: PRKAR1B were changed from Marbach-Schaaf neurodevelopmental syndrome, OMIM:619680 to Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Aggressive behavior; Abnormality of movement; Upslanted palpebral fissure
Intellectual disability - microarray and sequencing v5.96 PRKAR1B Achchuthan Shanmugasundram Phenotypes for gene: PRKAR1B were changed from Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Aggressive behavior; Abnormality of movement; Upslanted palpebral fissure to Marbach-Schaaf neurodevelopmental syndrome, OMIM:619680
Intellectual disability - microarray and sequencing v5.93 PRKAR1B Achchuthan Shanmugasundram reviewed gene: PRKAR1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 33833410; Phenotypes: Marbach-Schaaf neurodevelopmental syndrome, OMIM:619680; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.90 PPFIBP1 Achchuthan Shanmugasundram reviewed gene: PPFIBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35830857; Phenotypes: intellectual disability, MONDO:0001071; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.86 KDM2B Achchuthan Shanmugasundram reviewed gene: KDM2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 36322151; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.85 HNRNPD Achchuthan Shanmugasundram reviewed gene: HNRNPD: Rating: AMBER; Mode of pathogenicity: None; Publications: 33874999; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.80 WIPI2 Achchuthan Shanmugasundram reviewed gene: WIPI2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30968111, 34557665; Phenotypes: ?Intellectual developmental disorder with short stature and variable skeletal anomalies, OMIM:618453; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.75 PLXNA1 Achchuthan Shanmugasundram reviewed gene: PLXNA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28464511, 34054129, 34415653; Phenotypes: Dworschak-Punetha neurodevelopmental syndrome, OMIM:619955, developmental and epileptic encephalopathy, MONDO:0100062; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.75 PLXNA1 Achchuthan Shanmugasundram reviewed gene: PLXNA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28464511, 34054129, 34415653; Phenotypes: Dworschak-Punetha neurodevelopmental syndrome, OMIM:619955, developmental and epileptic encephalopathy, MONDO:0100062; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.71 KIF4A Achchuthan Shanmugasundram reviewed gene: KIF4A: Rating: GREEN; Mode of pathogenicity: None; Publications: 24812067, 34346154; Phenotypes: ?Intellectual developmental disorder, X-linked 100, OMIM:300923; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability - microarray and sequencing v5.70 DDX23 Achchuthan Shanmugasundram reviewed gene: DDX23: Rating: GREEN; Mode of pathogenicity: None; Publications: 34050707; Phenotypes: global developmental delay with speech and behavioral abnormalities, MONDO:0030995; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.67 GRIA1 Achchuthan Shanmugasundram changed review comment from: Four different heterozygous variants in GRIA1 (p.Ala636Thr, p.Gly745Asp, p.Ile627Thr & p.Arg345Gln) have been identified in six unrelated individuals and they were all reported with intellectual disability, moderate to severe cognitive impairment, delayed motor development, speech impairment and behavioural issues such as anxiety, autism spectrum disorder and attention deficit hyperactivity disorder.

Homozygous variant (p.Arg377Ter) has been identified in one individual, who presented with intellectual disability, severe cognitive impairment, delayed motor development, speech impairment (non-verbal) and self-injurious behaviour.

In vitro functional studies with major GluA1-containing AMPAR subtypes carrying the GRIA1 variant mutations showed that three of the four missense variants profoundly perturb receptor function. The homozygous stop-gain variant completely destroyed the expression of GluA1-containing AMPARs. The Xenopus gria1 models also show transient motor deficits, an intermittent seizure phenotype, and a significant impairment to working memory in mutants.; to: Four different heterozygous variants in GRIA1 (p.Ala636Thr, p.Gly745Asp, p.Ile627Thr & p.Arg345Gln) have been identified in six unrelated individuals and they were all reported with intellectual disability, moderate to severe cognitive impairment, delayed motor development, speech impairment and behavioural issues such as anxiety, autism spectrum disorder and attention deficit hyperactivity disorder.

Homozygous variant (p.Arg377Ter) has been identified in one individual, who presented with intellectual disability, severe cognitive impairment, delayed motor development, speech impairment (non-verbal) and self-injurious behaviour.

In vitro functional studies with major GluA1-containing AMPAR subtypes carrying the GRIA1 variant mutations showed that three of the four missense variants profoundly perturb receptor function. The homozygous stop-gain variant completely destroyed the expression of GluA1-containing AMPARs. The Xenopus gria1 models also show transient motor deficits, an intermittent seizure phenotype, and a significant impairment to working memory in mutants.

This gene has also been associated with relevant phenotypes in both OMIM (MIM #619927 & MIM #619931) and Gene2Phenotype (with 'moderate' rating).
Intellectual disability - microarray and sequencing v5.61 GRIA1 Achchuthan Shanmugasundram reviewed gene: GRIA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35675825; Phenotypes: Intellectual developmental disorder, autosomal dominant 67, OMIM:619927, ?Intellectual developmental disorder, autosomal recessive 76, OMIM:619931; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.57 TAF2 Achchuthan Shanmugasundram reviewed gene: TAF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 21937992, 24084144, 34474177; Phenotypes: Mental retardation, autosomal recessive 40, OMIM:615599; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.53 SHANK1 Achchuthan Shanmugasundram reviewed gene: SHANK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34113010; Phenotypes: neurocde; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.50 PLK1 Achchuthan Shanmugasundram reviewed gene: PLK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33875846; Phenotypes: intellectual disability, MONDO:0001071; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.47 OTUD7A Achchuthan Shanmugasundram reviewed gene: OTUD7A: Rating: GREEN; Mode of pathogenicity: None; Publications: 29395075, 31997314, 33381903, 36180924; Phenotypes: intellectual disability, MONDO:0001071; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.34 IQSEC2 Achchuthan Shanmugasundram reviewed gene: IQSEC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 20473311, 23674175, 30842726, 31415821, 33368194; Phenotypes: Intellectual developmental disorder, X-linked 1, OMIM:309530; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability - microarray and sequencing v5.30 HUWE1 Achchuthan Shanmugasundram reviewed gene: HUWE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29180823; Phenotypes: Intellectual developmental disorder, X-linked syndromic, Turner type, OMIM:309590; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability - microarray and sequencing v5.25 TRAPPC10 Achchuthan Shanmugasundram reviewed gene: TRAPPC10: Rating: AMBER; Mode of pathogenicity: None; Publications: 30167849, 35298461; Phenotypes: Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.24 KDM5A Achchuthan Shanmugasundram changed review comment from: PMID:21937992 reported a family with recessive missense KDM5A variant presenting with an undefined developmental disorder characterised with intellectual disability and facial dysmorphisms.

PMID:33350388 reported nine patients from seven unrelated families identified with variants in KDM5A, of which three unrelated patients harboured heterozygous variants, while six patients from four unrelated families had homozygous variants. These patients presented with autism spectrum disorder (ASD) and a spectrum of neurodevelopmental phenotypes including intellectual disability, lack of speech, developmental delay and motor impairment.

In addition, loss of KDM5A has resulted in repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis in mice.; to: PMID:21937992 reported a family with recessive missense KDM5A variant presenting with an undefined developmental disorder characterised with intellectual disability and facial dysmorphisms.

PMID:33350388 reported nine patients from seven unrelated families identified with variants in KDM5A, of which three unrelated patients harboured heterozygous variants, while six patients from four unrelated families had homozygous variants. These patients presented with autism spectrum disorder (ASD) and a spectrum of neurodevelopmental phenotypes including intellectual disability, lack of speech, developmental delay and motor impairment.

In addition, loss of KDM5A has resulted in repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis in mice.

This gene has already been associated with phenotype in Gene2Phenotype (biallelic inheritance with 'limited' rating), but not in OMIM.
Intellectual disability - microarray and sequencing v5.23 KDM5A Achchuthan Shanmugasundram changed review comment from: PMID:21937992 reported a family with recessive missense KDM5A variant presenting with an undefined developmental disorder characterised with intellectual disability and facial dysmorphisms.

PMID:33350388 reported nine patients from seven unrelated families identified with variants in KDM5A, of which three unrelated patients harboured heterozygous variants, while six patients from four unrelated families had homozygous variants. These patients presented with autism spectrum disorder (ASD) and a spectrum of neurodevelopmental phenotypes including intellectual disability, lack of speech, developmental delay and motor impairment.; to: PMID:21937992 reported a family with recessive missense KDM5A variant presenting with an undefined developmental disorder characterised with intellectual disability and facial dysmorphisms.

PMID:33350388 reported nine patients from seven unrelated families identified with variants in KDM5A, of which three unrelated patients harboured heterozygous variants, while six patients from four unrelated families had homozygous variants. These patients presented with autism spectrum disorder (ASD) and a spectrum of neurodevelopmental phenotypes including intellectual disability, lack of speech, developmental delay and motor impairment.

In addition, loss of KDM5A has resulted in repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis in mice.
Intellectual disability - microarray and sequencing v5.19 KDM5A Achchuthan Shanmugasundram reviewed gene: KDM5A: Rating: GREEN; Mode of pathogenicity: None; Publications: 21937992, 33350388; Phenotypes: autism spectrum disorder, MONDO:0005258, intellectual disability, MONDO:0001071; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.11 KDM5A Tracy Lester reviewed gene: KDM5A: Rating: AMBER; Mode of pathogenicity: None; Publications: 33350388; Phenotypes: ASD, lack of speech; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v4.120 TAB2 Achchuthan Shanmugasundram reviewed gene: TAB2: Rating: AMBER; Mode of pathogenicity: None; Publications: 35971781; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v4.117 TBX1 Arina Puzriakova reviewed gene: TBX1: Rating: ; Mode of pathogenicity: None; Publications: 14585638, 17273972, 30137364; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v4.114 GCSH Achchuthan Shanmugasundram reviewed gene: GCSH: Rating: GREEN; Mode of pathogenicity: None; Publications: 36190515; Phenotypes: ?Glycine encephalopathy, OMIM:605899, Neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v4.103 SARS Arina Puzriakova reviewed gene: SARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 35790048; Phenotypes: Neurodevelopmental disorder with microcephaly, ataxia, and seizures, OMIM:617709; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v4.98 CTR9 Achchuthan Shanmugasundram Mode of pathogenicity for gene: CTR9 was changed from None to None
Intellectual disability - microarray and sequencing v4.98 CTR9 Achchuthan Shanmugasundram Mode of pathogenicity for gene: CTR9 was changed from None to None
Intellectual disability - microarray and sequencing v4.99 CTR9 Achchuthan Shanmugasundram Mode of pathogenicity for gene: CTR9 was changed from None to None
Intellectual disability - microarray and sequencing v4.99 CTR9 Achchuthan Shanmugasundram Mode of pathogenicity for gene: CTR9 was changed from None to None
Intellectual disability - microarray and sequencing v4.98 CTR9 Achchuthan Shanmugasundram Mode of pathogenicity for gene: CTR9 was changed from None to None
Intellectual disability - microarray and sequencing v4.98 CTR9 Achchuthan Shanmugasundram Mode of pathogenicity for gene: CTR9 was changed from None to None
Intellectual disability - microarray and sequencing v4.98 CTR9 Achchuthan Shanmugasundram Mode of pathogenicity for gene: CTR9 was changed from None to None
Intellectual disability - microarray and sequencing v4.98 CTR9 Achchuthan Shanmugasundram Mode of pathogenicity for gene: CTR9 was changed from None to None
Intellectual disability - microarray and sequencing v4.99 CTR9 Achchuthan Shanmugasundram Mode of pathogenicity for gene: CTR9 was changed from None to None
Intellectual disability - microarray and sequencing v4.98 CTR9 Achchuthan Shanmugasundram Mode of pathogenicity for gene: CTR9 was changed from None to None
Intellectual disability - microarray and sequencing v4.98 CTR9 Achchuthan Shanmugasundram Mode of pathogenicity for gene: CTR9 was changed from None to None
Intellectual disability - microarray and sequencing v4.98 CTR9 Achchuthan Shanmugasundram Mode of pathogenicity for gene: CTR9 was changed from None to None
Intellectual disability - microarray and sequencing v4.98 CTR9 Achchuthan Shanmugasundram Mode of pathogenicity for gene: CTR9 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to None
Intellectual disability - microarray and sequencing v4.93 DPYSL2 Achchuthan Shanmugasundram changed review comment from: This gene should be rated AMBER, as it has been associated with intellectual disability (ID) from two unrelated cases displaying monoallelic variants in DPYSL2/ CRMP2, and supported by functional studies. However, the evidence is not sufficient for green rating as there are variants reported in other (but different) genes in the two patients.

PMID:35861646 reported two cases identified with heterozygous variants (patient1: c.1693C>T (p.Arg565Cys); patient 2: c.42C>A (p.Ser14Arg). These patients had overlapping phenotypes including dysmorphic features, severe global developmental delay and hypoplasia of the corpus callosum. In addition, patient 2 was bed-ridden and could not roll out and had a history of myoclonic seizures and status epilepticus.

It should be noted that patient 1 is compound heterozygous for 2 missense variants in the EFCAB5 gene and was hemizygous for a maternally inherited missense variant in the GPKOW gene and patient 2 had 1 de novo missense variant in the COBLL1 gene and was compound heterozygous for 2 missense variants in the POTEF gene. The severity of the phenotypes between the two cases differs significantly and the additional variants may have possibly contributed to this phenotype.

Brain-specific Crmp2 knockout mice display neuronal development deficits and behavioural impairments associated with hypoplasia of the corpus callosum. In addition, functional studies performed in zebrafish and cell lines that the CRMP2 variants lead to the loss-of-function of CRMP2 protein and can cause intellectual disability.
Sources: Literature; to: This gene should be rated AMBER, as it has been associated with intellectual disability (ID) from two unrelated cases displaying monoallelic variants in DPYSL2/ CRMP2, and supported by functional studies. However, the evidence is not sufficient for green rating as there are variants reported in other (but different) genes in the two patients.

PMID:35861646 reported two cases identified with heterozygous variants (patient1: c.1693C>T (p.Arg565Cys); patient 2: c.42C>A (p.Ser14Arg). These patients had overlapping phenotypes including dysmorphic features, severe global developmental delay and hypoplasia of the corpus callosum. In addition, patient 2 was bed-ridden and could not roll out and had a history of myoclonic seizures and status epilepticus.

It should be noted that patient 1 is compound heterozygous for 2 missense variants in the EFCAB5 gene and was hemizygous for a maternally inherited missense variant in the GPKOW gene and patient 2 had 1 de novo missense variant in the COBLL1 gene and was compound heterozygous for 2 missense variants in the POTEF gene. The severity of the phenotypes between the two cases differs significantly and the additional variants may have possibly contributed to this phenotype.

Brain-specific Crmp2 knockout mice display neuronal development deficits and behavioural impairments associated with hypoplasia of the corpus callosum. In addition, functional studies performed in zebrafish and cell lines that the CRMP2 variants lead to the loss-of-function of CRMP2 protein and can cause intellectual disability.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability - microarray and sequencing v4.93 DPYSL2 Achchuthan Shanmugasundram gene: DPYSL2 was added
gene: DPYSL2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DPYSL2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DPYSL2 were set to 27249678; 35861646
Phenotypes for gene: DPYSL2 were set to intellectual disability, MONDO:0001071; Aplasia/Hypoplasia of the corpus callosum, HP:0007370
Review for gene: DPYSL2 was set to AMBER
Added comment: This gene should be rated AMBER, as it has been associated with intellectual disability (ID) from two unrelated cases displaying monoallelic variants in DPYSL2/ CRMP2, and supported by functional studies. However, the evidence is not sufficient for green rating as there are variants reported in other (but different) genes in the two patients.

PMID:35861646 reported two cases identified with heterozygous variants (patient1: c.1693C>T (p.Arg565Cys); patient 2: c.42C>A (p.Ser14Arg). These patients had overlapping phenotypes including dysmorphic features, severe global developmental delay and hypoplasia of the corpus callosum. In addition, patient 2 was bed-ridden and could not roll out and had a history of myoclonic seizures and status epilepticus.

It should be noted that patient 1 is compound heterozygous for 2 missense variants in the EFCAB5 gene and was hemizygous for a maternally inherited missense variant in the GPKOW gene and patient 2 had 1 de novo missense variant in the COBLL1 gene and was compound heterozygous for 2 missense variants in the POTEF gene. The severity of the phenotypes between the two cases differs significantly and the additional variants may have possibly contributed to this phenotype.

Brain-specific Crmp2 knockout mice display neuronal development deficits and behavioural impairments associated with hypoplasia of the corpus callosum. In addition, functional studies performed in zebrafish and cell lines that the CRMP2 variants lead to the loss-of-function of CRMP2 protein and can cause intellectual disability.
Sources: Literature
Intellectual disability - microarray and sequencing v4.92 CTR9 Achchuthan Shanmugasundram reviewed gene: CTR9: Rating: AMBER; Mode of pathogenicity: None; Publications: 35717577; Phenotypes: Macrocephaly, HP:0000256, Motor delay, HP:0001270, intellectual disability, MONDO_000107; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v4.83 STXBP1 Sarah Leigh reviewed gene: STXBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v4.79 FOXP4 Achchuthan Shanmugasundram reviewed gene: FOXP4: Rating: AMBER; Mode of pathogenicity: None; Publications: 33110267, 36301021, 36646976; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v4.79 FOXP4 Achchuthan Shanmugasundram reviewed gene: FOXP4: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: 33110267, 36301021, 36646976; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v4.69 ROBO1 Achchuthan Shanmugasundram reviewed gene: ROBO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28286008, 30692597, 35227688, 35348658; Phenotypes: intellectual disability, MONDO:0001071; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v4.55 ISCA-37408-Loss Arina Puzriakova Phenotypes for Region: ISCA-37408-Loss were changed from PMID: 16963482 idiopathic intellectual disability including moderate to severe intellectual disability, autism/autistic features, microcephaly, structural brain anomalies including cortical dysplasia/pachygyria, renal anomalies (multicystic kidney, hydronephrosis), digital camptodactyly, visual impairment, strabismus, neuromotor deficits, communication and attention impairments, and a distinctive pattern of craniofacial features. Dysmorphic craniofacial features include progressive microcephaly, flat occiput, widened inner canthal distance, small palpebral fissures, ptosis, long and straight eyelashes, broad and high nasal root extending to a widened, prominent nasal tip with elongated, smooth philtrum, rounding of the upper vermillion border and everted lower lips. PMID: 18245392 A 32-year-old, mentally retarded male was referred to our centre for further clinical genetic analysis. He was born to non-consanguineous parents after 42 weeks gestation with a birth weight of 3500 g. He had a healthy older brother. In the neonatal period he was hypotonic and at 8 weeks of age he underwent surgery because of an inguinal hernia with removal of an atrophic right testis. His motor development was severely delayed with sitting at 3.5 years and walking at 5 years of age. Speech was poorly developed, characterised by the usage of only a few words. During infancy an optic nerve hypoplasia was diagnosed, and during childhood he frequently suffered from luxations of the patellae, which required surgery. At the age of 32 years his height is 163 cm (_3 SDS) and head circumference 52.5 cm (_2.5 SDS). He has a narrow receding forehead, widened inner canthal distance of 3.5 cm (90th centile), normal outer canthal distance of 8.5 cm (25th centile), telecanthus, short and down slanting palpebral fissures, epicanthal folds, ptosis, long, straight eyelashes, high nasal bridge, low set large ears, flat philtrum, small mouth with high, narrow palate and retrognathia. The thorax is broad with increased internipple distance and slight gynaecomastia. A recent renal ultrasound revealed multiple cysts in the left, dystrophic kidney and two uncomplicated cysts in the enlarged, right kidney. The patient has a normally sized phallus with absent right testis and small left testis. His hands show a simian crease right and tapering fingers with broad proximal interphalangeal joints. He shows sandal gaps on both flat feet with clinodactyly of the fourth and fifth toes (and more); 612513; PMID: 22579565 severe developmental delay, congenital microcephaly, intractable epilepsy, and renal anomalies, as well as a congenital choledochal cyst which has not been previously reported in other patients with this cytogenetic defect to Dysmorphic features, moderate to severe intellectual disability, microcephaly and renal anomalies
Intellectual disability - microarray and sequencing v4.54 ISCA-46553-Loss Arina Puzriakova reviewed Region: ISCA-46553-Loss: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v4.54 ISCA-46742-Loss Arina Puzriakova reviewed Region: ISCA-46742-Loss: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v4.54 ISCA-46297-Loss Arina Puzriakova reviewed Region: ISCA-46297-Loss: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v4.54 ISCA-37495-Loss Arina Puzriakova reviewed Region: ISCA-37495-Loss: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v4.54 ISCA-46304-Gain Arina Puzriakova reviewed Region: ISCA-46304-Gain: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v4.54 ISCA-37423-Gain Arina Puzriakova edited their review of Region: ISCA-37423-Gain: Added comment: Following Genomics England clinical review and NHS Genomic Medicine Service approval, the genomic coordinates and triplosensitivity score (from 3 to 2) of this region were updated based on ClinGen Region Curation Results (version on 05 Aug 2022). Regardless of the change in triplosensitivity score, it was deemed appropriate for this regions to remain green as evidence to support pathogenicity remains.; Changed rating: GREEN
Intellectual disability - microarray and sequencing v4.53 PHF14 Arina Puzriakova reviewed gene: PHF14: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v4.53 DROSHA Arina Puzriakova reviewed gene: DROSHA: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v4.53 PRODH Arina Puzriakova reviewed gene: PRODH: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v4.53 ZBTB7A Arina Puzriakova reviewed gene: ZBTB7A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v4.53 THUMPD1 Arina Puzriakova reviewed gene: THUMPD1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v4.53 SRRM2 Arina Puzriakova reviewed gene: SRRM2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v4.53 SPRED2 Arina Puzriakova reviewed gene: SPRED2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v4.53 SPATA5L1 Arina Puzriakova reviewed gene: SPATA5L1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v4.53 SNORD118 Arina Puzriakova reviewed gene: SNORD118: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v4.53 PRPF8 Arina Puzriakova reviewed gene: PRPF8: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v4.53 MED13 Arina Puzriakova reviewed gene: MED13: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v4.53 DTYMK Arina Puzriakova reviewed gene: DTYMK: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v4.53 CACNA2D1 Arina Puzriakova reviewed gene: CACNA2D1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v4.53 ZMYM2 Arina Puzriakova reviewed gene: ZMYM2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v4.53 TPP2 Arina Puzriakova reviewed gene: TPP2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v4.53 TMEM63C Arina Puzriakova reviewed gene: TMEM63C: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v4.53 TIAM1 Arina Puzriakova reviewed gene: TIAM1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v4.53 SLC38A3 Arina Puzriakova reviewed gene: SLC38A3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v4.53 SCAMP5 Arina Puzriakova reviewed gene: SCAMP5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v4.53 RAB11A Arina Puzriakova reviewed gene: RAB11A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v4.53 PRDM13 Arina Puzriakova reviewed gene: PRDM13: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v4.53 PDZD8 Arina Puzriakova reviewed gene: PDZD8: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v4.53 NRCAM Arina Puzriakova reviewed gene: NRCAM: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v4.53 GLRA2 Arina Puzriakova reviewed gene: GLRA2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v4.53 FBXW7 Arina Puzriakova reviewed gene: FBXW7: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v4.53 FBXO28 Arina Puzriakova reviewed gene: FBXO28: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v4.53 DOCK8 Arina Puzriakova reviewed gene: DOCK8: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v4.53 CHKA Arina Puzriakova reviewed gene: CHKA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v4.53 CCDC32 Arina Puzriakova reviewed gene: CCDC32: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v4.53 ATP6V0A1 Arina Puzriakova reviewed gene: ATP6V0A1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v4.53 ATP2B1 Arina Puzriakova reviewed gene: ATP2B1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v4.53 ANK3 Arina Puzriakova reviewed gene: ANK3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v4.53 ADD1 Arina Puzriakova reviewed gene: ADD1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Intellectual disability - microarray and sequencing v4.39 HIST1H4D Sarah Leigh reviewed gene: HIST1H4D: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v4.33 ZNF292 Sarah Leigh Phenotypes for gene: ZNF292 were changed from Intellectual disability; Autism; Attention deficit hyperactivity disorder; Abnormality of the face; Abnormal muscle tone; Abnormality of nervous system morphology; Growth abnormality; Feeding difficulties; Abnormality of the skeletal system; Abnormality of the cardiovascular system; Microcephaly; Seizures to Intellectual developmental disorder, autosomal dominant 64, OMIM:619188; intellectual developmental disorder, autosomal dominant 64, MONDO:0030934
Intellectual disability - microarray and sequencing v4.32 PAX6 Sarah Leigh reviewed gene: PAX6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v4.32 ZNF292 Ian Berry reviewed gene: ZNF292: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31723249; Phenotypes: Intellectual disability, mild, ASD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v4.16 KCNK3 Arina Puzriakova gene: KCNK3 was added
gene: KCNK3 was added to Intellectual disability. Sources: Literature
Q4_22_promote_green tags were added to gene: KCNK3.
Mode of inheritance for gene: KCNK3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KCNK3 were set to 36195757
Phenotypes for gene: KCNK3 were set to Developmental disorder with sleep apnea
Mode of pathogenicity for gene: KCNK3 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Added comment: Heterozygous variant in the KCNK3 gene already have a well-established link with pulmonary arterial hypertension (OMIM:615344).

However, Sormann et al. 2022 (PMID: 36195757) identified nine unrelated individuals harbouring one of six de novo missense variants in KCNK3 who presented with developmental delay and sleep apnea among other variable features (musculoskeletal and limb anomalies, abnormalities of male genitalia/groin and digestive disturbance). The variants were shown to cause defective X-gating leading to overactive channels that no longer respond to inhibition by G-protein-coupled receptor pathways (i.e. GOF), distinct from the PAH mechanism which is caused by LOF variants.
Sources: Literature
Intellectual disability - microarray and sequencing v4.15 RPL10 Dmitrijs Rots reviewed gene: RPL10: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 35876338; Phenotypes: ID, dysmorphic features, progressive postnatal microcephaly, and retinal anomalies; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability - microarray and sequencing v4.13 CAPRIN1 Dmitrijs Rots reviewed gene: CAPRIN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36136249; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v4.10 BAP1 Mafalda Gomes reviewed gene: BAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35051358; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v4.4 SUFU Arina Puzriakova reviewed gene: SUFU: Rating: GREEN; Mode of pathogenicity: None; Publications: 21289193, 28965847, 33024317, 34675124; Phenotypes: Joubert syndrome 32, OMIM:617757; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v4.2 KLHL20 Dmitrijs Rots gene: KLHL20 was added
gene: KLHL20 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: KLHL20 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KLHL20 were set to 36214804
Phenotypes for gene: KLHL20 were set to developmental disorder with intellectual disability, epilepsy, and autism spectrum disorder
Penetrance for gene: KLHL20 were set to unknown
Mode of pathogenicity for gene: KLHL20 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: KLHL20 was set to GREEN
Added comment: More 14 individuals with mostly recurrent missense variant reported in KLHL20
Sources: Literature
Intellectual disability - microarray and sequencing v4.2 PAX6 Tracy Lester reviewed gene: PAX6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v4.2 RARB Zornitza Stark reviewed gene: RARB: Rating: GREEN; Mode of pathogenicity: None; Publications: 30880327, 30281527, 24075189, 27120018, 25457163, 17506106; Phenotypes: Microphthalmia, syndromic 12, MIM# 615524, Neurodevelopmental disorder; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v4.2 BLM Zornitza Stark reviewed gene: BLM: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Bloom syndrome, MIM# 210900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1771 RARB Dmitrijs Rots reviewed gene: RARB: Rating: ; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 27120018; Phenotypes: Intellectual Disability with Progressive Motor Impairment; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1759 FMR1 Arina Puzriakova reviewed gene: FMR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21267007, 25171808, 28176767, 29178241; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability - microarray and sequencing v3.1759 FOXP4 Ian Berry reviewed gene: FOXP4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33110267; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.1748 ADAR Arina Puzriakova reviewed gene: ADAR: Rating: ; Mode of pathogenicity: None; Publications: 16225627, 16817193, 19017046; Phenotypes: Aicardi-Goutieres syndrome 6, OMIM:615010, Dyschromatosis symmetrica hereditaria, OMIM:127400; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1748 FBXW7 Julia Baptista reviewed gene: FBXW7: Rating: GREEN; Mode of pathogenicity: None; Publications: 35395208; Phenotypes: developmental delay, ID, language disorder, hypotonia, brain anomalies, gastrointestinal issues; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.1746 ADAR Tracy Lester reviewed gene: ADAR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual disability, developmental delay, delayed speech and language, learning disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1746 YARS Dmitrijs Rots reviewed gene: YARS: Rating: ; Mode of pathogenicity: None; Publications: PMID: 34536092; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.1737 PRRT2 Dmitrijs Rots reviewed gene: PRRT2: Rating: AMBER; Mode of pathogenicity: None; Publications: 36180924; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1737 OTUD7A Dmitrijs Rots reviewed gene: OTUD7A: Rating: GREEN; Mode of pathogenicity: None; Publications: 36180924, 33381903; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1735 ROR2 Tracy Lester reviewed gene: ROR2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Skeletal dysplasia; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1733 MTSS1L Arina Puzriakova gene: MTSS1L was added
gene: MTSS1L was added to Intellectual disability. Sources: Literature
new-gene-name, Q4_22_rating tags were added to gene: MTSS1L.
Mode of inheritance for gene: MTSS1L was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MTSS1L were set to 36067766
Phenotypes for gene: MTSS1L were set to Global developmental delay; Intellectual disability; Ophthalmological anomalies; Microcephaly; Mild facial dysmorphisms
Review for gene: MTSS1L was set to GREEN
Added comment: Huang et al. 2022 (PMID: 36067766) reported five unrelated individuals with the same heterozygous de novo variant (c.2011C>T; p.Arg671Trp) in MTSS2 (formally known as MTSS1L). Linkage analysis was not performed but given the variants arose de novo and the mixed ethnicity of the affected individuals (4 European, 1 Chinese) a founder effect can be ruled out.

Subjects displayed a shared phenotype of GDD and/or ID, ophthalmological anomalies (most commonly nystagmus), microcephaly (primary in 2, relative in 3) and shared mild facial dysmorphisms. The single adult patient also presented with seizures and optic atrophy.

Functional studies showed the variant leads to a decrease in mRNA level but does not impact protein levels of MTSS2. However, a Drosophila model demonstrated that loss of the fly ortholog results in defects in locomotor and visual functions which were rescued by human MTSS2 and only partially rescued by the MTSS2 c.2011C>T variant. Overexpression of the c.2011C>T variant caused similar phenotypes as the LoF mutant indicating a possible dominant-negative effect.
Sources: Literature
Intellectual disability - microarray and sequencing v3.1732 RELN Dmitrijs Rots reviewed gene: RELN: Rating: GREEN; Mode of pathogenicity: None; Publications: 35769015; Phenotypes: Lisencephaly, seizures, autism; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1726 SCAMP5 Sarah Leigh changed review comment from: Comment on list classification: Not associated with phenotype in OMIM (last edited on 10/06/2014) or in Gen2Phen. Two variants have been identified in three unrelated cases (one monoallelic, one biallelic). Supportive functional studies have been reported.
It would appear that the two variants reported so far in this gene result in differing mode of pathogenicity and phenotypic features. With heterozygous c.538G>T, p.Gly180Trp seeming to have a dominant-negative effect resulting in autistic spectrum disorder, intellectual disability and seizures. While homozygous c.271C>T, p.R91W seems to have a loss of function effect resulting in early onset epilepsy and Parkinson’s disease. This may be due to different functional domains of the mature protein being altered.
Based on this evidence, SCAMP5 is rated as Amber, with a Watchlist tag. This status may change if further cases are reported.; to: Comment on list classification: Not associated with phenotype in OMIM (last edited on 10/06/2014) or in Gen2Phen. Two variants have been identified in three unrelated cases (one monoallelic, one biallelic). Supportive functional studies have been reported.
It would appear that the two variants reported so far in this gene result in differing mode of pathogenicity and phenotypic features. With heterozygous c.538G>T, p.Gly180Trp seeming to have a dominant-negative effect resulting in autistic spectrum disorder, intellectual disability and seizures. While homozygous c.271C>T, p.R91W seems to have a loss of function effect resulting in early onset epilepsy and Parkinson’s disease. This may be due to different functional domains of the mature protein being altered.
Based on this evidence, SCAMP5 is rated as Amber, with a Watchlist tag. This status may change if further cases are reported.
Intellectual disability - microarray and sequencing v3.1720 HK1 Tracy Lester reviewed gene: HK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30778173; Phenotypes: Intellectual disability, developmental delay, delayed speech and language, learning disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.1713 ANK3 Sarah Leigh Phenotypes for gene: ANK3 were changed from ?Mental retardation, autosomal recessive, 37 615493 to Intellectual developmental disorder, autosomal recessive 37, OMIM:615493; intellectual disability-hypotonia-spasticity-sleep disorder syndrome, MONDO:0014210
Intellectual disability - microarray and sequencing v3.1710 DOCK8 Sarah Leigh reviewed gene: DOCK8: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal dominant 2, OMIM:614113; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.1701 ERMARD Dmitrijs Rots reviewed gene: ERMARD: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.1701 SMAD3 Dmitrijs Rots reviewed gene: SMAD3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.1701 CAPRIN1 Konstantinos Varvagiannis reviewed gene: CAPRIN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35979925, 35977029, 28135719, 31398340, https://doi.org/10.1101/2021.12.20.21267194; Phenotypes: Global developmental delay, Delayed speech and language development, Intellectual disability, Autistic behavior, Seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.1701 ANK3 Rachel Challis reviewed gene: ANK3: Rating: GREEN; Mode of pathogenicity: Other; Publications: 28687526, 34218362; Phenotypes: Intellectual disability; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.1696 DOCK8 Tracy Lester reviewed gene: DOCK8: Rating: RED; Mode of pathogenicity: None; Publications: 18060736, 1764478, 27891178, 19776401; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1687 NRCAM Sarah Leigh edited their review of gene: NRCAM: Added comment: Associated with relevant phenotype in OMIM and as moderate Gen2Phen gene for NRCAM neurodevelopmental disorder with dysmorphic features, hypotonia and spasticity. At least 12 variants have been reported in PMID: 35108495 in 8 unrelated cases (table 1). Global developmental delay / intellectual disabilty was evident in 5/7 unrelated cases (individual 1 was not considered as they also had homozygous loss-of-function variant in CD55 (OMIM: 125240)(PMID: 35108495).; Changed rating: GREEN
Intellectual disability - microarray and sequencing v3.1686 NRCAM Sarah Leigh Phenotypes for gene: NRCAM were changed from Hypotonia; Hypertonia; Spasticity; Global developmental delay; Intellectual disability; Microcephaly; Behavioral abnormality; Neuropathy; Hearing abnormality; Abnormality of the eye; Abnormality of the skeletal system; Scoliosis; Abnormality of the face to Neurodevelopmental disorder with neuromuscular and skeletal abnormalities, OMIM:619833
Intellectual disability - microarray and sequencing v3.1685 HEATR3 Sarah Leigh reviewed gene: HEATR3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.1682 CPSF3 Sarah Leigh reviewed gene: CPSF3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.1677 TAF4 Konstantinos Varvagiannis reviewed gene: TAF4: Rating: GREEN; Mode of pathogenicity: None; Publications: 35904126; Phenotypes: Delayed speech and language development, Intellectual disability, Behavioral abnormality, Joint laxity, Abnormality of the vertebral column, Abnormality of nervous system morphology, Abnormality of head or neck; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.1677 ZMYND8 Konstantinos Varvagiannis gene: ZMYND8 was added
gene: ZMYND8 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ZMYND8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZMYND8 were set to 35916866; 32530565
Phenotypes for gene: ZMYND8 were set to Delayed speech and language development; Motor delay; Intellectual disability; Abnormality of cardiovascular system morphology; Hearing abnormality; Abnormality of vision; Abnormality of the face; Seizures
Penetrance for gene: ZMYND8 were set to unknown
Review for gene: ZMYND8 was set to GREEN
Added comment: Dias et al (2022 - PMID: 35916866) describe the phenotype of 11 unrelated individuals with monoallelic de novo (or suspected de novo) missense (N=9) or truncating (N=2) ZMYND8 variants. One of these subjects was previously reported by Suzuki et al (2020 - PMID: 32530565).

Features included speech delay/language difficulties (9/11), motor delay (9/11), ID (in 10/11 - profound in 1, moderate in 2), CHD (7/11 - PDA, VSD, ASD, pulmonary stenosis, etc), hearing or vision impairment (7/11). Seizures were reported in few (in text 5/11, table 2/11). Variable non-familial facial features were present in (9/11).

As the authors discuss, ZMYND8 encodes a multidomain protein playing a role in transcription regulation, chromatin remodeling, regulation of super enhancers, DNA damage response/tumor suppression.

The protein is broadly expressed in brain and shows highest expression in early development.

Molecular modeling and/or a yeast two-hybrid system were suggestive of disrupted interaction of ZMYND8 with Drebrin (missense variants in PWWP domain) or GATAD2A (variants in MYND domain).

Neuronal Zmynd8 knockdown in Drosophila resulted in deficits in habituation learning.
Sources: Literature
Intellectual disability - microarray and sequencing v3.1677 ZMYND15 Konstantinos Varvagiannis gene: ZMYND15 was added
gene: ZMYND15 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ZMYND15 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZMYND15 were set to 35916866; 32530565
Phenotypes for gene: ZMYND15 were set to Delayed speech and language development; Motor delay; Intellectual disability; Abnormality of cardiovascular system morphology; Hearing abnormality; Abnormality of vision; Abnormality of the face; Seizures
Penetrance for gene: ZMYND15 were set to unknown
Review for gene: ZMYND15 was set to GREEN
Added comment: Dias et al (2022 - PMID: 35916866) describe the phenotype of 11 unrelated individuals with monoallelic de novo (or suspected de novo) missense (N=9) or truncating (N=2) ZMYND8 variants. One of these subjects was previously reported by Suzuki et al (2020 - PMID: 32530565).

Features included speech delay/language difficulties (9/11), motor delay (9/11), ID (in 10/11 - profound in 1, moderate in 2), CHD (7/11 - PDA, VSD, ASD, pulmonary stenosis, etc), hearing or vision impairment (7/11). Seizures were reported in few (in text 5/11, table 2/11). Variable non-familial facial features were present in (9/11).

As the authors discuss, ZMYND8 encodes a multidomain protein playing a role in transcription regulation, chromatin remodeling, regulation of super enhancers, DNA damage response/tumor suppression.

The protein is broadly expressed in brain and shows highest expression in early development.

Molecular modeling and/or a yeast two-hybrid system were suggestive of disrupted interaction of ZMYND8 with Drebrin (missense variants in PWWP domain) or GATAD2A (variants in MYND domain).

Neuronal Zmynd8 knockdown in Drosophila resulted in deficits in habituation learning.
Sources: Literature
Intellectual disability - microarray and sequencing v3.1667 TPP2 Eleanor Williams reviewed gene: TPP2: Rating: ; Mode of pathogenicity: None; Publications: 33586135, 25414442, 25525876, 30533531; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1659 ALKBH8 Arina Puzriakova reviewed gene: ALKBH8: Rating: GREEN; Mode of pathogenicity: None; Publications: Intellectual developmental disorder, autosomal recessive 71, OMIM:618504; Phenotypes: 31079898, 33544954, 34757492, 35571055; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1656 TAF8 Arina Puzriakova Added comment: Comment on list classification: New gene added by Jana Jezkova. There is sufficient evidence to promote this gene to Green at the next GMS panel update.

TAF8 is associated with a relevant phenotype in OMIM (MIM# 619972) but is not yet listed in G2P.

8 individuals from 5 families have been reported in literature (PMIDs: 29648665; 35759269). Four families from different ethnic backgrounds harboured the same c.781-1G>A homozygous variant while sequencing in a sib pair revealed different compound het splice variants (c.45+4A>G and c.489G>A) in the TAF8 gene. Patients presented with an overlapping phenotype including microcephaly (8/8), DD and ID (8/8), spasticity (7/8), and seizures (6/8). Brain MRI have shown hypoplastic corpus callosum, hypomyelination, enlarged ventricles in most subjects, and additionally generalised brain atrophy in two sibs.
Intellectual disability - microarray and sequencing v3.1654 TAF8 Arina Puzriakova Phenotypes for gene: TAF8 were changed from severe developmental delay; feeding problems; microcephaly; growth retardation; spasticity; epilepsy to Neurodevelopmental disorder with severe motor impairment, absent language, cerebral hypomyelination, and brain atrophy, OMIM:619972
Intellectual disability - microarray and sequencing v3.1649 SLC38A3 Catherine Snow Phenotypes for gene: SLC38A3 were changed from Infantile axial hypotonia; Global developmental delay; Intellectual disability; Seizures; Spasticity; Microcephaly; Cerebral atrophy; Cerebellar atrophy; Abnormality of the corpus callosum; Dysphagia; Constipation; Increased serum lactate; Hyperammonemia to Developmental and epileptic encephalopathy 102, 619881
Intellectual disability - microarray and sequencing v3.1648 SLC38A3 Catherine Snow reviewed gene: SLC38A3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental and epileptic encephalopathy 102, 619881; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1648 STT3A Tracy Lester reviewed gene: STT3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 34653363; Phenotypes: short stature, skeletal defects, intellectual disability, speech delay; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1645 ATP2B1 Catherine Snow reviewed gene: ATP2B1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.1643 OGDHL Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is sufficient evidence to promote to Green at the next GMS panel update.

The NSRP1 gene is not yet associated with any phenotype in OMIM but has a 'moderate' disease confidence rating in G2P for 'OGDHL-related neurodevelopmental disorder with seizures, hearing loss and gait ataxia'.

At least 10 individuals from 9 unrelated families identified with biallelic variants in this gene (PMIDs: 28017472; 34800363). Main clinical features include mild-to-severe DD/ID (9/10), seizures (5/10), gait ataxia (5/10), profound bilateral sensorineural hearing loss (4/10), spasticity (3/10).
Intellectual disability - microarray and sequencing v3.1641 NSRP1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is sufficient evidence to promote to Green at the next GMS panel update.

The NSRP1 gene is not yet associated with any phenotype in OMIM but has a 'strong' disease confidence rating in G2P for 'NSRP1-associated developmental delay, epilepsy and microcephaly'.

Six individuals from three families with different homozygous LoF NSRP1 variants identified by Calame et al. 2021 (PMID: 34385670). Main clinical features include ID/DD (6/6), epilepsy (6/6, drug-resistant in 3/6), hypotonia (6/6), appendicular spasticity (6/6), microcephaly (5/6, Z-scores −0.95 to −5.60). Brain abnormalities included under-opercularization (3/4), simplified gyral pattern (3/4), superior and/or inferior cerebellar vermian hypoplasia (3/4), corpus callosum dysgenesis (1/4), and thin brainstem (1/4).
Intellectual disability - microarray and sequencing v3.1634 BLOC1S1 Arina Puzriakova reviewed gene: BLOC1S1: Rating: ; Mode of pathogenicity: None; Publications: 33875846; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1632 TAF8 Jana Jezkova gene: TAF8 was added
gene: TAF8 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TAF8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TAF8 were set to PMID: 35759269
Phenotypes for gene: TAF8 were set to severe developmental delay; feeding problems; microcephaly; growth retardation; spasticity; epilepsy
Penetrance for gene: TAF8 were set to unknown
Review for gene: TAF8 was set to AMBER
Added comment: Eight patients reported in total. Six patients are homozygous for a recurrent NM_138572.2, c.781-1G>A variant. In two sibling patients, two novel compound heterozygous TAF8 splice site mutations, c.45+4A > G and c.489G>A were identified, which cause aberrant splicing as well as reduced expression and mislocalization of TAF8.
Sources: Literature
Intellectual disability - microarray and sequencing v3.1627 EMC1 Dmitrijs Rots reviewed gene: EMC1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35234901; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1625 MAL Sarah Leigh reviewed gene: MAL: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.1618 WNK3 Arina Puzriakova reviewed gene: WNK3: Rating: GREEN; Mode of pathogenicity: None; Publications: 35678782; Phenotypes: Intellectual disability, MONDO:0001071; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability - microarray and sequencing v3.1606 ATP6V0A1 Mike Spiller reviewed gene: ATP6V0A1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 34909687; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.1594 RYR2 Sarah Leigh reviewed gene: RYR2: Rating: ; Mode of pathogenicity: None; Publications: 30170228; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.1593 ZMYM2 Tracy Lester reviewed gene: ZMYM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32891193; Phenotypes: Intellectual disability, developmental delay, delayed speech and language, learning disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.1593 CUL3 Julie Evans reviewed gene: CUL3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual disability, seizures, autism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.1593 ACO2 Sarah Leigh reviewed gene: ACO2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1592 PHF14 Sarah Leigh reviewed gene: PHF14: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.1590 MED13 Catherine Snow reviewed gene: MED13: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33931951; Phenotypes: Intellectual developmental disorder, autosomal dominant 61 OMIM:618009; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.1583 DROSHA Sarah Leigh reviewed gene: DROSHA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.1580 SNORD118 Ian Berry reviewed gene: SNORD118: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.1580 SRRM2 Konstantinos Varvagiannis changed review comment from: Recent report of 22 unrelated individuals with nonsense / frameshift variants or microdeletions of SRRM2 reported. DD was a universal feature, with ID present in some (16/20 - in all cases mild). Note possible 'overlap' with the study by Kaplanis et al / DDD study cited in the previous review by Prof. Z. Stark.

The gene is not intolerant to missense variation (z-score of -6.28) and eventual contribution of missense variants is not known. While SRRM2 is known to encode a splicing factor promoting interaction between mRNA and the spliceosome catalytic machinery (discussed below) molecular and functional studies are required to characterize the pathogenesis of the disorder.

There is currently no SRRM2-related phenotype in OMIM. SRRM2 is included in the DD panel of G2P [confidence : definitive, SRRM2-related developmental disorder (monoallelic), cited : Kaplanis et al / DDD]. In PanelApp Australia SRRM2 has amber rating in the ID panel (based on the study by Kaplanis et al / DDD).

Consider inclusion with green rating (several individuals/families/variants - rather consistent phenotype) or amber rating (as for pathogenesis / also DD universal feature, ID observed in most but not all affected individuals, when present always mild).

-----

Cuinat et al. (2022 - PMID: 35567594) report on 22 individuals with LoF variants in SRRM2.

All subjects had DD (22/22) predominantly affecting language acquisition (16/19) while motor delay was less common. ID was present in 16/20 (in all cases mild) of the individuals with available neurocognitive evaluation. Some individuals displayed autistic features (9/22) although others had a friendly - in some cases excessively - sociable personality (8/22). Other features included hypotonia in some, growth abnormalities (12/22 overweight, 7/22 with obesity, 4/22 tall stature). Morphological features incl. facial (20/22 - e.g. deep-set eyes, bulbous nasal tip or smooth philtrum) or small hands and feet (6/22) were also reported. Visceral / skeletal abnormalities were uncommon.

SRRM2 encodes serine/arginine repetitive matrix protein 2 (or SRm300), a nuclear ubiquitous protein forming a complex with the protein encoded by SRRM1 (SRm160). As the authors summarize this complex is one of the main catalytic components of the spliceosome having a role in pre-mRNA maturation.

12 subjects harbored frameshift variants, 8 nonsense while 2 further ones had microdeletions (66-270kb) spanning - but not limited to - SRRM2 (other genes not predicted to be haploinsufficient). The gene has a pLI in gnomAD of 1 (o/e = 0.06) while it appears to be tolerant to missense variation (z-score of -6.28 / o/e = 1.43). With the exception of the 2 subjects harboring a microdeletion, all were investigated with singleton/trio ES with no other candidate variants.

Variants occurred de novo in 19/22. Mosaicism (in an asymptomatic parent) was suspected based on the reads in one case. One individual had inherited the variant (parent with DD). Segregation analyses was not possible in one case.

While one variant lied in ex2 (of 15) all others were in the large ex11 (encoding ~2000 of the 2752 total residues based on the schema provided / NM_016333.4), all predicted to lead to NMD.

There are no studies for pathogenesis of the disorder or the underlying effect of variants. Animal models not discussed.

The authors do a comparison with other 'spliceosomopathies', e.g. due to variants in SF3B4 or EFTUD2, where DD/ID can be a feature although these disorders have also prominent skeletal features.

Previously, as the authors note, the study by Kaplanis et al (2020 - PMID: 33057194) integrating exome sequence data from ~31,000 parent-offspring trios of individuals with developmental disorders had identified SRRM2 among 28 genes significantly enriched in LoF variants. [ The present study possibly includes individuals from the aforementioned cohort, e.g. from Radboudumc ].; to: Recent report of 22 unrelated individuals with nonsense / frameshift variants or microdeletions of SRRM2. DD was a universal feature, with ID present in some affected individuals (16/20 - in all cases mild). Note possible 'overlap' with the study by Kaplanis et al / DDD study cited in the previous review by Prof. Z. Stark.

The gene is not intolerant to missense variation (z-score of -6.28) and eventual contribution of missense variants is not known. While SRRM2 is known to encode a splicing factor promoting interaction between mRNA and the spliceosome catalytic machinery (discussed below) molecular and functional studies are required to characterize the pathogenesis of the disorder.

There is currently no SRRM2-related phenotype in OMIM. SRRM2 is included in the DD panel of G2P [confidence : definitive, SRRM2-related developmental disorder (monoallelic), cited : Kaplanis et al / DDD]. In PanelApp Australia SRRM2 has amber rating in the ID panel (based on the study by Kaplanis et al / DDD).

Consider inclusion with green rating (several individuals/families/variants - rather consistent phenotype) or amber rating (as for pathogenesis / also DD universal feature, ID observed in most but not all affected individuals, when present always mild).

-----

Cuinat et al. (2022 - PMID: 35567594) report on 22 individuals with LoF variants in SRRM2.

All subjects had DD (22/22) predominantly affecting language acquisition (16/19) while motor delay was less common. ID was present in 16/20 (in all cases mild) of the individuals with available neurocognitive evaluation. Some individuals displayed autistic features (9/22) although others had a friendly - in some cases excessively - sociable personality (8/22). Other features included hypotonia in some, growth abnormalities (12/22 overweight, 7/22 with obesity, 4/22 tall stature). Morphological features incl. facial (20/22 - e.g. deep-set eyes, bulbous nasal tip or smooth philtrum) or small hands and feet (6/22) were also reported. Visceral / skeletal abnormalities were uncommon.

SRRM2 encodes serine/arginine repetitive matrix protein 2 (or SRm300), a nuclear ubiquitous protein forming a complex with the protein encoded by SRRM1 (SRm160). As the authors summarize this complex is one of the main catalytic components of the spliceosome having a role in pre-mRNA maturation.

12 subjects harbored frameshift variants, 8 nonsense while 2 further ones had microdeletions (66-270kb) spanning - but not limited to - SRRM2 (other genes not predicted to be haploinsufficient). The gene has a pLI in gnomAD of 1 (o/e = 0.06) while it appears to be tolerant to missense variation (z-score of -6.28 / o/e = 1.43). With the exception of the 2 subjects harboring a microdeletion, all were investigated with singleton/trio ES with no other candidate variants.

Variants occurred de novo in 19/22. Mosaicism (in an asymptomatic parent) was suspected based on the reads in one case. One individual had inherited the variant (parent with DD). Segregation analyses was not possible in one case.

While one variant lied in ex2 (of 15) all others were in the large ex11 (encoding ~2000 of the 2752 total residues based on the schema provided / NM_016333.4), all predicted to lead to NMD.

There are no studies for pathogenesis of the disorder or the underlying effect of variants. Animal models not discussed.

The authors do a comparison with other 'spliceosomopathies', e.g. due to variants in SF3B4 or EFTUD2, where DD/ID can be a feature although these disorders have also prominent skeletal features.

Previously, as the authors note, the study by Kaplanis et al (2020 - PMID: 33057194) integrating exome sequence data from ~31,000 parent-offspring trios of individuals with developmental disorders had identified SRRM2 among 28 genes significantly enriched in LoF variants. [ The present study possibly includes individuals from the aforementioned cohort, e.g. from Radboudumc ].
Intellectual disability - microarray and sequencing v3.1580 SRRM2 Konstantinos Varvagiannis reviewed gene: SRRM2: Rating: AMBER; Mode of pathogenicity: None; Publications: 35567594, 33057194; Phenotypes: Global developmental delay, Intellectual disability, Behavioral abnormality, Abnormality of the head or neck, Small hand, Short foot; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.1580 DROSHA Konstantinos Varvagiannis gene: DROSHA was added
gene: DROSHA was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DROSHA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DROSHA were set to 35405010
Phenotypes for gene: DROSHA were set to Global developmental delay; Intellectual disability; Seizures; Cerebral white matter atrophy; Abnormality of the corpus callosum; Abnormality of movement; Stereotypic behavior; Abnormality of head or neck; Short foot
Penetrance for gene: DROSHA were set to unknown
Mode of pathogenicity for gene: DROSHA was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: DROSHA was set to AMBER
Added comment: Profound DD, ID and seizures have been reported in 2 unrelated subjects with de novo missense variants. The gene has a role in miRNA biogenesis. Both variants described have been shown to have effect on DROSHA's function in Drosophila / C. elegans (partial loss-of-function vs possibility of antimorphic effect discussed || in gnomAD several individuals with LoF alleles / Z=3.98 – pLI : 0.09).

There is currently no DROSHA-related phenotype in OMIM, G2P, SysNDD. In PanelApp Australia the gene has amber rating in genetic epilepsy and microcephaly panels (not currently included in the ID one).

Consider inclusion in the current panel with amber rating. Also consider inclusion in other possibly relevant panels (given postnatal microcephaly, abn. corpus callosum, progressive white matter atrophy, etc) [ NOT added ]

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Barish, Senturk, Schoch et al (2022 - PMID: 35405010) describe the phenotype of 2 unrelated individuals with de novo missense DROSHA variants.

Features included generalized hypotonia, postnatal microcephaly (-2,6 and -6 SD), feeding difficulties, profound DD and ID, seizures, abnormal movements (choreoathetosis / stereotypic movements), variable respiratory symptoms (in one case episodes of hyperventilation/apnea), cardiovascular or skeletal findings. Brain MRI demonstrated white matter atrophy and thin corpus callosum in both. Brachycephaly with broad face as well as short feet were also among the shared features.

Both were investigated by trio ES/GS which were otherwise non diagnostic and without other candidate variants. The 1st individual harbored a de novo htz missense DROSHA variant (c.3656A>G/p.Asp1219Gly) while the 2nd subject had another missense variant (c.4024C>T/p.Arg1342Trp) [NM_013235.4] confirmed by Sanger seq.

DROSHA (on 5p13.3) encodes a ribonuclease, subunit of the microprocessor complex, involved in miRNA biogenesis. Specifically, miRNAs are transcribed as part of pri-miRNAs (primary-miRNAs) which are cleaved to pre-miRNAs (precursor-miRNAs) in the nucleus by DROSHA (and its partner DGCR8 or Pasha) and then exported to the cytoplasm for further processing. Cleavage of pre-miRNAs by DICER1 generates mature miRNAs subsequently loaded to the RISC (RNA-induced silencing) complex which uses miRNA as template for recognition and cleavage of complementary mRNA with RNAse.

As the authors discuss, miRNA defects have a well-established role in development of model organisms e.g. (several Refs. provided):
- in C. elegans miRNA mutants causing lethality, developmental arrest and heterochronicity
- in Drosophila playing a role in the development of ovary, eye, nervous system etc.
- in mice mRNAs play a role in BMP and TGF-beta signaling while neuronal loss of miRNA processing leads to neurodegeneration/anatomical defects.

Feingold syndrome 2 is the single Mendelian disease associated to date with miRNAs, through deletion of a cluster containing 6 MIR genes.

miRNA dysregulation is also observed in Rett syndrome - and DROSHA implicated in the pathogenesis of the syndrome - as MECP2 and FOXG1 are cofactors of the microprocessor complex regulating processing of miRNA. One of the individuals here reported had a clinical diagnosis of Rett spectrum while both had overlapping features with Rett s.

Studies of DROSHA-dependent miRNAs in fibroblasts from one individual revealed significantly altered expression of mature miRNA (e.g. increased miR98, a miRNA with reduced expression in studies of somatic DROSHA variants) although this was not likely due to processing errors (given only a modest decrease of precursor miRNAs).

Previous studies have demonstrated that drosha (the Drosophila ortholog) null mutants die during post-embryonic development with 100% lethality before adulthood (3rd instar larval stage/beginning of pupariation). Mosaic flies with mutant eyes are small-eyed, while viable hypomorphic alleles display synaptic transmission defects (several Refs provided).

Here, homozygous flies for null alleles died at the end of 3rd instar larval stage/beginning of pupariation, while loss of drosha resulted in lack of imaginal disc tissue (which surrounds the larval brain) and severely reduced brain size, the latter similar to the microcephaly phenotype. [To the best of my understanding] introduction of a mutated genomic rescue construct (carrying similar substitutions as those observed in human subjects) in eye-specific drosha null (W1123X) flies was partially able to rescue eye/head size for wt or Asp1219Gly (human:Asp1084Gly) suggesting that the latter is a partial LoF allele. Arg1210Trp (corresponding to human Arg1342Trp) was able to rescue the eye phenotype and was not damaging to the function in the specific assay. Drosha expression levels were similar for genomic rescue flies either for wt or for the Asp-Gly variant suggesting that the effect was not due to expression levels (but rather function). Expression of mature miRNAs known to be regulated by Drosha were not affected when comparing wildtype larvae with genomic construct for wt or Asp1084Gly.

Upon expression of human cDNA using GAL4/UAS system in drosha mutant (null) eye clones, the reference partially rescued the eye size defect, Asp-Gly behaved as partial loss-of-function allele (~50% function compared to ref), while the Arg-Trp variant was shown to behave as a weaker loss-of-function allele.

The authors generated eye-specific drosha mutant clones to study the aging adult eye using ERG recordings. While null mutants display almost no response to light (7- and 20-day old flies), wt genomic rescue was shown to rescue ERG responses, Asp-Gly variant had significant defects (at both 7 and 20 days) and the Arg-Trp had defects approaching statistical significance only at the age of 20 days. Overall these data suggested that Arg-Trp had less severe effect compared to Asp-Gly (as above) while both variants led to progressive neuronal dysfunction.

Using CRISPR/Cas9 the authors generated C.elegans knock-ins for a variant analogous to the Asp1219Gly human one. Homozygous animals were inviable at larval stages, displayed a heterochronic phenotype (heterochronicity : development of cells or tissues at an abnormal time relative to other unaffected events in an organism / miRNAs are known to be involved in the heterochronic gene pathway) while this variant was deleterious to the Drosha's ability to process miRNAs.
Sources: Literature
Intellectual disability - microarray and sequencing v3.1580 SCAF4 Ian Berry reviewed gene: SCAF4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32730804; Phenotypes: Seizures, intellectual disability (mild); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.1576 PRPF8 Konstantinos Varvagiannis gene: PRPF8 was added
gene: PRPF8 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PRPF8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRPF8 were set to 35543142
Phenotypes for gene: PRPF8 were set to Global developmental delay; Intellectual disability; Seizures; Autism; Retinitis pigmentosa 13, MIM # 600059
Penetrance for gene: PRPF8 were set to unknown
Review for gene: PRPF8 was set to AMBER
Added comment: A recent study suggests that heterozygous PRPF8 variants are associated with a syndromic form of DD/ID, in some cases epilepsy with heterogeneous other clinical findings. However the authors acknowledge that not all variants within their cohort may be pathogenic (5 VUSs using ACMG criteria) and that conclusive evidence may necessitate functional studies.

Heterozygous variants (typically clustering in exon 42) have been reported to cause a non-syndromic form of RP with variable expressivity and incomplete penetrance (Retinitis pigmentosa 13, MIM # 600059) .

Overall consider inclusion with amber rating.

------

O'Grady et al. (2022 - PMID: 35543142) describe the phenotype of 14 unrelated individuals with heterozygous, mostly de novo, missense and pLoF variants in PRPF8.

Nearly all had some degree of global developmental delay or ID (13/14). 6/14 had a diagnosis of ASD. Seizures were reported in 4 or 5 subjects. Other features included short stature (6/14), abnormal gait, cardiac anomalies and somewhat overlapping facial features (11/14). Ages ranged from 4 - 19 years (median : 9y).

PRPF8 encodes a component of the spliceosomes which in turn are involved in removal of introns from mRNA precursors. The gene is ubiquitously expressed with expression within brain being highest in cerebral cortex, basal ganglia and cerebellum (Refs. provided).

Individuals were investigated with exome sequencing (12/14) or an autism/ID panel of >2500 genes (likely application of virtual panel on exome data).

13 individuals harbored a missense SNV and 1 further had a frameshift variant. In 12 individuals the variant had occurred de novo. 1 individual had inherited the variant from a possibly mosaic parent, while for 1 further a single parental sample was available.

PRPF8 is intolerant to both missense (Z = 8.28) and pLoF variants (pLI : 1). Variants in 5 individuals were formally classified as VUS while 2 variants were present in gnomAD.

Additional findings (CNVs/SNVs) were reported, in some cases possibly of relevance.

As the authors discuss, heterozygous pathogenic missense SNVs cause (and account for ~2-3% of) non-syndromic AD retinitis pigmentosa with variable expressivity and incomplete penetrance. Variants for this phenotype are typically missense - although nonsense ones have also been reported - clustering within ex42 (of 43) encoding the MPN domain (aa 2103-2335 / NP_006436) and weakening interaction with 2 other spliceosomal proteins.

Variants in the present study occurred throughout the gene. Although not universally assessed within the cohort, only one participant had RP (in this case variant within the MPN domain).

There were no variant studies performed.

Animal models: the authors cite a study by Graziotto et al (2011 - PMID: 20811066) where knock-in mice for a missense variant in ex42 displayed defects of the retinal pigment epithelium. A zebrafish ko model also cited (Keightley et al, 2013 - PMID: 23714367) displayed widespread apoptosis in brain and spinal cord.

The authors cite a previous bioinformatic study identifying PRPF8 as a major hub connecting gene-interaction networks for NDDs (Casanova et al, 2018 - PMID: 30420816) as well as 2 studies demonstrating enrichment of variants in individuals with NDDs compared to controls (da Silva Montenegro et al, 2020 - PMID: 31696658, Karczewski et al, 2020 - PMID: 32461654).
Sources: Literature
Intellectual disability - microarray and sequencing v3.1568 CELF2 Julia Baptista gene: CELF2 was added
gene: CELF2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CELF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CELF2 were set to 34107259; 33131106
Phenotypes for gene: CELF2 were set to Developmental delay; epileptic encephalopathy
Mode of pathogenicity for gene: CELF2 was set to Other
Review for gene: CELF2 was set to GREEN
Added comment: De novo missense variants in six individuals (PMID:34107259). The variants cluster on the C‐terminus, a nuclear localization sign. Phenotypic findings include global developmental delay with moderate to severe impairment of speech and language capacities, infantile spasms, stereotypic movements and/or aggressive behaviors, and one individual was diagnosed with ASD.

A previous publication (PMID: 33131106) reported five unrelated individuals (four de novo). Two missense variants, one frameshift predicted to escape NMD and one splice site variant, c.272‐1G>C were identified; these variants, except the splicing, clustered on the C‐terminus.
Sources: Literature
Intellectual disability - microarray and sequencing v3.1565 HIST1H4C Arina Puzriakova Mode of pathogenicity for gene: HIST1H4C was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability - microarray and sequencing v3.1564 ADD1 Konstantinos Varvagiannis gene: ADD1 was added
gene: ADD1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ADD1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ADD1 were set to 34906466
Phenotypes for gene: ADD1 were set to Global developmental delay; Intellectual disability; Seizures; Ventriculomegaly; Abnormality of the corpus callosum
Penetrance for gene: ADD1 were set to unknown
Review for gene: ADD1 was set to AMBER
Added comment: A recent study suggests an ADD1-related phenotype (3 subjects with monoallelic de novo variants/1 with biallelic variants) with DD/ID and ventriculomegaly or corpus callosum dysgenesis and possibly seizures among the features.

There is currently no associated phenotype in other databases (OMIM, G2P, SysID, PanelApp Australia).

Consider inclusion in the current panel with amber / green rating (3 subjects/variants/families, role of the gene and mouse models recapitulating ventriculomegaly/CC abnormalities, relevant expression, variant studies demonstrating abn. protein levels and/or disruption of adducin heterodimer formation || monoallelic vs bi-allelic variants).

Please consider inclusion in other possibly relevant gene panels (e.g. for corpus callosum / ventriculomegaly) [ Not added ].

--------

Qi et al (2022 - PMID: 34906466) describe the phenotype of 3 unrelated individuals with monoallelic de novo ADD1 pathogenic variants as well as of a fourth homozygous for a missense SNV.

Overall, the authors propose a common phenotype consisting of morphological brain abnormalities (incl. ventriculomegaly and corpus callosum dysgenesis) and neurological symptoms such as DD and/or ID and attention deficit.

All individuals were investigated with singleton/trio ES.

De novo variants - phenotype:
One individual investigated for hypotonia, DD & ID, partial ACC, well controlled seizures (on ketogenic diet) and proportional short stature harbored a de novo stopgain variant (NM_014189.3:c.1418G>A / p.Trp473*) absent from gnomAD.
Another affected subject with hypotonia, FTT/feeding difficulties, mild motor delays complete ACC, a seizure (2y11m), staring spells without EEG correlate, and fatigue (with low coenz. Q10, and complex I & IV deficiency in muscle biopsy) had a de novo fs variant (NM_001119:c.2029_2039del / p.Glu680Argfs*7 - gnomAD:0) and a VUS in a gene not associated with phenotype to date.
A 3rd subject investigated for seizures (onset:1y), speech delay, mild ID, ADHD, without MRI abnormalities harbored a de novo missense SNV (NM_001119:c.670C>T / p.His224Tyr - gnomAD:0) and with cmp htz for 2 missense SPTBN2 SNV not fitting the phenotype (no ataxia).

Biallelic variants - phenotype:
One individual with ID, and ACC, abnormal sulcation, enlarged lateral and 3rd ventricles, abnormal of white matter and hypoplastic vermis upon MRI was reported to harbor in homozygosity a missense SNV (NM_001119:c.169A>T / p.Arg57Trp). There was an additional variant in a gene without associated phenotype to date and not expressed in brain.

Role of the encoded protein:
ADD1 encodes adducin 1/alpha (similar to ADD2, ADD3 encoding other adducins). As the authors note, adducins are cytoskeleton proteins critical for osmotic rigidity and cell shape. In neurons they have been reported to form membrane associated periodic ring-like structures with actin and β-spectrin. Deletion of Add1 in mice results in increased MPS ring diameter and axonal degeneration (several refs provided).

ADD1/2/3 form heterodimers which in turn form heterotetramers. ADD1 is expressed in most tissues.

Mouse model:
Previous mouse models have demonstrated that Add1 null mice have also undetectable ADD2/3 (suggesting a role for stabilization of the latter) and exhibit growth delay, anemia and develop lethal hydrocephalus and ventriculomegaly with 50% penetrance (cited PMIDs: 27068466, 18723693). Here the authors demonstrated that surviving mice had ventriculomegaly and thinning of corpus callosum thus recapitulating the respective human phenotypes. Htz mice also presented thinner CC, though not to a statistically significant extent.

ADD1 expression and isoforms:
- Performing mRNA studies and W.Blot in (developing - GW15-17) human or mouse brain (E12.5-P40) the authors demonstrated dynamic expression of ADD1 with differentially expressed isoforms, notably alternative splicing of ex10 and ex15 with NM_176801 (extended ex10, inclusion of ex15) corresponding to a neuronal isoform and NM_001119 (shorter ex10, exclusion of ex15) corresponding to a neural progenitor cell (NPC) isoform.
- Variants here reported appear to affect both isoforms with the exception of NM_001119:c.2029_2039del / p.Glu680Argfs*7 affecting only the longer NPC one.
- PTBP1 is an RNA binding protein expressed in NPCs known to suppress neuronal exon insertion. The authors demonstrated in mouse Neuro2A cells, through shRNA targeting of Ptbp1, that the latter suppresses the neuronal Add1 isoform.

Variant studies demonstrated that effect of variants was mediated by decreased protein levels and/or disruption of adducin complex formation (ADD1-ADD2 dimer formation known to be mediated by N- and C- terminal ADD1 domains):
- Expression of Arg57Trp (found in hmz in one individual) NPC and neuronal isoforms in Neuro2a cells showed that while protein levels were not significantly affected, there were (also) truncated protein products for both isoforms suggesting that aberrant splicing or protein translation/cleavage may apply.
- The authors generated HEK293FT cells for the truncating variants demonstrating decreased protein levels (using N-/C- terminal antibodies).
- Reduced (HA-tagged)-ADD1-(V5-tagged)-ADD2 protein interaction was shown to apply for the Arg57Trp and Arg473* in HEK293FT cells. Similarly in Neuro2a cells, reduced ADD1-ADD2 interaction was shown for His224Tyr.
Sources: Literature
Intellectual disability - microarray and sequencing v3.1564 THUMPD1 Julia Baptista reviewed gene: THUMPD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35196516; Phenotypes: Intellectual disability, Microcephaly, Seizures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.1564 ZBTB7A Julia Baptista reviewed gene: ZBTB7A: Rating: GREEN; Mode of pathogenicity: None; Publications: 34515416; Phenotypes: intellectual disability, macrocephaly, overgrowth; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.1564 BUB1 Konstantinos Varvagiannis gene: BUB1 was added
gene: BUB1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: BUB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BUB1 were set to 35044816
Phenotypes for gene: BUB1 were set to Congenital microcephaly; Global developmental delay; Intellectual disability; Abnormal heart morphology; Growth delay
Penetrance for gene: BUB1 were set to Complete
Review for gene: BUB1 was set to AMBER
Added comment: A recent study provides evidence that this gene (biallelic variants) is relevant for inclusion in the DD/ID panel likely with amber / green rating (2 unrelated individuals with similar phenotype, 3 variants, role of this gene, extensive variant studies and demonstrated effects on cohesion and chromosome segregation, similarities with other disorders caused by mutations in mitosis-associated genes at the clinical and cellular level || number of affected subjects/families, different protein levels/kinase activity likely underlying few differences observed, role of monoallelic variants unclear).

This gene could probably be included in other panels e.g. for microcephaly (not added).

There is no BUB1-related phenotype in OMIM, G2P, SysID, PanelApp Australia.

------

Carvalhal, Bader et al (2022 - PMID: 35044816) describe the phenotype of 2 unrelated individuals with biallelic BUB1 pathogenic variants and provide evidence for the underlying mechanism for this condition.

Common features comprised congenital microcephaly (2/2 | -2,8 and -2.9 SDs respectively / -7 and -4,9 SDs on last evaluation), DD/ID (2/2 - in one case with formal evaluation mild), some degree of growth retardation (2/2) and cardiovascular findings (2/2 - small ASD type II). Other findings limited to one subject included Pierre-Robin sequence, Axenfeld-Rieger anomaly, choanal stenosis, hypospadias, tracheal stenosis, etc.

Initial genetic testing was normal (incl. CMA in both, metabolic testing and individual genes incl. PITX2, GREM1, FOXD3, FOXC1 for one proband).

Exome sequencing revealed homozygosity for a start-lost variant (NM_004336.4:c.2T>G / p.?) in the first subject (P1). The variant lied within a 14-Mb region of homozygosity (no reported consanguinity). The second individual (P2) was compound htz for a splice-site and a frameshift variant (c.2625+1G>A and c.2197dupG) with Sanger sequencing used for confirmation and segregation studies.

BUB1 encodes BUB1 Mitotic checkpoint serine/threonine kinase (/Budding uninhibited by benzimidazoles 1, s. cerevisiae, homolog of) a multifunctional component of the segregation machinery contributing to multiple mitotic processes. The protein has a kinetochore localization domain, multiple binding motifs and a C-terminal kinase domain (aa 784-1085) this structure allowing both kinase dependent/independent activities.

cDNA sequencing revealed that the splice variant leads to skipping of ex21 and in-frame deletion of 54 residues in the kinase domain (c.2625+1G>A / p.Val822_Leu875del).

Both individuals exhibited normal BUB1 mRNA levels (fibroblasts in both, tracheal tissue in one) but severely reduced protein levels (fibroblasts). A shorter protein product corresponding to the in-frame deletion variant was also detected.

The authors performed additional experiments to confirm small amounts of full-length protein produced by the start-lost variant. This was shown in SV40-transformed fibroblasts from the corresponding individual (treatment with a proteasome inhibitor resulted also in higher levels). Upon generation RPE1 cells using CRISPR for the start-lost variant, again, small amounts of full length protein were detected, which was not the case for complete knockout HAP1 cells. No shorter versions could be detected in the patient cells or RPE1 cells, arguing against utilization of an alternative start codon. (Use of non-AUG start codons discussed based on literature).

In line with small amounts of full-length protein the authors provided evidence for residual kinase activity for the start-loss variant (through proxy of phosphorylation of its substrate and use of a BUB1 kinase inhibitor). Cells from the individual with the frameshift variant and the splice variant had no residual kinase activity.

The authors provide evidence for mitotic defects in cells from both individuals with prolonged mitosis duration and chromosome segregation defects. Some patient-specific findings were thought to be related with BUB1 protein levels (affecting BUB1-mediated kinetochore recruitment of BUBR1, important for chromosome alignment) and others due to residual kinase activity [->phosphorylation of H2A at Threonine 120-> affecting centromeric recruitment of Aurora B, SGO1 (role in protection of centromeric cohesion), TOP2A (a protein preventing DNA breakage during sister chromatid separation), these correlated with high anaphase bridges (in P2), aneuploidy observed in lymphoblasts and primary fibroblasts from P2 but not P2's lymphocytes or lymphocytes from P1) and defective sister chromatid cohesion defects (in primary fibroblasts from P2, milder effect for P1).

Overall the authors provide evidence for overlapping clinical and cellular phenotype for this condition with primary microcephalies (MCPH - mutations in genes for mitotic regulators incl. kinetochore proteins or regulators of chromosome organization), mosaic variegated aneuploidy (biallelic variants in genes for kinetochore proteins, with random aneuploidies occurring in >5% cells of different tissues) and cohesinopathies (mostly Roberts or Warsaw breakage syndromes - characterized by cohesion loss and/or spontaneous railroad chromosomes).

Mouse model: Hmz disruption in mice is lethal shortly after E3.5 (cited PMID: 19772675), while a hypomorphic mutant mouse (lacking exons 2-3, expressing <5% of wt protein levels) is viable but exhibits increased tumorigenesis with aging and aneuploidy (cited PMID: 19117986). Mutant mice that lack kinase activity though with preserved Bub1 protein abundance, did not display increased susceptibility, despite substantial segregation errors and aneuploidies (cited PMID: 23209306).

The authors note that monoallelic germline BUB1 variants have been described in small number of individuals with CRC, exhibiting reduced expression levels and variegated aneuploidy in multiple tissues (cited PMID: 23747338) although the role of BUB1 is debated (cited PMIDs: 27713038, 29448935).

Based on the discussion, complete loss of BUB1 activity is presumed to be embryonically lethal based on the mouse study (PMID: 19772675) and reduced BUB1 expression associated with spontaneous miscarriages (cited PMID: 20643875, to my understanding in this study mRNA levels remained relatively constant despite reduced Bub1 protein levels, mRNA RT-PCR followed by sequencing revealed only 2 synonymous BUB1 variants).
Sources: Literature
Intellectual disability - microarray and sequencing v3.1562 PABPC1 Konstantinos Varvagiannis gene: PABPC1 was added
gene: PABPC1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PABPC1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PABPC1 were set to 35511136
Phenotypes for gene: PABPC1 were set to Global developmental delay; Expressive language delay; Intellectual disability; Behavioral abnormality; Seizures
Penetrance for gene: PABPC1 were set to unknown
Review for gene: PABPC1 was set to AMBER
Added comment: Wegler et al (2022 - PMID: 35511136) describe the phenotype of 4 individuals with de novo variants in the PABP domain of PABPC1.

Overlapping features included DD (4/4) with weak expressive language (4/4), learning disability/borderline intellectual functioning (in 2) to more severe ID (in 2 others), treatable/self-limiting seizures (in 3 for whom this information was available) as well as variable behavioral issues (impaired social skills, concentration/sleeping problems, ADHD, anxiety or autism). Other features involved feeding difficulties (3/4), hearing impairment (in 2/3) or variable other phenotypes. Contribution of de novo variants found in other genes was thought possible.

All 4 were investigated by trio exome sequencing following negative previous routine diagnostic work-up. WES revealed heterozygous de novo PABPC1 variants, 3 of which were missense SNVs (c.1687G>A/p.Gly563Ser, c.1691A>C/p.Glu564Gly, c.1709T>C/p.Ile570Thr using NM_002568.3) and a fourth an in-frame deletion (c.1664_1666del/p.Pro555del).

Additional de novo variants were reported in 3 cases (IGF2R missense SNV, htz KDM5B stopgain, RBBP4 - the latter not associated with any phenotype to date).

PABPC1 encodes Polyadenylate-binding protein, cytoplasmic, 1 which as the authors summarize has an important role overall in regulation of gene expression (poly(A) tail length, mRNA formation, export of processed mRNAs to cytoplasm, translation initiation promotion and termination, mRNA stability, NMD). Translation is regulated by Polyadenylate-binding protein–interacting proteins (PAIPs) which control PABP activity. PAIP2 in particular, which is highly expressed in CNS, is known to inhibit translation via binding to the PABP domain of PABPC1 and is thought to play an important role through transcriptional regulation for synaptic plasticity and memory.

To evaluate plausibility as a DD gene the authors performed analyses using publicly available data, with PABPC1 ranking high in terms of protein-protein interaction (PPI) and co-expression with known DD genes.

Variants were absent from gnomAD with in silico predictions in favour of a deleterious effect.

While PABPC1 is intolerant to both missense and LoF variants (z-score 4.49, pLI of 1), occurrence of these 4 dn variants and their clustering in the PABP domain appeared to be of statistical significance (p=0.002 and p=2.8x10-8) rather than being explained by random occurrence.

Structural modeling of variants suggested that all were in close spatial vicinity within the PABP domain, likely influencing PAIP2 binding.

In HeLa cells the variants were shown not to affect subcellular localization (to the cytoplasm) compared to wt. In addition, there were no significant differences upon stress conditions under which the protein localizes to stress granules.

In HeLa cells, co-immunoprecipitation assays using C-terminal HA tagged PABPC1, revealed that 3 variants (Gly563Ser, Glu564Gly, Ile570Thr) significantly reduced physical PABPC1-PAIP2 interaction compared with wt, which was also observed though to a not significant extent for Pro555del. (Other variants from literature also studied as discussed below).

Pabpc1 is highly expressed in all regions of the developing mouse brain with remarkable decrease after birth, suggesting a critical role in prenatal brain development. Through electroporation with Pabpc1-directed shRNA the authors provided evidence that Pabpc1 LoF results in abnormal neural progenitor cell proliferation with rescue experiments using human WT or missense variants (Gly563Ser, Glu564Gly, Ile570Thr) showing that only the WT could rescue the proliferation phenotype.

Overall a model whereby weakened PABPC1-PAIP2 interaction, leading to dysregulation to gene expression homeostasis and interference with proliferation of neural progenitors and the later to the NDD phenotype is proposed.

Given previous reports in the literature for de novo PABPC1 variants, namely Lys138Glu, Asp204Val, Arg481His, Pro456Leu the authors noted that the phenotypes reported in the respective individuals were rather explained by other variants (16p11.2 dup, ARID1A dn, TBL1XR1 dn variants). These PABPC1 variants do not lie in the PABP domain, have lower in silico pathogenicity scores (MPC/CADD), with structural modelling suggestive of no significant effect. Importantly, upon co-immunoprecipitation studies with PAIP2 which were here performed, these variants had no effect. Pathogenicity of these variants - not located within the PABP domain - through another mechanism cannot be however ruled out. (PMIDs cited, though not reviewed based on this discussion: De Rubeis et al, 2014 - PMID: 25363760, Guo et al, 2019 - PMID: 30504930, Kaplanis et al, 2020 - PMID: 33057194).

Currently there is no PABPC1-related phenotype in other databases (incl. OMIM, G2P, SysID, PanelApp Australia).

Consider inclusion in the gene panels for ID and epilepsy with amber / green rating (DD with or without ID in >= 3 individuals/families/variants – also the case for seizures, role of the gene, statistical evidence for the gene/occurrence and clustering of variants, functional studies with strong evidence for at least 3 variants || learning difficulties/borderline intellectual functioning in 2 affected individuals, phenotype in few might be "blended" due to additional de novo variants).
Sources: Literature
Intellectual disability - microarray and sequencing v3.1562 CTR9 Konstantinos Varvagiannis reviewed gene: CTR9: Rating: AMBER; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 35499524, 2815719, 25363760, 27479843, 25099282, 29292210; Phenotypes: Delayed speech and language development, Motor delay, Intellectual disability, Behavioral abnormality, Autistic behavior, Failure to thrive, Feeding difficulties, Abnormality of the cardiovascular system; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.1562 CTR9 Konstantinos Varvagiannis gene: CTR9 was added
gene: CTR9 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CTR9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTR9 were set to 35499524; 2815719; 25363760; 27479843; 25099282; 29292210
Phenotypes for gene: CTR9 were set to Delayed speech and language development; Motor delay; Intellectual disability; Behavioral abnormality; Autistic behavior; Failure to thrive; Feeding difficulties; Abnormality of the cardiovascular system
Penetrance for gene: CTR9 were set to unknown
Mode of pathogenicity for gene: CTR9 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: CTR9 was set to AMBER
Added comment: Meuwissen, Verstraeten, Ranza et al (2022 - PMID: 35499524) describe the phenotype of 13 unrelated individuals harboring heterozygous - predominantly de novo - CTR9 missense variants.

Overlapping features included delayed speech and/or motor development (each in 9 cases) with the latter complicated by hypotonia or hyperlaxity in some cases. Balance or coordination problems were also reported in some. Variable degrees of ID ranging from mild to severe were observed in all individuals of relevant age except for 3 who however experienced impairment in other domains and/or learning difficulties (8/11 - 2 individuals were too young for evaluation). Few had evidence of regression. Other features included behavioral abnormalities (incl. ASD in 4), FTT/feeding problems (in 5), cardiovascular findings (in 4 - incl. infantile thoracic aortic aneurysm, VSD, pulm. valve stenosis, SVAS). The authors reported variable/nonspecific dysmorphic features.

WES revealed heterozygous CTR9 missense variants in all cases (NM_014633.5 as RefSeq). The variants occurred de novo in most (11/13) individuals with a one proband having inherited the variant from his affected parent. For one case, a single parental sample was available. Most SNVs were absent from gnomAD with the exception of c.1364A>G/p.Asn455Ser and c.2633G>A/p.Arg878Gln present once in the database (Z-score for CTR9: 4.3 / pLI : 1). The variants affected highly conserved residues with in silico predictions mostly in favor of a deleterious effect.

CTR9 encodes a subunit of the PAF1 complex (PAF1C) with the other subunits encoded by PAF1, LEO1, CDC73, RTF1 and WDR61/SKI8. The complex acts as a transcriptional regulator with CTR9 binding RNA polymerase II. The complex influences gene expression by promoting H2BK123 ubiquitylation, H3K4 and H3K36 methylation. In yeast, Paf1 and Ctr9 appear to mediate involvement of Paf1C in induction of mitophagy (several Refs provided).

In silico modeling: a group of N-terminal variants likely destabilize structure, another group possibly perturbs CTR9-PAF1 interactions and a 3rd class influences interactions with other subunits. p.Glu15Lys did not appear to influence protein stability.

Functional studies: H3K4/H3K36 methylation analysis, mitochondrial quality assessment and RNA-seq studies in fibroblasts did not provide conclusive evidence for downstream consequences of the variants (albeit a brain-specific effect - as demonstrated for other disorders – cannot be excluded).

Animal models: In zebrafish, the Paf1C complex has been shown to play a role in cardiac specification and heart morphogenesis with ctr9 mutants showing severe defects in morphogenesis of primitive heart tube (cited PMID: 21338598). This supports a role of the CTR9 variants in the cardiac abnormalities observed in 4 individuals. Although Paf1C zebrafish homologues are required for Notch-regulated transcription (cited PMID: 17721442), there was no supporting evidence from RNA-seq analyses performed by the authors. In Drosophila, Ctr9 has a key role at multiple stages of nervous system development in Drosophila (cited PMID: 27520958). In rat, Ctr9 is expressed in dopaminergic neurons, with its expression not restricted to the nucleus, regulating dopamine transporter activity (cited PMID: 26048990).

As commented, de novo CTR9 variants have been identified in indivdiduals with developmental disorders in larger cohorts, though without phenotypic details (DDD study - PMID:2815719, De Rubeis et al, 2014 - PMID: 25363760, Lelieveld et al PMID: 27479843) [ https://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=CTR9 ]

Two previous studies (Hanks et al, 2014 - PMID: 25099282, Martins et al 2018, PMID: 29292210) have identified individuals with pLoF variants [in almost all cases leading to skipping of ex9 e.g. NM_014633.4:c.958-9A>G or (RefSeq not provided) c.1194+2T>C, c.1194+3A>C, the single exception being c.106C>T/p.Q36*] in individuals and families with Wilms tumor after exclusion of other genetic causes. Analyses of tumor samples revealed in several of these cases either LOH (most commonly) or truncating variants as second hits. These individuals did not display neurodevelopmental phenotypes (despite detailed clinical information provided in the 2 studies). CTR9 is included in the gene panels for WT and Tumor predisposition - childhood onset with green rating. [In addition few individuals with hyperparathyroidism jaw tumor syndrome due to heterozygous variants in CDC73 - another subunit of the PAF1 complex - have been reported with WT].

Given these reports, commenting on the embryonic lethality of Ctr9 homozygous ko mice (MGI) and the observation of only missense variants in their cohort Meuwissen, Verstraeten, Ranza et al presume that a dominant-negative effect may apply for the variants they report.

Consider inclusion in the current panel with amber (variant effect/underlying mechanism unknown) or green rating (>3 individuals/families/variants, multiple reports, some supporting evidence from animal models).
Sources: Literature
Intellectual disability - microarray and sequencing v3.1562 ZBTB7A Julia Baptista reviewed gene: ZBTB7A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:34515416; Phenotypes: intellectual disability, macrocephaly, overgrowth; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.1561 DNAH14 Konstantinos Varvagiannis gene: DNAH14 was added
gene: DNAH14 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DNAH14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH14 were set to 35438214
Penetrance for gene: DNAH14 were set to unknown
Review for gene: DNAH14 was set to RED
Added comment: Li et al (2022 - PMID: 35438214) describe 3 individuals harboring biallelic DNAH14 variants. In addition the authors perform a review of cases previously published in the literature.

The reported phenotype does not appear to be very consistent or specific (seizures with highly variable age of onset with or without DD / cognitive delay). Comparison with previously reported subjects (not further reviewed) - discussed in text and appearing mixed in table 1 - does not seem to support an overlapping phenotype.

The authors comment that DNAH14 encodes a heavy chain of axonemal dyneins. Little evidence is provided to support the role of the gene in the pathogenesis of the disorder and pathogenicity of the variants (ultra-rare and predicted in silico to be deleterious).
Sources: Literature
Intellectual disability - microarray and sequencing v3.1561 DALRD3 Konstantinos Varvagiannis changed review comment from: Biallelic pathogenic DALRD3 variants cause ?Developmental and epileptic encephalopathy 86 (# 618910).

Lentini et al (2020 - PMID: 32427860) report 2 sibs born to first cousin parents, homozygous for a DALRD3 pathogenic variant.

Both exhibited hypotonia, severe global DD and epilepsy (onset of seizures at the age 6-7m, poorly controlled by AEDs in one) corresponding overall to an developmental and epileptic encephalopathy. The authors reported subtle dysmorphic features. Other findings included GI concerns (in both) with microcephaly, CHD or renal anomalies in the younger.

WES guided by autozygome analysis revealed homozygosity for a DALRD3 stopgain variant (NM_001009996.3:c.1251C>A/pTyr417*) with Sanger sequencing confirming status of the children and carrier state of the parents.

DALRD3 encodes DALR anticodon-binding domain-containing protein 3. A DALR

It's DALR anticodon-binding domain is similar to those found in arginyl-tRNA synthetases RARS1/2.

As the authors demonstrate, and (better) summarized in OMIM, its product is a tRNA-binding protein that interacts with METTL2 to facilitate 3-methylcytosine (m3C) modification - by METTL2 - at position 32 of the anticodon loop in specific arginine tRNAs, namely tRNA-Arg-UCU and tRNA-Arg-CCU. In particular, DALRD3 seems to serve as discrimination factor required for recognition of these specific tRNAs.

In addition to DALRD3, a DALR anticodon-binding domain is also found in arginyl-tRNA synthetases (the cytoplasmic RARS1, and mitochondrial RARS2).

Given the variant type observed, predicting truncation of the protein and/or NMD, in LCLs from the 2 sibs (and comparison with controls) the authors demonstrated that the levels of full-length DALRD3 were decreased in cell lysates, with severe reduction (/loss) of m3C modification of the specific arginine tRNAs, which was not observed for other tRNAs (eg. tRNA-Ser-UGA) or controls. These findings were suggestive of c.1251C>A / pTyr417* being a partial LoF allele.

As the authors discuss, defects in tRNA modification have been associated with numerous human - among others neurological and neurodevelopmental - disorders (cited PMID: 30529455, table 1 of this review summarizing these incl. ADAT3-, PUS3-, TRMT1- related NDDs, etc).

Consider inclusion in the current panel with amber rating.
Sources: Literature; to: Biallelic pathogenic DALRD3 variants cause ?Developmental and epileptic encephalopathy 86 (# 618910).

Lentini et al (2020 - PMID: 32427860) report 2 sibs born to first cousin parents, homozygous for a DALRD3 pathogenic variant.

Both exhibited hypotonia, severe global DD and epilepsy (onset of seizures at the age 6-7m, poorly controlled by AEDs in one) corresponding overall to an developmental and epileptic encephalopathy. The authors reported subtle dysmorphic features. Other findings included GI concerns (in both) with microcephaly, CHD or renal anomalies in the younger.

WES in both followed by autozygome analysis revealed homozygosity for a DALRD3 stopgain variant (NM_001009996.3:c.1251C>A/pTyr417*) with Sanger sequencing confirming status of the children and carrier state of the parents.

DALRD3 encodes DALR anticodon-binding domain-containing protein 3. A DALR

As the authors demonstrate, and (better) summarized in OMIM, its product is a tRNA-binding protein that interacts with METTL2 to facilitate 3-methylcytosine (m3C) modification - by METTL2 - at position 32 of the anticodon loop in specific arginine tRNAs, namely tRNA-Arg-UCU and tRNA-Arg-CCU. In particular, DALRD3 seems to serve as discrimination factor required for recognition of these specific tRNAs.

In addition to DALRD3, a DALR anticodon-binding domain is also found in arginyl-tRNA synthetases (the cytoplasmic RARS1, and mitochondrial RARS2).

Given the variant type observed, predicting truncation of the protein and/or NMD, in LCLs from the 2 sibs (and comparison with controls) the authors demonstrated that the levels of full-length DALRD3 were decreased in cell lysates, with severe reduction (/loss) of m3C modification of the specific arginine tRNAs, which was not observed for other tRNAs (eg. tRNA-Ser-UGA) or controls. These findings were suggestive of c.1251C>A / pTyr417* being a partial LoF allele.

As the authors discuss, defects in tRNA modification have been associated with numerous human - among others neurological and neurodevelopmental - disorders (cited PMID: 30529455, table 1 of this review summarizing these incl. ADAT3-, PUS3-, TRMT1- related NDDs, etc).

Consider inclusion in the current panel with amber rating.

Sources: Literature
Intellectual disability - microarray and sequencing v3.1561 DALRD3 Konstantinos Varvagiannis gene: DALRD3 was added
gene: DALRD3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DALRD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DALRD3 were set to 32427860
Phenotypes for gene: DALRD3 were set to ?Developmental and epileptic encephalopathy 86, # 618910
Penetrance for gene: DALRD3 were set to Complete
Review for gene: DALRD3 was set to AMBER
Added comment: Biallelic pathogenic DALRD3 variants cause ?Developmental and epileptic encephalopathy 86 (# 618910).

Lentini et al (2020 - PMID: 32427860) report 2 sibs born to first cousin parents, homozygous for a DALRD3 pathogenic variant.

Both exhibited hypotonia, severe global DD and epilepsy (onset of seizures at the age 6-7m, poorly controlled by AEDs in one) corresponding overall to an developmental and epileptic encephalopathy. The authors reported subtle dysmorphic features. Other findings included GI concerns (in both) with microcephaly, CHD or renal anomalies in the younger.

WES guided by autozygome analysis revealed homozygosity for a DALRD3 stopgain variant (NM_001009996.3:c.1251C>A/pTyr417*) with Sanger sequencing confirming status of the children and carrier state of the parents.

DALRD3 encodes DALR anticodon-binding domain-containing protein 3. A DALR

It's DALR anticodon-binding domain is similar to those found in arginyl-tRNA synthetases RARS1/2.

As the authors demonstrate, and (better) summarized in OMIM, its product is a tRNA-binding protein that interacts with METTL2 to facilitate 3-methylcytosine (m3C) modification - by METTL2 - at position 32 of the anticodon loop in specific arginine tRNAs, namely tRNA-Arg-UCU and tRNA-Arg-CCU. In particular, DALRD3 seems to serve as discrimination factor required for recognition of these specific tRNAs.

In addition to DALRD3, a DALR anticodon-binding domain is also found in arginyl-tRNA synthetases (the cytoplasmic RARS1, and mitochondrial RARS2).

Given the variant type observed, predicting truncation of the protein and/or NMD, in LCLs from the 2 sibs (and comparison with controls) the authors demonstrated that the levels of full-length DALRD3 were decreased in cell lysates, with severe reduction (/loss) of m3C modification of the specific arginine tRNAs, which was not observed for other tRNAs (eg. tRNA-Ser-UGA) or controls. These findings were suggestive of c.1251C>A / pTyr417* being a partial LoF allele.

As the authors discuss, defects in tRNA modification have been associated with numerous human - among others neurological and neurodevelopmental - disorders (cited PMID: 30529455, table 1 of this review summarizing these incl. ADAT3-, PUS3-, TRMT1- related NDDs, etc).

Consider inclusion in the current panel with amber rating.
Sources: Literature
Intellectual disability - microarray and sequencing v3.1561 DPH5 Konstantinos Varvagiannis gene: DPH5 was added
gene: DPH5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DPH5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DPH5 were set to 35482014
Phenotypes for gene: DPH5 were set to Abnormality of prenatal development or birth; Neonatal hypotonia; Global developmental delay; Intellectual disability; Seizures; Abnormality of the cardiovascular system; Abnormality of the globe; Feeding difficulties; Short stature; Abnormality of head or neck
Penetrance for gene: DPH5 were set to unknown
Review for gene: DPH5 was set to AMBER
Added comment: Shankar et al (2022 - PMID: 35482014) present evidence for a diphthamide-deficiency syndrome due to biallelic DPH5 pathogenic variants.

As the authors summarize, DPH5 encodes a methyltransferase critical to the biosynthesis of diphthamide. Diphthamide is a post translationally modified histidine residue found in eukaryotic elongation factor 2 (eEF2). eEF2 is essential for mRNA translation and protein synthesis. The role of diphthamide is not clear, although it serves as a target for ADP-ribosylation, the latter resulting in inactivation of the eEF2 (inhibition of its translocation activity) and arrest of protein synthesis. Biosynthesis of diphthamide is complex involving multiple components (DPH1-DPH7) and the methylating co-factor S-adenosyl methionine, with 2 diphthamide-deficiency disorders due to biallelic DPH1 or DPH2 pathogenic variants and a NDD phenotype reported to date.

The authors describe a phenotypic spectrum associated with biallelic DPH5 variants ranging from a prenatally lethal presentation to profound neurodevelopmental disorder. Details are provided on 5 individuals from 3 unrelated families. While one subject died at the age of few days due to multisystem complications, the phenotype appeared to be relatively consistent with prenatal findings (decreased fetal movements in 2 from 2 families, polyhydramnios in 2 from 2 families), hypotonia, global DD and ID (4/4 from 2 families - profound in 3), seizures (3/5 from 2 families - abnormal EEG in 4/4), cardiovascular findings (5/5, MVP and regurgitation in 2 from Fam1 || aortic dilatation in 2 sibs from Fam2 || VSD, ASD and hypopl. PA, pericardial effusion in 5th), GI issues (5/5, poor feeding in 4), short stature (4/4). Ocular findings were reported in 3/4 (gray sclerae in 2, ocular melanocytosis in 2). The authors describe some common craniofacial findings incl. broad/prominent forehead (5/5), sparse eyebrows (4/5), downturned corners of mouth or triangular chin (each in 3/5).

WES/WGS revealed biallelic DPH5 variants in all affected individuals, namely: homozygosity for a missense variant in 2 sibs (NM_001077394.2:c.779A>G/p.His260Arg). Homozygosity for c.521dupA/p.Asn174LysTer10 for the individual deceased in the neonatal period (for this family there was significant history of spontaneous miscarriages/stillbirth/neonatal death). Two sibs born to non-consanguineous parents were compound htz for a stopgain and a missense SNV (c.619C>T/p.Arg207*, c.329A>G/p.Asn110Ser).

In silico modeling revealed that the pLoF variants, not predicted to lead to NMD, likely remove the domain for interaction with eEF2 while the missense ones also affected interaction with eEF2.

In recombinant MCF7 breast cancer cell line-derived DPH5-knockouts, transfected with recombinant expr. plasmids encoding wt or the 4 variants, the 2 truncating variants were shown to affect ADP-ribosylation of eEF2's diphthamide (total lack / minimal enzymatic activity for Arg207* and Asn174Lysfs respectively). Asn110Ser and His260Arg had residual activities which was thought to be explained by high expression levels compensating partial inactivation (given the multicopy plasmid-driven expression).

ADP-ribosylation assays in S. cerevisiae demonstrated loss of function for the 2 truncating variants. Although the 2 missense variants retained sufficient activity to produce diphthamide (assayed through toxin induced ADP-ribosylation of eEF2), more sensitive assays indicated that diphthamide synthesis was also partially compromised for both variants.

Generation of a knockin mouse model for His260Arg, appeared to recapitulate the human phenotypes with craniofacial, ophthalmologic, cardiac and visceral abnormalities and hmz mice being subviable. A single homozygous liveborn mouse had low birthweight, FTT, craniofacial dysmorphology, polydactyly, abnormal grooming behavior and early death. Few heterozygous embryos had craniofacial features, decreased body weight, reduced neuromuscular function without other abnormalities, either due to their inbred background or in the context of milder phenotype of heterozygosity in mice.

DPH5 is ubiquitously expressed in all human tissues. The gene has a pLI of 0 and LOEUF score of 0.77 (0.48-1.27) in gnomAD. The authors refer to unpublished data, noting that complete absence of DPH5 is incompatible with life with embryonic lethality of a Dph5(ko/ko) line.

The phenotype bears similarities to DPH1- and DPH2- related NDDs (both AR / green and amber respectively in ID panel) and appears to be more severe compared to the phenotype of de novo EEF2 variants (cited PMID: 33355653).

Please consider inclusion in the ID panel with amber (4 individuals from 2 families with ID) / green rating (rather consistent phenotype in 3 families probably representing a continuous spectrum, variant studies, mouse model, similarities with diphthamide-deficiency syndromes). Also consider amber rating in the epilepsy panel (3 individuals from 2 families reported). The gene may be also relevant in other gene panels e.g. for congenital heart disease, short stature, etc (not added).
Sources: Literature
Intellectual disability - microarray and sequencing v3.1561 CCDC82 Konstantinos Varvagiannis gene: CCDC82 was added
gene: CCDC82 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CCDC82 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC82 were set to 27457812; 28397838; 35118659; 35373332
Phenotypes for gene: CCDC82 were set to Global developmental delay; Intellectual disability; Spastic paraparesis
Penetrance for gene: CCDC82 were set to Complete
Review for gene: CCDC82 was set to AMBER
Added comment: The phenotype of individuals with biallelic CCDC82 variants has been reported - in most cases briefly - in the following reports (each summarizing the findings of previous ones):

Riazzudin et al (2017 - PMID: 27457812) in a large consanguineous pedigree from Pakistan (PKMR206) identified 4 individuals homozygous for a fs variant [NM_024725.3:c.373delG / p.(Asp125Ilefs*6)] (V3,V4,V5,V10). There was no other variant segregating with the phenotype of ID (Delayed CMS, moderate ID and speech delay probably common to all, V3,4,5 had also mild hypotonia and motor weakness). There was one unaffected sib tested (homozygous for ref. alelle). 2 further affected males (V1, V2) with similar phenotype were not tested.

Harripaul et al (2018 - PMID: 28397838) reported 2 sibs with nonsyndromic ID belonging to a consanguineous family (AS17) from the Middle-East. Both were homozygous for NM_024725.3:c.535C>T / p.Arg179*. The variant was confirmed with Sanger sequencing and parents were heterozygous carriers. Two additional affected sibs were probably not tested.

Yahia et al (2022 - PMID: 35118659) described 2 sibs belonging to a consanguineous family from Sudan. These presented global DD (last evaluation at 4y and 9m) and spasticity. There was a common history of infantile spasms with the elder developing GTC convulsions with spontaneous resolution. Additionaly, both presented microcephaly (<-2 and <-3SD). Exome sequencing revealed homozygosity for c.535C>T / p.Arg179* (previously reported by Harripaul et al). Sanger sequencing was used for confirmation and demonstration of carrier state of parents. Two similarly affected sibs were not available for testing.

Bauer et al (2022 - PMID: 35373332) reported a 21 y.o. male born to consanguineous parents from Pakistan. Features included short stature, ID, spastic paraparesis (at the age of 3y). Gelastic seizures were suspected but not confirmed (repeated normal EEGs). WES revealed homozygosity for a fs CCDC82 variant [NM_001318736.1:c.183del / p.(Phe61Leufs*27)] with Sanger confirmation in proband and heterozygous parents. There was another hmz variant, albeit classified as VUS and not thought to fit the clinical presentation.

As proposed by Bauer et al. overlapping features include spastic paraparesis, DD and dysmorphic features. As commented, CCDC82 encodes coiled-coil domain protein 82, a protein with unknown function.

Consider inclusion probably with amber rating (>3 individuals/families/variants, role of the gene not known, variant studies not performed to date, animal models not discussed).
Sources: Literature
Intellectual disability - microarray and sequencing v3.1561 ENTPD1 Konstantinos Varvagiannis reviewed gene: ENTPD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35471564; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1561 PRODH Tracy Lester reviewed gene: PRODH: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual disabilty; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1561 GJB2 Dmitrijs Rots reviewed gene: GJB2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.1561 CCDC32 Konstantinos Varvagiannis reviewed gene: CCDC32: Rating: AMBER; Mode of pathogenicity: None; Publications: 32307552, 35451546; Phenotypes: Cardiofacioneurodevelopmental syndrome (# 619123); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1561 CDK9 Konstantinos Varvagiannis changed review comment from: There are 4 studies reporting on the phenotype associated with biallelic CDK9 pathogenic variants. DD and ID are part of the phenotype which appears to be relatively consistent.

CDK9 encodes Cyclin-dependent kinase 9. There are 4 missense variants reported to date - one of which recurrent (NM_001261.3:c.673C>T / p.Arg225Cys) - with studies for 3 variants suggesting a LoF effect (loss of kinase activity) [Ref4].

Animal models also provide some supporting evidence [discussed Ref4].

Consider inclusion in the current panel (probably with green rating) as well as other possibly relevant ones. Details provided below.

[1]-----
Shaheen et al (2016 - PMID: 26633546) studied patients with apparently novel phenotypes with positive family history consistent with AR inheritance mode due to consanguinity.

After autozygome analysis the authors determined the shared autozygome (ROH >1 Mb / Axiom SNP Chip) in families with multiple affected individuals. This analysis was followed by whole exome/genome sequencing.

Using this approach, they managed to map the phenotype of interest to a single novel locus in some families, which was also the case in a large consanguineous family with 2 similarly affected cousins (11DG0424, 11DG1630).

Within a 20 Mb region of homozygosity, followed by WES in a single affected individual and Sanger confirmation with compatible segregation studies in parents and 10 unaffected sibs, the authors identified a homozygous CDK9 missense SNV (NM_001261.3:c.673C>T / p.Arg225Cys) responsible for this phenotype. In silico predictions were concordant in favor of a deleterious effect.

Features (detailed in the suppl.) included global DD (2/2), severe ID (1/1), cerebral and (mild) cerebellar atrophy (2/2), microcephaly (2/2), ocular anomalies (2/2, coloboma in 2/2, congenital cataract 2/2, etc), heart defects (2/2, PDA in both, ASD), variable genitourinary anomalies (2/2 incl. hydronephrosis, VUR reflux/recurrent UTIs, kidney atrophy, abn. genitalia in 1), abnormalities of the limbs (2/2, bilateral talipes equinovarus : 2/2) or the skeleton (1/2 - butterfly vertebrae). One was reported to have some degree of growth delay (<10th centile for length, <5th for weight and OFC). There was no hearing defect reported (large ears in 1/2). Overall, the authors used the term CHARGE-like phenotype.

[2]-----
Maddirevula et al (2019 - PMID: 30237576) performed autozygome and exome analysis of individuals with suspected Mendelian disorders. They reported 3 individuals (18DG0161, 18DG0162, 18DG0165) born to 3 different consanguineous families (information in fig2) from Qatar, homozygous for CDK9 p.Arg225Cys.

All presented a CHARGE-like phenotype with features ophtalmologic findings (3/3 - abnormal ERG in one, congenital cataracts the other, visual impairment in the 3rd, though NO evidence of coloboma in at least two), heart defect (2/3 had VSD), choanal atresia (3/3), retarded growth/FTT (1/3) or global DD (3/3 - in suppl. table 1), (genito)urinary anomalies (1/3 - dysplastic atrophic kidney) or ear anomalies (3/3 - preauricular tags 2/3, bilateral deafness 1/3, bilat.ossicular anomalies 1/3). Other features incl. epilepsy (2/3), brain MRI abnormalities (2/3), facial asymmetry in one, vertebral segmentation defect in 1/3.

[3]-----
Hu et al (2019 - PMID: 29302074) performed WES/WGS in 404 consanguineous families from Iran, having 2 or more offspring with ID.

In this context they reported 2 females and a male (III:1,4,3 belonging to fam. M9100018 - details in suppl. text) born to first cousin parents from Iran. Features included DD (3/3 - walking at 3y, words at 4y), moderate ID (3/3 - WAIS-IV IQ of 40-43), short stature (3/3 below 3rd %le). Vision and hearing were normal.

All three were homozygous for a missense SNV (NM_001261:c.280C>T, p.Arg94Cys) which was ultrarare in ExAC, with severa in silico tools in favor of a deleterious effect.

The authors commented that CDK9 is the catalytic core of transcription elongation factor p-TEFb essential for transcription elongation of numerous genes, Cdk9/Cyclin T1 complex may participate in neuronal differentiation, CDK9-cyclinK in maintenance of genomic integrity, with the protein encoded also interacted with AF4/FMR2.

In addition the gene was commented to have ubiquitous expression with high protein expression in glial and neuronal cells of the cortex (based on Uniprot and Human Protein Atlas).

[4]-----
Nishina et al (2021 - PMID: 33640901) described an 8 y.o. male with facial asymmetry, ear/hearing anomalies (microtia, preauricular tags, bilateral hearing loss), ocular/vision anomalies (blepharophimosis, lacrimal obstruction, eyelid dermoids, duane-like anomaly, congenital cataracts, retinal dystrophy), cleft lip and palate, abnormalities of the limbs (finger contractures with associated absence of creases, cutaneous syndactyly, etc). Other features included cardiac dysrhythmia and undescended testes. Development was delayed with associated ID (walking 3y, words 7y, at 10y: could count to 20, 4 word sentences). There was no evidence of coloboma or choanal atresia.

Trio exome sequencing revealed that the child was compound htz for 2 missense SNVs (NM_001261.3:c.862G>A / p.Ala288Thr and c.907C>T /p.Arg303Cys) with Sanger confirmation. These were ultrarare/not present in gnomAD. Both lied in the protein kinase catalytic domain of CDK9, with high conservation across different species and in silico predictions in favor of deleterious effect.

In vitro studies in HEK293 cells demonstrated that the kinase activity for both variants was significantly reduced compared to wt. Kinase activity was also reduced for the Arg225Cys variant (reported in Refs 1 & 2).

The authors briefly discuss evidence from zebrafish (regulates larval morphogenesis incl. brain, heart, eye, blood vessels) and mouse models. In the latter complete LoF is lethal while heterozygous LoF is associated with abnormal morphology of heart, skin and epididymis (PMIDs cited by the authors : 27715402, 30100824).
Sources: Literature; to: There are 4 studies reporting on the phenotype associated with biallelic CDK9 pathogenic variants. DD and ID are part of the phenotype which appears to be relatively consistent.

CDK9 encodes Cyclin-dependent kinase 9. There are 4 missense variants reported to date - one of which recurrent (NM_001261.3:c.673C>T / p.Arg225Cys) - with studies for 3 variants suggesting a LoF effect (loss of kinase activity) [Ref4].

Animal models also provide some supporting evidence [discussed Ref4].

Consider inclusion in the current panel (probably with green rating) as well as other possibly relevant ones. Details provided below.

[1]-----
Shaheen et al (2016 - PMID: 26633546) studied patients with apparently novel phenotypes with positive family history consistent with AR inheritance due to consanguinity.

Using autozygome analysis the authors determined the shared autozygome (ROH >1 Mb / Axiom SNP Chip) in families with multiple affected individuals. This analysis was followed by whole exome/genome sequencing.

Using this approach, they managed to map the phenotype of interest to a single novel locus in some families, which was also the case in a large consanguineous family with 2 similarly affected cousins (11DG0424, 11DG1630).

Within a 20 Mb region of homozygosity, followed by WES in a single affected individual and Sanger confirmation with compatible segregation studies in parents and 10 unaffected sibs, the authors identified a homozygous CDK9 missense SNV (NM_001261.3:c.673C>T / p.Arg225Cys) responsible for this phenotype. In silico predictions were concordant in favor of a deleterious effect.

Features (detailed in the suppl.) included global DD (2/2), severe ID (1/1), cerebral and (mild) cerebellar atrophy (2/2), microcephaly (2/2), ocular anomalies (2/2, coloboma in 2/2, congenital cataract 2/2, etc), heart defects (2/2, PDA in both, ASD), variable genitourinary anomalies (2/2 incl. hydronephrosis, VUR/recurrent UTIs, kidney atrophy, abn. genitalia in 1), abnormalities of the limbs (2/2, bilateral talipes equinovarus : 2/2) or the skeleton (1/2 - butterfly vertebrae). One was reported to have some degree of growth delay (<10th centile for length, <5th for weight and OFC). There was no hearing defect reported (large ears in one case). Overall, the authors used the term CHARGE-like for this phenotype.

[2]-----
Maddirevula et al (2019 - PMID: 30237576) performed autozygome and exome analysis of individuals with suspected Mendelian disorders. They reported 3 individuals (18DG0161, 18DG0162, 18DG0165) born to 3 different consanguineous families (information in fig2) from Qatar, homozygous for CDK9 p.Arg225Cys.

All presented a CHARGE-like phenotype with ophthalmologic findings (3/3 - abnormal ERG in one, congenital cataracts the other, visual impairment in the 3rd, though NO evidence of coloboma in at least two of them), heart defect (2/3 with VSD), choanal atresia (3/3), retarded growth/FTT (1/3) or global DD (3/3 - in suppl. table 1), (genito)urinary anomalies (1/3 - dysplastic atrophic kidney) or ear anomalies (3/3 - preauricular tags in 2/3, bilateral deafness 1/3, bilateral ossicular anomalies 1/3). Other features incl. epilepsy (2/3), brain MRI abnormalities (2/3), facial asymmetry in one, vertebral segmentation defect in 1/3.

[3]-----
Hu et al (2019 - PMID: 29302074) performed WES/WGS in 404 consanguineous families from Iran, having 2 or more offspring with ID.

In this context they reported 2 females and a male (III:1,4,3 belonging to fam. M9100018 | suppl. text) born to first cousin parents from Iran. Features included DD (3/3 - walking at 3y, words at 4y), moderate ID (3/3 - WAIS-IV IQ of 40-43), short stature (3/3 below 3rd %le). Vision and hearing were normal.

All three were homozygous for a missense SNV (NM_001261:c.280C>T, p.Arg94Cys) which was ultrarare in ExAC, with several in silico tools in favor of a deleterious effect.

The authors commented that CDK9 is the catalytic core of transcription elongation factor p-TEFb essential for transcription elongation of numerous genes, Cdk9/Cyclin T1 complex may participate in neuronal differentiation, CDK9-cyclinK in maintenance of genomic integrity, with the protein encoded also interacting with AF4/FMR2.

In addition the gene was commented to have ubiquitous expression with high protein expression in glial and neuronal cells of the cortex (based on Uniprot and Human Protein Atlas).

[4]-----
Nishina et al (2021 - PMID: 33640901) described an 8 y.o. male with facial asymmetry, ear/hearing anomalies (microtia, preauricular tags, bilateral hearing loss), ocular/vision anomalies (blepharophimosis, lacrimal obstruction, eyelid dermoids, duane-like anomaly, congenital cataracts, retinal dystrophy), cleft lip and palate, abnormalities of the limbs (finger contractures with associated absence of creases, cutaneous syndactyly, etc). Other features included cardiac dysrhythmia and undescended testes. Development was delayed with ID (walking 3y, words 7y, at 10y: could count to 20, 4 word sentences). There was no evidence of coloboma or choanal atresia.

Trio exome revealed that the child was compound htz for 2 missense SNVs (NM_001261.3:c.862G>A / p.Ala288Thr and c.907C>T /p.Arg303Cys) with Sanger confirmation. These were ultrarare/not present in gnomAD. Both lied in the protein kinase catalytic domain of CDK9, with high conservation across different species and in silico predictions in favor of deleterious effect.

In vitro studies in HEK293 cells demonstrated that the kinase activity for both variants was significantly reduced compared to wt. Kinase activity was also reduced for the Arg225Cys variant (reported in Refs 1 & 2).

The authors briefly discuss evidence from zebrafish (regulates larval morphogenesis incl. brain, heart, eye, blood vessels) and mouse models. In the latter complete LoF is lethal while heterozygous LoF is associated with abnormal morphology of heart, skin and epididymis (PMIDs cited : 27715402, 30100824).
Sources: Literature
Intellectual disability - microarray and sequencing v3.1561 CDK9 Konstantinos Varvagiannis gene: CDK9 was added
gene: CDK9 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CDK9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDK9 were set to 26633546; 30237576; 29302074; 33640901
Phenotypes for gene: CDK9 were set to Global developmental delay; Intellectual disability; Abnormality of vision; Congenital cataract; Iris coloboma; Abnormal heart morphology; Choanal atresia; Abnormality of the ear; Preauricular skin tag; Hearing impairment; Abnormality of the genitourinary system; Abnormality of limbs; Abnormality of the vertebrae; Abnormality of nervous system morphology; Seizures
Penetrance for gene: CDK9 were set to Complete
Review for gene: CDK9 was set to GREEN
Added comment: There are 4 studies reporting on the phenotype associated with biallelic CDK9 pathogenic variants. DD and ID are part of the phenotype which appears to be relatively consistent.

CDK9 encodes Cyclin-dependent kinase 9. There are 4 missense variants reported to date - one of which recurrent (NM_001261.3:c.673C>T / p.Arg225Cys) - with studies for 3 variants suggesting a LoF effect (loss of kinase activity) [Ref4].

Animal models also provide some supporting evidence [discussed Ref4].

Consider inclusion in the current panel (probably with green rating) as well as other possibly relevant ones. Details provided below.

[1]-----
Shaheen et al (2016 - PMID: 26633546) studied patients with apparently novel phenotypes with positive family history consistent with AR inheritance mode due to consanguinity.

After autozygome analysis the authors determined the shared autozygome (ROH >1 Mb / Axiom SNP Chip) in families with multiple affected individuals. This analysis was followed by whole exome/genome sequencing.

Using this approach, they managed to map the phenotype of interest to a single novel locus in some families, which was also the case in a large consanguineous family with 2 similarly affected cousins (11DG0424, 11DG1630).

Within a 20 Mb region of homozygosity, followed by WES in a single affected individual and Sanger confirmation with compatible segregation studies in parents and 10 unaffected sibs, the authors identified a homozygous CDK9 missense SNV (NM_001261.3:c.673C>T / p.Arg225Cys) responsible for this phenotype. In silico predictions were concordant in favor of a deleterious effect.

Features (detailed in the suppl.) included global DD (2/2), severe ID (1/1), cerebral and (mild) cerebellar atrophy (2/2), microcephaly (2/2), ocular anomalies (2/2, coloboma in 2/2, congenital cataract 2/2, etc), heart defects (2/2, PDA in both, ASD), variable genitourinary anomalies (2/2 incl. hydronephrosis, VUR reflux/recurrent UTIs, kidney atrophy, abn. genitalia in 1), abnormalities of the limbs (2/2, bilateral talipes equinovarus : 2/2) or the skeleton (1/2 - butterfly vertebrae). One was reported to have some degree of growth delay (<10th centile for length, <5th for weight and OFC). There was no hearing defect reported (large ears in 1/2). Overall, the authors used the term CHARGE-like phenotype.

[2]-----
Maddirevula et al (2019 - PMID: 30237576) performed autozygome and exome analysis of individuals with suspected Mendelian disorders. They reported 3 individuals (18DG0161, 18DG0162, 18DG0165) born to 3 different consanguineous families (information in fig2) from Qatar, homozygous for CDK9 p.Arg225Cys.

All presented a CHARGE-like phenotype with features ophtalmologic findings (3/3 - abnormal ERG in one, congenital cataracts the other, visual impairment in the 3rd, though NO evidence of coloboma in at least two), heart defect (2/3 had VSD), choanal atresia (3/3), retarded growth/FTT (1/3) or global DD (3/3 - in suppl. table 1), (genito)urinary anomalies (1/3 - dysplastic atrophic kidney) or ear anomalies (3/3 - preauricular tags 2/3, bilateral deafness 1/3, bilat.ossicular anomalies 1/3). Other features incl. epilepsy (2/3), brain MRI abnormalities (2/3), facial asymmetry in one, vertebral segmentation defect in 1/3.

[3]-----
Hu et al (2019 - PMID: 29302074) performed WES/WGS in 404 consanguineous families from Iran, having 2 or more offspring with ID.

In this context they reported 2 females and a male (III:1,4,3 belonging to fam. M9100018 - details in suppl. text) born to first cousin parents from Iran. Features included DD (3/3 - walking at 3y, words at 4y), moderate ID (3/3 - WAIS-IV IQ of 40-43), short stature (3/3 below 3rd %le). Vision and hearing were normal.

All three were homozygous for a missense SNV (NM_001261:c.280C>T, p.Arg94Cys) which was ultrarare in ExAC, with severa in silico tools in favor of a deleterious effect.

The authors commented that CDK9 is the catalytic core of transcription elongation factor p-TEFb essential for transcription elongation of numerous genes, Cdk9/Cyclin T1 complex may participate in neuronal differentiation, CDK9-cyclinK in maintenance of genomic integrity, with the protein encoded also interacted with AF4/FMR2.

In addition the gene was commented to have ubiquitous expression with high protein expression in glial and neuronal cells of the cortex (based on Uniprot and Human Protein Atlas).

[4]-----
Nishina et al (2021 - PMID: 33640901) described an 8 y.o. male with facial asymmetry, ear/hearing anomalies (microtia, preauricular tags, bilateral hearing loss), ocular/vision anomalies (blepharophimosis, lacrimal obstruction, eyelid dermoids, duane-like anomaly, congenital cataracts, retinal dystrophy), cleft lip and palate, abnormalities of the limbs (finger contractures with associated absence of creases, cutaneous syndactyly, etc). Other features included cardiac dysrhythmia and undescended testes. Development was delayed with associated ID (walking 3y, words 7y, at 10y: could count to 20, 4 word sentences). There was no evidence of coloboma or choanal atresia.

Trio exome sequencing revealed that the child was compound htz for 2 missense SNVs (NM_001261.3:c.862G>A / p.Ala288Thr and c.907C>T /p.Arg303Cys) with Sanger confirmation. These were ultrarare/not present in gnomAD. Both lied in the protein kinase catalytic domain of CDK9, with high conservation across different species and in silico predictions in favor of deleterious effect.

In vitro studies in HEK293 cells demonstrated that the kinase activity for both variants was significantly reduced compared to wt. Kinase activity was also reduced for the Arg225Cys variant (reported in Refs 1 & 2).

The authors briefly discuss evidence from zebrafish (regulates larval morphogenesis incl. brain, heart, eye, blood vessels) and mouse models. In the latter complete LoF is lethal while heterozygous LoF is associated with abnormal morphology of heart, skin and epididymis (PMIDs cited by the authors : 27715402, 30100824).
Sources: Literature
Intellectual disability - microarray and sequencing v3.1561 TAB2 Andrea Haworth reviewed gene: TAB2: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 34741306; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.1561 GLRA2 Konstantinos Varvagiannis reviewed gene: GLRA2: Rating: GREEN; Mode of pathogenicity: Other; Publications: 20531469, 20479760, 26370147, 28588452, 35294868; Phenotypes: Global developmental delay, Intellectual disability, Autism, Behavioral abnormality, Seizures, Microcephaly, Abnormality of eye movement; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability - microarray and sequencing v3.1558 PRSS12 Zornitza Stark reviewed gene: PRSS12: Rating: AMBER; Mode of pathogenicity: None; Publications: 12459588; Phenotypes: Intellectual disability, PRSS12 related MIM#249500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1558 SLC35B2 Konstantinos Varvagiannis gene: SLC35B2 was added
gene: SLC35B2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SLC35B2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC35B2 were set to 35325049
Phenotypes for gene: SLC35B2 were set to Abnormality of the skeletal system; Short long bone; Short stature; Abnormality of epiphysis morphology; Scoliosis; Multiple joint dislocation; Global develpmental delay; Intellectual disability; CNS hypomyelination; Abnormality of the corpus callosum; Cerebral atrophy; Abnormality of the amniotic fluid
Penetrance for gene: SLC35B2 were set to Complete
Review for gene: SLC35B2 was set to AMBER
Added comment: 2 unrelated individuals with biallelic SLC35B2 variants have been reported. DD and ID were part of the phenotype.

There is currently no associated phenotype in OMIM/G2P/SysID. The gene has amber rating in the leukodystrophies panel of PanelApp Australia.

Consider inclusion in the current panel (or other possibly relevant ones eg. for skeletal disorders, short stature, white matter disorders, corpus callosum, etc) with amber rating.

---

Guasto et al (2022 - PMID:35325049) report 2 unrelated individuals with biallelic SLC35B2 variants.

SLC35B2 encodes solute carrier family 35 (3'-phosphoadenosine 5'-phosphosulfate (PAPS) transporter), member B2.

The protein is located in the Golgi membrane and serves as transporter of the activated nucleotide sulfate PAPS from the cytosol, where it is synthesized to the Golgi lumen. Another PAPS transporter is encoded by SLC35B3. In the Golgi apparatus PAPS serves as substrate of sulfotransferases for the addition sulfate to the covalently attached GAG chains of proteoglycans (PGs).

The phenotype corresponded to a chondrodysplasia manifesting as severe pre- and postnatal growth retardation (height <-4 SD and -8 SD), early scoliosis, multiple joint dislocations (in one). There was severe DD affecting motor and expressive language development with associated ID. Brain imaging was suggestive of hypomyelinating leukodystrophy with thin corpus callosum and cerebral atrophy. One individual had a cleft palate in the context of Pierre Robin sequence.

Both individuals were investigated with exome sequencing.

The first individual - born to consanguineous parents - was homozygous for an in-frame del (NM_178148.3:c.1218_1220del, p.Leu407del) with Sanger sequencing confirming the variants, and heterozygosity in parents and 2 unaffected sibs. There was an initially identified hmz CUL7 variant (for 3M syndrome), which was not felt sufficient to explain the severity of the phenotype and notably ID.

The 2nd proband was homozygous for a fs variant (c.1224_1225delAG / p.Arg408SerfsTer18 - leading to loss of the last 8 amino acids) occurring in the context of uniparental isodisomy [iUPD(6)] spanning the complete chr6 based on the exome data.

Among the evidence presented for SLC35B2 and the variants :
- SLC35B2 has high mRNA expression in fetal and adult mouse brain and other tissues.
- Upon qPCR analysis of mRNA expression in human brain samples, the gene had expression across the brain (frontal lobe grey matter, subcortical frontal white matter/cerebellum).
- High expression was shown upon analysis of mouse brain single cell RNA data (EMBL) in oligodendrocytes and microglial cells.
- RT-PCR on mRNA from skin fibroblasts (both individuals) revealed significant decrease of SCL35B2 mRNA levels compared to controls.
- Transfection of C-terminal c-myc tagged wt or mutant proteins in HEK293F cells, followed by western blotting did not reveal significant difference at the protein level. Wt SLC35B2 localized at the Golgi apparatus as suggested by colocalization with GM130 marker. The 2 variants however displayed only partial colocalization (/loss of localization specificity) with diffuse signal in the cell.
- Chondroitin sulfate disaccharide sulfation was decreased upon HPLC disaccharide analysis in patient fibroblasts and bikunin (a circulating proteoglycan in blood) electrophoretic pattern in patient sera.
- Disorders due to variants in genes implicated in proteoglycan biogenesis (e.g. XYLT1, B3GALT6, CHSY1) are associated with skeletal/connective tissue manifestations with DD/ID.
- C-elegans model lacking pst-1 (SLC35B2 ortholog) provides support that the protein is required for migration, axonal guidance, and presynaptic development in a subset of neurons.
- dsm-1 - the rat ortholog - is expressed in rat brain in D-serine and NMDA receptor rich regions. When expressed in Xenopus oocytes it accelerated the efflux of D-serine (a co-agonist for NMDA receptor).
- Variants in other members of SLC superfamily (e.g. SLC17A5, SLC35A3, SLC29A3, SLC35A2) have been associated with brain-bone phenotypes.
Sources: Literature
Intellectual disability - microarray and sequencing v3.1556 CACNA2D1 Sarah Leigh reviewed gene: CACNA2D1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.1556 FBXW7 Konstantinos Varvagiannis gene: FBXW7 was added
gene: FBXW7 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FBXW7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FBXW7 were set to 33057194; 35395208; 30885698; 26482194; 19963109; 20332316
Phenotypes for gene: FBXW7 were set to Neurodevelopmental abnormality; Global developmental delay; Intellectual disability; Macrocephaly; Microcephaly; Abnormality of brain morphology; Abnormality of the corpus callosum; Abnormality of the cerebellum; Abnormality of the cardiovascular system; Seizures; Strabismus; Abnormality of the palate
Penetrance for gene: FBXW7 were set to unknown
Review for gene: FBXW7 was set to AMBER
Added comment: While Kaplanis et al (2020 - Ref1), identified FBXW7 among 285 genes significantly associated with developmental disorders, a recent study by Stephenson et al (2022 - Ref2) describes the neurodevelopmental phenotype of 35 individuals making this gene relevant to the current panel. There are previous reports of dn/inh germline variants in individuals (likely 7) with tumor predisposition although a neurodevelopmental phenotype was not reported in most cases.

There is currently no FBXW7-related phenotype in OMIM.

The gene is included in the DD panel of G2P [associated with: FBXW7-related developmental disorder (monoallelic), confidence: definitive, citing the study by Kaplanis et al]. SysID lists FBXW7 among the candidate ID genes (same Ref.). The gene has a green rating for ID in PanelApp Australia (VCGS participating in the recent publication).

Consider inclusion with amber/green rating. Also consider inclusion in other panels that may be relevant(macro/microcephaly, seizures, CHD, corpus callosum / cerebellar abnormalities, cleft palate, WT, etc).

[1]------------
Kaplanis et al (2020 - PMID: 33057194), by combining exome data from 31,058 parent offspring trios from the DDD study, Radboudumc and GeneDx, identified 285 genes significantly associated with developmental disorders, 28 of which (incl. FBXW7) not previously robustly associated with these disorders.

[2]------------
Stephenson et al (2022 - PMID: 35395208) provide clinical information on 35 individuals harboring germline monoallelic FBXW7 variants or chromosomal deletions spanning this gene.

The phenotype corresponded to a phenotypically variable NDD characterized by hypotonia (in about 2/3), neurodevelopmental abnormality (34/35 - as discussed later), seizures (8/35), abnormal brain morphology (13/17 - in 7/17 abnormal CC, in 5/17 abn. cerebellum, etc), head circumference (macrocephaly in 10/35, microcephaly in 2/35). Additional features included abnormal palate or uvula morphology (10/35 - cleft palate in 3 from 2 families while 1 individual from a 3rd family had bifid uvula) or abnormal heart morphology (11/35), ophthalmologic features (e.g. strabismus in 5/35) or hearing impairment (2/35). There was no recognizable gestalt (deeply set eyes with upper eyelid fullness in 9/35).

As for the DD/ID this ranged from borderline to severe, characterized as mild-moderate in 27/35, severe in 3/35. One individual did not present neurodevelopmental abnormality 1/35.

FBXW7 encodes F-box and WD40 domain protein 7 which is part of the SCF E3 ligase complex (SKP1/CUL1/F-box protein) exerting a role of recognition and binding of target proteins for degradation by the ubiquitin proteasome system. In this way FBWX7 participates in regulating a network of proteins involved in cell division, growth, differentiation (as summarized by Roversi et al - Ref2).

Most individuals were investigated by trio-WES/WGS (few with singleton WES or CMA only). 28 germline FBXW7 variants were identified incl. missense (N=21), pLoF (predicted or not to undergo NMD) and 2 deletions encompassing but not limited to FBXW7.

Additional SNVs/CNVs (e.g. an inh intragenic DPP6 dup in one individual (#9) with deletion, other de novo 4q CNVs (#10), an inh 22q spanning partially an ISCA TS region, a CACNA1A and KMT2D SNV, etc) were reported in few individuals.

Most variants arose dn (N=30) with two individuals displaying mosaicism (2/30) and three individuals having inherited the variant from their affected parent. CNVs had occurred dn.

3 missense SNVs were recurrent in unrelated individuals.

All variants identified affected all FBXW7 isoforms.

As the authors comment missense variants clustered at the C-terminal half of the protein with most (16/21) occurring within the WD40 domain. [The N-terminal part commented in the literature to affect localization].

The crystal structure of FBXW7 and SKP1 complex has been determined with CYCLIN E1/DISC1 as substrates, and in silico modeling revealed that all missense variants aligned with residues required for this interaction, or adjacent ones.

All were absent from gnomAD, while missense variants from gnomAD (N=78) were not predicted have significant effect on the binding affinity.

Variant studies revealed that most missense variants (6/7 tested - Arg689Gln being the exception) are unlikely to cause protein instability or degradation in vivo.

Co-expression of these missense variants with CYCLIN E1 / E2, known FBXW7 substrates revealed that variants were less efficient at degrading the substrate with variants in the WD40 domain having greater impact (in some cases E1 / E2 - specific).

Elav-Gal4 mediated neuronal knockdown of the Drosophila ortholog archipelago (ago) using 2 RNAi-s with different efficiency was shown to affect learning or compromise neuronal function (also related to the level of knockdown).

The authors summarize results from animal models for the role of this gene in development and the nervous system.

KO mice die in utero at E10.5 manifesting abn. of hematopoietic or vascular development and heart-chamber maturation(*). Some htz knock-in for human cancer variants, display perinatal lethality, abn lung, cleft palate (30%)(*),etc. Conditional gut specific deletion results in impaired differentiation of intestinal goblet cells (*)(constipation in 16/35 in cohort). KO limited to CNS and PNS results in defective sucking and morphological brain abnormalities. Haploinsufficiency in the nervous system was associated with impaired differentiation of neural stem cells (possibly through a Notch-mediated mechanism). KO in Schwann cells of the peripheral nervous system resulted in enhanced myelination.

Excessive oligodendrocyte cells and hypermyelination (as a result of elevated Notch & mTOR signaling) are observed in homozygous mutant zebrafish or after morpholino-mediated fbxw7 knockdown.

Overall, the authors propose haploinsufficiency or loss-of-function as the underlying mechanism.

Finally, as the authors comment, FBXW7 is a tumor suppressor among the most commonly mutated genes in human cancer (3.5%). Germline variants have been previously reported in individuals with cancer (Wilms tumor, rhabdoid, etc - most summarized below). However, none of the 35 individuals in this cohort (oldest 44 y.o.) had any history of cancer.

Reports of individuals with germline variants causing (monoallelic) disruption of FBXW7 - cases without DD/ID:

[3]------------
Mahamdallie et al (2019 - PMID: 30885698) investigated with WES a cohort of 890 individuals with Wilms tumor (799 non-familial disease, 91 from WT pedigrees). In this context they identified 4 individuals having developed WT (ages: 28-76m) with FBXW7 dn or inherited LoF variants (710G>A / p.Trp237* dn - 1972C>T / p.Arg658* - inh:NA, 1017_1021del5, 670C>T - paternal / p.Arg224* inh:NA - RefSeq not provided). One additional individual with a missense variant (1753A>T / p.Ser585Cys - dn) had developed rhabdoid tumor. While the authors mentioned additional features for other subjects in their cohort, among the 5 individuals with FBXW7 variants, only one had hypotonia (ID_0592) and another (ID_7520) had two febrile convulsions.

[4]------------
Roversi et al (2015 - PMID: 26482194) described the phenotype of a 34 y.o. female with syndromic presentation (macrocephaly, nephrotic syndrome due to FSGS, Hodgkin's lymphoma, Wilms tumor, ovarian cystadenoma, breast carcinoma) harboring a 157 kb deletion of 4q31.3.

Eventual DD/ID was not reported despite detailed clinical description.

The deletion spanned almost the entire FBXW7 gene and a pseudogene (hg19 - chr4:153205202-153362047). The authors provided evidence that the del affected the maternal allele as dn event (maternal mosaicism excluded). Expression of FBXW7 in patient-derived EBV lymphoblastoid cell line revealed decreased levels of expression compared to controls. At somatic level, the authors looked for eventual 2nd hit in tumor tissue (which was not the case) while they demonstrated decreased FBXW7 expression in a WT sample compared to normal renal tissue. Previously, variants in other genes candidate for the phenotype were ruled out (Sanger & MLPA for TP53, BRCA1/2, PALB2, WT1, 11p15 MS-MLPA, std karyotype).

[5]------------
Kuiper et al (2015 - PMID: 19963109), in a 58 y.o. patient with recurrence of RCC, identified a constitutional translocation [t(3;4)(q21;q31)]. Using long-range PCR they defined the breakpoints at 3q21.3 (128379059 - hg18) between the PLXNA1 and C3orf56 genes while the chr4 breakpoint was located within the second intron of FBXW7 (pos. 153500813 - hg18). There were no additional phenotypes reported.

[6]------------
Williams et al (2010 - PMID: 20332316) reported a patient with WT harboring germline variants in WT1 and FBXW7. While the phenotype was sufficiently explained by a germline stopgain WT1 variant with a frameshift WT1 variant (as 2nd hit) confined to the tumor, the authors identified a germline in-frame FBXW7 insertion in the same individual (c.45_46insCCT / p.Thr15_Gly16insPro - RefS : NA) [if correct corresponding to: https://gnomad.broadinstitute.org/variant/4-153332910-C-CAGG - 345/281696 alleles in gnomAD].
Sources: Literature
Intellectual disability - microarray and sequencing v3.1555 DTYMK Sarah Leigh reviewed gene: DTYMK: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.1546 CLIC2 Sarah Leigh reviewed gene: CLIC2: Rating: RED; Mode of pathogenicity: None; Publications: 28333917, 31349857, 22814392; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.1534 ZBTB7A Konstantinos Varvagiannis gene: ZBTB7A was added
gene: ZBTB7A was added to Intellectual disability. Sources: Literature,Other
Mode of inheritance for gene: ZBTB7A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZBTB7A were set to 31645653; 34515416
Phenotypes for gene: ZBTB7A were set to Global developmental delay; Intellectual disability; Macrocephaly; Abnormality of the lymphatic system; Sleep apnea; Increased body weight; Autism; Persistence of hemoglobin F; Abnormal leukocyte count; Recurrent infections; Umbilical hernia
Penetrance for gene: ZBTB7A were set to unknown
Review for gene: ZBTB7A was set to AMBER
Added comment: Monoallelic pathogenic ZBTB7A variants cause Macrocephaly, neurodevelopmental delay, lymphoid hyperplasia, and persistent fetal hemoglobin (#619769).
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Ohishi et al (2020 - PMID: 31645653) described the phenotype of a 6y5m-old male harboring a heterozygous, de novo ZBTB7A missense variant. Features included macrocephaly, mild intellectual disability (tIQ 65) and sleep apnea. Available hemoglobin levels (in the 1st month) supported high Hb and HbF levels. Other features included PDA and an umbilical hernia.

Initial investigations incl. karyotype and CMA were normal.

The ZBTB7A variant (NM_015898.3:c.1152C>G / p.Cys384Tyr) was identified following trio WES with a list of additional findings (in suppl.) not explaining the phenotype. This SNV, confirmed by Sanger sequencing, was absent from public db with several in silico predictions in favor of a deleterious effect.

ZBTB7A on 19p encodes zinc finger- and BTB domain-containing protein 7 (or Pokemon).

The authors performed a review of 19p13.3 microdeletion cases supporting a minimum region of overlap spanning PIAS4, ZBTB7A and MAP2K2 and common features of DD and ID, macrocephaly with prominent forehead, sleep apnea. The authors argue that loss of ZBTB7A explains part of - but probably not all - features of 19p13.3 microdeletions.

ZBTB7A is known to repress expression of HBG1 and HBG2 (γ-globin), with the few available HbF patient measurements in line with this role.

Based on the structure of the protein, Cys384 (along with 3 other residues) forms a coordinate bond with the Zn+2 ion, this bond predicted to be disrupted by Tyr. Further they favor a dominant negative effect given that ZBTB7A protein is known to form dimer via interaction at the BTB domain [hetero (variant+wt) and homodimers (variant+variant) having compromised function]. To support this notion, 3 previously reported somatic variants within the zinc-finger domain have been shown to exert a dominant-negative effect (PMID cited: 26455326).
----
In a collaborative study, von der Lippe et al (2022 - PMID: 34515416) identified 12 additional individuals (from 10 families) harboring monoallelic ZBTB7A missense/pLoF variants most commonly as de novo events.

The authors describe a consistent phenotype with motor (9/11) and speech delay (9/12), cognitive impairment/ID (12/12 - commonly mild, ranged from specific learning difficulties to severe ID), macrocephaly (>90%le in 11/12, >97% in 7/12), lymphoid hypertrophy of pharyngeal tissue/adenoid overgrowth (12/12), sleep apnea (9/12). Autistic features were observed in 7/12. Other phenotypes included frequent upper airway infections (10/11), weight above 97th percentile (7/11). HbF levels were elevated in 4/5 individuals with available measurements (range: 2.2% to 11.2% - ref. for subjects above 6m of age : <2% ). Other hematological issues were observed in few individuals (abn. monocyte/neutrophil counts in 3-4). Cardiovascular issues were reported in 4 (2 fam). 3 subjects had umbilical hernia. There was no common dysmorphic feature.

Various initial investigations were normal or did not appear to explain the NDD phenotype and incl. standard karyotype, CMA, targeted testing for genes/disorders previously considered (PTEN, FMR1, NSD1, BWS and PWS methylation studies, CFTR, etc). One male had a maternally inherited chrX dup not thought to explain his complex phenotype, while another had a concurrent diagnosis of thalassemia.

Individuals were investigated with singleton (or trio) WES. Of note some individuals were DDD study participants.

8 had de novo ZBTB7A variants, incl. one who harbored 2 de novo missense SNVs several residues apart. 2 sibs had inherited a fs variant from their affected parent. For the latter as well as for another subject parental samples were unavailable.

There were no other variants of interest upon exome analysis.

5 different missense, 2 nonsense and 3 fs variants were identified with pLoF all predicted to lead to NMD.

All variants were absent from gnomAD (pLI of 0.96, LOEUF 0.33 and missense Z-score of 4.04) which lists one individual with htz LoF, likely not an artifact.

Given this individual (and the familial case) the authors discuss on the mild phenotype and/or eventual reduced penetrance or underdiagnosis of the disorder.

There was no difference in severity between those with missense/truncating variants.

ZBTB7A transcription factor (or pokemon or lymphoma/leukemia-related factor) is widely expressed. It is involved in several activities being among others required to block Notch signaling which in turn drives T-cell at the expense of B-cell development. Notch pathway activation has been demonstrated in Zbtba7 ko mouse models. Finally, the authors discuss the role of notch signaling in thymus and the nervous system, as well as that ZBTB7A up/down-regulation known to repress/increase respectively HbF expression (several refs in text).
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MGI (1335091) for Zbtb7a : "Mice homozygous for a knock-out allele die around E16.5 due to anemia and exhibit a cell autonomous defect in early B cell development". (Phenotypes from nervous system not commented on).
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Apart from OMIM (#619769), ZBTB7A is included in the DD panel of G2P (ZBTB7A-associated developmental disorder / monoallelic_autosomal / absent gene product / confidence limited) as well as among the primary ID genes in SysID. In PanelApp Australia the gene is incl. with green rating in the ID and Macrocephaly gene panels.
----
Consider inclusion with amber or green rating (several individuals/families/variants, highly consistent phenotype, overlap with 19p microdeletions || variant effect not studied, animal models supporting contribution of the gene to the phenotype though no data on associated NDD ones).

Please also consider inclusion in other relevant panels (macrocephaly, lymphatic disorders, ASD, etc).
Sources: Literature, Other
Intellectual disability - microarray and sequencing v3.1530 PEX6 Sarah Leigh reviewed gene: PEX6: Rating: ; Mode of pathogenicity: Other; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1530 MAN2C1 Konstantinos Varvagiannis gene: MAN2C1 was added
gene: MAN2C1 was added to Intellectual disability. Sources: Literature,Other
Mode of inheritance for gene: MAN2C1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAN2C1 were set to 35045343
Phenotypes for gene: MAN2C1 were set to Global developmental delay; Intellectual disability; Abnormality of nervous system morphology; Abnormality of the corpus callosum; Ventriculomegaly; Polymicrogyria; Abnormality of the face; Macrocephaly
Penetrance for gene: MAN2C1 were set to unknown
Review for gene: MAN2C1 was set to GREEN
Added comment: Biallelic pathogenic MAN2C1 variants cause Congenital disorder of deglycosylation 2 (# 619775). Mild to moderate impairment of intellectual development is a feature in most patients as in the OMIM's clinical synopsis for this disorder.
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Specifically, Maia et al (2022 - PMID: 35045343) report the clinical features based of 6 relevant individuals (4/6 aged 4-18years and 2/6 fetuses) from 4 families. These individuals had non-specific dysmorphic features (micro/retrognathia being the most common in 5/6), different congenital anomalies, variable degrees of ID (3/4), as well as brain MRI abnormalities (PMG in 3/6 from 3 fam, ventriculomegaly in 3/6 from 2 fam, callosal anomalies in 4/6 from 3 fam, cerebellar hypoplasia 2/6 - 2 fam, vermis hypoplasia 4/6 - 3 fam etc). Macrocephaly was reported for 2/6 individuals (2 fam).

While ID was observed in 3/4 individuals of relevant age (mild in 1/4, moderate in 1/4, unk in 1/4), delayed motor and language development was reported for all (4/4).

All individuals harbored biallelic MAN2C1 variants following exome sequencing (previous investigations not reported), and Sanger sequencing was used for validation and segregation (parents/sibs).

There were no putative pathogenic variants in known disease genes.

MAN2C1 encodes mannosidase, alpha, class 2c, member 1, an enzyme playing a role in deglycosylation of free oligosaccharides (fOSs). The latter are generated and released in the cytoplasm or the ER lumen during N-glycosylation of proteins. fOSs are generated from two different pathways (ERAD and LLO) with a defect in an enzyme of the NGLY1 already described to cause a NDD due to defect of deglycosylation. In a later step oligossaccharides are trimmed by the action of ENGase to form fOS containing one GlcNAc (N-Acetylglucosamine) residue (fOSGn1) at the reducing end. Processing of these fOSs by the cytosolic α-mannosidase (MAN2C1) converts Man7-9Gn1 to Man5Gn1 subsequently transported to lysosomes for degradation.

Variants incl. 3 missense SNVs incl. c.2612G>C/p.Cys871Ser, c.2303G>A/p.Arg768Gln, c.607G>A/p.Gly203Arg, one splice variant (c.601-2A>G/p.Gly201Profs*10) and one indel (c.2733_2734del/p.His911Glnfs*67). [RefSeq NM_006715.3]

Most were present in gnomAD with low AF ranging from 0.013% to 0.11% while c.2303G>A/p.Arg768 has an AF of 0.33% with 5 homozygotes(*) in the database. Conservation and in silico predictions supported their effect.

For the variant affecting the splicing acceptor site (c.601-2A>G) studies in patient fibroblasts confirmed skipping of ex6. Fibroblasts from 2 sibs cmp htz for Arg768Gln and c.601-2A>G (Gly201Profs*10) were studied for protein levels, demonstrating 90% reduction in the amount of MAN2C1. There was no truncated protein observed upon immunoblot. Protein abundance was not affected in fibroblasts from the individual who was homozygous for Gly203Arg.

Mannosidase activities were studied upon overexpression in a HEK293 model, with Gly203Arg presenting similar activity to WT and Arg768Gln exhibiting only a tiny residual activity. Cys871Ser showed increased activity compared to WT.

Using fibroblasts from controls and the same individuals as above, the authors showed that pathogenic MAN2C1 variants caused defects in fOS processing (delayed processing of high oligomannose species, reduced production of M5Gn1 with M8 and M9Gn1/2 species remaining at high levels) supporting a total/partial loss of mannosidase activity for Arg768Gln and Gly203Arg.

In MAN2C1-KO HAP1 cell lines, M7-M9Gn1 species accumulated while M5Gn1 - the product of MAN2C1 - were absent. Complementation of KO HAP1 cells with Gly203Arg, Arg768Gln and Cys871Ser suggested impaired fOS processing for Gly203Arg and Arg768Gln (with significant amounts of M7-M9Gn1 species). Cells complemented with Cys871Ser did not exhibit fOS processing defects.

The authors speculate that Cys871Ser could affect a non-mannosidase function of the enzyme relevant to brain development or that it might lead to abnormal inter-subunit interactions or tetramer formation.

Finally, Maia et al summarize findings in previously described Man2c1-KO mice (cited PMID: 24550399). These appeared normal, did not exhibit differences in growth or lifespan and did not present behavioral alterations. Man2c1-KO mice had CNS involvement with histological analyses in favor of neuronal and glial degeneration with multiple vacuoles in deep neocortical layers and telencephalic white matter tracts. Vacuolization was not observed upon brain histology for the 2 fetuses studied which Maia et al speculate may occur at a later stage. In KO mice there was considerable accumulation of Man8–9GlcNAc oligosaccharides.
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G2P includes MAN2C1 in it's DD panel (confidence: strong, MAN2C1-associated neurodevelopmental disorder with cerebral malformations). In PanelApp Australia, this gene is rated green in the ID, polymicrogyria, cerebellar hypoplasia and fetal anomalies gene panels.

Consider inclusion in the current panel with green (3 individuals/families/variants, role of the gene, NDD phenotype also reported for NGLY1-related disorder of deglycosylation, variant studies) or amber rating (ID not a universal feature, still DD observed in all affected individuals).

Please consider adding this gene in other relevant panels (as in PanelApp Australia, also for corpus callosum abnormalities, metabolic disorders, etc).
Sources: Literature, Other
Intellectual disability - microarray and sequencing v3.1529 SLC38A3 Konstantinos Varvagiannis gene: SLC38A3 was added
gene: SLC38A3 was added to Intellectual disability. Sources: Literature,Other
Mode of inheritance for gene: SLC38A3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC38A3 were set to 34605855
Phenotypes for gene: SLC38A3 were set to Infantile axial hypotonia; Global developmental delay; Intellectual disability; Seizures; Spasticity; Microcephaly; Cerebral atrophy; Cerebellar atrophy; Abnormality of the corpus callosum; Dysphagia; Constipation; Increased serum lactate; Hyperammonemia
Penetrance for gene: SLC38A3 were set to Complete
Review for gene: SLC38A3 was set to GREEN
Added comment: Marafi et al (2021 - PMID: 34605855) describe the phenotype of 10 individuals, belonging to 7 families (6/7 consanguineous), harboring biallelic deleterious SLC38A3 variants. One subject (from fam3) was previously reported in the context of a larger cohort of consanguineous families investigated with exome sequencing (2017, PMID: 31130284).

The phenotype overall corresponded to a DEE and features included axial hypotonia (10/10), severe global DD or ID (10/10), seizures (8/10, onset : 1w-15m, NOT observed in 2/10 aged 1y3m and 4y | s. types: tonic-clonic in 3/8, tonic 2/8, focal 2/8 with secondary generalization, myoclonic 1/8, gelastic 1/8 | EEG burst-suppression, hypsarrhythmia in few). Microcephaly was observed in (8/10) and was more commonly postnatal and/or progressive. Variable abnormalities were observed upon brain imaging incl. cerebral (5/10) or cerebellar atrophy (2/10) and abnormal CC (6/10), abnormal myelination for age (6/10). Other phenotypes included visual impairment (9/10), peripheral hypertonia (8/9) constipation (8/9) and dysphagia (7/9), FTT (4/8), movement disorder (3/10). Metabolic studies indicated (transient) elevation of lactate (7/8 - also pyruvate in 2) and elevated plasma ammonia (4/7).

Individuals from the 1st family were investigated with ES, and the SLC38A3 splice site variant (NM_006841.6:c.855+1G>T) was the most likely candidate, additional SNVs not contributing to the NDD phenotype. Other affected subjects were ascertained through GeneMatcher/collaborations.

In total, 3 different missense and 4 pLoF (1 fs, 2 nonsense, 1 splicing) variants were identified with individuals from 2 families being hmz or cmd htz for missense variants. Variants were absent/ultrarare with no homozygotes in public/in-house databases with several in silico predictions in favor of a deleterious effect. Regions of AOH (around SLC38A3/total) are provided for some individuals/families.

Sanger sequencing was used for confirmation and segregation studies (apart from carrier parents in 7/7 fam, 11 unaffected sibs tested in 6/7 fam).

The solute carrier (SLC) superfamily of transmembrane transporters - highly expressed in mammalian brain - is involved in exchange of amino-acids (AAs), nutrients, ions, neurotransmitters and metabolites etc across biological membranes with >100 SLC-encoding genes associated with NDDs.

SLC38A3 specifically encodes SNAT3, a sodium-coupled neutral amino-acid transporter, principal transporter of Asn, His, Gln (precursor for GABA and glutamate), expressed in brain, liver, kidney, retina and pancreas. In the brain, it localizes to peri-synaptic astrocytes playing an important role in glutamate/GABA-glutamine cycle.

While the pLoF variants are predicted to undergo NMD or result in non-functional protein, protein modelling suggested that missense ones affect protein activity or stability.

Biochemical and metabolic screening was carried out for several individuals with plasma AAs reported normal (10/10), urinary OAs normal in 9/9, CSF AAs (incl. GABA/glutamine) normal in 2 sibs, CSF lactate normal in 1 indiv. studied. As discussed above plasma ammonia was elevated in 4/7 (2 fam), and 7/10 had elevated lactate and/or pyruvate (2/7).

Untargeted metabolomic profiles performed in biofluids (plasma from 3 subjects, CSF:1, urine:1) were suggestive of altered AA and nitrogen metabolism. In particular, alterations in levels of AA known to be transported by SNAT3 were found. 676 molecules overall showed deviation in plasma samples, 630 in urine and 241 in CSF (albeit with no consistent pattern). Perturbations in several biochemical pathways were shown to occur (incl. Gln-,Asn- and His- pathways).

Slc38a3-/- mice have reductions in brain glutamate and GABA neurotransmitters in homogenized brain tissue (GABA analytes being normal in plasma samples or the single CSF sample available from affected subjects). Snat3-deficient mice had elevation of plasma urea and normal ammonia levels (urea was low in all human samples and ranged from -2 to -3.5 SD in plasma, ammonia was elevated in 4/7). Slc38a3-/- mice have impaired growth, lethargy and ataxic gait, altered plasma AAs, normal glutamine in plasma with abundance in brain and exhibit early lethality. Plasma AAs were normal in 4 affected individuals, impaired growth observed in 4 and gait impairment was observed in 9/10. Hypoglycemia, previously reported in Slc38a3-/- mice, was not observed in any of the patients although this is presumably explained by diet/feeding intervals with abnormalities in pentose phosphate pathway in one individual hypothesized to be reflective of abn. glucose metabolism. The human phenotypes of microcephaly and seizures were not observed in mice. For mouse studies PMIDs cited by the authors : 27362266, 26490457.

There is currently no SLC38A3-related phenotype reported in OMIM. In G2P this gene is incl. in the DD panel (biallelic, confidence: strong, SLC38A3-associated epileptic encephalopathy). SLC38A3 is listed among the primary ID genes in SysID. In PanelApp Australia, SLC38A3 is included with green rating in the epilepsy, ID and microcephaly panels.

Consider inclusion with green rating (10 individuals, 7 families, 7 variants, role of SLCs and SLC38A3, alterations in AA/nitrogen metabolism etc) or amber rating (if discordances with mouse model considered).

Please consider inclusion in other panels e.g. for microcephaly, CC abnormalities, metabolic disorders, etc.
Sources: Literature, Other
Intellectual disability - microarray and sequencing v3.1525 CACNA2D1 Konstantinos Varvagiannis gene: CACNA2D1 was added
gene: CACNA2D1 was added to Intellectual disability. Sources: Literature,Other
Mode of inheritance for gene: CACNA2D1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CACNA2D1 were set to 35293990; 28097321
Phenotypes for gene: CACNA2D1 were set to Abnormal muscle tone; Feeding difficulties; Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormality of the corpus callosum; Cerebral atrophy; Abnormality of movement; Cortical visual impairment; Pain insensitivity
Penetrance for gene: CACNA2D1 were set to Complete
Review for gene: CACNA2D1 was set to GREEN
Added comment: Consider inclusion in the current panel with green rating.

Recent report of 2 unrelated individuals with DEE due to biallelic CACNA2D1 variants. Both referred to neurology/genetics for hypotonia/severe DD prior to onset of seizures.

One further individual with hypotonia and severe ID (seizures not discussed, age unknown).

Gene with established role, encoding α2δ-1 subunit of Cav channels. Studies for the variants support loss-of-function as the underlying effect.

Eventual contribution of monoallelic variants to NDD-phenotypes discussed (and put in question) in Ref [1] below.

There is currently no phenotype for CACNA2D1 in OMIM/G2P. In SysID this gene is listed among the candidates for ID, based on a previous report. CACNA2D1 is not currently included in the ID/epilepsy panels in PanelApp Australia.

See also relevant review in epilepsy panel (Dr. H. Lord).

Please consider also inclusion in other panels (e.g. microcephaly, corpus callosum, movement disorders, etc).

[1] ----
Dahimene et al (2022 - PMID: 35293990) describe the phenotype of 2 unrelated individuals with biallelic CACNA2D1 variants.

Overall, the phenotype corresponded to an early-onset DEE, characterized by abnormal muscle tone (axial hypotonia 2/2 with spasticity in extremities in 2/2), feeding difficulties (2/2), profound DD and ID (2/2), microcephaly (2/2 - approx. -2 SD in both), seizures (2/2 - 1st : onset 9m with absences and later generalized seizures, 2nd : onset 11m with hemi-clonic seizures and atypical absences). Other features included cortical visual impairment (2/2) and movement disorder (incl. choreiform movements 2/2, orofacial dyskinesia 2/2 and dystonic episodes 1/2). Brain MRI revealed corpus callosum anomalies (2/2) and cerebral atrophy (2/2). Both had echocardiography (abnormal in 1/2 - tiny PFO) and electrocardiography which was normal. Both exhibited insensibility to pain.

Presentation is relevant to the current panel as first symptoms in the first 3 months with severe hypotonia and poor head control (2/2) with evaluation in neurology/genetics preceding onset of seizures in both.

Trio ES was performed for both individuals and their (healthy) parents and revealed homozygosity for a fs variant in the first [NM_000722.3:c.818_822dup / p.(Ser275Asnfs*13)] and compound htz for a fs and a missense variant [c.13_23dup / p.(Leu9Alafs*5) and c.626G>A / p.(Gly209Asp)] in the second affected individual, respectively.

Eventual additional variants were not discussed.

Previous investigations are only provided for the 2nd and were all normal (karyotype, CMA, 15q methylation, epilepsy/neurometabolic gene panels).

Voltage-gated calcium channels are heteromultimers comprising different subunits incl. an alpha-1 (α1), α2δ (alpha-2/delta), beta (β) and gamma (γ). CACNA2D1 is one of the 4 genes (CACNA2D1-4) encoding the alpha-2/delta subunit. Its product is post-translationally processed into 2 peptides, an alpha-2 and a delta subunit, held by a disulfide bond.

Biallelic variants in CACNA2D2 - also encoding an alpha-2/delta subunit - cause cerebellar atrophy with seizures and variable developmental delay (# 618501).

Variant studies support loss-of-function effect for the studied variants, notably by NMD for the fs one, and severe impairment of the Cav2 channel function for the missense one :
- CACNA2D1 mRNA was reduced to 6-9% compared with control in fibroblasts from the 1st individual. mRNA levels for the 2nd subject were similar to control.
- Quantification of the protein in whole-cell lysates from fibroblasts revealed lower α2δ levels compared to control (10-12% and 31-38% applying to the 1st and 2nd individual).
- CACNA2D3 mRNA levels in fibroblasts from the 2nd patient were 2-7x higher compared to the 1st or controls suggesting a possible compensatory effect. CACNA2D2/4 mRNA levels were too low for quantification.
- Gly209 lies within the gabapentin and amino-acid binding pocket and this residue is invariable in CACNA2D1/CACNA2D2 in all vertebrates and paralogs.
- Transfection of tsA-201 cells with either WT or G209D HA-tagged α2δ revealed reduced cell surface expression for this missense variant (~80, for biotinylated form ~86%).
- In tsA-201 cells transfected with HA-tagged Cav2.2/β1b and either α2δ-1-WT, no α2δ-1 or α2δ-1-G209D, WT resulted in increased 13x currents with no increase applying to G209D (or in absence of α2δ). Plasma membrane expression of double (GFP/HA) tagged Cav2.2 was increased upon co-expression with WT α2δ-1 which was not the case for α2δ-1-G209D.
- In hippocampal neurons, double (GFP/HA)-tagged Cav2.2 could not be detected at the cell surface in the presence of α2δ-1-G209D (or no α2δ) in contrast with strong expression in presence of α2δ-1-WT. α2δ-1-G209D did not promote trafficking of Cav2.2 into hippocampal neurites, as indicated by reduced signals for both HA and GFP (for cell surface and total Cav2.2 respectively).
- Co-expression of double (GFP/HA) tagged Cav2.2 with β1b and either HA-α2δ-1-WT or HA-α2δ-1-G209D in tsA-201 cells, revealed reduced complex formation of G209D with Cav2.2 Co-immunoprecipitated HA-α2δ-1-G209D had higher molecular weight compared to HA-α2δ-1-WT which suggests that α2δ-1-G209D remains as the uncleaved immature form (probably in the ER).

Mouse model (several Refs in text):
Mild cardiac phenotype and reduced ventricular myocyte Ca current density was observed in hmz ko mice. Similarly to the insensibility to pain human phenotype, mice had delayed neuropathic pain-related responses. Overexpression of a2δ-1 resulted in epileptiform EEG and behavioral arrest, overall supporting a critical role of α2δ-1 for mouse brain.

The authors underscore that the parents of both patients (htz carriers) were healthy and review previous literature for association of monoallelic variants with epilepsy, ID and arrhythmogenic disorders (in suppl.) [Refs not here reviewed].

As for the NDD phenotype, CACNA2D1 is within a previously defined small region of overlap for 7q21.11 microdeletions associated with ID+/-epilepsy. The same study did not reveal de novo SNVs in any of the 3 contained genes within this SRO (HGF, CACNA2D1, PCLO) in 4293 patients with NDD [cited PMID: 28240412]. A frameshift variant (c.2625del) was identified in a 13-yo girl with infantile spasms and normal intelligence [cited PMID: 25877686]. A 1-bp insertion (c.659-2_659-1insT / not studied at the mRNA level) was identified in another 14-yo female with ID and epilepsy [cited PMID: 34356170]. The authors state that the phenotype (/differences) of these individuals as well as presence of pLoF CACNA2D1 variants in gnomAD [still pLI of 1] put in question pathogenicity of monoallelic variants for these phenotypes.

The role of heterozygous missense variants described in relation to arrhythmogenic disorders is also discussed extensively (some downgraded to LB/VUS, others having a relatively high MAF and presence of 1-2 homozygotes in gnomAD).

[2] ----
In an article cited by SysID for CACNA2D1 (2017 - PMID: 28097321), Reuter et al studied with WES and autozygosity mapping individuals with NDD belonging to consanguineous families.

As in eTables1/3, a male - single affected individual born to consanguineous parents from Turkey (MR150) - was investigated by singleton ES.

This individual was homozygous for a missense CACNA2D1 SNV [NM_000722.2:c.1514C>T;p.(Thr505Ile)].

Prior investigations are unavailable (although individuals with previously known P/LP CNVs were excluded).

The phenotype - briefly reported - included hypotonia, severe ID, stereotypic behaviors, inguinal hernia and omphalocele. Presence of seizures was not commented on. The age of this individual was not reported.
Sources: Literature, Other
Intellectual disability - microarray and sequencing v3.1523 TRAPPC10 Konstantinos Varvagiannis reviewed gene: TRAPPC10: Rating: AMBER; Mode of pathogenicity: None; Publications: 35298461, 30167849; Phenotypes: Abnormal muscle tone, Global developmental delay, Intellectual disability, Microcephaly, Short stature, Gait disturbance; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1523 SLC12A5 Sarah Leigh reviewed gene: SLC12A5: Rating: ; Mode of pathogenicity: None; Publications: 24928908, 24668262, 26333769; Phenotypes: Developmental and epileptic encephalopathy 34, OMIM:616645; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1520 ZNF292 Rachel Challis reviewed gene: ZNF292: Rating: ; Mode of pathogenicity: None; Publications: PMID: 31723249; Phenotypes: Intellectual disability, autism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.1520 PAN2 Konstantinos Varvagiannis gene: PAN2 was added
gene: PAN2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PAN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAN2 were set to 29620724; https://doi.org/10.1038/s41431-022-01077-y
Phenotypes for gene: PAN2 were set to Global developmental delay; Intellectual disability; Sensorineural hearing impairment; Abnormality of the genitourinary system; Abnormality of the cardiovascular system; Abnormality of blood and blood-forming tissues; EEG abnormality; Seizures; Anorectal anomaly; Abnormality of the skeletal system; Abnormality of the eye; Abnormality of head or neck
Penetrance for gene: PAN2 were set to Complete
Review for gene: PAN2 was set to AMBER
Added comment: 1.
Maddirevula et al (2018 - PMID: 29620724) first reported on the phenotype associated with biallelic pathogenic variants in PAN2.

This concerned a male (15DG2222) born to consanguineous parents and exhibiting MCA, dysmorphic features and global DD (age of 34 m). Features incl. imperforate anus, metopic craniosynostosis, scoliosis, CHD (PFO, PDA, VSD), renal anomalies (duplicated collecting system) and abnormalities of the eye (posterior embryotoxon, maculopathy).

As the other 411 individuals from the cohort, the child had 1st-tier testing genetic testing using a dysmorphology/skeletal dysplasia panel of 296 genes.

Subsequent autozygome analysis (Axiom genotyping platform) was used to identify ROH (authors state "segregating within the family", in pedigree the proband was the single affected person and single child).

WES revealed a PAN2 indel. [NM_001166279.1:c.3162delC / p.(Ser1055Profs*4)].

There were no additional studies.

Role of PAN2 and animal models discussed as below.
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2.
Reuter et al. (2022 - https://doi.org/10.1038/s41431-022-01077-y) describe the phenotype of 5 additional individuals - from 3 unrelated families (2 consanguineous) - harboring biallelic PAN2 variants. The authors review the phenotype of the previously described case.

Features included DD (6/6), ID (4/5 with relevant age in the mild-moderate range, 1/5 had borderline IF), sensorineural hearing loss (5/6) and incompletely penetrant congenital anomalies of the heart (4/6 - TOF, septal defects, Ao root dilat), urinary malformations (4/6 - hypoplasia/agenesis, anovesical fistula), ophthalmological anomalies (2/6 - Rieger, posterior embryotoxon, etc). EEG anomalies or seizures were noted in 4/6. Craniofacial feat. in >=2/6 included cleft palate/bifid uvula, ptosis, hypertelorism, abn. of the nose, low-set ears, short neck. There was no comprehensive evaluation for skeletal dysplasia despite short stature/skeletal anomalies in multiple individuals. Hematological anomalies were reported in 2, possibly explained by another concurrent diagnosis (of GSD) in one individual.

WGS was performed for 1 individual, and WES for 4 members of the 2nd family and the proband in the 3rd. ROH identified in all 3 families (1 non-consanguineous but from the same region of Italy) are mentioned in the suppl. Sanger sequencing for parents and affected/unaffected sibs was mentioned for the 2 families with solo WGS/WES. One individual had a dual - previously established - diagnosis (of SLC37A4-related GSD) not related to his NDD. There were no other candidate variants except for VUS or variants in 'genes of uncertain significance'.

The majority of mammalian mature mRNAs have polyA tails, added during RNA processing. PAN2 encodes a subunit of the Pan2-Pan3 deadenylation complex which shortens mRNA 3' polyA tails, regulating mRNA stability/translation efficiency.

Specifically Pan2 is the catalytic subunit, while the interaction with Pan3 mediates efficient mRNA binding. Deadenylation in cytoplasm is mostly carried out by the Pan2-Pan3 or Ccr4-Not compexes. While perturbations of mRNA metabolism/decay are established causes of NDD and ID. In particular, monoallelic variants in genes of Ccr4-Not complex (inc. CNOT1/2/3) already causative of NDDs.

All affected individuals were homozygous for pLoF PAN2 variants, namely (NM_001166279.2): c.2335G>T / p.(Glu779*) [Fam1], c.3408dupT / p.(Glu1137*) [Fam2], c.574-2A>G / p.? [Fam3].

Variants were absent from gnomAD (where PAN2 has a pLI:0.94, o/e:0.19).

There were no variant studies performed. The splicing variant is predicted in silico to abolish the splice-acceptor site, with in-frame skippling of ex5 which codes a repeat within the WD40 domain. Previous studies in yeast have shown that this domain is important for sensing the length of the polyA tail, with absence of this domain resulting in impaired deadenylation of 90A tails (similarly to complete Pan2 del) [cited PMID: 31104843].

Overall PAN2 loss-of-function is thought to be the underlying disease mechanism.

Partial functional redundancy of Pan2/Pan3 (initiation of deadenylation) and Ccr4-Not complexes (further shortening of polyA) is speculated to mitigate consequences of PAN2 LoF in humans.

In yeast Pan2Δ, Ccr4Δ and Pan2Δ/Ccr4Δ have been studied with more severe phenotypes in double mutants where ability to shorten mRNA polyA tails was abolished [cited PMID:11239395]. In yeast extracts lacking Pan2p and Pan3p, transcripts were polyadenylated to >90-200 adenosines [cited PMID: 9774670]

Mouse mutants (MGI:1918984) had increased heart weight, increased eosinophil cell number while homozygosity for a stopgain allele (by ENU mutagenesis) was shown to result in embyonic lethality.

Finally, given the presence of thrombocytopenia and anemia in 3 individuals (2 families) as well as the link between mRNA deadenylation and telomere disease, telomere length analyses from WGS data were performed (TelSeq/Expansion Hunter dn), but there was no evidence for telomeric shortening.
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Currently, there is no PAN2-related phenotype in OMIM/G2P/SysID/PanelApp Australia.
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Consider inclusion in the ID panel with amber rating [>3 individuals/families/variants, though variant studies not performed (NMD/splicing) and authors of 2nd study recognize possibility of additional/concurrent diagnoses in individuals from consanguineous families, possibility of missed dn variants due to singleton WGS/WES in 2 fam. Also the presumed deadenylation defect not studied to date].

Please consider adding this gene to other panels - eg. for sens. hearing loss (5/6 - 3 fam), urinary tract anomalies (4/6 - 4 fam), congenital (4/6 - 3fam), anorectal malformations (2/6 - 2 families, incl. fistula or imperforate anus), clefting (2/6 - 1 fam), hematological disorders, etc.

For the time being, not added in epilepsy panel as some individuals had only EEG anomalies, few had also clinical seizures not necessarily requiring treatment.
Sources: Literature
Intellectual disability - microarray and sequencing v3.1520 HIST1H4C Konstantinos Varvagiannis reviewed gene: HIST1H4C: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 28920961, 35202563; Phenotypes: Tessadori-van Haaften neurodevelopmental syndrome 1, #619758; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.1520 HIST1H4J Konstantinos Varvagiannis reviewed gene: HIST1H4J: Rating: AMBER; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 31804630, 35202563; Phenotypes: ?Tessadori-van Haaften neurodevelopmental syndrome 2, #619759; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.1520 HIST1H4D Konstantinos Varvagiannis gene: HIST1H4D was added
gene: HIST1H4D was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HIST1H4D was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HIST1H4D were set to 35202563
Phenotypes for gene: HIST1H4D were set to Global developmental delay; Intellectual disability; Microcephaly; Growth abnormality; Abnormality of the face
Penetrance for gene: HIST1H4D were set to Complete
Mode of pathogenicity for gene: HIST1H4D was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: HIST1H4D was set to AMBER
Added comment: Histone H4 is a core component of the nucleosome, the basic repeating unit of eukaryotic chromatin. Each nucleosome consists of ~150 bp of DNA wrapped around a histone octamer. Each histone octamer is composed of 2 copies of each of the histones H2A, H2B, H3, H4. This organization is important for DNA replication, transcription and repair.

There are 14 canonical histone H4 genes in the human genome, which despite being different at the nucleotide level encode an identical protein. These cluster in 3 genomic loci. Their transcription is independently regulated with differing expression during brain development and in human tissues.

Histone H4 forms a dimer with H3 (which however has variant isoforms linked to specific cellular processes).

Pathogenic variants in genes encoding H4 have been reported in several individuals. Irrrespective of the gene for H4 involved, all patients presented with highly overlapping features, DD and ID being universal. Available reports to date concern :
- H4C3/HIST1H4C (9 subjects - PMID: 28920961, 35202563),
- H4C11/HIST1H4J (1 subject - PMID: 31804630, 35202563),
- H4C4/HIST1H4D (1 subject - PMID:35202563),
- H4C5/HIST1H4E (17 subjects - PMID: 35202563),
- H4C6/HIST1H4F (1 subject - PMID: 35202563),
- H4C9/HIST1H4I (3 subjects - PMID: 35202563).

Variants in all cases were missense SNVs, occurring (in almost all cases) as dn variants and affecting the same residue in the same and/or different H4 genes (details for clusters below). Eg. Arg45Cys was a recurrent variant for H4C5 (>=7 subjects), while variants affecting Arg40 have been reported in H4C4, H4C5, H4C9, H4C11 (7 subjects overall).

Zebrafish studies for all genes reported have included most - if not all - patient variants and recapitulate features observed in affected individuals (head size/structure and growth).

Additional studies specificaly for H4C3/HIST1H4C have been performed in patient fibroblasts (demonstrating among others transcriptional dysregulation) and zebrafish (accumulation of DSBs, increased apoptosis in head/tail, abn. cell cycle progression).

Note that the nomenclature for variants - at the protein level - used in literature commonly takes into consideration cleavage of Met1, thus the numbering may not correspond to the HGVS one.

Relevant entries exist in OMIM, G2P and SysID only for H4C3/HIST1H4C (Tessadori-van Haaften neurodevelopmental syndrome 1, #619758) and H4C11/HIST1H4J (?Tessadori-van Haaften neurodevelopmental syndrome 2, #619759) but not for other genes.

Rating in PanelApp Australia - ID Panel : HIST1H4C Green, H4J Amber, H4D Amber, H4E Green, H4F Amber, H4I Green.

Please consider inclusion in other possibly relevant panels (microcephaly, short stature/FTT, etc).

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Initial work from Tessadori et al (incl. DDD study, 2017 - PMID:28920961) identified monoallelic missense SNVs affecting the same residue of H4C3 (HIST1H4C), in 3 individuals from 2 families. [c.274A>C/ HGVS p.(Lys92Gln) dn in 1 subject and c.275A>C/ HGVS p.(Lys92Arg) inherited from unaffected mosaic parent].

Individuals from both families having relevant age had intellectual disability (2/2 - 2 families). Other features incl. growth delay (3/3) and microcephaly (3/3).

Expression of the variants in zebrafish severely affected structural development recapitulating the patient phenotypes (microcephaly and short stature).

RNA sequencing in fibroblasts from 2 unrelated patients and a control, revealed that expression of H4C3 variants was similar to wt. The authors estimated that ~8% of H4 cDNA molecules contained the variant. LC-MS/MS analysis suggested that the mutant protein was present in nucleosomes at a level of 1-2% while RNA-seq identified 115 differential expressed genes, with enrichment for relevant procedures (chr. organization, histone binding, DNA packaging, nucleosomal organization, cell cycle).

Post-translational modifications of Lys92 (H4K91) are highly conserved and have been previously associated with processes from chromatin assembly , DNA damage sensitivity, etc. Post-translational marks on Lys92 (K91) were absent in patient derived cells as a result of each variant.

Zebrafish models for both variants were suggestive for accumulation of double strand breaks (DSBs) more visible in heads and tails of larvae. Embryos expressing mutants displayed increased apoptosis in head and tail. Additional studies in larvae were suggestive of abnormal cell cycle progression (rel. increase in cellls in S/G2/M phase, increased occurrence of activated CHK2 with p53 stabilization) applying to both variants studied.

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In a subsequent publication, Tessadori et al. (2020 - PMID: 31804630) described the phenotype of a 14 y.o. boy harboring a dn heterozygous missense H4C11 (HIST1H4J) variant following trio-ES [c.274A>G / HGVS p.(Lys92Glu)]. Features incl. profound ID, microcephaly, short stature with some dysmorphic features (uplsanting p-f, hypertelorism, etc). Previous work-up was normal/non-diagnostic and incl. FMR1, MECP2 and a CMA showing an inherited 207 kb CNV involving KCNV1. Upon mRNA microinjection in zebrafish embryos - either for wt or for Lys92Glu HIST1H4J - effect for wt was very mild. Lys92Glu expression led to defective development of head structures (brain, eyes), faulty body axis growth and dysmorphic tail reproducing the microcephaly and short stature phenotype. This was similar to previous zebrafish studies for HIS1H4C variants (above).

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Tessadori et al. (2022 - PMID: 35202563) describe 29 *additional individuals with de novo missense variants in genes encoding H4, namely:
- H4C3 (HIST1H4C/N=6 subjects),
- H4C11 (HIST1H4J/N=1),
- H4C4 (HIST1H4D/N=1),
- H4C5 (HIST1H4E/N=17),
- H4C6 (HIST1H4F/N=1),
- H4C9 (HIST1H4I/N=3).

All individuals, exhibited DD and ID (29/29). Other features incl. hypotonia (10/29), seizures (5/29), autism (5/29), ataxia (4/29). Abnormal growth incl. progressive microcephaly (2/19 prenatal, 20/29 postnatal onset), short stature/FTT (each 11/29). Few had skeletal features (craniosynostosis 2/29, abn. digits 4/29, vertebral 4/29). Some had visual (17/28) or hearing impairment (7/29). Facial features incl. hypertelorism (5/29), upslanting p-f (3/29), broad nasal tip (11/29), thin upper lip (4/29) and teeth anomalies (6/29 - notably gap between central incisors).

The authors state that the cohort was collected with trio WES but also after data sharing via Genematcher / DECIPHER.

Identified variants were in all cases missense and de novo, the latter either by trio WES or Sanger sequencing of parents.

Previous work-up or presence of additional variants are not discussed.

At the protein level 10 aa were affected, 6 of which recurrently within the same gene (Arg45, His75, Lys91, Tyr98) as well among several genes for H4 (Pro32, Arg40). Variants lied within two clusters, one corresponding to the α-helix of H4 (reported variants affected Lys31 - Arg45) important for DNA contacts, interactions with H3 and histone chaperones. The other within the core of nucleosome (reported patient variants : His75-Tyr98) with important strucural contact between H3-H4 dimer and histone chaperones.

There were no detectable genotype-phenotype patterns separating individual H4 genes or protein regions. Of note, variability was observed even among 7 individuals with the same dn H4C5 variant (Arg45Cys).

All variants were absent from control databases incl. gnomAD and affected residues conserved through to S. cerevisiae. Substitutions affecting Arg45 and Gly94 and His75 have been studied previously with effect in growth/fitness/chromatin remodeling/DNA damage repair depending on variant (5 studies cited).

Zebrafish embryos at the 1 cell stage were injected with mRNA encoding either wt or identified variants, the latter inducing significant developmental defects with the exception of Pro32Ala (H4C3) and Arg40Cys (H4C5, H4C11).

For Pro32Ala and Arg40Cys however, the strong recurrence in this cohort supports pathogenicity. A dosage dependent effect was observed for 2 variants.

H4 genes appear to be tolerant to both missense and loss-of-function variation (the latter even in homozygous form) suggesting a dominant effect of the variants.

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[RefSeqs : H4C3/HIST1H4C - NM_0035242.4 | H4C4/HIST1H4D - NM_003539.4 | H4C5/HIST1H4E - NM_003545.3 | H4C6/HIST1H4F - NM_003540.4 | H4C9/HIST1H4I - NM_003495.2 | H4C11/HIST1H4J - NM_021968.4 // Variants at the protein level above are according to the HGVS nomenclature. However as the N-terminal methionine is cleaved, numbering relative to the mature peptide has also been used in publications eg. p.Pro33Ala HGVS corresponding to Pro32Ala]
Sources: Literature
Intellectual disability - microarray and sequencing v3.1520 HIST1H4E Konstantinos Varvagiannis gene: HIST1H4E was added
gene: HIST1H4E was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HIST1H4E was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HIST1H4E were set to 35202563
Phenotypes for gene: HIST1H4E were set to Global developmental delay; Intellectual disability; Microcephaly; Growth abnormality; Abnormality of the face
Penetrance for gene: HIST1H4E were set to unknown
Mode of pathogenicity for gene: HIST1H4E was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: HIST1H4E was set to GREEN
Added comment: Histone H4 is a core component of the nucleosome, the basic repeating unit of eukaryotic chromatin. Each nucleosome consists of ~150 bp of DNA wrapped around a histone octamer. Each histone octamer is composed of 2 copies of each of the histones H2A, H2B, H3, H4. This organization is important for DNA replication, transcription and repair.

There are 14 canonical histone H4 genes in the human genome, which despite being different at the nucleotide level encode an identical protein. These cluster in 3 genomic loci. Their transcription is independently regulated with differing expression during brain development and in human tissues.

Histone H4 forms a dimer with H3 (which however has variant isoforms linked to specific cellular processes).

Pathogenic variants in genes encoding H4 have been reported in several individuals. Irrrespective of the gene for H4 involved, all patients presented with highly overlapping features, DD and ID being universal. Available reports to date concern :
- H4C3/HIST1H4C (9 subjects - PMID: 28920961, 35202563),
- H4C11/HIST1H4J (1 subject - PMID: 31804630, 35202563),
- H4C4/HIST1H4D (1 subject - PMID:35202563),
- H4C5/HIST1H4E (17 subjects - PMID: 35202563),
- H4C6/HIST1H4F (1 subject - PMID: 35202563),
- H4C9/HIST1H4I (3 subjects - PMID: 35202563).

Variants in all cases were missense SNVs, occurring (in almost all cases) as dn variants and affecting the same residue in the same and/or different H4 genes (details for clusters below). Eg. Arg45Cys was a recurrent variant for H4C5 (>=7 subjects), while variants affecting Arg40 have been reported in H4C4, H4C5, H4C9, H4C11 (7 subjects overall).

Zebrafish studies for all genes reported have included most - if not all - patient variants and recapitulate features observed in affected individuals (head size/structure and growth).

Additional studies specificaly for H4C3/HIST1H4C have been performed in patient fibroblasts (demonstrating among others transcriptional dysregulation) and zebrafish (accumulation of DSBs, increased apoptosis in head/tail, abn. cell cycle progression).

Note that the nomenclature for variants - at the protein level - used in literature commonly takes into consideration cleavage of Met1, thus the numbering may not correspond to the HGVS one.

Relevant entries exist in OMIM, G2P and SysID only for H4C3/HIST1H4C (Tessadori-van Haaften neurodevelopmental syndrome 1, #619758) and H4C11/HIST1H4J (?Tessadori-van Haaften neurodevelopmental syndrome 2, #619759) but not for other genes.

Rating in PanelApp Australia - ID Panel : HIST1H4C Green, H4J Amber, H4D Amber, H4E Green, H4F Amber, H4I Green.

Please consider inclusion in other possibly relevant panels (microcephaly, short stature/FTT, etc).

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Initial work from Tessadori et al (incl. DDD study, 2017 - PMID:28920961) identified monoallelic missense SNVs affecting the same residue of H4C3 (HIST1H4C), in 3 individuals from 2 families. [c.274A>C/ HGVS p.(Lys92Gln) dn in 1 subject and c.275A>C/ HGVS p.(Lys92Arg) inherited from unaffected mosaic parent].

Individuals from both families having relevant age had intellectual disability (2/2 - 2 families). Other features incl. growth delay (3/3) and microcephaly (3/3).

Expression of the variants in zebrafish severely affected structural development recapitulating the patient phenotypes (microcephaly and short stature).

RNA sequencing in fibroblasts from 2 unrelated patients and a control, revealed that expression of H4C3 variants was similar to wt. The authors estimated that ~8% of H4 cDNA molecules contained the variant. LC-MS/MS analysis suggested that the mutant protein was present in nucleosomes at a level of 1-2% while RNA-seq identified 115 differential expressed genes, with enrichment for relevant procedures (chr. organization, histone binding, DNA packaging, nucleosomal organization, cell cycle).

Post-translational modifications of Lys92 (H4K91) are highly conserved and have been previously associated with processes from chromatin assembly , DNA damage sensitivity, etc. Post-translational marks on Lys92 (K91) were absent in patient derived cells as a result of each variant.

Zebrafish models for both variants were suggestive for accumulation of double strand breaks (DSBs) more visible in heads and tails of larvae. Embryos expressing mutants displayed increased apoptosis in head and tail. Additional studies in larvae were suggestive of abnormal cell cycle progression (rel. increase in cellls in S/G2/M phase, increased occurrence of activated CHK2 with p53 stabilization) applying to both variants studied.

------
In a subsequent publication, Tessadori et al. (2020 - PMID: 31804630) described the phenotype of a 14 y.o. boy harboring a dn heterozygous missense H4C11 (HIST1H4J) variant following trio-ES [c.274A>G / HGVS p.(Lys92Glu)]. Features incl. profound ID, microcephaly, short stature with some dysmorphic features (uplsanting p-f, hypertelorism, etc). Previous work-up was normal/non-diagnostic and incl. FMR1, MECP2 and a CMA showing an inherited 207 kb CNV involving KCNV1. Upon mRNA microinjection in zebrafish embryos - either for wt or for Lys92Glu HIST1H4J - effect for wt was very mild. Lys92Glu expression led to defective development of head structures (brain, eyes), faulty body axis growth and dysmorphic tail reproducing the microcephaly and short stature phenotype. This was similar to previous zebrafish studies for HIS1H4C variants (above).

------
Tessadori et al. (2022 - PMID: 35202563) describe 29 *additional individuals with de novo missense variants in genes encoding H4, namely:
- H4C3 (HIST1H4C/N=6 subjects),
- H4C11 (HIST1H4J/N=1),
- H4C4 (HIST1H4D/N=1),
- H4C5 (HIST1H4E/N=17),
- H4C6 (HIST1H4F/N=1),
- H4C9 (HIST1H4I/N=3).

All individuals, exhibited DD and ID (29/29). Other features incl. hypotonia (10/29), seizures (5/29), autism (5/29), ataxia (4/29). Abnormal growth incl. progressive microcephaly (2/19 prenatal, 20/29 postnatal onset), short stature/FTT (each 11/29). Few had skeletal features (craniosynostosis 2/29, abn. digits 4/29, vertebral 4/29). Some had visual (17/28) or hearing impairment (7/29). Facial features incl. hypertelorism (5/29), upslanting p-f (3/29), broad nasal tip (11/29), thin upper lip (4/29) and teeth anomalies (6/29 - notably gap between central incisors).

The authors state that the cohort was collected with trio WES but also after data sharing via Genematcher / DECIPHER.

Identified variants were in all cases missense and de novo, the latter either by trio WES or Sanger sequencing of parents.

Previous work-up or presence of additional variants are not discussed.

At the protein level 10 aa were affected, 6 of which recurrently within the same gene (Arg45, His75, Lys91, Tyr98) as well among several genes for H4 (Pro32, Arg40). Variants lied within two clusters, one corresponding to the α-helix of H4 (reported variants affected Lys31 - Arg45) important for DNA contacts, interactions with H3 and histone chaperones. The other within the core of nucleosome (reported patient variants : His75-Tyr98) with important strucural contact between H3-H4 dimer and histone chaperones.

There were no detectable genotype-phenotype patterns separating individual H4 genes or protein regions. Of note, variability was observed even among 7 individuals with the same dn H4C5 variant (Arg45Cys).

All variants were absent from control databases incl. gnomAD and affected residues conserved through to S. cerevisiae. Substitutions affecting Arg45 and Gly94 and His75 have been studied previously with effect in growth/fitness/chromatin remodeling/DNA damage repair depending on variant (5 studies cited).

Zebrafish embryos at the 1 cell stage were injected with mRNA encoding either wt or identified variants, the latter inducing significant developmental defects with the exception of Pro32Ala (H4C3) and Arg40Cys (H4C5, H4C11).

For Pro32Ala and Arg40Cys however, the strong recurrence in this cohort supports pathogenicity. A dosage dependent effect was observed for 2 variants.

H4 genes appear to be tolerant to both missense and loss-of-function variation (the latter even in homozygous form) suggesting a dominant effect of the variants.

------
[RefSeqs : H4C3/HIST1H4C - NM_0035242.4 | H4C4/HIST1H4D - NM_003539.4 | H4C5/HIST1H4E - NM_003545.3 | H4C6/HIST1H4F - NM_003540.4 | H4C9/HIST1H4I - NM_003495.2 | H4C11/HIST1H4J - NM_021968.4 // Variants at the protein level above are according to the HGVS nomenclature. However as the N-terminal methionine is cleaved, numbering relative to the mature peptide has also been used in publications eg. p.Pro33Ala HGVS corresponding to Pro32Ala]
Sources: Literature
Intellectual disability - microarray and sequencing v3.1520 HIST1H4F Konstantinos Varvagiannis gene: HIST1H4F was added
gene: HIST1H4F was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HIST1H4F was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HIST1H4F were set to 35202563
Phenotypes for gene: HIST1H4F were set to Global developmental delay; Intellectual disability; Microcephaly; Growth abnormality; Abnormality of the face
Penetrance for gene: HIST1H4F were set to unknown
Mode of pathogenicity for gene: HIST1H4F was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: HIST1H4F was set to AMBER
Added comment: Histone H4 is a core component of the nucleosome, the basic repeating unit of eukaryotic chromatin. Each nucleosome consists of ~150 bp of DNA wrapped around a histone octamer. Each histone octamer is composed of 2 copies of each of the histones H2A, H2B, H3, H4. This organization is important for DNA replication, transcription and repair.

There are 14 canonical histone H4 genes in the human genome, which despite being different at the nucleotide level encode an identical protein. These cluster in 3 genomic loci. Their transcription is independently regulated with differing expression during brain development and in human tissues.

Histone H4 forms a dimer with H3 (which however has variant isoforms linked to specific cellular processes).

Pathogenic variants in genes encoding H4 have been reported in several individuals. Irrrespective of the gene for H4 involved, all patients presented with highly overlapping features, DD and ID being universal. Available reports to date concern :
- H4C3/HIST1H4C (9 subjects - PMID: 28920961, 35202563),
- H4C11/HIST1H4J (1 subject - PMID: 31804630, 35202563),
- H4C4/HIST1H4D (1 subject - PMID:35202563),
- H4C5/HIST1H4E (17 subjects - PMID: 35202563),
- H4C6/HIST1H4F (1 subject - PMID: 35202563),
- H4C9/HIST1H4I (3 subjects - PMID: 35202563).

Variants in all cases were missense SNVs, occurring (in almost all cases) as dn variants and affecting the same residue in the same and/or different H4 genes (details for clusters below). Eg. Arg45Cys was a recurrent variant for H4C5 (>=7 subjects), while variants affecting Arg40 have been reported in H4C4, H4C5, H4C9, H4C11 (7 subjects overall).

Zebrafish studies for all genes reported have included most - if not all - patient variants and recapitulate features observed in affected individuals (head size/structure and growth).

Additional studies specificaly for H4C3/HIST1H4C have been performed in patient fibroblasts (demonstrating among others transcriptional dysregulation) and zebrafish (accumulation of DSBs, increased apoptosis in head/tail, abn. cell cycle progression).

Note that the nomenclature for variants - at the protein level - used in literature commonly takes into consideration cleavage of Met1, thus the numbering may not correspond to the HGVS one.

Relevant entries exist in OMIM, G2P and SysID only for H4C3/HIST1H4C (Tessadori-van Haaften neurodevelopmental syndrome 1, #619758) and H4C11/HIST1H4J (?Tessadori-van Haaften neurodevelopmental syndrome 2, #619759) but not for other genes.

Rating in PanelApp Australia - ID Panel : HIST1H4C Green, H4J Amber, H4D Amber, H4E Green, H4F Amber, H4I Green.

Please consider inclusion in other possibly relevant panels (microcephaly, short stature/FTT, etc).

------
Initial work from Tessadori et al (incl. DDD study, 2017 - PMID:28920961) identified monoallelic missense SNVs affecting the same residue of H4C3 (HIST1H4C), in 3 individuals from 2 families. [c.274A>C/ HGVS p.(Lys92Gln) dn in 1 subject and c.275A>C/ HGVS p.(Lys92Arg) inherited from unaffected mosaic parent].

Individuals from both families having relevant age had intellectual disability (2/2 - 2 families). Other features incl. growth delay (3/3) and microcephaly (3/3).

Expression of the variants in zebrafish severely affected structural development recapitulating the patient phenotypes (microcephaly and short stature).

RNA sequencing in fibroblasts from 2 unrelated patients and a control, revealed that expression of H4C3 variants was similar to wt. The authors estimated that ~8% of H4 cDNA molecules contained the variant. LC-MS/MS analysis suggested that the mutant protein was present in nucleosomes at a level of 1-2% while RNA-seq identified 115 differential expressed genes, with enrichment for relevant procedures (chr. organization, histone binding, DNA packaging, nucleosomal organization, cell cycle).

Post-translational modifications of Lys92 (H4K91) are highly conserved and have been previously associated with processes from chromatin assembly , DNA damage sensitivity, etc. Post-translational marks on Lys92 (K91) were absent in patient derived cells as a result of each variant.

Zebrafish models for both variants were suggestive for accumulation of double strand breaks (DSBs) more visible in heads and tails of larvae. Embryos expressing mutants displayed increased apoptosis in head and tail. Additional studies in larvae were suggestive of abnormal cell cycle progression (rel. increase in cellls in S/G2/M phase, increased occurrence of activated CHK2 with p53 stabilization) applying to both variants studied.

------
In a subsequent publication, Tessadori et al. (2020 - PMID: 31804630) described the phenotype of a 14 y.o. boy harboring a dn heterozygous missense H4C11 (HIST1H4J) variant following trio-ES [c.274A>G / HGVS p.(Lys92Glu)]. Features incl. profound ID, microcephaly, short stature with some dysmorphic features (uplsanting p-f, hypertelorism, etc). Previous work-up was normal/non-diagnostic and incl. FMR1, MECP2 and a CMA showing an inherited 207 kb CNV involving KCNV1. Upon mRNA microinjection in zebrafish embryos - either for wt or for Lys92Glu HIST1H4J - effect for wt was very mild. Lys92Glu expression led to defective development of head structures (brain, eyes), faulty body axis growth and dysmorphic tail reproducing the microcephaly and short stature phenotype. This was similar to previous zebrafish studies for HIS1H4C variants (above).

------
Tessadori et al. (2022 - PMID: 35202563) describe 29 *additional individuals with de novo missense variants in genes encoding H4, namely:
- H4C3 (HIST1H4C/N=6 subjects),
- H4C11 (HIST1H4J/N=1),
- H4C4 (HIST1H4D/N=1),
- H4C5 (HIST1H4E/N=17),
- H4C6 (HIST1H4F/N=1),
- H4C9 (HIST1H4I/N=3).

All individuals, exhibited DD and ID (29/29). Other features incl. hypotonia (10/29), seizures (5/29), autism (5/29), ataxia (4/29). Abnormal growth incl. progressive microcephaly (2/19 prenatal, 20/29 postnatal onset), short stature/FTT (each 11/29). Few had skeletal features (craniosynostosis 2/29, abn. digits 4/29, vertebral 4/29). Some had visual (17/28) or hearing impairment (7/29). Facial features incl. hypertelorism (5/29), upslanting p-f (3/29), broad nasal tip (11/29), thin upper lip (4/29) and teeth anomalies (6/29 - notably gap between central incisors).

The authors state that the cohort was collected with trio WES but also after data sharing via Genematcher / DECIPHER.

Identified variants were in all cases missense and de novo, the latter either by trio WES or Sanger sequencing of parents.

Previous work-up or presence of additional variants are not discussed.

At the protein level 10 aa were affected, 6 of which recurrently within the same gene (Arg45, His75, Lys91, Tyr98) as well among several genes for H4 (Pro32, Arg40). Variants lied within two clusters, one corresponding to the α-helix of H4 (reported variants affected Lys31 - Arg45) important for DNA contacts, interactions with H3 and histone chaperones. The other within the core of nucleosome (reported patient variants : His75-Tyr98) with important strucural contact between H3-H4 dimer and histone chaperones.

There were no detectable genotype-phenotype patterns separating individual H4 genes or protein regions. Of note, variability was observed even among 7 individuals with the same dn H4C5 variant (Arg45Cys).

All variants were absent from control databases incl. gnomAD and affected residues conserved through to S. cerevisiae. Substitutions affecting Arg45 and Gly94 and His75 have been studied previously with effect in growth/fitness/chromatin remodeling/DNA damage repair depending on variant (5 studies cited).

Zebrafish embryos at the 1 cell stage were injected with mRNA encoding either wt or identified variants, the latter inducing significant developmental defects with the exception of Pro32Ala (H4C3) and Arg40Cys (H4C5, H4C11).

For Pro32Ala and Arg40Cys however, the strong recurrence in this cohort supports pathogenicity. A dosage dependent effect was observed for 2 variants.

H4 genes appear to be tolerant to both missense and loss-of-function variation (the latter even in homozygous form) suggesting a dominant effect of the variants.

------
[RefSeqs : H4C3/HIST1H4C - NM_0035242.4 | H4C4/HIST1H4D - NM_003539.4 | H4C5/HIST1H4E - NM_003545.3 | H4C6/HIST1H4F - NM_003540.4 | H4C9/HIST1H4I - NM_003495.2 | H4C11/HIST1H4J - NM_021968.4 // Variants at the protein level above are according to the HGVS nomenclature. However as the N-terminal methionine is cleaved, numbering relative to the mature peptide has also been used in publications eg. p.Pro33Ala HGVS corresponding to Pro32Ala]
Sources: Literature
Intellectual disability - microarray and sequencing v3.1520 HIST1H4I Konstantinos Varvagiannis gene: HIST1H4I was added
gene: HIST1H4I was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HIST1H4I was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HIST1H4I were set to 35202563
Phenotypes for gene: HIST1H4I were set to Global developmental delay; Intellectual disability; Microcephaly; Growth abnormality; Abnormality of the face
Penetrance for gene: HIST1H4I were set to unknown
Mode of pathogenicity for gene: HIST1H4I was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: HIST1H4I was set to GREEN
Added comment: Histone H4 is a core component of the nucleosome, the basic repeating unit of eukaryotic chromatin. Each nucleosome consists of ~150 bp of DNA wrapped around a histone octamer. Each histone octamer is composed of 2 copies of each of the histones H2A, H2B, H3, H4. This organization is important for DNA replication, transcription and repair.

There are 14 canonical histone H4 genes in the human genome, which despite being different at the nucleotide level encode an identical protein. These cluster in 3 genomic loci. Their transcription is independently regulated with differing expression during brain development and in human tissues.

Histone H4 forms a dimer with H3 (which however has variant isoforms linked to specific cellular processes).

Pathogenic variants in genes encoding H4 have been reported in several individuals. Irrrespective of the gene for H4 involved, all patients presented with highly overlapping features, DD and ID being universal. Available reports to date concern :
- H4C3/HIST1H4C (9 subjects - PMID: 28920961, 35202563),
- H4C11/HIST1H4J (1 subject - PMID: 31804630, 35202563),
- H4C4/HIST1H4D (1 subject - PMID:35202563),
- H4C5/HIST1H4E (17 subjects - PMID: 35202563),
- H4C6/HIST1H4F (1 subject - PMID: 35202563),
- H4C9/HIST1H4I (3 subjects - PMID: 35202563).

Variants in all cases were missense SNVs, occurring (in almost all cases) as dn variants and affecting the same residue in the same and/or different H4 genes (details for clusters below). Eg. Arg45Cys was a recurrent variant for H4C5 (>=7 subjects), while variants affecting Arg40 have been reported in H4C4, H4C5, H4C9, H4C11 (7 subjects overall).

Zebrafish studies for all genes reported have included most - if not all - patient variants and recapitulate features observed in affected individuals (head size/structure and growth).

Additional studies specificaly for H4C3/HIST1H4C have been performed in patient fibroblasts (demonstrating among others transcriptional dysregulation) and zebrafish (accumulation of DSBs, increased apoptosis in head/tail, abn. cell cycle progression).

Note that the nomenclature for variants - at the protein level - used in literature commonly takes into consideration cleavage of Met1, thus the numbering may not correspond to the HGVS one.

Relevant entries exist in OMIM, G2P and SysID only for H4C3/HIST1H4C (Tessadori-van Haaften neurodevelopmental syndrome 1, #619758) and H4C11/HIST1H4J (?Tessadori-van Haaften neurodevelopmental syndrome 2, #619759) but not for other genes.

Rating in PanelApp Australia - ID Panel : HIST1H4C Green, H4J Amber, H4D Amber, H4E Green, H4F Amber, H4I Green.

Please consider inclusion in other possibly relevant panels (microcephaly, short stature/FTT, etc).

------
Initial work from Tessadori et al (incl. DDD study, 2017 - PMID:28920961) identified monoallelic missense SNVs affecting the same residue of H4C3 (HIST1H4C), in 3 individuals from 2 families. [c.274A>C/ HGVS p.(Lys92Gln) dn in 1 subject and c.275A>C/ HGVS p.(Lys92Arg) inherited from unaffected mosaic parent].

Individuals from both families having relevant age had intellectual disability (2/2 - 2 families). Other features incl. growth delay (3/3) and microcephaly (3/3).

Expression of the variants in zebrafish severely affected structural development recapitulating the patient phenotypes (microcephaly and short stature).

RNA sequencing in fibroblasts from 2 unrelated patients and a control, revealed that expression of H4C3 variants was similar to wt. The authors estimated that ~8% of H4 cDNA molecules contained the variant. LC-MS/MS analysis suggested that the mutant protein was present in nucleosomes at a level of 1-2% while RNA-seq identified 115 differential expressed genes, with enrichment for relevant procedures (chr. organization, histone binding, DNA packaging, nucleosomal organization, cell cycle).

Post-translational modifications of Lys92 (H4K91) are highly conserved and have been previously associated with processes from chromatin assembly , DNA damage sensitivity, etc. Post-translational marks on Lys92 (K91) were absent in patient derived cells as a result of each variant.

Zebrafish models for both variants were suggestive for accumulation of double strand breaks (DSBs) more visible in heads and tails of larvae. Embryos expressing mutants displayed increased apoptosis in head and tail. Additional studies in larvae were suggestive of abnormal cell cycle progression (rel. increase in cellls in S/G2/M phase, increased occurrence of activated CHK2 with p53 stabilization) applying to both variants studied.

------
In a subsequent publication, Tessadori et al. (2020 - PMID: 31804630) described the phenotype of a 14 y.o. boy harboring a dn heterozygous missense H4C11 (HIST1H4J) variant following trio-ES [c.274A>G / HGVS p.(Lys92Glu)]. Features incl. profound ID, microcephaly, short stature with some dysmorphic features (uplsanting p-f, hypertelorism, etc). Previous work-up was normal/non-diagnostic and incl. FMR1, MECP2 and a CMA showing an inherited 207 kb CNV involving KCNV1. Upon mRNA microinjection in zebrafish embryos - either for wt or for Lys92Glu HIST1H4J - effect for wt was very mild. Lys92Glu expression led to defective development of head structures (brain, eyes), faulty body axis growth and dysmorphic tail reproducing the microcephaly and short stature phenotype. This was similar to previous zebrafish studies for HIS1H4C variants (above).

------
Tessadori et al. (2022 - PMID: 35202563) describe 29 *additional individuals with de novo missense variants in genes encoding H4, namely:
- H4C3 (HIST1H4C/N=6 subjects),
- H4C11 (HIST1H4J/N=1),
- H4C4 (HIST1H4D/N=1),
- H4C5 (HIST1H4E/N=17),
- H4C6 (HIST1H4F/N=1),
- H4C9 (HIST1H4I/N=3).

All individuals, exhibited DD and ID (29/29). Other features incl. hypotonia (10/29), seizures (5/29), autism (5/29), ataxia (4/29). Abnormal growth incl. progressive microcephaly (2/19 prenatal, 20/29 postnatal onset), short stature/FTT (each 11/29). Few had skeletal features (craniosynostosis 2/29, abn. digits 4/29, vertebral 4/29). Some had visual (17/28) or hearing impairment (7/29). Facial features incl. hypertelorism (5/29), upslanting p-f (3/29), broad nasal tip (11/29), thin upper lip (4/29) and teeth anomalies (6/29 - notably gap between central incisors).

The authors state that the cohort was collected with trio WES but also after data sharing via Genematcher / DECIPHER.

Identified variants were in all cases missense and de novo, the latter either by trio WES or Sanger sequencing of parents.

Previous work-up or presence of additional variants are not discussed.

At the protein level 10 aa were affected, 6 of which recurrently within the same gene (Arg45, His75, Lys91, Tyr98) as well among several genes for H4 (Pro32, Arg40). Variants lied within two clusters, one corresponding to the α-helix of H4 (reported variants affected Lys31 - Arg45) important for DNA contacts, interactions with H3 and histone chaperones. The other within the core of nucleosome (reported patient variants : His75-Tyr98) with important strucural contact between H3-H4 dimer and histone chaperones.

There were no detectable genotype-phenotype patterns separating individual H4 genes or protein regions. Of note, variability was observed even among 7 individuals with the same dn H4C5 variant (Arg45Cys).

All variants were absent from control databases incl. gnomAD and affected residues conserved through to S. cerevisiae. Substitutions affecting Arg45 and Gly94 and His75 have been studied previously with effect in growth/fitness/chromatin remodeling/DNA damage repair depending on variant (5 studies cited).

Zebrafish embryos at the 1 cell stage were injected with mRNA encoding either wt or identified variants, the latter inducing significant developmental defects with the exception of Pro32Ala (H4C3) and Arg40Cys (H4C5, H4C11).

For Pro32Ala and Arg40Cys however, the strong recurrence in this cohort supports pathogenicity. A dosage dependent effect was observed for 2 variants.

H4 genes appear to be tolerant to both missense and loss-of-function variation (the latter even in homozygous form) suggesting a dominant effect of the variants.

------
[RefSeqs : H4C3/HIST1H4C - NM_0035242.4 | H4C4/HIST1H4D - NM_003539.4 | H4C5/HIST1H4E - NM_003545.3 | H4C6/HIST1H4F - NM_003540.4 | H4C9/HIST1H4I - NM_003495.2 | H4C11/HIST1H4J - NM_021968.4 // Variants at the protein level above are according to the HGVS nomenclature. However as the N-terminal methionine is cleaved, numbering relative to the mature peptide has also been used in publications eg. p.Pro33Ala HGVS corresponding to Pro32Ala]
Sources: Literature
Intellectual disability - microarray and sequencing v3.1519 FAR1 Sarah Leigh reviewed gene: FAR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25439727, 30561787; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1518 CPSF3 Konstantinos Varvagiannis gene: CPSF3 was added
gene: CPSF3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CPSF3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CPSF3 were set to 35121750
Phenotypes for gene: CPSF3 were set to Failure to thrive; Abnormal muscle tone; Global developmental delay; Intellectual disability; Microcephaly; Seizures
Penetrance for gene: CPSF3 were set to Complete
Review for gene: CPSF3 was set to AMBER
Added comment: Arnadottir (2022 - PMID: 35121750) describe the phenotype associated with biallelic CPSF3 pathogenic variants.

Based on WGS of 56,969 Icelanders and imputing the genotype of another 153,054 chip-genotyped Icelanders, the authors identified missense variants with a deficit of homozygous carriers to what would be expected based on AF. (For variants with MAF>0.4%, for which >=3 hmz carriers would be expected by H-W equilibrium, no identified hmz carriers within this cohort/dataset). A total of 114 such missense variants was identified.

5 of these SNVs, among which a CPSF3 one (NM_016207.3:c.1403G>A / p.Gly468Glu), were however observed in a series of 764 individuals investigated with clinical WGS at the National University Hospital.

The CPSF3 variant with a MAF of 0.41% (3 hmz expected but none observed in the population set) was found in homozygosity in 2 closely related individuals, both investigated for FTT, severe DD, ID, microcephaly, seizures but remaining unresolved following WGS with no other candidate variants.

Using genealogical information from the db of deCODE genetics, the authors identified 3 couples from the 153k genotyped Icelanders where both partners were htz carriers for this SNV. These 3 couples had 10 offspring, 4 of whom deceased but with the same phenotypic features as above (hypotonia 4/4, ID 4/4, seizures 3/4, microcephaly 2/4). Paraffin embedded samples of 2 of these children and WG & Sanger sequencing confirmed hmz for Gly468Glu in 2 sibs, without other candidate variants. Samples of the 2 other individuals were N/A.

Through GeneMatcher 2 additional first-cousin patients from Mexico were identified, being hmz for another CPSF3 variant (c.1061T>C/p.Ile354Thr) and having overlapping phenotype of abnormal muscle tone, ID, seizures and microcephaly. There were no other variants in WES analysis.

mRNA studies in WBCs from Gly468Glu htz carriers did not reveal reduced levels and W.Blot of lymphocytes from a hmz individual confirmed expression, overall suggesting that the variant does not affect the protein levels but presumably the function.

CPSF3 encodes cleavage and polyadenylation specificity factor 3, a 684 aa protein, subunit of the cleavage and polyadenylation specificity factor compex. As discussed, cleavage and polyadenylation of the 3' of pre-mRNAs is necessary before transport out of the nucleus with CPSF playing a crucial role in the process of cleavage.

CPSF3 ko mice exhibit embryonic lethality, while in yeast mutations in key residues of the CPSF3 homolog are lethal.

In gnomAD, CPSF3 has a pLI of 0, z-score of 3.61 with no homozygotes for pLoF variants in 141k individuals (or ~57k WGS Icelanders).

The 2 missense variants concerned highly conserved residues (GERP ~5.8). Both are hypothesized to affect the ability of the protein to bind other factors involved in pre-mRNA cleavage.

Overall the authors speculate that not only complete loss of CPSF3 would result in drastic phenotypic effects - as in the murine model - but also variants altering its enzymatic function.

There is currently no CPSF3-related phenotype in OMIM, G2P, SysID, The gene is included with green rating in the ID, epilepsy and microcephaly panels in PanelApp Australia.

Consider inclusion probably with amber rating (Highly consistent phenotype, biological function, evidence from animal models. 2 identified variants, authors state that follow-up functional studies are needed). Also consider inclusion in other possibly relevant panels.
Sources: Literature
Intellectual disability - microarray and sequencing v3.1518 NRCAM Konstantinos Varvagiannis gene: NRCAM was added
gene: NRCAM was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NRCAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NRCAM were set to 35108495
Phenotypes for gene: NRCAM were set to Hypotonia; Hypertonia; Spasticity; Global developmental delay; Intellectual disability; Microcephaly; Behavioral abnormality; Neuropathy; Hearing abnormality; Abnormality of the eye; Abnormality of the skeletal system; Scoliosis; Abnormality of the face
Penetrance for gene: NRCAM were set to Complete
Review for gene: NRCAM was set to GREEN
Added comment: Kurolap et al (2022 - PMID: 35108495) describe the phenotype of 10 individuals (from 8 families) with biallelic variants in NRCAM.

Features included tone abnormalities (hypotonia in 4/10, hypertonia/spasticity in 4/10), DD (8/10 - 7 families) and cognitive impairment (in 7/10 - 6 fam), neuropathy (4/10 - incl. 2 sibs without DD/ID). Other phenotypes incl. FTT (2/8), microcephaly (3/6), variable behavioral issues (3/5), abnormalities from the eyes/vision (6/8 - cataract in 2), abnormal hearing (3/7) or skeletal findings (8/9 - incl. scoliosis in 5). Nonspecific facial features were reported in 5/8.

Previous metabolic, genetic (incl. karyotype or CMA, FMR1, testing for Steinert disease or SMA) or other work-up (e.g. muscle biopsy) is reported for several subjects but was normal/non-diagnostic.

All were investigated by WES/WGS which revealed biallelic NRCAM variants. Sanger sequencing was used for confirmation and segregation analyses, with compatible results in several affected/unaffected sibs tested. There were no alternative explanations for the NDD phenotype with the exception of one subject with a mosaic functionally characterized LP KRAS variant suspected to contribute to his phenotype.

NRCAM encodes neuronal cell adhesion molecule (CAM). CAMs are membrane bound proteins with important role in tissue morphogenesis and maintenance. They mediate interactions between neighboring cells or cells and the extracellular matrix. The L1 subgroup of immunoglobulin CAMS - consisting of L1CAM, neurofascin, NRCAM, CHL1 - is the most abundant in the CNS with several critical functions in CNS development, among others in neural cell differentiation, axonal growth and guidance, myelination, synapse formation. Pathogenic L1CAM (XL) and NFASC variants (AR) are associated with NDD.

Different missense (N=7), stopgain/frameshift (N=3), a splice variant (NM_001037132.2:c.2647-2A>G) as well as a deep intronic one (c.230+824G>C / rs575851831). Variants occurred in different domains with a cluster (42%) in the fibronectin III domain.

Missense SNVs were ultrarare or not present in gnomAD, occurred in conserved residues, with several in silico predictions in favor of a deleterious effect. Structural modelling suggested that all substitutions occurred at residues exposed to solvent and possible abrogated interaction with other proteins.

There were no expression studies performed at the mRNA/protein level. The splice variant is predicted to cause ex22 skipping leading to frameshift. The deep intronic variant is predicted to disrupt a site for spl. regulator SC35 and may cause activation of a cryptic acceptor site with inclusion of a cryptic exon.

The zebrafish nrcama gene is the sole ortholog of human NRCAM, with another gene proposed as possible ortholog (nrcamb) mapping upon BLAST analysis to cntn1a. The authors performed CRISPR-Cas9 mutagenesis in zebrafish introducing a partial deletion of ex18 and 19. Mutant zebrafish were viable, displayed altered axonal projections and abnormal swimming behavior (increased movement in darkness).

Currently, there is no NRCAM-associated phenotype in OMIM/G2P/SysID. PanelApp Australia includes NRCAM in its ID panel with green rating.

Consider inclusion probably with green (>3 individuals/families/variants, segregation, gene in the L1-Ig CAM family causing NDD, zebrafish model) or amber rating (ID not a universal feature, variant effect not studied).
Sources: Literature
Intellectual disability - microarray and sequencing v3.1518 TIAM1 Konstantinos Varvagiannis gene: TIAM1 was added
gene: TIAM1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TIAM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TIAM1 were set to 35240055; 33328293
Phenotypes for gene: TIAM1 were set to Delayed speech and language development; Global developmental delay; Intellectual disability; Seizures; Behavioral abnormality; Abnormality of the endocrine system; Hypothyroidism; Abnormality of nervous system morphology
Penetrance for gene: TIAM1 were set to Complete
Review for gene: TIAM1 was set to AMBER
Added comment: Lu et al (2022 - PMID: 35240055) describe 5 individuals (from 4 families) with biallelic TIAM1 missense variants.

The phenotype overall corresponded to a neurodevelopmental disorder with DD (5/5), ID (4/4 individuals of relevant age - 3 families), speech delay (5/5), seizures (5/5 - onset: 2m-13y) and behavioral abnormalities (2/2, sibs with autism and ADHD). Several subjects had endocrine symptoms, namely hypothyroidism (N=3 - 2 families), Addison's disease (1) or hypomagnesemia (1). Non-consistent abnormalities were reported in (3/3) subjects who had a brain MRI.

Previous investigations were mentioned for 3 individuals (incl. 2 sibs) and included normal CMA and/or metabolic workup.

Singleton or trio exome sequencing (in one family) revealed biallelic missense TIAM1 variants.

6 different missense variants were reported, all ultra-rare or not present in gnomAD (also o/e:0.2, pLI:0.96), with CADD scores in favor of deleterious effect (NM_001353694.2): c.67C>T/p.Arg23Cys*, c.2584C>T/p.Leu862Phe*, c.983G>T/p.Gly328Val*, c.4640C>A/p.Ala1547Glu, c.1144G>C/p.Gly382Arg, c.4016C>T/p.Ala1339Val.

TIAM1 encodes a RAC1-specific guanine exchange factor (GEF), regulating RAC1 signaling pathways that in turn affect cell shape, migration, adhesion, growth, survival, and polarity, and influence actin cytoskeletal organization, endocytosis, and membrane trafficking. RAC1 signaling plays important role in control of neuronal morphogenesis and neurite outgrowth (based on the summary by Entrez and authors).

TIAM1 is highly expressed in human brain (GTEx).

The authors provide evidence that sif, the Drosophila ortholog, is expressed primarily in neurons of the fly CNS (but not in glia). Using different sif LoF mutant flies they demonstrate that loss of sif impairs viability. Surviving flies exhibited climbing defects and seizure-like behaviors, both significantly rescued upon UAS-sif expression. Neuronal specific sif knockdown resulted in similar phenotypes to ubiquitous knockdown, while glial knockdown did not result in climbing defects.

The semi-lethal phenotype could be fully rescued by expression of the fly sif cDNA, but only partially by human TIAM1 cDNA reference. Upon expression, 3 patient-variants (R23C, L862F, G328V) had variable rescue abilities similar to or lower (R23C) than TIAM1 Ref. TIAM1 Ref and variants could not rescue the neurological phenotypes though. Higher/ectopic expression of sif or TIAM1 Ref was toxic, which was also observed to a lesser extent for variants.

Overall, the evidence provided suggests that the 3 variants tested induce partial LoF.

In a recent study cited (PMID: 33328293), Tiam1 KO mice had simplified dendritic arbors, reduced spine density and diminished excitatory transmission in dentate gyrus. The authors comment that this mouse model presented only subtle behavioral abnormalities which they speculate may be secondary to GEF redundancy (eg. Tiam2).

There is no TIAM1-associated phenotype in OMIM/G2P/SysID. TIAM1 is included in PanelApp Australia in the ID and epilepsy panels with green rating.

Consider inclusion in the current panel with amber rating [As authors discuss: some phenotypic features differed in their small cohort and the contribution of other recessive conditions in 2 consanguineous families cannot be excluded. Also: in fig S1 only status of parents but not of affected/unaffected sibs is specified with the exception of Fam1].
Sources: Literature
Intellectual disability - microarray and sequencing v3.1518 THUMPD1 Konstantinos Varvagiannis reviewed gene: THUMPD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30237576, 35196516; Phenotypes: Global developmental delay, Intellectual disability, Microcephaly, Hearing abnormality, Abnormality of the eye, Febrile seizures, Behavioral abnormality, Abnormality of brain morphology, Abnormality of the face; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.1506 PDZD8 Konstantinos Varvagiannis changed review comment from: Al-Amri et al (2022 - PMID: 35227461) describe 4 affected individuals, belonging to 2 independent consanguineous families, harboring biallelic pLoF PDZD8 variants. The phenotype corresponded to a syndromic form of ID with autistic features. Animal models provide additional evidence for a role of the gene.

Details are provided concerning 3 affected sibs born to consanguineous parents (Fam-A) and a male proband born to first cousin parents (Fam-B) from different countries of the Arabian Peninsula.

Features included DD (4/4), ID (4/4 - moderate to severe), autistic features[*](4/4), other behavioral problems (3/4 - 2 families). Variable facial features were observed (4/4 - incl. hypertelorism 4/4, myopathic face, open mouth, low-set ears, ptosis). 3 sibs presented with myopathy[*](3/4 overall - 1 fam - see below), and marfanoid habitus was observed in 2 (2/4 - 1 fam). 2 sibs had epilepsy (2/4 - from 1 family). 1 individual had congenital heart defect. [* -also to consider for MOI]Autistic features were however observed in a parent and a htz sib. Mild myopathy/reduced facial expression was also observed in both parents. Contribution of another variant - also within the region of shared homozygosity - to the phenotype of myopathy was deemed to be possible within this family.

Previous genetic testing was not reported.

Homozygosity mapping in the 1st family identified 3 homozygous regions (2.57 - 28 Mb) shared by all affected sibs. Singleton WES revealed 2 candidate variants within these regions, a PDZD8 frameshift variant [NM_173791.5:c.2197_2200del;p.(S733*)] lying in the last exon and an ANKRD2 missense one (discussed above).

The proband in Fam-B was hmz for a nonsense variant in ex2 (of 5), namely c.894C>G/p.(Y298*) considered to be the most likely cause of his phenotype following singleton WES.

Sanger sequencing was used for validation and segregation studies confirming carrier status of the parents and compatible results in unaffected sibs (tested : 2 in Fam-A, 3 in Fam-B).

Both variants were absent from gnomAD (the first also from a pool of 50 control individuals of the same origin) where PDZD8 has a pLI of 1 (5 different pLoF variants, none hmz).

Expression was not studied for the 2 variants. As a result, it is not known whether they escape NMD (as could be expected for the variant in the last exon).

PDZD8 encodes an endoplasmatic reticulum (ER) transmembrane protein (TM). As the authors discuss, it has been previously shown that depletion of PDZD8 in neurons impairs endosomal homeostasis, decreases proximity of ER-mitochondria and decreases Ca+2 uptake mitochondria following synaptic transmission-induced release from the ER (sev. refs. provided).

The gene is highly expressed in the human brain (incl. subclasses of GABAergic / glutamatergic neurons in adult primary motor cortex). The authors analyzed RNA-seq data from the BrainSpan project, demonstrating stable expression in human brain from 8 wks after conception to adulthood. The gene is not expressed in blood.

The authors performed in vivo functional studies. Knockdown of the orthologous gene (CG10362) in Drosophila via RNA interference was shown to result in impairment of long-term memory. Mice homozygous for a variant introducing a premature termination codon exhibited restricted growth, brain structural alterations (incl. relative reduction of the CC, as in one subject), spontaneous stereotypies, decreased anxiety-like behavior with deficits in spatial memory and impaired hippocampal neurophysiology.

Currently, there is no associated phenotype in OMIM, Gene2Phenotype, SysID or PanelApp Australia.

Overall, this gene can be considered for inclusion in the ID panel probably with amber rating pending further reports.
Sources: Literature; to: Al-Amri et al (2022 - PMID: 35227461) describe 4 affected individuals, belonging to 2 independent consanguineous families, harboring biallelic pLoF PDZD8 variants. The phenotype corresponded to a syndromic form of ID with autistic features. Animal models provide additional evidence for a role of the gene.

Details are provided concerning 3 affected sibs born to consanguineous parents (Fam-A) and a male proband born to first cousin parents (Fam-B) from different countries of the Arabian Peninsula.

Features included DD (4/4), ID (4/4 - moderate to severe), autistic features[*](4/4), other behavioral problems (3/4 - 2 families). Variable facial features were observed (4/4 - incl. hypertelorism 4/4, myopathic face, open mouth, low-set ears, ptosis). 3 sibs presented with myopathy[*](3/4 overall - 1 fam - see below), and marfanoid habitus was observed in 2 (2/4 - 1 fam). 2 sibs had epilepsy (2/4 - from 1 family). 1 individual had congenital heart defect. [*] (also to consider for MOI) : Autistic features were however observed in a parent and a htz sib. Mild myopathy/reduced facial expression was also observed in both parents. Contribution of another variant - also within the region of shared homozygosity - to the phenotype of myopathy was deemed to be possible within this family.

Previous genetic testing was not reported.

Homozygosity mapping in the 1st family identified 3 homozygous regions (2.57 - 28 Mb) shared by all affected sibs. Singleton WES revealed 2 candidate variants within these regions, a PDZD8 frameshift variant [NM_173791.5:c.2197_2200del;p.(S733*)] lying in the last exon and an ANKRD2 missense one (discussed above).

The proband in Fam-B was hmz for a nonsense variant in ex2 (of 5), namely c.894C>G/p.(Y298*) considered to be the most likely cause of his phenotype following singleton WES.

Sanger sequencing was used for validation and segregation studies confirming carrier status of the parents and compatible results in unaffected sibs (tested : 2 in Fam-A, 3 in Fam-B).

Both variants were absent from gnomAD (the first also from a pool of 50 control individuals of the same origin) where PDZD8 has a pLI of 1 (5 different pLoF variants, none hmz).

Expression was not studied for the 2 variants. As a result, it is not known whether they escape NMD (as could be expected for the variant in the last exon).

PDZD8 encodes an endoplasmatic reticulum (ER) transmembrane protein (TM). As the authors discuss, it has been previously shown that depletion of PDZD8 in neurons impairs endosomal homeostasis, decreases proximity of ER-mitochondria and decreases Ca+2 uptake mitochondria following synaptic transmission-induced release from the ER (sev. refs. provided).

The gene is highly expressed in the human brain (incl. subclasses of GABAergic / glutamatergic neurons in adult primary motor cortex). The authors analyzed RNA-seq data from the BrainSpan project, demonstrating stable expression in human brain from 8 wks after conception to adulthood. The gene is not expressed in blood.

The authors performed in vivo functional studies. Knockdown of the orthologous gene (CG10362) in Drosophila via RNA interference was shown to result in impairment of long-term memory. Mice homozygous for a variant introducing a premature termination codon exhibited restricted growth, brain structural alterations (incl. relative reduction of the CC, as in one subject), spontaneous stereotypies, decreased anxiety-like behavior with deficits in spatial memory and impaired hippocampal neurophysiology.

Currently, there is no associated phenotype in OMIM, Gene2Phenotype, SysID or PanelApp Australia.

Overall, this gene can be considered for inclusion in the ID panel probably with amber rating pending further reports.
Sources: Literature
Intellectual disability - microarray and sequencing v3.1506 PDZD8 Konstantinos Varvagiannis gene: PDZD8 was added
gene: PDZD8 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PDZD8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDZD8 were set to 35227461
Phenotypes for gene: PDZD8 were set to Global developmental delay; Intellectual disability; Autistic behavior; Behavioral abnormality; Myopathy; Abnormality of the face; Hypertelorism; Seizures; Disproportionate tall stature
Penetrance for gene: PDZD8 were set to Complete
Review for gene: PDZD8 was set to AMBER
Added comment: Al-Amri et al (2022 - PMID: 35227461) describe 4 affected individuals, belonging to 2 independent consanguineous families, harboring biallelic pLoF PDZD8 variants. The phenotype corresponded to a syndromic form of ID with autistic features. Animal models provide additional evidence for a role of the gene.

Details are provided concerning 3 affected sibs born to consanguineous parents (Fam-A) and a male proband born to first cousin parents (Fam-B) from different countries of the Arabian Peninsula.

Features included DD (4/4), ID (4/4 - moderate to severe), autistic features[*](4/4), other behavioral problems (3/4 - 2 families). Variable facial features were observed (4/4 - incl. hypertelorism 4/4, myopathic face, open mouth, low-set ears, ptosis). 3 sibs presented with myopathy[*](3/4 overall - 1 fam - see below), and marfanoid habitus was observed in 2 (2/4 - 1 fam). 2 sibs had epilepsy (2/4 - from 1 family). 1 individual had congenital heart defect. [* -also to consider for MOI]Autistic features were however observed in a parent and a htz sib. Mild myopathy/reduced facial expression was also observed in both parents. Contribution of another variant - also within the region of shared homozygosity - to the phenotype of myopathy was deemed to be possible within this family.

Previous genetic testing was not reported.

Homozygosity mapping in the 1st family identified 3 homozygous regions (2.57 - 28 Mb) shared by all affected sibs. Singleton WES revealed 2 candidate variants within these regions, a PDZD8 frameshift variant [NM_173791.5:c.2197_2200del;p.(S733*)] lying in the last exon and an ANKRD2 missense one (discussed above).

The proband in Fam-B was hmz for a nonsense variant in ex2 (of 5), namely c.894C>G/p.(Y298*) considered to be the most likely cause of his phenotype following singleton WES.

Sanger sequencing was used for validation and segregation studies confirming carrier status of the parents and compatible results in unaffected sibs (tested : 2 in Fam-A, 3 in Fam-B).

Both variants were absent from gnomAD (the first also from a pool of 50 control individuals of the same origin) where PDZD8 has a pLI of 1 (5 different pLoF variants, none hmz).

Expression was not studied for the 2 variants. As a result, it is not known whether they escape NMD (as could be expected for the variant in the last exon).

PDZD8 encodes an endoplasmatic reticulum (ER) transmembrane protein (TM). As the authors discuss, it has been previously shown that depletion of PDZD8 in neurons impairs endosomal homeostasis, decreases proximity of ER-mitochondria and decreases Ca+2 uptake mitochondria following synaptic transmission-induced release from the ER (sev. refs. provided).

The gene is highly expressed in the human brain (incl. subclasses of GABAergic / glutamatergic neurons in adult primary motor cortex). The authors analyzed RNA-seq data from the BrainSpan project, demonstrating stable expression in human brain from 8 wks after conception to adulthood. The gene is not expressed in blood.

The authors performed in vivo functional studies. Knockdown of the orthologous gene (CG10362) in Drosophila via RNA interference was shown to result in impairment of long-term memory. Mice homozygous for a variant introducing a premature termination codon exhibited restricted growth, brain structural alterations (incl. relative reduction of the CC, as in one subject), spontaneous stereotypies, decreased anxiety-like behavior with deficits in spatial memory and impaired hippocampal neurophysiology.

Currently, there is no associated phenotype in OMIM, Gene2Phenotype, SysID or PanelApp Australia.

Overall, this gene can be considered for inclusion in the ID panel probably with amber rating pending further reports.
Sources: Literature
Intellectual disability - microarray and sequencing v3.1500 CHKA Konstantinos Varvagiannis gene: CHKA was added
gene: CHKA was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CHKA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHKA were set to 35202461
Phenotypes for gene: CHKA were set to Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormality of movement; Abnormality of nervous system morphology; Short stature
Penetrance for gene: CHKA were set to Complete
Review for gene: CHKA was set to GREEN
Added comment: Klöckner (2022 - PMID: 35202461) describe the phenotype of 6 individuals (from 5 unrelated families) harboring biallelic CHKA variants.

Shared features incl. abnormal muscle tone(6/6 - hypertonia or hypotonia, 3/6 each), DD/ID (6/6,severe in 4, severe/profound in 2), epilepsy (6/6 - onset: infancy - 3y2m | epileptic spasms or GS at onset), microcephaly (6/6), movement disorders (3/6 - incl. dyskinesia, rigidity, choreoatetotic movements). 2/5 individuals exhibited MRI abnormalities, notably hypomyelination. Short stature was observed in 4/6.

Eventual previous genetic testing was not discussed.

Exome sequencing (quattro ES for 2 sibs, trio ES for 1 individual, singleton for 3 probands) revealed biallelic CHKA variants in all affected individuals. Sanger sequencing was performed for confirmation and segregation studies.

Other variants (in suppl.) were not deemed to be causative for the neurodevelopmental phenotype.

3 different missense, 1 start-loss and 1 truncating variant were identified, namely (NM_0012772.2):
- c.421C>T/p.(Arg141Trp) [3 hmz subjects from 2 consanguineous families],
- c.580C>T/p.Pro194Ser [1 hmz individual born to consanguineous parents],
- c.2T>C/p.(Met1?) [1 hmz individual born to related parents],
- c.14dup/p.(Cys6Leufs*19) in trans with c.1021T>C/p.(Phe341Leu) in 1 individual.

CHKA encodes choline kinase alpha, an enzyme catalyzing the first step of phospholipid synthesis in the Kennedy pathway. The pathway is involved in de novo synthesis of glycerophospholipids, phosphatidylcholine and phosphatidylethanolamine being the most abundant in eukaryotic membranes.

CHKA with its paralog (CHKB) phosphorylates either choline or ethanolamine to phosphocholine or phosphoethanolamine respectively with conversion of ATP to ADP.

As the authors comment, biallelic pathogenic variants in CHKB cause a NDD with muscular dystrophy, hypotonia, ID, microcephaly and structural mitochondrial anomalies (MIM 602541). [Prominent mitochondrial patterning was observed in a single muscle biopsy available from an individual with biallelic CHKA variants].

Other disorders of the Kennedy pathway (due to biallelic PCYT2, SELENOI, PCYT1A variants) present with overlapping features incl. variable DD/ID (no-severe), microcephaly, seizures, visual impairment etc.

CHKA variants were either absent or observed once in gnomAD, affected highly conserved AAs with multiple in silico predictions in favor of a deleterious effect.

In silico modeling suggests structural effects for several of the missense variants (Arg141Trp, Pro194Ser presumably affect ADP binding, Phe341 lying close to the binding site of phosphocholine).

Each of the missense variants was expressed in yeast cells and W. Blot suggested expression at the expected molecular weight at comparative levels. The 3 aforementioned variants exhibited reduced catalytic activity (20%, 15%, 50% respectively).

NMD is thought to underly the deleterious effect of the frameshift one (not studied).

The start-loss variant is expected to result in significantly impaired expression and protein function as eventual utilization of the next possible start codon - occurring at position 123 - would remove 26% of the protein.

Chka(-/-) is embryonically lethal in mice, suggesting that complete loss is not compatible with life. Reduction of choline kinase activity by 30% in heterozygous mice did not appear to result in behavioral abnormalities although this was not studied in detail (PMID cited: 18029352). Finally, screening of 1566 mouse lines identified 198 genes whose disruption yields neuroanatomical phenotypes, Chka(+/-) mice being among these (PMID cited: 31371714).

There is no associated phenotype in OMIM, Gene2Phenotype or SysID.

Overall this gene can be considered for inclusion in the ID and epilepsy panes with green or amber rating (>3 individuals, >3 variants, variant studies, overlapping phenotype of disorders belonging to the same pathway, etc). Consider also inclusion in the microcephaly panel (where available this seemed to be of postnatal onset).
Sources: Literature
Intellectual disability - microarray and sequencing v3.1496 PRKAR1B Zornitza Stark reviewed gene: PRKAR1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 33833410; Phenotypes: Marbach-Schaaf neurodevelopmental syndrome MIM#619680; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.1496 CSTF2 Zornitza Stark reviewed gene: CSTF2: Rating: AMBER; Mode of pathogenicity: None; Publications: 32816001; Phenotypes: Intellectual disability; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability - microarray and sequencing v3.1493 XPNPEP3 Sarah Leigh reviewed gene: XPNPEP3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.1490 SPATA5L1 Ivone Leong Phenotypes for gene: SPATA5L1 were changed from Neurodevelopmental disorder with hearing loss and spasticity, MIM# 619616 to Neurodevelopmental disorder with hearing loss and spasticity, OMIM:619616
Intellectual disability - microarray and sequencing v3.1480 KCND2 Eleanor Williams gene: KCND2 was added
gene: KCND2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: KCND2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KCND2 were set to 34245260; 16934482; 24501278
Phenotypes for gene: KCND2 were set to global developmental delay, HP:0001263
Mode of pathogenicity for gene: KCND2 was set to Other
Added comment: 6 new unrelated cases with developmental delay reported in PMID: 34245260 (Zhang et al 2021), 3 of whom had seizures. All had heterozygous missense variants of KCND2 in sites known to be critical for channel gating (E323K, P403A, two individuals, V404L, two individuals and V404M). Functional studies suggest that these missense changes cause both a partial loss-of-function (LOF) and gain-of-function (GOF). The V404 change appears to increase epileptic seizure susceptibility with the 3 patients with a V404 change showing this phenotype.

PMID:16934482 - Singh et al, 2006 - reports a patient with cognitive impairment who also went on to have seizures starting from age 13 with a 5 bp deletion in KCND2 leading to premature stop codon. The proband's asymptomatic father also shared this variant.

Also:
PMID:24501278 - Lee et al, 2014 - reports pair of monozygotic twin boys with infantile onset severe refractory epilepsy and autism. A de novo heterozygous missense variant was identified by WES - V404M.
Sources: Literature
Intellectual disability - microarray and sequencing v3.1478 SPATA5L1 Zornitza Stark gene: SPATA5L1 was added
gene: SPATA5L1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SPATA5L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPATA5L1 were set to 34626583
Phenotypes for gene: SPATA5L1 were set to Neurodevelopmental disorder with hearing loss and spasticity, MIM# 619616
Review for gene: SPATA5L1 was set to GREEN
gene: SPATA5L1 was marked as current diagnostic
Added comment: 47 individuals from 26 unrelated families from various ethnicities with biallelic variants reported. Phenotypes include ID, hearing impairment, movement disorder, abnormal MRI, hypotonia, visual impairment, epilepsy, and microcephaly.

~53% of patients had ID.
Sources: Literature
Intellectual disability - microarray and sequencing v3.1478 FOXR1 Zornitza Stark gene: FOXR1 was added
gene: FOXR1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FOXR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOXR1 were set to 34723967
Phenotypes for gene: FOXR1 were set to Postnatal microcephaly, progressive brain atrophy and global developmental delay
Review for gene: FOXR1 was set to AMBER
Added comment: 1 patient described with a de novo missense variant. Phenotypes include: postnatal microcephaly, progressive brain atrophy, skeletal abnormalities, brain abnormalities, ophthalmic abnormalities, neuromuscular abnormalities, and dysmorphic features. A variant in ATP1A3 was considered to have contributed to the final phenotype.

In vitro functional evidence is supportive of pathogenicity (variant causes protein instability and abnormal nuclear aggregation).

A mouse knockout has comparable phenotypes, and a severe survival deficit.

Rated amber (1 patient, functional evidence, mouse model).
Sources: Literature
Intellectual disability - microarray and sequencing v3.1475 ANK3 Dmitrijs Rots reviewed gene: ANK3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34218362; Phenotypes: Intellectual disability; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1475 HMGB1 Dmitrijs Rots reviewed gene: HMGB1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.1475 PHF6 Ivone Leong reviewed gene: PHF6: Rating: ; Mode of pathogenicity: None; Publications: 24092917, 25099957; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability - microarray and sequencing v3.1468 GPT2 Arina Puzriakova Phenotypes for gene: GPT2 were changed from Microcephaly; Mental retardation, autosomal recessive 49, 138210; Intellectual disability; Progressive spasticity to Neurodevelopmental disorder with microcephaly and spastic paraplegia, OMIM:616281
Intellectual disability - microarray and sequencing v3.1463 HCCS Ivone Leong reviewed gene: HCCS: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability - microarray and sequencing v3.1457 GABRD Arina Puzriakova gene: GABRD was added
gene: GABRD was added to Intellectual disability. Sources: Literature
Q4_21_rating tags were added to gene: GABRD.
Mode of inheritance for gene: GABRD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GABRD were set to 34633442
Phenotypes for gene: GABRD were set to {Epilepsy, idiopathic generalized, 10}, OMIM:613060; {Epilepsy, juvenile myoclonic, susceptibility to}, OMIM:613060
Mode of pathogenicity for gene: GABRD was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: GABRD was set to GREEN
Added comment: Ahring et al., 2021 (PMID: 34633442) reports on at least 3 unrelated individuals with de novo variants and one family with 3 affected individuals harbouring an inherited variant in the GABRD gene. All variants exerted a gain-of-function effect and all carriers displayed a homogenous phenotype of generalised epilepsy (median age of onset 10.5 months, medically refractory in 5/6) and various degrees of learning difficulties or ID (learning difficulties in 1, mild ID in 2, mild to moderate ID in 1, and severe to profound ID in 2).

NB. A further three individuals were excluded from phenotypic analysis as their variants (p.M87L and p.V442I) did not show any detectable functional changes. There was also another patient with a loss-of-function variant but they displayed ASD, normal intelligence and no seizure history.
Sources: Literature
Intellectual disability - microarray and sequencing v3.1448 PPP2R2B Arina Puzriakova Mode of pathogenicity for gene: PPP2R2B was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability - microarray and sequencing v3.1443 TBP Arina Puzriakova Mode of pathogenicity for gene: TBP was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability - microarray and sequencing v3.1425 C9orf72 Arina Puzriakova Mode of pathogenicity for gene: C9orf72 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability - microarray and sequencing v3.1418 ATXN3 Arina Puzriakova Mode of pathogenicity for gene: ATXN3 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability - microarray and sequencing v3.1414 ATXN2 Arina Puzriakova Mode of pathogenicity for gene: ATXN2 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability - microarray and sequencing v3.1406 KIDINS220 Dmitrijs Rots reviewed gene: KIDINS220: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 33763417; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.1396 RAP1GDS1 Dmitrijs Rots reviewed gene: RAP1GDS1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33875846; Phenotypes: Intellectual disability, developmental delay; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1396 RAB11A Dmitrijs Rots reviewed gene: RAB11A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33875846, 26902202; Phenotypes: microcephaly, brain anomalies, intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.1381 CLPB Dmitrijs Rots reviewed gene: CLPB: Rating: ; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: PMID: 34140661; Phenotypes: Neutropenia, intellectual disability; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1371 ZC4H2 Ivone Leong reviewed gene: ZC4H2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability - microarray and sequencing v3.1367 FAAH2 Dmitrijs Rots reviewed gene: FAAH2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34645488; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability - microarray and sequencing v3.1359 RAD51 Arina Puzriakova reviewed gene: RAD51: Rating: AMBER; Mode of pathogenicity: None; Publications: 26681308, 26253028, 30907510; Phenotypes: Fanconi anemia, complementation group R, OMIM:617244; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.1353 ATP11A Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is currently only 1 case and a mouse model which showed neurological deficit phenotypes (including tremors, abnormal gait, hind limb clasping and reduction in brain size. The patient was a 26 yo male born to healthy non-consanguineous Japanese parents. At birth his length was -3.3. SD and OFC was -1.3 SD. Developed epilepsy at 2 weeks followed by global developmental delay and mild hypothyroidism and cataracts.He suffered gradual lost of developmental milestones. At 18 yo, height was -4.6 SD and OFC was -4.0 SD.

As there is currently not enough evidence to support a gene-disease association, this gene has been given an Amber rating.
Intellectual disability - microarray and sequencing v3.1341 GRIK2 Ivone Leong reviewed gene: GRIK2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1338 SHANK1 Zornitza Stark reviewed gene: SHANK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34113010, 22503632, 25188300; Phenotypes: Neurodevelopmental disorder; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.1335 ZDHHC15 Zornitza Stark reviewed gene: ZDHHC15: Rating: RED; Mode of pathogenicity: None; Publications: 34345675; Phenotypes: Mental retardation, X-linked 91, 300577, cerebral palsy, intellectual disability, autism spectrum disorder, epilepsy; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability - microarray and sequencing v3.1334 ABHD16A Zornitza Stark gene: ABHD16A was added
gene: ABHD16A was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ABHD16A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABHD16A were set to 34587489
Phenotypes for gene: ABHD16A were set to Spastic paraplegia; Intellectual disability
Review for gene: ABHD16A was set to GREEN
gene: ABHD16A was marked as current diagnostic
Added comment: 11 individuals from 6 families with a complicated form of hereditary spastic paraplegia who carry bi-allelic deleterious variants in ABHD16A. Affected individuals present with a similar phenotype consisting of global developmental delay/intellectual disability, progressive spasticity affecting the upper and lower limbs, and corpus callosum and white matter anomalies. Immunoblot analysis on extracts from fibroblasts from four affected individuals demonstrated little to no ABHD16A protein levels compared to controls.
In 5 of the families the affected members were homozygous, 3 of these families were consanguineous. 2 families have the same variant- both families are French-Canadian.
4 missense variants, 1 frameshift, 1 nonsense.
Sources: Literature
Intellectual disability - microarray and sequencing v3.1332 KIF4A Zornitza Stark reviewed gene: KIF4A: Rating: GREEN; Mode of pathogenicity: None; Publications: 24812067, 34346154; Phenotypes: Mental retardation, X-linked 100, MIM# 300923; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability - microarray and sequencing v3.1332 TAF2 Zornitza Stark reviewed gene: TAF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34474177, 21937992, 22633631, 26350204; Phenotypes: Mental retardation, autosomal recessive 40, OMIM # 615599; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1327 TCF7L2 Ivone Leong Phenotypes for gene: TCF7L2 were changed from Developmental disorders to Developmental disorders; Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Myopia; Abnormality of skeletal system
Intellectual disability - microarray and sequencing v3.1321 ARF3 Ivone Leong Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID:34346499, individual 1 also has severe microcephaly (-3.3SD), spasticity, cerebellum atrophy and brainstem atrophy. Individual 2 does not have microcephaly, but has cerebellar hypoplasia.

Based on the available evidence, there is currently not enough evidence to support a gene-disease association, therefore this gene has been given an Amber rating.
Intellectual disability - microarray and sequencing v3.1317 GTF2E2 Arina Puzriakova reviewed gene: GTF2E2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26996949, 28973399; Phenotypes: Trichothiodystrophy 6, nonphotosensitive, OMIM:616943; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1313 MED12 Eleanor Williams reviewed gene: MED12: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability - microarray and sequencing v3.1313 CDH15 Zornitza Stark reviewed gene: CDH15: Rating: RED; Mode of pathogenicity: None; Publications: 19012874, 12052883, 28422132, 26506440; Phenotypes: Mental retardation, autosomal dominant 3, MIM#612580; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.1311 EIF2AK2 Arina Puzriakova edited their review of gene: EIF2AK2: Added comment: A further 5 families reported (PMID: 33236446) harbouring 3 different variants in this gene (including the first homozygous case). Clinical presentation was prominent in all cases for dystonia with onset in infancy or childhood, with subsequent generalisation. 3 unrelated individuals additionally developed mild ID, spasticity, and brain MRI alterations; while 6 individuals from the remaining 2 families had only isolated dystonia.; Changed publications to: 32197074, 33236446
Intellectual disability - microarray and sequencing v3.1306 KIRREL3 Aleš Maver reviewed gene: KIRREL3: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 33853164; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.1301 TNPO2 Arina Puzriakova reviewed gene: TNPO2: Rating: ; Mode of pathogenicity: None; Publications: 34314705; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.1299 IMPDH2 Arina Puzriakova reviewed gene: IMPDH2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33098801; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.1299 CLCN3 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to promote this gene to Green at the next GMS panel update. Sufficient number of unrelated cases with relevant phenotype to add to the ID and epilepsy panels. Functional studies and animal model support pathogenicity. CLCN3 is also associated with a relevant phenotype in OMIM (MIM# 619512 and 619517)
Intellectual disability - microarray and sequencing v3.1292 AP1G1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Usmani et al., 2021 (PMID: 34102099) identified 9 families with heterozygous and 2 families with homozygous variants in this gene. All individuals (12) had GDD and ID of various severity (mild to severe), except one patient who died at 22 days. Other features include hypotonia (9/10), seizures (6/10) and spasticity (4/10). Some supportive functional data included.

There is sufficient evidence to promote this gene to Green at the next GMS panel update, with 'monoallelic' MOI. Biallelic cases would still be picked up by the Genomics England pipeline - but this may be reviewed if additional cases are discovered.
Intellectual disability - microarray and sequencing v3.1288 CAMK4 Arina Puzriakova Mode of pathogenicity for gene: CAMK4 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability - microarray and sequencing v3.1283 HIST1H4C Ivone Leong reviewed gene: HIST1H4C: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.1282 CPE Dmitrijs Rots reviewed gene: CPE: Rating: GREEN; Mode of pathogenicity: None; Publications: 34383079; Phenotypes: Obesity, intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1282 RFX3 Arina Puzriakova Phenotypes for gene: RFX3 were changed from ID, ASD, ADHD to Intellectual disability, MONDO:0001071; Autism spectrum disorder, MONDO:0005258; Attention deficit-hyperactivity disorder, MONDO:0007743
Intellectual disability - microarray and sequencing v3.1282 RFX7 Arina Puzriakova Phenotypes for gene: RFX7 were changed from Intellectual disability, MONDO:0001071, autism spectrum disorder, MONDO:0005258, attention deficit-hyperactivity disorder, MONDO:0007743 to Intellectual disability, MONDO:0001071; Autism spectrum disorder, MONDO:0005258; Attention deficit-hyperactivity disorder, MONDO:0007743
Intellectual disability - microarray and sequencing v3.1277 EIF2AK2 Dmitrijs Rots reviewed gene: EIF2AK2: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.1272 HID1 Arina Puzriakova reviewed gene: HID1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33999436; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1272 GNB1 Sarah Leigh Added comment: Comment on mode of pathogenicity: Gen2Phen entry for GNB1 (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=2121) lists the mutation consequence summary as Activating
Intellectual disability - microarray and sequencing v3.1272 GNB1 Sarah Leigh Mode of pathogenicity for gene: GNB1 was changed from to None
Intellectual disability - microarray and sequencing v3.1266 PGRMC1 Ivone Leong reviewed gene: PGRMC1: Rating: ; Mode of pathogenicity: None; Publications: 33867527; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.1262 PARP6 Arina Puzriakova reviewed gene: PARP6: Rating: ; Mode of pathogenicity: None; Publications: 34067418; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.1262 PRICKLE2 Zornitza Stark reviewed gene: PRICKLE2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34092786; Phenotypes: Neurodevelopmental disorder, global developmental delay, behavioural difficulties ± epilepsy, autistic features, attention deficit hyperactive disorder, psychiatric symptoms; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.1262 CACNA1I Zornitza Stark gene: CACNA1I was added
gene: CACNA1I was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CACNA1I was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CACNA1I were set to 33704440
Phenotypes for gene: CACNA1I were set to Neurodevelopmental disorder
Mode of pathogenicity for gene: CACNA1I was set to Other
Review for gene: CACNA1I was set to GREEN
gene: CACNA1I was marked as current diagnostic
Added comment: 4 different missense variants identified and shown to result in a gain of function.

2 individuals with de novo variants (a 3rd also suspected de novo but their father was unavailable for testing) - these patients all had severe neurodevelopmental disorders, involving severe global developmental delay, absence of speech, gross motor delay, muscular hypotonia, early-onset seizures, cortical visual impairment, and feeding difficulties. Variable clinical features include various brain malformations, startle response or seizures, postnatal growth retardation, gastroesophageal reflux, and gastrostomy.

1 family had three affected individuals - variable cognitive impairment in all, involving borderline intellectual functioning or mild or moderate intellectual disability as main clinical feature, with late-onset seizures in the mother and speech retardation in one of the children. This variant had a milder functional effect than the variants in sporadic cases.
Sources: Literature
Intellectual disability - microarray and sequencing v3.1262 GRIK2 Zornitza Stark reviewed gene: GRIK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34375587, 17847003, 25039795; Phenotypes: Mental retardation, autosomal recessive, 6 MIM# 611092, Non-syndromic neurodevelopmental disorder (NDD), autosomal dominant; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1262 JAKMIP1 Zornitza Stark gene: JAKMIP1 was added
gene: JAKMIP1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: JAKMIP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: JAKMIP1 were set to 29158550; 26627310; 27799067
Phenotypes for gene: JAKMIP1 were set to Intellectual disability; seizures
Review for gene: JAKMIP1 was set to AMBER
Added comment: Identified in two independent patients in the literature with a mouse model. Patient 1 (27799067) with developmental delay, speech delay, and cognitive impairment; self-injurious and aggressive behaviour, seizures, dysmorphic features. De-novo missense JAKMIP1 (p.D586H). Patient 2 (29158550) with feeding difficulties, hypotonia, epilepsy, severe ID, no active speech, kyphoscoliosis, constipation, autism, short stature. Splice variant c.1432-2A>G, no segregation or RNA data available. KO mouse model (27799067) displays social deficits, stereotyped activity, abnormal postnatal vocalizations, and other autistic-like behaviors.
Sources: Literature
Intellectual disability - microarray and sequencing v3.1246 SLC25A15 Arina Puzriakova Phenotypes for gene: SLC25A15 were changed from Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome, 238970 -3; HYPERORNITHINEMIA-HYPERAMMONEMIA-HOMOCITRULLINURIA SYNDROME (HHH SYNDROME) to Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome, OMIM:238970
Intellectual disability - microarray and sequencing v3.1238 WDR11 Konstantinos Varvagiannis reviewed gene: WDR11: Rating: AMBER; Mode of pathogenicity: None; Publications: 34413497; Phenotypes: Intellectual disability, Microcephaly, Short stature; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1227 HNMT Ivone Leong reviewed gene: HNMT: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.1223 ENTPD1 Arina Puzriakova reviewed gene: ENTPD1: Rating: AMBER; Mode of pathogenicity: None; Publications: 24482476, 29691679, 30652007; Phenotypes: Spastic paraplegia 64, autosomal recessive, OMIM:615683; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1220 ARF3 Konstantinos Varvagiannis gene: ARF3 was added
gene: ARF3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ARF3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ARF3 were set to 34346499
Phenotypes for gene: ARF3 were set to Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system
Penetrance for gene: ARF3 were set to unknown
Review for gene: ARF3 was set to AMBER
Added comment: Sakamoto et al (2021 - PMID: 34346499) provide some evidence that monoallelic ARF3 pathogenic variants may be associated with a NDD with brain abnormality.

Using trio exome sequencing, the authors identified 2 individuals with NDD harboring de novo ARF3 variants, namely: NM_001659.2:c.200A>T / p.Asp67Val and c.296G>T / p.Arg99Leu.

Individual 1 (with Asp67Val / age : 4y10m), appeared to be more severelely affected with prenatal onset progressive microcephaly, severe global DD, epilepsy. Upon MRI there was cerebellar and brainstem atrophy. Individual 2 (Arg99Leu / 14y) had severe DD and ID (IQ of 23), epilepsy and upon MRI cerebellar hypoplasia. This subject did not exhibit microcephaly. Common facial features incl. broad nose, full cheeks, small philtrum, strabismus, thin upper lips and abnormal jaw. There was no evidence of systemic involvement in both.

ARF3 encodes ADP-ribosylation factor 3. Adenosine diphosphate ribosylation factors (ARFs) are key proteins for regulation of cargo sorting at the Golgi network, with ARF3 mainly working at the trans-Golgi network. ARFs belong to the small GTP-binding protein (G protein) superfamily. ARF3 switches between an active GTP-bound form and an inactive GDP-bound form, regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) respectively.

Members of the ARF superfamily regulate various aspects of membrane traffic, among others in neurons.

There are 5 homologs of ARF families, divided in 3 classes. ARF3 and ARF1 belong to class I. Monoallelic ARF1 mutations are associated with Periventricular nodular heterotopia 8 (MIM 618185).

In vivo, in vitro and in silico studies for the 2 variants suggest that both impair the Golgi transport system although each variant most likely exerts a different effect (gain-of-function for Arg99Leu vs loss-of-function/dominant-negative for Asp67Val).

This was also reflected in somewhat different phenotype of the subjects with the respective variants. Common features included severe DD, epilepsy and brain abnormalities although Asp67Val was associated with diffuse brain atrophy as well as congenital microcephaly and Arg99Leu with cerebellar hypoplasia.

Evidence to support the effect of each variant include:

Arg99Leu:
Had identical Golgi localization to that of wt
Had increased binding activity with GGA1, a protein recruited by the GTP-bound active form of ARF3 to the TGN membrane (supporting GoF)
In silico structural analysis suggested it may fail to stabilize the conformation of Asp26, resulting in impaired GTP hydrolysis (GoF).
In transgenic fruit flies, evaluation of the ARF3 variant toxicity using the rough eye phenotype this variant was associated with increased severity of the r-e phenotype similar to a previously studied GoF variant (Gln71Leu)

Asp67Val:
Did not show a Golgi-like pattern of localization (similar to Thr31Asn a previously studied dominant-negative variant)
Displayed decreased protein stability
In silico structural analysis suggested that Asp67Val may lead to compromised binding of GTP or GDP (suggestive of LoF)
In transgenic Drosophila eye-specific expression of Asp67Val (similar to Thr31Asn, a known dominant-negative variant) was lethal possibly due to high toxicity in very small amounts in tissues outside the eye.

There is no associated phenotype in OMIM, G2P or SysID.
Sources: Literature
Intellectual disability - microarray and sequencing v3.1220 HNMT Sarah Graham reviewed gene: HNMT: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 26206890, 33310825, 33739554; Phenotypes: Intellectual disability, 616739; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1217 TCF7L2 Konstantinos Varvagiannis reviewed gene: TCF7L2: Rating: AMBER; Mode of pathogenicity: None; Publications: 34003604; Phenotypes: Global developmental delay, Intellectual disability, Autism, Attention deficit hyperactivity disorder, Myopia, Abnormality of skeletal system; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.1217 RFX7 Ivone Leong Phenotypes for gene: RFX7 were changed from ID, ASD, ADHD to Intellectual disability, MONDO:0001071, autism spectrum disorder, MONDO:0005258, attention deficit-hyperactivity disorder, MONDO:0007743
Intellectual disability - microarray and sequencing v3.1216 CLCN3 Zornitza Stark gene: CLCN3 was added
gene: CLCN3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CLCN3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CLCN3 were set to 34186028
Phenotypes for gene: CLCN3 were set to Neurodevelopmental disorder
Mode of pathogenicity for gene: CLCN3 was set to Other
Review for gene: CLCN3 was set to GREEN
gene: CLCN3 was marked as current diagnostic
Added comment: 11 individuals reported, 9 that carried 8 different rare heterozygous missense variants in CLCN3, and 2 siblings that were homozygous for an NMD-predicted frameshift variant likely abolishing ClC-3 function. All missense variants were confirmed to be de novo in eight individuals for whom parental data was available.

The 11 individuals in the cohort share clinical features of variable severity. All 11 have GDD or ID and dysmorphic features, and a majority has mood or behavioural disorders and structural brain abnormalities:
- Structural brain abnormalities on MRI (9/11) included partial or full agenesis of the corpus callosum (6/9), disorganized cerebellar folia (4/9), delayed myelination (3/9), decreased white matter volume (3/9), pons hypoplasia (3/9), and dysmorphic dentate nuclei (3/9). Six of those with brain abnormalities also presented with seizures.
- Nine have abnormal vision, including strabismus in four and inability to fix or follow in the two with homozygous loss-of-function variants.
- Hypotonia ranging from mild to severe was reported in 7 of the 11 individuals.
- Six have mood or behavioural disorders, particularly anxiety (3/6).
- Consistent dysmorphic facial features included microcephaly, prominent forehead, hypertelorism, down-slanting palpebral fissures, full cheeks, and micrognathia.

The severity of disease in the two siblings with homozygous disruption of ClC-3 is consistent with the drastic phenotype seen in Clcn3 KO mice. The disease was more severe in two siblings carrying homozygous loss-of-function variants with the presence of GDD, absent speech, seizures, and salt and pepper fundal pigmentation in both individuals, with one deceased at 14 months of age. The siblings also had significant neuroanatomical findings including diffusely decreased white matter volume, thin corpora callosa, small hippocampi, and disorganized cerebellar folia. Supporting biallelic inheritance for LoF variants, disruption of mouse Clcn3 results in drastic neurodegeneration with loss of the hippocampus a few months after birth and early retinal degeneration. Clcn3−/− mice display severe neurodegeneration, whereas heterozygous Clcn3+/− mice appear normal.

Patch-clamp studies were used to investigate four of the missense variants. These suggested a gain of function in two variants with increased current in HEK cells, however they also showed reduced rectification of voltage and a loss of transient current, plus decreased current amplitude, glycosylation and surface expression when expressed in oocytes, and were suspected to interfere with channel gating and a negative feedback mechanism. These effects were also shown to vary depending on pH levels. The current of the remaining two variants did not differ from WT. For heterozygous missense variants, the disruption induced may be at least partially conferred to mutant/WT homodimers and mutant/ClC-4 heterodimers.

Both loss and gain of function in this gene resulted in the same phenotype.

Green for mono-allelic variants, Amber/Red for bi-allelic.
Sources: Literature
Intellectual disability - microarray and sequencing v3.1216 TNPO2 Zornitza Stark reviewed gene: TNPO2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34314705; Phenotypes: Intellectual disability, dysmorphic features; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.1214 COG5 Ivone Leong reviewed gene: COG5: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1207 BSCL2 Arina Puzriakova Added comment: Comment on mode of inheritance: Monoallelic variants lead to a motor neuropathy (MIM# 619112) or spastic paraplegia (MIM# 270685) presentation, both characterised by motor symptoms, but neither are associated with any cognitive deficits. On the other hand, biallelic variants cause encephalopathy (MIM# 615924) or generalised lipodystrophy (MIM# 269700) which do include cognitive decline and intellectual impairment, respectively.

Therefore, the MOI should be changed from 'Both mono- and biallelic' to 'Biallelic' only at the next GMS panel review.
Intellectual disability - microarray and sequencing v3.1201 SYNCRIP Konstantinos Varvagiannis reviewed gene: SYNCRIP: Rating: AMBER; Mode of pathogenicity: None; Publications: 34157790, 30504930, 27479843, 23020937; Phenotypes: Global developmental delay, Intellectual disability, Autism, Myoclonic atonic seizures, Abnormality of nervous system morphology; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.1201 CAMK4 Konstantinos Varvagiannis gene: CAMK4 was added
gene: CAMK4 was added to Intellectual disability. Sources: Literature,Other
Mode of inheritance for gene: CAMK4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CAMK4 were set to 30262571; 33098801; 33211350
Phenotypes for gene: CAMK4 were set to Global developmental delay; Intellectual disability; Autism; Behavioral abnormality; Abnormality of movement; Dystonia; Ataxia; Chorea; Myoclonus
Penetrance for gene: CAMK4 were set to Complete
Review for gene: CAMK4 was set to GREEN
Added comment: 3 publications by Zech et al (2018, 2020 - PMIDs : 30262571, 33098801, 33211350) provide clinical details on 3 individuals, each harboring a private de novo CAMK4 variant.

Overlapping features included DD, ID, behavoral issues, autism and abnormal hyperkinetic movements. Dystonia and chorea in all 3 appeared 3-20 years after initial symptoms.

CAMK4 encodes Calcium/Calmodulin-dependent protein kinase IV, an important mediator of calcium-mediated activity and dynamics, particularly in the brain. It is involved in neuronal transmission, synaptic plasticity, and neuronal gene expression required for brain development and neuronal homeostasis (summary by OMIM based on Zech et al, 2018).

The 473 aa enzyme has a protein kinase domain (aa 46-300) and a C-terminal autoregulatory domain (aa 305-341) the latter comprising an autoinhibitory domain (AID / aa 305-321) and a calmodulin-binding domain (CBD / aa 322-341) [NP_001735.1 / NM_001744.4 - also used below].

Variants in all 3 subjects were identified following trio-WES and were in all cases protein-truncating, mapping to exon 10 or exon 10-intron 10 junction, expected to escape NMD and cause selective abrogation of the autoinhibitory domain (aa 305-321) leading overall to gain-of-function.

Variation databases include pLoF CAMK4 variants albeit in all cases usptream or downstream of this region (pLI of this gene in gnomAD: 0.51). Variants leading to selective abrogation of the autoregulatory domain have not been reported.

Extensive evidence for the GoF effect of the variant has been provided in the first publication. Several previous studies have demonstrated that abrogation of the AID domain leads to consitutive activation (details below).

Mouse models - though corresponding to homozygous loss of function - support a role for CAMKIV in cognitive and motor symptoms. Null mice display tremulous and ataxic movements, deficiencies in balance and sensorimotor performance associated with reduced number of Purkinje neurons (Ribar et al 2000, PMID: 11069976 - not reviewed). Wei et al (2002, PMID: 12006982 - not reviewed) provided evidence for alteration in hippocampal physiology and memory function.

Heterozygous mutations in other genes for calcium/calmodulin-dependent protein kinases (CAMKs) e.g. CAMK2A/CAMK2B (encoding subunits of CAMKII) have been reported in individuals with ID.

---

The proband in the first publication (PMID: 30262571) was a male with DD, ID, behavioral difficulties (ASD, autoaggression, stereotypies) and hyperkinetic movement disorder (myoclonus, chorea, ataxia) with severe generalized dystonia (onset at the age of 13y). Brain MRI demonstrated cerebellar atrophy.

Extensive work-up incl. karyotyping, CMA, DYT-TOR1A, THAP1, GCH1, SCA1/2/3/6/7/8/12/17, Friedreich's ataxia and FMR1 analysis was negative.F

Trio WES identified a dn splice site variant (c.981+1G>A) in the last exon-intron junction. RT-PCR followed by gel electrophoresis and Sanger in fibroblasts from an affected and control subject revealed that the proband had - as predicted by the type/location of the variant - in equal amount 2 cDNA products, a normal as well as a truncated one.

Sequencing of the shortest revealed utilization of a cryptic donor splice site upstream of the mutated donor leading to a 77bp out-of-frame deletion and introduction of a premature stop codon in the last codon (p.Lys303Serfs*28). Western blot in fibroblast cell lines revealed 2 bands corresponding to the normal protein product as well as to the p.Lys303Serfs*28 although expression of the latter was lower than that of the full length protein.

Several previous studies have shown that mutant CAMKIV species that lack the autoinhibitory domain are consitutively active (several Refs provided). Among others Chatila et al (1996, PMID: 8702940) studied an in vitro-engineered truncation mutant (Δ1-317 - truncation at position 317 of the protein) with functionally validated gain-of-function effect.

To prove enhanced activity of the splicing variant, Zech et al assessed phosphorylation of CREB (cyclic AMP-responsive element binding protein), a downstream substrate of CAMKIV. Immunobloting revealed significant increase of CREB phosphorylation in patient fibroblasts compared to controls. Overactivation of CAMKIV signaling was reversed when cells were treated with STO-609 an inhibitor of CAMKK, the ustream activator of CAMKIV.

Overall the authors demonstrated that loss of CAMKIV autoregulatory domain due to this splice variant had a gain-of-function effect.

----

Following trio-WES, Zech et al (2020 - PMID: 33098801) identified another relevant subject within cohort of 764 individuals with dystonia. This 12-y.o. male, harboring a different variant affecting the same donor site (c.981+1G>T), presented DD, ID, dystonia (onset at 3y) and additional movement disorders (myoclonus, ataxia) as well as similar behavior (ASD, autoaggression, stereotypies). [Details in suppl. p20].

----

Finally Zech et al (2020 - PMID: 33211350) reported on a 24-y.o. woman with adolescence onset choreodystonia. Other features included DD, moderate ID, absence seizures in infancy, OCD with anxiety and later diagnosis of ASD. Trio WES revealed a dn stopgain variant (c.940C>T; p.Gln314*).

----

There is no associated phenotype in OMIM, G2P, PanelApp AUS.

In SysID CAMK4 is listed among the current primary ID genes.

----

Please consider inclusion in other relevant panels.
Sources: Literature, Other
Intellectual disability - microarray and sequencing v3.1179 NAA20 Sarah Leigh changed review comment from: Not associated with a phenotype in OMIM nor Gen2Phen. Two missense variants reported as homozygotes in one family each. In silico predictions and in vitro functional studies provide evidence that these variants will adversely affect their capacity to form a NatB complex with NAA25, and in vitro acetylation assays revealed reduced catalytic activities toward different NatB substrates (PMID 34230638). Children from these two families had developmental delay, intellectual disability (mild to moderate family 1, severe family 2).
The two children in family 1 in this study had a head circumcernces of -2.3 & -1.9 SD (which is not regarded as severe microcephaly).
The three children from family 2 this study had a head circumcernces of -3.5, -3.0 & -3.5 SD (which is regarded as severe microcephaly). Subtle dysmorphic features were also reported.
Sources: Literature; to: Not associated with a phenotype in OMIM nor Gen2Phen. Two missense variants reported as homozygotes in one family each. In silico predictions and in vitro functional studies provide evidence that these variants will adversely affect their capacity to form a NatB complex with NAA25, and in vitro acetylation assays revealed reduced catalytic activities toward different NatB substrates (PMID 34230638). Children from these two families had developmental delay, intellectual disability (mild to moderate family 1, severe family 2).
The two children in family 1 in this study had a head circumcernces of -2.3 & -1.9 SD (which is not regarded as severe microcephaly).
The three children from family 2 in this study had a head circumcernces of -3.5, -3.0 & -3.5 SD (which is regarded as severe microcephaly). Subtle dysmorphic features were also reported.
Sources: Literature
Intellectual disability - microarray and sequencing v3.1177 NAA20 Sarah Leigh gene: NAA20 was added
gene: NAA20 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NAA20 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAA20 were set to 34230638
Phenotypes for gene: NAA20 were set to autosomal recessive developmental delay, intellectual disability, and microcephaly
Review for gene: NAA20 was set to AMBER
Added comment: Not associated with a phenotype in OMIM nor Gen2Phen. Two missense variants reported as homozygotes in one family each. In silico predictions and in vitro functional studies provide evidence that these variants will adversely affect their capacity to form a NatB complex with NAA25, and in vitro acetylation assays revealed reduced catalytic activities toward different NatB substrates (PMID 34230638). Children from these two families had developmental delay, intellectual disability (mild to moderate family 1, severe family 2).
The two children in family 1 in this study had a head circumcernces of -2.3 & -1.9 SD (which is not regarded as severe microcephaly).
The three children from family 2 this study had a head circumcernces of -3.5, -3.0 & -3.5 SD (which is regarded as severe microcephaly). Subtle dysmorphic features were also reported.
Sources: Literature
Intellectual disability - microarray and sequencing v3.1167 ACSL4 Ivone Leong reviewed gene: ACSL4: Rating: ; Mode of pathogenicity: None; Publications: 12525535, 11889465; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.1167 ACSL4 Ivone Leong changed review comment from: ACSL4 is said to be X-linked dominant in OMIM.

PMID: 12525535 - a family with 4 affected males, 1 unaffected male, 2 carrier females and 1 non-carrier female. All affected males full scale IQ (FSIQ) ranged from 43-71, unaffected male FSIQ is 116, carrier females ranged from 74-83 and non-carrier female is 133. All carrier females showed 100% skewed inactivation.

PMID: 11889465 - Family MRX63, all carrier females showed complete skewed X-inactivation. All affected males showed non-specific, non-progressive mental deficiency (moderate - severe). Carrier females showed highly variable cognitive capacities (normal to moderate).

Based on the available evidence the MOI should be changed from "X-LINKED: hemizygous mutation in males, biallelic mutations in females" to "X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)".; to: ACSL4 is said to be X-linked dominant in OMIM.

PMID: 12525535 - a family with 4 affected males, 1 unaffected male, 2 carrier females and 1 non-carrier female. All affected males full scale IQ (FSIQ) ranged from 43-71, unaffected male FSIQ is 116, carrier females ranged from 74-83 and non-carrier female is 133. All carrier females showed 100% skewed inactivation.

PMID: 11889465 - Family MRX63, all carrier females showed complete skewed X-inactivation. All affected males showed non-specific, non-progressive mental deficiency (moderate - severe). Carrier females showed highly variable cognitive capacities (normal to moderate).

As there are only 2 cases where carrier females have a phenotype, the MOI should be kept as "X-LINKED: hemizygous mutation in males, biallelic mutations in females".
Intellectual disability - microarray and sequencing v3.1167 ZC3H14 Zornitza Stark reviewed gene: ZC3H14: Rating: AMBER; Mode of pathogenicity: None; Publications: 21734151, 33710394, 28666327; Phenotypes: Mental retardation, autosomal recessive 56 MIM#617125; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1156 ACSL4 Ivone Leong reviewed gene: ACSL4: Rating: ; Mode of pathogenicity: None; Publications: 12525535, 11889465; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability - microarray and sequencing v3.1149 CUX2 Tracy Lester reviewed gene: CUX2: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.1146 JMJD1C Arina Puzriakova reviewed gene: JMJD1C: Rating: AMBER; Mode of pathogenicity: None; Publications: 26181491, 31954878, 32996679, 28378413, 22495311, 25363768, 17290275, 33591602; Phenotypes: Intellectual disability, Autism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.1145 GEMIN5 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is sufficient evidence to promote this gene to Green at the next GMS panel update (see details below).
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Kour et al. 2021 (PMID: 33963192) report 30 individuals from 22 unrelated families with biallelic variants in the GEMIN5 gene. All affected individuals displayed predominantly motor DD, although cognitive and speech delays were also seen in most patients (18/19). 23/30 had central hypotonia, and variable appendicular spasticity was observed in 13/30 cases. 8 individuals were nonambulatory, while all ambulatory patients (19) had a gait ataxia. Brain MRI in all cases showed cerebellar atrophy.

Variants perturbed the subcellular distribution, stability, and expression of GEMIN5 protein and its interacting partners, and disrupted snRNP complex assembly formation in patient iPSC-derived neurons, suggesting a LoF mechanism. Knockdown in Drosophila lead to developmental defects, motor dysfunction, and a reduced lifespan

GEMIN5 is associated with a relevant phenotype in OMIM (Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction, MIM# 619333) but is not yet listed in G2P.
Intellectual disability - microarray and sequencing v3.1143 BCAS3 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is sufficient evidence to promote this gene to Green at the next GMS panel update (see details below).
-----
Hengel et al. 2021 (PMID: 34022130) report 8 unrelated families, all with different biallelic variants in the BCAS3 gene. All affected individuals (15 total, +1 additional proband but with unphased variants but consistent phenotype) had severe GDD and ID, with 10 subjects having minimal vocabulary and 4 never learning to speak. All probands had a severe motor disorder with pyramidal tract involvement resulting in hyperreflexia and spasticity of the lower limbs (15/15). Other variable features observed in the cohort include microcephaly, short stature, seizures, and dysmorphic facial features.
Intellectual disability - microarray and sequencing v3.1136 RUBCN Arina Puzriakova reviewed gene: RUBCN: Rating: ; Mode of pathogenicity: None; Publications: 32450808; Phenotypes: Spinocerebellar ataxia, autosomal recessive 15, OMIM:615705; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.1132 POLR3B Arina Puzriakova Phenotypes for gene: POLR3B were changed from Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:614381 to Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:614381; POLR3B-related neurodevelopmental disorder; Ataxia, spasticity, and demyelinating neuropathy
Intellectual disability - microarray and sequencing v3.1126 CTC1 Zornitza Stark reviewed gene: CTC1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebroretinal microangiopathy with calcifications and cysts, MIM# 612199; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1123 SRCAP Zornitza Stark reviewed gene: SRCAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 33909990; Phenotypes: Neurodevelopmental disorder, non-Floating Harbor; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.1120 GEMIN5 Zornitza Stark gene: GEMIN5 was added
gene: GEMIN5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: GEMIN5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GEMIN5 were set to 33963192
Phenotypes for gene: GEMIN5 were set to Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction, MIM# 619333
Review for gene: GEMIN5 was set to GREEN
gene: GEMIN5 was marked as current diagnostic
Added comment: Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction (NEDCAM) is an autosomal recessive disorder characterized by global developmental delay with prominent motor abnormalities, mainly axial hypotonia, gait ataxia, and appendicular spasticity. Affected individuals have cognitive impairment and speech delay; brain imaging shows cerebellar atrophy.

30 individuals from 22 unrelated families reported.
Sources: Literature
Intellectual disability - microarray and sequencing v3.1120 MYCN Zornitza Stark reviewed gene: MYCN: Rating: GREEN; Mode of pathogenicity: None; Publications: 21224895, 8470948; Phenotypes: Feingold syndrome 1, Megalencephaly, intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.1120 SMARCA5 Zornitza Stark reviewed gene: SMARCA5: Rating: GREEN; Mode of pathogenicity: None; Publications: 33980485; Phenotypes: Neurodevelopmental disorder, microcephaly, dysmorphic features; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.1110 PDCD6IP Arina Puzriakova changed review comment from: Comment on list classification: Phenotype is relevant to this panel but additional cases required to validate pathogenicity of variants in this gene. Therefore Rating Amber, awaiting further publications.; to: Comment on list classification: Phenotype is relevant to this panel with a supportive animal model that recapitulates features such as microcephaly. However, additional cases required to validate pathogenicity prior to inclusion as diagnostic-grade. Therefore Rating Amber, awaiting further publications.
Intellectual disability - microarray and sequencing v3.1110 PDCD6IP Arina Puzriakova changed review comment from: Comment on list classification: Phenotype is relevant to this panel but additional cases required to validate pathogenicity of variants in this gene.; to: Comment on list classification: Phenotype is relevant to this panel but additional cases required to validate pathogenicity of variants in this gene. Therefore Rating Amber, awaiting further publications.
Intellectual disability - microarray and sequencing v3.1097 SCYL1 Sarah Leigh reviewed gene: SCYL1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.1094 UFSP2 Konstantinos Varvagiannis changed review comment from: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)].

Members of a broader consanguineous pedigree from Pakistan with 3 affected children with epilepsy and DD and ID underwent exome sequencing. All affected individuals were homozygous for the specific SNV with their parents (2 parent pairs, in both cases first cousins) being heterozygous. An unaffected sib was homozygous for the wt allele. Through genematching platforms 3 additional families with similarly affected individuals and homozygosity for the same variant were recruited. These additional families were from Pakistan (1/3) and Afganistan (2/3).

Based on ROH analysis from the broader first pedigree and an additional family the authors concluded on a single shared region of homozygosity on chr 4q. Lack of ES data did not allow verification of whether 2/4 families shared the same haplotype with the other 2.

The authors calculated the probability of the genotype-phenotype cosegragation occurring by chance (0.009) and this was lower than the recommended criterion (0.06) for strong evidence of pathogenicity.

Shared features included abnormal tone in most (hypotonia 6/8, limb hypertonia 1/8), seizures (8/8 - onset 2d - 7m), severe DD with speech delay/absent speech (8/8), ID (8/8), strabismus (6/8).

UFSP2 encodes UFM1-specific protease 2 involved in UFmylation, a post-translational protein modification. As summarized by the authors the cysteine protease encoded by this gene (as is also the case for UFSP1) cleaves UFM1 in the initial step of UFMylation. Apart from producing mature UFM1, the 2 proteases have also the ability to release UFM1 from UFMylated proteins, in the process of de-UFMylation. [several refs. provided]

UFMylation is important in brain development with mutations in genes encoding other components of the pathway reported in other NDD disorders (incl. UFM1, UBA5, UFC1).

Additional studies were carried to provide evidence for pathogenicity of this variant.

Skin biopsies from 3 individuals were carried out to establish fibroblast cultures. Immunoblotting revealed reduced UFSP2 levels relative to controls. mRNA levels measured by qRT-PCR revealed no differences compared to controls altogether suggesting normal mRNA but reduced protein stability.

The authors demonstrated increased levels of UFM1-conjugated proteins (incl. DDRGK1, or TRIP4). Ectopic expression of wt UFSP2 normalized the levels of UFMylated proteins in the fibroblasts which was not the case for the V115E variant. Further the variant was difficult to detect by immunoblotting consistent with an effect on protein destabilization.

Although disruption of UFMylation induces ER stress, this was not shown to occur in patient fibroblast lines, when assessed for ER stress markers.

Evaluation of data from the GTEx project, concerning UFSP2 as well as well as DDRGK1 or TRIP4 - an UFMylation target - revealed relevant expression in multiple regions of the human brain.

Overall the authors provide evidence for defective de-UFMylation in patient fibroblasts (presence of increased UFMylation marks). The authors stress out that the effect of the variant in UFMylation in brain is unknown, as UFSP1 or other enzymes might compensate in the presence of hypomorphic UFSP2 mutants.

Biallelic UFSP2 variants have previously been reported in 2 skeletal dysplasias [# 142669. BEUKES HIP DYSPLASIA; BHD and # 617974. SPONDYLOEPIMETAPHYSEAL DYSPLASIA, DI ROCCO TYPE; SEMDDR]. These disorders are not characterized by neurological dysfunction or epilepsy. The authors underscore the fact that variants identified in these disorders (Y290H, D526A, H428R) localize within the C-terminal catalytic (peptidase) domain [aa 278 – 461] while the variant here identified lies in the N-terminal substrate binding domain affecting protein stability/abundance.

In OMIM, only the 2 aforementioned disorders are currently associated with biallelic UFSP2 mutations. There is no associated phenotype in G2P. SysID includes UFSP2 among the primary ID genes.

You may consider inclusion in the current panel with amber/green rating.
Sources: Literature; to: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)].

Members of a broader consanguineous pedigree from Pakistan with 3 affected children with epilepsy and DD and ID underwent exome sequencing. All affected individuals were homozygous for the specific SNV with their parents (2 parent pairs, in both cases first cousins) being heterozygous. An unaffected sib was homozygous for the wt allele. Through genematching platforms 3 additional families with similarly affected individuals and homozygosity for the same variant were recruited. These additional families were from Pakistan (1/3) and Afganistan (2/3).

Based on ROH analysis from the broader first pedigree and an additional family the authors concluded on a single shared region of homozygosity on chr 4q. Lack of ES data did not allow verification of whether 2/4 families shared the same haplotype with the other 2.

The authors calculated the probability of the genotype-phenotype cosegragation occurring by chance (0.009) and this was lower than the recommended criterion (0.06) for strong evidence of pathogenicity.

Shared features included abnormal tone in most (hypotonia 6/8, limb hypertonia 1/8), seizures (8/8 - onset 2d - 7m), severe DD with speech delay/absent speech (8/8), ID (8/8), strabismus (6/8).

UFSP2 encodes UFM1-specific protease 2 involved in UFmylation, a post-translational protein modification. As summarized by the authors the cysteine protease encoded by this gene (as is also the case for UFSP1) cleaves UFM1 in the initial step of UFMylation. Apart from producing mature UFM1, the 2 proteases have also the ability to release UFM1 from UFMylated proteins, in the process of de-UFMylation. [several refs. provided]

UFMylation is important in brain development with mutations in genes encoding other components of the pathway reported in other NDD disorders (incl. UFM1, UBA5, UFC1).

Additional studies were carried to provide evidence for pathogenicity of this variant.

Skin biopsies from 3 individuals were carried out to establish fibroblast cultures. Immunoblotting revealed reduced UFSP2 levels relative to controls. mRNA levels measured by qRT-PCR revealed no differences compared to controls altogether suggesting normal mRNA but reduced protein stability.

The authors demonstrated increased levels of UFM1-conjugated proteins (incl. DDRGK1, or TRIP4). Ectopic expression of wt UFSP2 normalized the levels of UFMylated proteins in the fibroblasts which was not the case for the V115E variant. Further the variant was difficult to detect by immunoblotting consistent with an effect on protein destabilization.

Although disruption of UFMylation induces ER stress, this was not shown to occur in patient fibroblast lines, when assessed for ER stress markers.

Evaluation of data from the GTEx project, concerning UFSP2 as well as well as DDRGK1 or TRIP4 - an UFMylation target - revealed relevant expression in multiple regions of the human brain.

Overall the authors provide evidence for defective de-UFMylation in patient fibroblasts (presence of increased UFMylation marks). The authors stress out that the effect of the variant in UFMylation in brain is unknown, as UFSP1 or other enzymes might compensate in the presence of hypomorphic UFSP2 mutants.

**Monoallelic** (correction to previous review) UFSP2 variants have previously been reported in 2 skeletal dysplasias [# 142669. BEUKES HIP DYSPLASIA; BHD and # 617974. SPONDYLOEPIMETAPHYSEAL DYSPLASIA, DI ROCCO TYPE; SEMDDR]. These disorders are not characterized by neurological dysfunction or epilepsy. The authors underscore the fact that variants identified in these disorders (Y290H, D526A, H428R) localize within the C-terminal catalytic (peptidase) domain [aa 278 – 461] while the variant here identified lies in the N-terminal substrate binding domain affecting protein stability/abundance.

In OMIM, only the 2 aforementioned disorders are currently associated with biallelic UFSP2 mutations. There is no associated phenotype in G2P. SysID includes UFSP2 among the primary ID genes.

You may consider inclusion in the current panel with amber/green rating.
Sources: Literature
Intellectual disability - microarray and sequencing v3.1092 UFSP2 Konstantinos Varvagiannis gene: UFSP2 was added
gene: UFSP2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: UFSP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UFSP2 were set to 33473208
Phenotypes for gene: UFSP2 were set to Abnormal muscle tone; Seizures; Global developmental delay; Delayed speech and language development; Intellectual disability; Strabismus
Penetrance for gene: UFSP2 were set to Complete
Added comment: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)].

Members of a broader consanguineous pedigree from Pakistan with 3 affected children with epilepsy and DD and ID underwent exome sequencing. All affected individuals were homozygous for the specific SNV with their parents (2 parent pairs, in both cases first cousins) being heterozygous. An unaffected sib was homozygous for the wt allele. Through genematching platforms 3 additional families with similarly affected individuals and homozygosity for the same variant were recruited. These additional families were from Pakistan (1/3) and Afganistan (2/3).

Based on ROH analysis from the broader first pedigree and an additional family the authors concluded on a single shared region of homozygosity on chr 4q. Lack of ES data did not allow verification of whether 2/4 families shared the same haplotype with the other 2.

The authors calculated the probability of the genotype-phenotype cosegragation occurring by chance (0.009) and this was lower than the recommended criterion (0.06) for strong evidence of pathogenicity.

Shared features included abnormal tone in most (hypotonia 6/8, limb hypertonia 1/8), seizures (8/8 - onset 2d - 7m), severe DD with speech delay/absent speech (8/8), ID (8/8), strabismus (6/8).

UFSP2 encodes UFM1-specific protease 2 involved in UFmylation, a post-translational protein modification. As summarized by the authors the cysteine protease encoded by this gene (as is also the case for UFSP1) cleaves UFM1 in the initial step of UFMylation. Apart from producing mature UFM1, the 2 proteases have also the ability to release UFM1 from UFMylated proteins, in the process of de-UFMylation. [several refs. provided]

UFMylation is important in brain development with mutations in genes encoding other components of the pathway reported in other NDD disorders (incl. UFM1, UBA5, UFC1).

Additional studies were carried to provide evidence for pathogenicity of this variant.

Skin biopsies from 3 individuals were carried out to establish fibroblast cultures. Immunoblotting revealed reduced UFSP2 levels relative to controls. mRNA levels measured by qRT-PCR revealed no differences compared to controls altogether suggesting normal mRNA but reduced protein stability.

The authors demonstrated increased levels of UFM1-conjugated proteins (incl. DDRGK1, or TRIP4). Ectopic expression of wt UFSP2 normalized the levels of UFMylated proteins in the fibroblasts which was not the case for the V115E variant. Further the variant was difficult to detect by immunoblotting consistent with an effect on protein destabilization.

Although disruption of UFMylation induces ER stress, this was not shown to occur in patient fibroblast lines, when assessed for ER stress markers.

Evaluation of data from the GTEx project, concerning UFSP2 as well as well as DDRGK1 or TRIP4 - an UFMylation target - revealed relevant expression in multiple regions of the human brain.

Overall the authors provide evidence for defective de-UFMylation in patient fibroblasts (presence of increased UFMylation marks). The authors stress out that the effect of the variant in UFMylation in brain is unknown, as UFSP1 or other enzymes might compensate in the presence of hypomorphic UFSP2 mutants.

Biallelic UFSP2 variants have previously been reported in 2 skeletal dysplasias [# 142669. BEUKES HIP DYSPLASIA; BHD and # 617974. SPONDYLOEPIMETAPHYSEAL DYSPLASIA, DI ROCCO TYPE; SEMDDR]. These disorders are not characterized by neurological dysfunction or epilepsy. The authors underscore the fact that variants identified in these disorders (Y290H, D526A, H428R) localize within the C-terminal catalytic (peptidase) domain [aa 278 – 461] while the variant here identified lies in the N-terminal substrate binding domain affecting protein stability/abundance.

In OMIM, only the 2 aforementioned disorders are currently associated with biallelic UFSP2 mutations. There is no associated phenotype in G2P. SysID includes UFSP2 among the primary ID genes.

You may consider inclusion in the current panel with amber/green rating.
Sources: Literature
Intellectual disability - microarray and sequencing v3.1092 SIN3B Konstantinos Varvagiannis reviewed gene: SIN3B: Rating: AMBER; Mode of pathogenicity: None; Publications: 33811806; Phenotypes: Global developmental delay, Intellectual disability, Behavioral abnormality; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.1083 AFG3L2 Sarah Leigh reviewed gene: AFG3L2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic ataxia 5, autosomal recessive OMIM:614487, spastic ataxia 5 MONDO:0013776, Spinocerebellar ataxia 28 OMIM:610246, spinocerebellar ataxia type 28 MONDO:0012450; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1075 NSF Sarah Leigh reviewed gene: NSF: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.1069 CHD5 Zornitza Stark gene: CHD5 was added
gene: CHD5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CHD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHD5 were set to 33944996
Phenotypes for gene: CHD5 were set to Intellectual disability; Epilepsy
Review for gene: CHD5 was set to GREEN
gene: CHD5 was marked as current diagnostic
Added comment: 16 unrelated individuals reported with language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), epilepsy (62%), and motor delay (56%).
Sources: Literature
Intellectual disability - microarray and sequencing v3.1069 PTPN4 Zornitza Stark gene: PTPN4 was added
gene: PTPN4 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PTPN4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTPN4 were set to 17953619; 25424712; 30238967; DOI: https://doi.org/10.1016/j.xhgg.2021.100033
Phenotypes for gene: PTPN4 were set to Intellectual disability
Review for gene: PTPN4 was set to GREEN
gene: PTPN4 was marked as current diagnostic
Added comment: >3 unrelated probands and supportive mouse model
PMID: 17953619 - knockout mouse model has impaired motor learning and cerebellar synaptic plasticity
PMID: 25424712 - twins with a de novo whole gene deletion and a Rett-like neurodevelopmental disorder
PMID: 30238967 - mosaic de novo variant (p.Leu72Ser) identified in a child with developmental delay, autistic features, hypotonia, increased immunoglobulin E and dental problems. Also supporting mouse assays demonstrating loss of protein expression in dendritic spines
DOI: https://doi.org/10.1016/j.xhgg.2021.100033 - missense and truncating variants in six unrelated individuals with varying degrees of intellectual disability or developmental delay. 5 were able to undergo segregation analysis and found to be de novo.
Sources: Literature
Intellectual disability - microarray and sequencing v3.1068 UBTF Arina Puzriakova Mode of pathogenicity for gene: UBTF was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability - microarray and sequencing v3.1064 DNA2 Arina Puzriakova reviewed gene: DNA2: Rating: RED; Mode of pathogenicity: None; Publications: 24389050, 31045292; Phenotypes: Seckel syndrome 8, OMIM:615807; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1062 WDR4 Ivone Leong reviewed gene: WDR4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.1059 OCRL Eleanor Williams reviewed gene: OCRL: Rating: ; Mode of pathogenicity: None; Publications: 33517444; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.1056 HTT Eleanor Williams reviewed gene: HTT: Rating: ; Mode of pathogenicity: None; Publications: 33432339; Phenotypes: Lopes-Maciel-Rodan syndrome OMIM:617435; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1055 FAR1 Arina Puzriakova reviewed gene: FAR1: Rating: ; Mode of pathogenicity: None; Publications: 25439727, 30561787, 33239752; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.1038 PIGC Arina Puzriakova reviewed gene: PIGC: Rating: GREEN; Mode of pathogenicity: None; Publications: 32707268; Phenotypes: Glycosylphosphatidylinositol biosynthesis defect 16, OMIM:617816; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1037 LAMA1 Sarah Leigh reviewed gene: LAMA1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.1021 B4GALT1 Arina Puzriakova reviewed gene: B4GALT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 11901181, 21920538, 30653653, 32157688; Phenotypes: Congenital disorder of glycosylation, type IId, OMIM:607091; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1018 CDH11 Zornitza Stark reviewed gene: CDH11: Rating: GREEN; Mode of pathogenicity: None; Publications: 33811546, 27431290, 28988429, 29271567, 33811546; Phenotypes: Elsahy-Waters syndrome, MIM# 211380, Teebi hypertelorism syndrome; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.1018 INPP4A Zornitza Stark reviewed gene: INPP4A: Rating: AMBER; Mode of pathogenicity: None; Publications: 31978615, 31938306, 25338135, 20011524; Phenotypes: Intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1015 KCNH1 Arina Puzriakova reviewed gene: KCNH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33811134; Phenotypes: Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.1003 NCKAP1 Zornitza Stark reviewed gene: NCKAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33157009; Phenotypes: Intellectual disability, autism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.1003 LARS2 Zornitza Stark reviewed gene: LARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29205794, 32423379, 30737337, 26537577, 23541342; Phenotypes: Perrault syndrome 4, Hydrops, lactic acidosis, and sideroblastic anemia, MIM# 617021, Leukodystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1003 DPM2 Zornitza Stark edited their review of gene: DPM2: Added comment: Further unrelated individual reported, main clinical features were truncal hypotonia, hypertonicity, congenital heart defects, intellectual disability, and generalized muscle wasting.; Changed rating: GREEN; Changed publications: 23109149, 33129689
Intellectual disability - microarray and sequencing v3.1003 B4GALT1 Zornitza Stark reviewed gene: B4GALT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 11901181, 30653653, 21920538; Phenotypes: Congenital disorder of glycosylation, type Iid, MIM#607091; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1003 AGO1 Zornitza Stark reviewed gene: AGO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30213762, 22495306, 23020937, 25363768, 25356899, 27620904, 29346770, 28135719; Phenotypes: Intellectual disability, autism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.995 MED27 Arina Puzriakova Phenotypes for gene: MED27 were changed from Intellectual disability; cerebellar hypoplasia; dystonia to Intellectual disability; Axial hypotonia; Spasticity; Dystonia; Cerebellar hypoplasia; Cataracts; Epilepsy
Intellectual disability - microarray and sequencing v3.993 MED27 Arina Puzriakova reviewed gene: MED27: Rating: GREEN; Mode of pathogenicity: None; Publications: 33443317; Phenotypes: Intellectual disability, Axial hypotonia, Spasticity, Dystonia, Cerebellar hypoplasia, Cataracts, Epilepsy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.984 TMPRSS9 Arina Puzriakova gene: TMPRSS9 was added
gene: TMPRSS9 was added to Intellectual disability. Sources: Other
watchlist tags were added to gene: TMPRSS9.
Mode of inheritance for gene: TMPRSS9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMPRSS9 were set to 31943016
Phenotypes for gene: TMPRSS9 were set to Progressive intellectual and neurological deterioration; Global developmental delay; Intellectual disability; Autism; Epilepsy
Review for gene: TMPRSS9 was set to RED
Added comment: TMPRSS9 is currently not associated with any phenotype in OMIM or Gene2Phenotype.

- PMID: 31943016 (2020) - Single female subject with compound heterozygous nonsense variants (paternal: c.286C>T, p.R96*; maternal: c.1267C>T; p.R423*) in TMPRSS9. Early childhood development was normal until 2.5 years of age when she experienced profound developmental regression, including speech, social interaction and motor skills, resulting in ASD and profound ID. Knockout mice showed decreased social interest and recognition, and additionally borderline recognition memory deficit in aged female mice.

- Conference poster (Genomics of Rare Disease 2021) - 'ZOEMBA: combining metabolomics and genomics data to solve the unsolved' by Oud et al, United for Metabolic Diseases (UMD), Netherlands -
Trio WES revealed compound heterozygous variants (paternal: c.143-1G>A, p.?; maternal: c.1864G>A; p.V622M) in the TMPRSS9 gene in a female proband with GDD, PIND, aggression, autism and epilepsy. The individual was recruited on the basis of 'suspicion of an inherited metabolic disorder and extensive genetic and metabolic work-up with no diagnosis'.
Sources: Other
Intellectual disability - microarray and sequencing v3.975 SPEN Zornitza Stark edited their review of gene: SPEN: Added comment: PMID: 33596411
- 34 individuals with truncating variants in SPEN reported, most are de novo variants.
- Clinical profile includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females.
- Authors showed haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females.; Changed rating: GREEN; Changed publications: 33057194, 33596411; Changed phenotypes: Developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI; Set current diagnostic: yes
Intellectual disability - microarray and sequencing v3.966 KCNN3 Arina Puzriakova changed review comment from: Comment on mode of pathogenicity: Gain-of-function variants identified in all patients, reported to date.; to: Comment on mode of pathogenicity: Gain-of-function variants identified in all patients reported to date.
Intellectual disability - microarray and sequencing v3.963 KCNH1 Julia Baptista reviewed gene: KCNH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33594261; Phenotypes: Temple-Baraitser syndrome, Zimmermann-Laband syndrome 1; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.963 KCNN3 Julia Baptista reviewed gene: KCNN3: Rating: GREEN; Mode of pathogenicity: Other; Publications: 33594261; Phenotypes: developmental delay, ID, hypotonia, gingival enlargement, hypertrichosis, nail anomalies; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.963 CDK19 Julia Baptista reviewed gene: CDK19: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33495529, 33568421, 32330417; Phenotypes: developmental delay, hypotonia, seizures, autism/autistic traits; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.867 HECW2 Ivone Leong Mode of pathogenicity for gene: HECW2 was changed from to Other
Intellectual disability - microarray and sequencing v3.779 LMBRD2 Sarah Leigh Added comment: Comment on mode of pathogenicity: Both of the references for this entry suggest a gain-of-function action for LMBRD2 variants.
Intellectual disability - microarray and sequencing v3.779 LMBRD2 Sarah Leigh Mode of pathogenicity for gene: LMBRD2 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability - microarray and sequencing v3.777 KCNN2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to promote this gene to Green at the next GMS panel update - variable degrees of cognitive impairment were a universal feature amongst individuals with KCNN2 variants (at least 10 unrelated cases with unique variants). Pathogenicity was supported by functional data.
Intellectual disability - microarray and sequencing v3.776 KCNN2 Arina Puzriakova reviewed gene: KCNN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33242881; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.774 SATB1 Arina Puzriakova reviewed gene: SATB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33513338; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.767 HPDL Arina Puzriakova reviewed gene: HPDL: Rating: GREEN; Mode of pathogenicity: None; Publications: 32707086, 33188300; Phenotypes: Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, OMIM:619026, Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, MONDO:0033613; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.767 HPDL Arina Puzriakova Phenotypes for gene: HPDL were changed from spastic paraplegia; spastic tetraplegia; microcephaly; brain atrophy; epilepsy; severe intellectual; motor disability to Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, OMIM:619026; Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, MONDO:0033613
Intellectual disability - microarray and sequencing v3.765 HIRA Arina Puzriakova reviewed gene: HIRA: Rating: AMBER; Mode of pathogenicity: None; Publications: 25363760, 28135719, 33417013; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.761 DDX58 Arina Puzriakova reviewed gene: DDX58: Rating: ; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.756 PRUNE1 Eleanor Williams reviewed gene: PRUNE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33105479; Phenotypes: Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies OMIM:617481, neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies MONDO:0060490; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.756 VPS4A Arina Puzriakova Added comment: Comment on list classification: New gene added by Evan Reid (University of Cambridge). At least 5 different variants reported in 10 unrelated individuals with a comparable phenotype, including severe-to-profound ID/DD. Pathogenicity is supported by functional data.

There is enough evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability - microarray and sequencing v3.754 VPS4A Arina Puzriakova reviewed gene: VPS4A: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 33186545, 33186543; Phenotypes: CIMDAG syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.751 ADAM22 Sarah Leigh reviewed gene: ADAM22: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.751 VPS4A Evan Reid gene: VPS4A was added
gene: VPS4A was added to Intellectual disability. Sources: Literature,Research
Mode of inheritance for gene: VPS4A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VPS4A were set to (PMID: 33186545; 33186543; 33460484)
Phenotypes for gene: VPS4A were set to developmental delay; intellectual disability; cerebellar hypoplasia; pontine hypoplasia; thin corpus callosum; microcephaly; growth retardation; congenital anaemia; dyserythropeoitic anaemia; dystonia; congenital cataracts; deafness
Penetrance for gene: VPS4A were set to Complete
Mode of pathogenicity for gene: VPS4A was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: VPS4A was set to GREEN
Added comment: Multiple families (now 10) described with a consistent phenotype (we have termed it CIMDAG as an acronym for the major features). All have de novo heterozygous missense mutations of VPS4A, with a distinct mutational hotspot (R284) in many families. Mechanism is likely dominant negative. Haplo-insufficiency of VPS4A is tolerated and present in general population databases, so loss of function mutations likely do not cause this disease.
Sources: Literature, Research
Intellectual disability - microarray and sequencing v3.744 TOR1A Arina Puzriakova reviewed gene: TOR1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 30244176, 29053766, 28516161; Phenotypes: Arthrogryposis multiplex congenita 5, OMIM:618947, Arthrogryposis multiplex congenita 5, MONDO:0100218; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.742 TMX2 Arina Puzriakova Phenotypes for gene: TMX2 were changed from Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormal cortical gyration; Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730 to Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, OMIM:618730; Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, MONDO:0032887
Intellectual disability - microarray and sequencing v3.734 RNU7-1 Arina Puzriakova reviewed gene: RNU7-1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33230297; Phenotypes: Aicardi–Goutières syndrome-like, Type I interferonopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.731 FGFR1 Arina Puzriakova reviewed gene: FGFR1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.729 TANC2 Arina Puzriakova reviewed gene: TANC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31616000, 33160097, 30021165; Phenotypes: TANC2-related neurodevelopmental and psychiatric disorder, OMIM:618906; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.728 PPIL1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Currently not associated with any phenotype in OMIM (last edited on: 10/07/2001) but has a 'probable' gene rating for 'PPIL1-related Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly' in Gene2Phenotype.

At least 12 variants identified in 17 individuals from 9 unrelated families (PMID: 33220177). All displayed pontocerebellar hypoplasia and congenital microcephaly. Severe ID, with or without seizures, was noted in all subjects (14) where information was provided (see table S1). Pathogenicity is supported by animal model.

Sufficient evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability - microarray and sequencing v3.721 FBRSL1 Arina Puzriakova reviewed gene: FBRSL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32424618; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.720 CDC40 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. CDC40 currently not associated with any phenotype in OMIM (last edited: 23/08/19) but has a 'possible' disease confidence for 'CDC40-related Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly' in Gene2Phenotype.

Rating Red as currently only a single individual reported in PMID: 33220177 (2021). There is some functional and animal model data to support pathogenicity, so have added 'watchlist' tag. If additional cases arise, CDC40 may also be considered for other panels (e.g. Malformations of cortical development, Genetic epilepsy syndromes, Cytopenia - NOT Fanconi anaemia, etc)
Intellectual disability - microarray and sequencing v3.717 ABCC9 Arina Puzriakova reviewed gene: ABCC9: Rating: ; Mode of pathogenicity: None; Publications: 31575858; Phenotypes: mild ID, similar facies, myopathy, cerebral white matter hyperintensities, cardiac systolic dysfunction; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.716 TRAPPC12 Arina Puzriakova Phenotypes for gene: TRAPPC12 were changed from Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, 617669; Developmental delay to Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, OMIM:617669; Early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome, MONDO:0044696
Intellectual disability - microarray and sequencing v3.714 TRAPPC12 Arina Puzriakova reviewed gene: TRAPPC12: Rating: GREEN; Mode of pathogenicity: None; Publications: 32369837; Phenotypes: Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, OMIM:617669, Early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome, MONDO:0044696; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.710 GLS Arina Puzriakova Added comment: Comment on mode of inheritance: As evidence for pathogenicity of monoallelic variants is limited (currently only 1 case), MOI will remain as 'Biallelic' until further cases emerge that support an association between monoallelic variants and disease.
Intellectual disability - microarray and sequencing v3.708 GLS Arina Puzriakova reviewed gene: GLS: Rating: GREEN; Mode of pathogenicity: None; Publications: 30970188; Phenotypes: Global developmental delay, progressive ataxia, and elevated glutamine, OMIM: 618412; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.696 ZNF526 Arina Puzriakova reviewed gene: ZNF526: Rating: GREEN; Mode of pathogenicity: None; Publications: 21937992, 25558065, 33397746; Phenotypes: Intellectual disability, Microcephaly, Cataracts, Epilepsy, Hypertonia, Dystonia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.694 FGF13 Zornitza Stark gene: FGF13 was added
gene: FGF13 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FGF13 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: FGF13 were set to 33245860
Phenotypes for gene: FGF13 were set to Intellectual disability; epilepsy
Mode of pathogenicity for gene: FGF13 was set to Other
Review for gene: FGF13 was set to GREEN
gene: FGF13 was marked as current diagnostic
Added comment: Two sibling pairs and three unrelated males reported who presented in infancy with intractable focal seizures and severe developmental delay. The variants were located in the N-terminal domain of the A isoform of FGF13/FHF2 (FHF2A). The X-linked FHF2 gene (also known as FGF13) has alternative first exons which produce multiple protein isoforms that differ in their N-terminal sequence. The variants were located at highly conserved residues in the FHF2A inactivation particle that competes with the intrinsic fast inactivation mechanism of Nav channels. Functional characterization of mutant FHF2A co-expressed with wild-type Nav1.6 (SCN8A) revealed that mutant FHF2A proteins lost the ability to induce rapid-onset, long-term blockade of the channel while retaining pro-excitatory properties. These gain-of-function effects are likely to increase neuronal excitability consistent with the epileptic potential of FHF2 variants.
Sources: Literature
Intellectual disability - microarray and sequencing v3.694 UBR7 Zornitza Stark reviewed gene: UBR7: Rating: GREEN; Mode of pathogenicity: None; Publications: 33340455; Phenotypes: Intellectual disability, epilepsy, hypothyroidism, congenital anomalies, dysmorphic features; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.686 MPI Arina Puzriakova reviewed gene: MPI: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.685 AGO2 Arina Puzriakova reviewed gene: AGO2: Rating: AMBER; Mode of pathogenicity: None; Publications: 33199684; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.678 KCNMA1 Arina Puzriakova reviewed gene: KCNMA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26195193, 27567911, 29330545, 29545233, 31152168, 31427379; Phenotypes: Cerebellar atrophy, developmental delay, and seizures, OMIM:617643, Cerebellar atrophy, developmental delay, and seizures, MONDO:0060551, Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, OMIM:609446, Generalized epilepsy-paroxysmal dyskinesia syndrome, MONDO:0012276, Liang-Wang syndrome, OMIM:618729, Liang-Wang syndrome, MONDO:0032886, {Epilepsy, idiopathic generalized, susceptibility to, 16}, OMIM:618596, Epilepsy, idiopathic generalized, susceptibility to, 16, MONDO:0032827; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.673 H3F3B Arina Puzriakova reviewed gene: H3F3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 33268356; Phenotypes: Developmental delay, Neurodegeneration, Epilepsy, Facial dysmorphism, Congenital anomalies; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.669 H3F3A Arina Puzriakova reviewed gene: H3F3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 31942419, 33268356; Phenotypes: Developmental delay, Neurodegeneration, Epilepsy, Facial dysmorphism, Congenital anomalies; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.665 SHMT2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Sufficient number of unrelated cases (>3) with ID of relevant severity to this panel. Some functional data indicating variants result in impaired SHMT2 enzymatic function. Rating Amber but should be promoted to Green at the next GMS panel update (added 'for-review' tag)

SHMT2 is listed in Gene2Phenotype with a 'probable' disease confidence rating for 'SHMT2-related neurodevelopmental syndrome', and is also associated with 'Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities, MIM# 619121' in OMIM.
Intellectual disability - microarray and sequencing v3.664 SHMT2 Arina Puzriakova Phenotypes for gene: SHMT2 were changed from Congenital microcephaly; Infantile axial hypotonia; Spastic paraparesis; Global developmental delay; Intellectual disability; Abnormality of the corpus callosum; Abnormal cortical gyration; Hypertrophic cardiomyopathy; Abnormality of the face; Proximal placement of thumb; 2-3 toe syndactyly to Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities, OMIM:619121
Intellectual disability - microarray and sequencing v3.661 RAP1B Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype but not OMIM.

PMID: 32627184 describes 2 patients.
36 yo patient of non-consanguineous parents. Had unclear pancytopenia, multiple congenital malformations, mild intellectual disability, endocrine disorders (short stature with growth hormone deficiency), dysmorphism and other features. Parents and sibling unaffected.
13 yo of non-consanguineous parents with thrombocytopenia, multiple congenital anomalies and learning difficulties. He had normal developmental milestones, walk was achieved at 14 months and there was no speech delay. He attended mainstream school with auxiliary help because of learning difficulties with graphism, syntaxic comprehension, logical reasoning and attention deficit. Parents and siblings unaffected.

PMID: 26280580 describes another patient with variant in RAP1B. The clinical features can be found in supplementary table 2. The table lists ID, but doesn't say severity and lists a host of other features including short stature, facial dysmorphism and skeletal findings.

All 3 cases seem to have a very wide spectrum of differing phenotypes and therefore, this gene has been given an Amber rating until further evidence is available.
Intellectual disability - microarray and sequencing v3.660 MPI Zornitza Stark reviewed gene: MPI: Rating: RED; Mode of pathogenicity: None; Publications: 12414827, 9585601, 10980531, 33098580, 33204592, 32905087, 32266963, 30242110; Phenotypes: Congenital disorder of glycosylation, type Ib, MIM# 602579, MPI-CDG MONDO:0011257; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.647 NARS Arina Puzriakova reviewed gene: NARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 32738225, 32788587; Phenotypes: Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive, OMIM:619091, Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant, OMIM:619092; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.645 ATP2A2 Ivone Leong reviewed gene: ATP2A2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.645 ISCA-37418-Loss Arina Puzriakova Phenotypes for Region: ISCA-37418-Loss were changed from Potocki-Lupski syndrome; hypotonia, poor feeding, failure to thrive, developmental delay particularly cognitive and language deficity, mild-moderate intellectual deficit, and neuropsychiatric disorders; Smith-Magenis syndrome; Structural cardiovascular anomalies (dilated aortic root, bicommissural aortic valve, atrial/ventricular and septal defects) and sleep disturbance; 182290; moderate intellectual disability, delayed speech and language skills, distinctive facial features, sleep disturbances, and behavioral problems; hypotonia, failure to thrive, mental retardation, pervasive developmental disorders, congenital anomalies; Dental abnormalities to Smith-Magenis syndrome, OMIM:182290; Smith-Magenis syndrome, MONDO:0008434
Intellectual disability - microarray and sequencing v3.644 H3F3B Zornitza Stark reviewed gene: H3F3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 33268356; Phenotypes: Intellectual disability, regression, seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.644 H3F3A Zornitza Stark reviewed gene: H3F3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 33268356; Phenotypes: Intellectual disability, regression, seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.638 MORC2 Arina Puzriakova reviewed gene: MORC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32693025; Phenotypes: Developmental delay, Intellectual disability, Growth retardation, Microcephaly, Craniofacial dysmorphism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.574 ALDH7A1 Eleanor Williams reviewed gene: ALDH7A1: Rating: ; Mode of pathogenicity: None; Publications: 32969477; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.573 ISCA-37418-Loss Zornitza Stark reviewed Region: ISCA-37418-Loss: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Smith-Magenis syndrome, MIM# 182290; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.573 CDH2 Arina Puzriakova reviewed gene: CDH2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31650526; Phenotypes: Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, OMIM:618929; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.569 ISCA-37415-Gain Zornitza Stark reviewed Region: ISCA-37415-Gain: Rating: GREEN; Mode of pathogenicity: None; Publications: 30287593; Phenotypes: Intellectual disability, autism, aortopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.569 ATP2A2 Andrea Nemeth reviewed gene: ATP2A2: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 25704118; Phenotypes: Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.568 DNMT3A Sarah Leigh Mode of pathogenicity for gene: DNMT3A was changed from None to Other
Intellectual disability - microarray and sequencing v3.567 DNMT3A Sarah Leigh Added comment: Comment on mode of pathogenicity: Tatton-Brown-Rahman syndrome 615879 is associated with loss of function variants and Heyn-Sproul-Jackson syndrome OMIM:618724 is associated with gain of function variants.
Intellectual disability - microarray and sequencing v3.567 DNMT3A Sarah Leigh Mode of pathogenicity for gene: DNMT3A was changed from to None
Intellectual disability - microarray and sequencing v3.565 LMNB2 Sarah Leigh reviewed gene: LMNB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33033404; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.562 AGAP1 Arina Puzriakova reviewed gene: AGAP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31700678, 30472483, 25666757; Phenotypes: Cerebral palsy, Developmental delay; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.559 JARID2 Arina Puzriakova reviewed gene: JARID2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33077894; Phenotypes: Neurodevelopmental syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.557 PJA1 Arina Puzriakova Added comment: Comment on list classification: Upgraded rating from Red to Amber - 7 individuals reported in PMID:32530565 all with ID, albeit due to a founder variant. Some cases with deletions encompassing this gene reported with mild DD, however contribution of other affected genes cannot be ruled out. Evidence of pathogenicity of other PJA1 variants is required prior to inclusion on a diagnostic panel.
Intellectual disability - microarray and sequencing v3.553 MAPK1 Catherine Snow reviewed gene: MAPK1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 32721402; Phenotypes: Noonan syndrome 13, OMIM:619087, MONDO:0018997; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.541 TFE3 Sarah Leigh reviewed gene: TFE3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.532 ABCA2 Arina Puzriakova reviewed gene: ABCA2: Rating: ; Mode of pathogenicity: None; Publications: 30237576, 29302074, 31047799; Phenotypes: Intellectual developmental disorder with poor growth and with or without seizures or ataxia, OMIM: 618808; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.528 PET100 Eleanor Williams reviewed gene: PET100: Rating: GREEN; Mode of pathogenicity: None; Publications: 24462369, 25293719, 31406627; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 12 OMIM:619055, Leigh syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.526 PIGH Eleanor Williams reviewed gene: PIGH: Rating: GREEN; Mode of pathogenicity: None; Publications: 33156547, 29573052, 29603516; Phenotypes: Glycosylphosphatidylinositol biosynthesis defect 17 OMIM:618010; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.522 KCNC3 Catherine Snow reviewed gene: KCNC3: Rating: AMBER; Mode of pathogenicity: None; Publications: 32655623; Phenotypes: Spinocerebellar ataxia 13, OMIM:605259, MONDO:0011529; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.520 TMEM106B Arina Puzriakova reviewed gene: TMEM106B: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 29186371, 29444210, 30643851, 32595021; Phenotypes: Leukodystrophy, hypomyelinating, 16 OMIM:617964; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.513 MAPRE2 Arina Puzriakova reviewed gene: MAPRE2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26637975, 31903734, 31502381; Phenotypes: Symmetric circumferential skin creases, congenital, 2, 616734; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.510 MAP1B Arina Puzriakova reviewed gene: MAP1B: Rating: AMBER; Mode of pathogenicity: None; Publications: 30150678, 29738522, 30214071, 31317654; Phenotypes: Periventricular nodular heterotopia 9, 618918; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.510 HDAC4 Sarah Leigh reviewed gene: HDAC4: Rating: AMBER; Mode of pathogenicity: None; Publications: 30848064; Phenotypes: Chromosome 2q37 deletion syndrome 600430; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.510 ISCA-37394-Loss Sarah Leigh reviewed Region: ISCA-37394-Loss: Rating: GREEN; Mode of pathogenicity: None; Publications: 30848064; Phenotypes: Chromosome 2q37 deletion syndrome 600430; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.510 ZFHX4 Zornitza Stark reviewed gene: ZFHX4: Rating: AMBER; Mode of pathogenicity: None; Publications: 33057194, 24038936; Phenotypes: Developmental disorders, intellectual disability, dysmorphic features; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.510 SATB1 Zornitza Stark reviewed gene: SATB1: Rating: AMBER; Mode of pathogenicity: None; Publications: 33057194; Phenotypes: Developmental disorders; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.510 FBXO31 Zornitza Stark edited their review of gene: FBXO31: Changed phenotypes: Mental retardation, autosomal recessive 45, MIM#615979, Intellectual disability, spasticity, autosomal dominant
Intellectual disability - microarray and sequencing v3.510 FBXO31 Zornitza Stark gene: FBXO31 was added
gene: FBXO31 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FBXO31 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: FBXO31 were set to 24623383; 32989326
Phenotypes for gene: FBXO31 were set to Mental retardation, autosomal recessive 45, MIM#615979; Intellectual disability, autosomal dominant
Review for gene: FBXO31 was set to AMBER
Added comment: Bi-allelic variants: Single consanguineous family reported with homozygous truncating variant, limited functional evidence.

Mono-allelic variants: 2 unrelated probands reported as part of a 'cerebral palsy' cohort harbouring the same de novo missense variant (p.Asp334Asn). The variant affects the cyclin D interaction site, leading to an apparent gain of function of cyclin D degradation, supported by Western blots from patient fibroblasts which showed decreased cyclin D expression.

Patient phenotypes: Spastic diplegia, with esotropia, ID, dysarthria, mixed receptive/expressive language disorder, ADHD, cleft palate, intestinal malrotation and midgut volvulus (patient 1); Spastic paraplegia with ventricular dilation and thin corpus callosum, ID, attention deficit, anxiety, language impairments, strabismus, severe constipation (patient 2).
Sources: Literature
Intellectual disability - microarray and sequencing v3.504 NEMF Arina Puzriakova reviewed gene: NEMF: Rating: GREEN; Mode of pathogenicity: None; Publications: 27431290, 33048237; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.502 JARID2 Konstantinos Varvagiannis reviewed gene: JARID2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.500 NUDT2 Zornitza Stark reviewed gene: NUDT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27431290, 30059600, 33058507; Phenotypes: Muscular hypotonia, Global developmental delay, Intellectual disability, Polyneuropathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.500 PRKAR1B Konstantinos Varvagiannis gene: PRKAR1B was added
gene: PRKAR1B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PRKAR1B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRKAR1B were set to https://doi.org/10.1101/2020.09.10.20190314; 25414040
Phenotypes for gene: PRKAR1B were set to Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Aggressive behavior; Abnormality of movement; Upslanted palpebral fissure
Penetrance for gene: PRKAR1B were set to unknown
Review for gene: PRKAR1B was set to AMBER
Added comment: Please consider inclusion of this gene with amber rating pending publication of the preprint and/or additional evidence.

Marbach et al. (2020 - medRxiv : https://doi.org/10.1101/2020.09.10.20190314 - last author : C. Schaaf) report 6 unrelated individuals with heterozygous missense PRKAR1B variants.

All presented formal ASD diagnosis (6/6), global developmental delay (6/6) and intellectual disability (all - formal evaluations were lacking though). Additional features included neurologic anomalies (movement disorders : dyspraxia, apraxia, clumsiness in all, with tremor/dystonia or involuntary movements as single occurrences). Three displayed high pain tolerance. Regression in speech was a feature in two. Additional behavior anomalies included ADHD (4-5/6) or aggression (3/6). There was no consistent pattern of malformations, physical anomalies or facial features (with the exception of uplsanted palpebral fissures reported in 4).

3 different missense variants were identified (NM_00116470:c.1003C>T - p.Arg335Trp, c.586G>A - p.Glu196Lys, c.500_501delAAinsTT - p.Gln167Leu) with Arg355Trp being a recurrent one within this cohort (4/6 subjects). A possible splicing effect may apply for the MNV. All variants are absent from gnomAD and the SNVs had CADD scores > 24.

In all cases were parental samples were available (5/6), the variant had occurred as a de novo event.

Protein kinase A (PKA) is a tetrameric holoenzyme formed by the association of 2 catalytic (C) subunits with a regulatory (R) subunit dimer. Activation of PKA is achieved through binding of 2 cAMP molecules to each R-subunit, and unleashing(/dissociation) of C-subunits to engage substrates. PRKACA/B genes encode the Cα- and Cβ-subunits while the 4 functionally non-redundant regulatory subunits are encoded by PRKAR1A/1B/2A/2B genes. As the authors comment, the RIβ subunit is primarily expressed in brain with higher expression in cortex and hypothalamus.

The functional consequences of the variants at cellular level were not studied.

Previous studies have demonstrated that downregulation of RIβ in murine hippocampal cultures, reduced phosphorylation of CREB, a transcription factor involved in long-term memory formation. The authors speculate that a similar effect on cAMP/PKA/CREB cascade may mediate the cognitive effects in humans. RIβ deficient mice also display diminished nociceptive pain, similar to the human phenotype. [Several refs provided].

The authors cite the study by Kaplanis et al (2020 - PMID: 33057194), where in a large sample of 31,058 trio exomes of children with developmental disorders, PRKAR1B was among the genes with significant enrichment for de novo missense variants. [The gene has a pLI score of 0.18 in gnomAD / o/e = 0.26 - so pLoF variants may not be deleterious].

Please note that a specific PRKAR1B variant (NM_002735.2:c.149T>G - p.Leu50Arg) has been previous reported to segregate with a late-onset neurodegenerative disorder characterized by dementia and/or parkinsonism within a large pedigree with 12 affected individuals [Wong et al 2014 - PMID: 25414040].
Sources: Literature
Intellectual disability - microarray and sequencing v3.500 MPP5 Konstantinos Varvagiannis gene: MPP5 was added
gene: MPP5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MPP5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MPP5 were set to 33073849
Phenotypes for gene: MPP5 were set to Global developmental delay; Intellectual disability; Delayed speech and language development; Developmental regression; Behavioral abnormality
Penetrance for gene: MPP5 were set to unknown
Review for gene: MPP5 was set to GREEN
Added comment: Sterling et al (2020 - PMID: 33073849) provide information on the phenotype of 3 individuals with de novo MPP5 variants.

Common features included global developmental delay, intellectual disability (3/3 - severe in 2/3), speech delay/regression (the latter in at least 2) and behavioral abnormalities. Variable other features were reported, among others microcephaly (1/3), abnormal vision (1/3 : CVI, retinal dystrophy, nystagmus), brain MRI abnormalities (2/3), late-onset seizures (1/3). These subjects displayed variable and non-specific dysmorphic features.

All were investigated by exome sequencing (previous tests not mentioned).

One subject was found to harbor a de novo mosaic (5/25 reads) stopgain variant, further confirmed by Sanger sequencing [NM_022474.4:c.1555C>T - p.(Arg519Ter). The specific variant is reported once in gnomAD (1/251338). Two de novo missense variants were identified in the remaining individuals [c.1289A>G - p.Glu430Gly / c.974A>C - p.His325Pro).

All variants had in silico predictions in favor of a deleterious effect (CADD score >24).

The authors comment that MPP5 encodes an apical complex protein with asymmetric localization to the apical side of polarized cells. It is expressed in brain, peripheral nervous system and other tissues. MPP5 is a member of the membrane-associated guanylate kinase family of proteins (MAGUK, p55 subfamily), determining cell polarity at tight junctions.

Previous animal models suggest that complete Mpp5(Pals1) KO in mice leads to near absence of cerebral cortical neurons. Htz KO mice display reduction in size of cerebral cortex and hippocampus. The gene is expressed in proliferating cell populations of cerebellum and important for establishment cerebellar architecture. Conditional KO of Mpp5(Pals1) in retinal progenitor cells mimics the retinal pathology observed in LCA. [Several refs. provided]

The authors studied a heterozygous CNS-specific Mpp5 KO mouse model. These mice presented microcephaly, decreased cerebellar volume and cortical thickness, decreased ependymal cells and Mpp5 at the apical surface of cortical vertrical zone. The proportion of cortical cells undergoing apoptotic cell death was increased. Mice displayed behavioral abnormalities (hyperactivity) and visual deficits, with ERG traces further suggesting retinal blindness.

Overall the mouse model was thought to recapitulate the behavioral abnormalities observed in affected subjects as well as individual rare features such as microcephaly and abnormal vision.

Haploinsufficiency (rather than a dominant negative effect) is favored as the underlying disease mechanism. This is also in line with a dose dependent effect observed in mice.
Sources: Literature
Intellectual disability - microarray and sequencing v3.498 METTL5 Arina Puzriakova reviewed gene: METTL5: Rating: ; Mode of pathogenicity: None; Publications: 29302074, 31564433; Phenotypes: Intellectual developmental disorder, autosomal recessive 72, 618665; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.497 MFSD2A Arina Puzriakova Phenotypes for gene: MFSD2A were changed from NA to Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain imaging abnormalities, 616486
Intellectual disability - microarray and sequencing v3.494 MFSD2A Arina Puzriakova reviewed gene: MFSD2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 26005868, 26005865, 29302074, 30043326, 32572202; Phenotypes: Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain imaging abnormalities, 616486; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.492 NPHP3 Arina Puzriakova reviewed gene: NPHP3: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Nephronophthisis 3, 604387, Renal-hepatic-pancreatic dysplasia 1, 208540, Meckel syndrome 7, 267010; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.489 ZIC1 Arina Puzriakova reviewed gene: ZIC1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 26340333, 30391508; Phenotypes: ?Craniosynostosis 6, 616602, Structural brain anomalies with impaired intellectual development and craniosynostosis, 618736; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.487 ZNF335 Arina Puzriakova reviewed gene: ZNF335: Rating: GREEN; Mode of pathogenicity: None; Publications: 23178126, 27540107, 29652087, 30500859, 31187448; Phenotypes: Microcephaly 10, primary, autosomal recessive, 615095; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.485 ZNF148 Arina Puzriakova reviewed gene: ZNF148: Rating: AMBER; Mode of pathogenicity: None; Publications: 27964749; Phenotypes: Global developmental delay, absent or hypoplastic corpus callosum, and dysmorphic facies, 617260; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.484 COX6B1 Zornitza Stark reviewed gene: COX6B1: Rating: RED; Mode of pathogenicity: None; Publications: 18499082, 24781756; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 7, MIM# 619051; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.484 SCO1 Zornitza Stark reviewed gene: SCO1: Rating: RED; Mode of pathogenicity: None; Publications: 11013136, 19295170, 31352446, 23878101; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 4, MIM# 619048; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.484 PRKACB Konstantinos Varvagiannis gene: PRKACB was added
gene: PRKACB was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PRKACB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRKACB were set to 33058759
Phenotypes for gene: PRKACB were set to Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability
Penetrance for gene: PRKACB were set to unknown
Mode of pathogenicity for gene: PRKACB was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: PRKACB was set to AMBER
Added comment: ID was a feature in 2/4 individuals with PRKACB pathogenic variant reported to date.

Please consider inclusion of PRKACB (and PRKACA) in other relevant gene panels e.g. for polydactyly, congenital heart defects. The disorder may be considered in the DD of ciliopathies.

-----


Palencia-Campos et al (2020 - PMID: 33058759) report on the phenotype of 3 individuals heterozygous for PRKACA and 4 individuals heterozygous for PRKACB pathogenic variants.

The most characteristic features in all individuals with PRKACA/PRKACB mutation, included postaxial polydactyly of hands (6/7 bilateral, 1/7 unilateral) and feet (4/7 bilateral, 1/7 unilateral), brachydactyly and congenital heart defects (CHD 5/7) namely a common atrium or AVSD. Two individuals with PRKACA variant who did not have CHD had offspring with the same variant and an AVSD.

Other variably occurring features included short stature, limbs, narrow chest, abnormal teeth, oral frenula, nail dysplasia. One individual with PRKACB variant presented tumors.

Intellectual disability was reported in 2/4 individuals with PRKACB variant (1/4: mild, 1/4: severe). The 3 individuals with PRKACA variant did not present ID.

As the phenotype was overall suggestive of Ellis-van Creveld syndrome (or the allelic Weyers acrofacial dysostosis), although these diagnoses were ruled out following analysis of EVC and EVC2 genes.

WES was carried out in all.

PRKACA : A single heterozygous missense variant was identified in 3 individuals from 3 families (NM_002730.4:c.409G>A / p.Gly137Arg) with 1 of the probands harboring the variant in mosaic state (28% of reads) and having 2 similarly affected offspring. The variant was de novo in one individual and inherited in a third one having a similarly affected fetus (narrow thorax, postaxial polyd, AVSD).

PRKACB : 4 different variants were identified (NM_002731.3: p.His88Arg/Asn, p.Gly235Arg, c.161C>T - p.Ser54Leu). One of the individuals was mosaic for the latter variant, while in all other cases the variant had occurred de novo.

Protein kinase A (PKA) is a tetrameric holoenzyme formed by the association of 2 catalytic (C) subunits with a regulatory (R) subunit dimer. Activation of PKA is achieved through binding of 2 cAMP molecules to each R-subunit, and unleashing(/dissociation) of C-subunits to engage substrates. PRKACA/B genes encode the Cα- and Cβ-subunits while the 4 functionally non-redundant regulatory subunits are encoded by PRKAR1A/1B/2A/2B genes.

The authors provide evidence that the variants confer increased sensitivity of PKA holoenzymes to activation by cAMP (compared to wt).

By performing ectopic expression of wt or mt PRKACA/B (variants studied : PRKACA p.Gly137Arg / PRKACB p.Gly235Arg) in NIH 3T3 fibroblasts, the authors demonstrate that inhibition of hedgehog signaling likely underlyies the developmental defects observed in affected individuals.

As for PRKACA, the authors cite another study where a 31-month old female with EvC syndrome diagnosis was found to harbor the aforementioned variant (NM_001304349.1:c.637G>A:p.Gly213Arg corresponding to NM_002730.4:c.409G>A / p.Gly137Arg) as a de novo event. Without additional evidence at the time, the variant was considered to be a candidate for this subject's phenotype (Monies et al 2019 – PMID: 31130284).
Sources: Literature
Intellectual disability - microarray and sequencing v3.484 FA2H Sarah Leigh reviewed gene: FA2H: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.483 CDH2 Sarah Leigh reviewed gene: CDH2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.456 XYLT1 Arina Puzriakova reviewed gene: XYLT1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Desbuquois dysplasia 2, 615777; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.456 CSNK1G1 Konstantinos Varvagiannis reviewed gene: CSNK1G1: Rating: AMBER; Mode of pathogenicity: None; Publications: 33009664; Phenotypes: Global developmental delay, Intellectual disability, Autism, Seizures, Abnormality of the face, Abnormality of limbs; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.456 LMNB2 Konstantinos Varvagiannis gene: LMNB2 was added
gene: LMNB2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: LMNB2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LMNB2 were set to 33033404
Phenotypes for gene: LMNB2 were set to Congenital microcephaly; Global developmental delay; Intellectual disability
Penetrance for gene: LMNB2 were set to Complete
Mode of pathogenicity for gene: LMNB2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: LMNB2 was set to GREEN
Added comment: Parry et al (2020 - PMID: 33033404) in a study to identify novel microcephaly genes using the DDD and 100k genomes project (100kGP) patient cohort, report on the phenotype of 13 individuals with heterozygous variant in LMNB1 (N=7) and LMNB2 (N=6).

LMNB1 : The authors identified 3 recurrent variants (c.97A>G - p.Lys33Glu (3), c.97_99del - p.Lys33del (2) , c.269G>C - p.Arg90Pro (2) / NM_005573.4) in seven individuals (3 from the DDD study, 4 from the 100kGP). In all cases were segregation studies were possible, the variant had occurred as a de novo event.

LMNB2 : 4 individuals from the DDD cohort and 1 from the 100kGP were found to harbor the same missense SNV (NM_032737.4:c.1192G>A, p.Glu398Lys). The variant had occurred de novo in 3 subjects and was inherited from a mosaic - unaffected - parent in a further case. Another individual was found to harbor c.160A>C - p.Asn54His.

LMNB1/2 common phenotypes :
All cases had congenital microcephaly (OFC -5.85 +/- 1.14 SD) apart from one individual, without history of IUGR or postnatally abnormal height (the latter in most).

Neuroimaging suggested structurally normal brain without abnormal migration. Gyral simplification / global reduction in white matter / increased extra axial spaces / enlarged ventricles were reported in 2.

LMNB1 - Global developmental delay was a feature in all (mild to severe) with some having occasional words at 7y (P3), absent speech (P9 - age category 5-10y) or ID not further specified (P13).

LMNB2 - DD was a feature in all 6 subjects (5/6 moderate to severe - 1/6 GDD). 5/6 were 10y or older with language (in 3 language not achieved) and motor deficits (walking not achieved in 1/6 - occurred at the age of 6y in 1/6).

Facial features were not consistent nor suggestive of a syndromic diagnosis (sloping forehead in some).

Overall, as the authors comment, the phenotype corresponded to a severe nonsyndromic microcephaly (although additional features were reported in some).

Animal model:
Microcephaly is supported by Lmnb1 ko mouse model. Lmnb1/2 ko mice however display migration defects, while Lmnb2 ko mice do not have reduced size at birth. Heterozygous Lmnb1 mice do not present microcephaly. It is suggested that while animal models support a similar (to the human) phenotype the underlying mechanism is different.

Variant effect :
variants were shown to affect highly conserved residues within the lamin a-helical rod-domain. As affected residues are conserved in LMNA, modelling with available LMNA PDB structures, suggested disrupted interactions required for higher-order assembly of lamin filaments.

Recurrence of specific variants at specific residues, absence of pLoF ones, the htz mouse Lmnb1 phenotype (absence of microcephaly) and the proposed mechanism (perturbation of complex formation) suggest a gain-of-function/dominant-negative effect rather than happloinsufficiency.

[Please also note the additional OMIM phenotypes for LMNB1 / LMNB2 - not here reviewed]
Sources: Literature
Intellectual disability - microarray and sequencing v3.456 LMNB1 Konstantinos Varvagiannis edited their review of gene: LMNB1: Added comment: There is an additional report on LMBN1/2-associated phenotypes supporting green rating of the gene in the current panel.

Parry et al (2020 - PMID: 33033404) in a study to identify novel microcephaly genes using the DDD and 100k genomes project (100kGP) patient cohort, report on the phenotype of 13 individuals with heterozygous variant in LMNB1 (N=7) and LMNB2 (N=6).

LMNB1 : The authors identified 3 recurrent variants (c.97A>G - p.Lys33Glu (3), c.97_99del - p.Lys33del (2) , c.269G>C - p.Arg90Pro (2) / NM_005573.4) in seven individuals (3 from the DDD study, 4 from the 100kGP). In all cases were segregation studies were possible, the variant had occurred as a de novo event.

LMNB2 : 4 individuals from the DDD cohort and 1 from the 100kGP were found to harbor the same missense SNV (NM_032737.4:c.1192G>A, p.Glu398Lys). The variant had occurred de novo in 3 subjects and was inherited from a mosaic - unaffected - parent in a further case. Another individual was found to harbor c.160A>C - p.Asn54His.

LMNB1/2 common phenotypes :
All cases had congenital microcephaly (OFC -5.85 +/- 1.14 SD) appart from one individual, without history of IUGR or postnatally abnormal height (the latter in most).

Neuroimaging suggested structurally normal brain without abnormal migration. Gyral simplification / global reduction in white matter / increased extra axial spaces / enlarged ventricles were reported in 2.

LMNB1 - Global developmental delay was a feature in all (mild to severe) with some having occasional words at 7y (P3), absent speech (P9 - age category 5-10y) or ID not further specified (P13).

LMNB2 - DD was a feature in all 6 subjects (5/6 moderate to severe - 1/6 GDD). 5/6 were 10y or older with language (in 3 language not achieved) and motor deficits (walking not achieved in 1/6 - occured at the age of 6y in 1/6).

Facial features were not consistent nor suggestive of a syndromic diagnosis (sloping forehead in some).

Overall, as the authors comment, the phenotype corresponded to a severe nonsyndromic microcephaly (although additional features were reported in some).

Animal model:
Microcephaly is supported by Lmnb1 ko mouse model. Lmnb1/2 ko mice however display migration defects, while Lmnb2 ko mice do not have reduced size at birth. Heterozygous Lmnb1 mice do not present microcephaly. It is suggested that while animal models support a similar (to the human) phenotype the underlying mechanism is different.

Variant effect :
variants were shown to affect highly conserved residues within the lamin a-helical rod-domain. As affected residues are conserved in LMNA, modelling with available LMNA PDB structures, suggested disrupted interactions required for higher-order assembly of lamin filaments.

Recurrence of specific variants at specific residues, absence of pLoF ones, the htz mouse Lmnb1 phenotype (absence of microcephaly) and the proposed mechanism (perturbation of complex formation) suggest a gain-of-function/dominant-negative effect rather than happloinsufficiency.

[Please also note the additional OMIM phenotypes for LMNB1 / LMNB2 - not here reviewed]; Changed publications: 32910914, 33033404
Intellectual disability - microarray and sequencing v3.451 USP7 Arina Puzriakova reviewed gene: USP7: Rating: GREEN; Mode of pathogenicity: None; Publications: 26365382, 30679821, 33012787; Phenotypes: Hao-Fountain syndrome, 616863; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.446 TRPM3 Arina Puzriakova reviewed gene: TRPM3: Rating: ; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 32439617, 32343227, 32427099; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.446 FGF14 Arina Puzriakova Added comment: Comment on list classification: Cognitive impairment has been reported in several patients, mostly mild but few cases with moderate deficits have also been described. However, the phenotype is mainly characterised by ataxia which would be the expected CI for diagnostic testing - FGF14 is already Green on Ataxia panels.

The utility of calling variants in this gene in a cohort of ID patients without the ataxic component is unlikely to be of benefit, and therefore the rating has been kept Amber on this panel.
Intellectual disability - microarray and sequencing v3.438 CEP104 Arina Puzriakova reviewed gene: CEP104: Rating: GREEN; Mode of pathogenicity: None; Publications: 31625690; Phenotypes: Joubert syndrome 25, 616781; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.432 C2CD3 Arina Puzriakova reviewed gene: C2CD3: Rating: ; Mode of pathogenicity: None; Publications: 24997988, 26092869, 26477546, 27094867; Phenotypes: Orofaciodigital syndrome XIV, 615948, Joubert-related disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.420 SHMT2 Konstantinos Varvagiannis gene: SHMT2 was added
gene: SHMT2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SHMT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHMT2 were set to 33015733
Phenotypes for gene: SHMT2 were set to Congenital microcephaly; Infantile axial hypotonia; Spastic paraparesis; Global developmental delay; Intellectual disability; Abnormality of the corpus callosum; Abnormal cortical gyration; Hypertrophic cardiomyopathy; Abnormality of the face; Proximal placement of thumb; 2-3 toe syndactyly
Penetrance for gene: SHMT2 were set to Complete
Review for gene: SHMT2 was set to GREEN
Added comment: García‑Cazorla et al. (2020 - PMID: 33015733) report 5 individuals (from 4 families) with a novel brain and heart developmental syndrome caused by biallelic SHMT2 pathogenic variants.

All affected subjects presented similar phenotype incl. microcephaly at birth (5/5 OFC < -2 SD though in 2/5 cases N OFC was observed later), DD and ID (1/5 mild-moderate, 1/5 moderate, 3/5 severe), motor dysfunction in the form of spastic (5/5) paraparesis, ataxia/dysmetria (3/4), intention tremor (in 3/?) and/or peripheral neuropathy (2 sibs). They exhibited corpus callosum hypoplasia (5/5) and perisylvian microgyria-like pattern (4/5). Cardiac problems were reported in all, with hypertrophic cardiomyopathy in 4/5 (from 3 families) and atrial-SD in the 5th individual (1/5). Common dysmorphic features incl. long palpebral/fissures, eversion of lateral third of lower eylids, arched eyebrows, long eyelashes, thin upper lip, short Vth finger, fetal pads, mild 2-3 toe syndactyly, proximally placed thumbs.

Biallelic variants were identified following exome sequencing in all (other investigations not mentioned). Identified variants were in all cases missense SNVs or in-frame del, which together with evidence from population databases and mouse model might suggest a hypomorphic effect of variants and intolerance/embryonic lethality for homozygous LoF ones.

SHMT2 encodes the mitohondrial form of serine hydroxymethyltransferase. The enzyme transfers one-carbon units from serine to tetrahydrofolate (THF) and generates glycine and 5,10,methylene-THF.

Mitochondrial defect was suggested by presence of ragged red fibers in myocardial biopsy of one patient. Quadriceps and myocardial biopsies of the same individual were overall suggestive of myopathic changes.

While plasma metabolites were within N range and SHMT2 protein levels not significantly altered in patient fibroblasts, the authors provide evidence for impaired enzymatic function eg. presence of the SHMT2 substrate (THF) in patient but not control (mitochondria-enriched) fibroblasts , decrease in glycine/serine ratios, impared folate metabolism. Patient fibroblasts displayed impaired oxidative capacity (reduced ATP levels in a medium without glucose, diminished oxygen consumption rates). Mitochondrial membrane potential and ROS levels were also suggestive of redox malfunction.

Shmt2 ko in mice was previously shown to be embryonically lethal attributed to severe mitochondrial respiration defects, although there was no observed brain metabolic defect.

The authors performed Shmt2 knockdown in motoneurons in Drosophila, demonstrating neuromuscular junction (# of satellite boutons) and motility defects (climbing distance/velocity).

Overall this gene can be considered for inclusion with (probably) green rating in gene panels for ID, metabolic / mitochondrial disorders, cardiomyopathy, congenital microcephaly, corpus callosum anomalies, etc.
Sources: Literature
Intellectual disability - microarray and sequencing v3.407 NEDD4L Eleanor Williams reviewed gene: NEDD4L: Rating: GREEN; Mode of pathogenicity: None; Publications: 27694961; Phenotypes: Periventricular nodular heterotopia 7, 617201; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.404 NUP214 Eleanor Williams reviewed gene: NUP214: Rating: AMBER; Mode of pathogenicity: None; Publications: 31178128; Phenotypes: {Encephalopathy, acute, infection-induced, susceptibility to, 9}, 618426; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.397 USP18 Arina Puzriakova reviewed gene: USP18: Rating: ; Mode of pathogenicity: None; Publications: 12833411, 27325888, 31940699; Phenotypes: Pseudo-TORCH syndrome 2, 617397; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.395 HYLS1 Catherine Snow reviewed gene: HYLS1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Hydrolethalus syndrome, MIM#236680; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.395 MGP Sarah Leigh reviewed gene: MGP: Rating: RED; Mode of pathogenicity: None; Publications: 24458983, 29928182, 25123378, 26349188, 26758921; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.393 LGI4 Sarah Leigh reviewed gene: LGI4: Rating: RED; Mode of pathogenicity: None; Publications: 28318499; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.387 DLL1 Catherine Snow reviewed gene: DLL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31353024, 31602192; Phenotypes: Neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures 618709; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.367 PRKD1 Arina Puzriakova reviewed gene: PRKD1: Rating: AMBER; Mode of pathogenicity: None; Publications: 27479907, 32817298; Phenotypes: Congenital heart defects and ectodermal dysplasia, 617364; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.363 CUL3 Arina Puzriakova reviewed gene: CUL3: Rating: ; Mode of pathogenicity: None; Publications: 25969726; Phenotypes: Autism spectrum disorder, Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.360 SETD1A Zerin Hyder reviewed gene: SETD1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 32346159; Phenotypes: Epilepsy, early-onset, with or without developmental delay, craniofacial dysmorphisms, behavioural/psychiatric abnormalities; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.355 NUP188 Arina Puzriakova reviewed gene: NUP188: Rating: GREEN; Mode of pathogenicity: None; Publications: 32021605, 32275884; Phenotypes: Sandestig-Stefanova syndrome, 618804; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.349 KDM6B Arina Puzriakova reviewed gene: KDM6B: Rating: GREEN; Mode of pathogenicity: None; Publications: 31124279; Phenotypes: Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities, 618505; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.347 HADH Arina Puzriakova reviewed gene: HADH: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Hyperinsulinemic hypoglycemia, familial, 4, 609975, 3-hydroxyacyl-CoA dehydrogenase deficiency, 231530; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.341 ABAT Arina Puzriakova reviewed gene: ABAT: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: GABA-transaminase deficiency, 613163; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.338 ACADSB Arina Puzriakova reviewed gene: ACADSB: Rating: ; Mode of pathogenicity: None; Publications: 30730842; Phenotypes: 2-methylbutyrylglycinuria, 610006; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.336 AHCY Arina Puzriakova reviewed gene: AHCY: Rating: GREEN; Mode of pathogenicity: None; Publications: 15024124, 16435181, 16736098, 20852937, 22959829, 26095522, 26527160, 28779239, 30121674, 31957987; Phenotypes: Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, 613752; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.335 DDOST Eleanor Williams reviewed gene: DDOST: Rating: AMBER; Mode of pathogenicity: None; Publications: 22305527; Phenotypes: ?Congenital disorder of glycosylation, type Ir, 614507, CONGENITAL DISORDER OF GLYCOSYLATION, TYPE IR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.335 CYP2U1 Eleanor Williams reviewed gene: CYP2U1: Rating: AMBER; Mode of pathogenicity: None; Publications: 23176821; Phenotypes: Spastic paraplegia 56, autosomal recessive, 615030; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.332 AGPS Arina Puzriakova reviewed gene: AGPS: Rating: AMBER; Mode of pathogenicity: None; Publications: 7807941, 11152660, 11152660, 21990100; Phenotypes: Rhizomelic chondrodysplasia punctata, type 3, 600121; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.332 MECP2 Arina Puzriakova reviewed gene: MECP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32469049; Phenotypes: Rett syndrome, 312750; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability - microarray and sequencing v3.332 UPF3B Arina Puzriakova reviewed gene: UPF3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 32667670; Phenotypes: Mental retardation, X-linked, syndromic 14, 300676; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability - microarray and sequencing v3.325 WASHC4 Arina Puzriakova reviewed gene: WASHC4: Rating: ; Mode of pathogenicity: None; Publications: 21498477, 31953988; Phenotypes: Mental retardation, autosomal recessive 43, 615817; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.315 TRAK1 Arina Puzriakova reviewed gene: TRAK1: Rating: ; Mode of pathogenicity: None; Publications: 28940097, 28364549, 29846532; Phenotypes: Epileptic encephalopathy, early infantile, 68, 618201; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.315 SLC12A2 Konstantinos Varvagiannis reviewed gene: SLC12A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28135719, 32658972, 27900370, 32294086, 29288388, 30740830, 32754646; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.314 DHX37 Arina Puzriakova reviewed gene: DHX37: Rating: GREEN; Mode of pathogenicity: None; Publications: 26539891, 31256877; Phenotypes: Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies, 618731; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.314 LMNB1 Konstantinos Varvagiannis gene: LMNB1 was added
gene: LMNB1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: LMNB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LMNB1 were set to 32910914
Phenotypes for gene: LMNB1 were set to Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis
Penetrance for gene: LMNB1 were set to unknown
Mode of pathogenicity for gene: LMNB1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: LMNB1 was set to GREEN
Added comment: Cristofoli et al (2020 - PMID: 32910914) report 7 individuals (from 5 families) harboring mostly de novo LMNB1 variants.

The common phenotype consisted of primary microcephaly (7/7 ranging from -4.4 to -10 SD), DD/ID (7/7), relative short stature in most (+0.7 to -4 SD). Additional features included brain MRI abnormalities (abnormal CC in 3, simplified gyral pattern in 3, small structurally normal brain, etc), seizures (4 individuals from 2 families), limb spasticity (1/7), cortical visual impairment (in 3), feeding difficulties (5/7), scoliosis (4/7). Non-overlapping dysmorphic features were reported in some.

Variants were identified by WES or custom-designed gene panel and included 3 missense variants, 1 in-frame deletion and a splice variant. The in-frame deletion was inherited from a similarly affected parent in whom the variant occurred as a dn event. The splice SNV(NM_005573.3:c.939+1G>A) occurred in 3 sibs and was present as mosaic variant (15%) in the parent. This variant was predicted to result to extension of exon 5 by 6 amino-acids (samples were unavailable for mRNA studies).

LMNB1 encodes a B-type lamin (the other being encoded by LMNB2). A- and B- type lamins are major components of the nuclear lamina. As the authors comment, LMNB1 is expressed in almost all cell types beginning at the earliest stages of development.

Lamin-deficient mouse models support an essential role of B-type lamins in organogenesis, neuronal migration, patterning during brain development.

Functional studies performed, demonstrated impaired formation of LMNB1 nuclear lamina in LMNB1-null HeLa cells transfected with cDNAs for 3 missense variants.

Two variants (Lys33Glu/Arg42Trp) were shown to result in decreased nuclear localization with increased abundance in the cytosolic fraction. In patient derived LCLs these variants led to abnormal nuclear morphology. A missense variant in another domain (Ala152Gly - 1st coil domain) resulted also in lower abundance of lamin B1, irregular lamin A/C nuclear lamina, as well as more condensed nuclei (HeLa cells).

LMNB1 duplications or missense mutations increasing LMNB1 expression are associated with a different presentation of AD leuodystrophy. A variant previously associated with leukodystrophy (Arg29Trp) was shown to behave differently (present in the nuclear extract but not in the cytosol, lamin B1 to A/C ratio in nuclear extract was not significantly altered compared to wt as was the case for Arg42Trp, Lys33Glu).

Given the pLI score of 0.55 as well as the phenotype of individuals with deletions (not presenting microcephaly) the authors predict that a dominant-negative effect applies (rather than haploinsufficiency).

Consider inclusion in the following panels : DD/ID (green), epilepsy (amber - 4 of 7 patients belonging to 2 families), primary microcephaly (green), callosome (amber/green - 3 individuals belonging to 3 families), mendeliome (green), etc.
Sources: Literature
Intellectual disability - microarray and sequencing v3.312 CAMK2G Arina Puzriakova Mode of pathogenicity for gene: CAMK2G was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability - microarray and sequencing v3.304 VAMP1 Arina Puzriakova Added comment: Comment on list classification: Literature search revealed that developmental delay primarily affects motor function, and it is unclear whether patients exhibit any cognitive deficit. Additional cases would help delineate the association with this phenotype.

Therefore, recommending a rating downgrade from Green to Amber/Red at the next major review, awaiting further publications/clinical evidence.
Intellectual disability - microarray and sequencing v3.295 RAD50 Zornitza Stark reviewed gene: RAD50: Rating: AMBER; Mode of pathogenicity: None; Publications: 32212377; Phenotypes: Nijmegen breakage syndrome-like disorder, MIM# 613078; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.295 ANKH Sarah Leigh reviewed gene: ANKH: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.293 TNR Arina Puzriakova reviewed gene: TNR: Rating: GREEN; Mode of pathogenicity: None; Publications: 22730557, 32099069; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.287 SLC12A2 Arina Puzriakova reviewed gene: SLC12A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28940097, 30740830, 32754646; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.281 PAK3 Arina Puzriakova reviewed gene: PAK3: Rating: ; Mode of pathogenicity: None; Publications: 31943058; Phenotypes: Intellectual disability; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability - microarray and sequencing v3.274 ADARB1 Arina Puzriakova edited their review of gene: ADARB1: Added comment: PMID: 32719099 (2020) - Three additional patients from two consanguineous families with novel biallelic variants in the ADARB1 gene. All affected individuals presented global DD, severe-profound ID, intractable early infantile-onset seizures, severe microcephaly, axial hypotonia and progressive appendicular spasticity. In vitro RNA editing assays showed that both variants resulted in severe impairment or loss of ADAR2 enzymatic activity.; Changed publications: 32220291, 32719099
Intellectual disability - microarray and sequencing v3.272 TKFC Arina Puzriakova reviewed gene: TKFC: Rating: AMBER; Mode of pathogenicity: None; Publications: 32004446; Phenotypes: Triokinase and FMN cyclase deficiency syndrome, 618805; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.271 TP73 Arina Puzriakova reviewed gene: TP73: Rating: RED; Mode of pathogenicity: None; Publications: 31130284; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.270 SMG8 Arina Puzriakova reviewed gene: SMG8: Rating: RED; Mode of pathogenicity: None; Publications: 31130284; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.269 RAP1GDS1 Arina Puzriakova reviewed gene: RAP1GDS1: Rating: ; Mode of pathogenicity: None; Publications: 32431071; Phenotypes: Intellectual disability, Global developmental delay, Hypotonia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.269 PDCD6IP Arina Puzriakova Added comment: Comment on list classification: Phenotype is relevant to this panel but additional cases required to validate pathogenicity of variants in this gene.
Intellectual disability - microarray and sequencing v3.267 TUBGCP2 Arina Puzriakova reviewed gene: TUBGCP2: Rating: AMBER; Mode of pathogenicity: None; Publications: 31630790; Phenotypes: Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures, 618737; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.265 PPP1R12A Arina Puzriakova reviewed gene: PPP1R12A: Rating: GREEN; Mode of pathogenicity: None; Publications: 31883643; Phenotypes: Genitourinary and/or/brain malformation syndrome, 618820; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.262 TENM3 Arina Puzriakova reviewed gene: TENM3: Rating: ; Mode of pathogenicity: None; Publications: 22766609, 27103084, 30513139, 29753094; Phenotypes: Microphthalmia, syndromic 15, 615145, ?Microphthalmia, isolated, with coloboma 9, 615145; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.262 KAT5 Konstantinos Varvagiannis reviewed gene: KAT5: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 32822602; Phenotypes: Severe global developmental delay, Intellectual disability, Seizures, Microcephaly, Behavioral abnormality, Sleep disturbance, Morphological abnormality of the central nervous system, Short stature, Oral cleft, Abnormality of the face; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.262 LMBRD2 Konstantinos Varvagiannis gene: LMBRD2 was added
gene: LMBRD2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: LMBRD2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LMBRD2 were set to 32820033; https://doi.org/10.1101/797787
Phenotypes for gene: LMBRD2 were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Abnormality of nervous system morphology; Abnormality of the eye
Penetrance for gene: LMBRD2 were set to unknown
Review for gene: LMBRD2 was set to AMBER
Added comment: You may consider inclusion with green (13 individuals with dn missense SNVs overall, overlapping features for 10 with available phenotype / a recurring variant has been identified in 2 different studies) or amber rating (role of the gene not known, no variant studies, animal model probably not available).

► Malhotra et al (2020 - PMID: 32820033) report on 10 unrelated individuals with de novo missense LMBRD2 variants.

Features included DD (9/10), ID (6/8 of relevant age), microcephaly (7/10), seizures (5/10 - >=3 different variants), structural brain abnormalities (e.g. thin CC in 6/9), highly variable ocular abnormalities (5/10) and dysmorphic features in some (7/10 - nonspecific).

All had variable prior non-diagnostic genetic tests (CMA, gene panel, mendeliome, karyotype). WES/WGS revealed LMBRD2 missense variants, in all cases de novo. A single individual had additional variants with weaker evidence of pathogenicity.

5 unique missense SNVs and 2 recurrent ones (NM_001007527:c.367T>C - p.Trp123Arg / c.1448G>A - p.Arg483His) were identified. These occurred in different exons. Variants were not present in gnomAD and all had several in silico predictions in favor of a deleterious effect.

There was phenotypic variability among individuals with the same variant (e.g. seizures in 1/3 and microchephaly in 2/3 of those harboring R483H).

The gene has a pLI of 0 (although o/e ranges from 0.23 to 0.55), %HI of 15.13 and z-score of 2.27. The authors presume that haploinsufficiency may not apply, and consider a gain-of-function/dominant-negative effect more likely.

As the authors comment LMBRD2 (LMBR1 domain containing 2) encodes a membrane bound protein with poorly described function. It is widely expressed across tissues with notable expression in human brain (also in Drosophila, or Xenopus laevis). It displays high interspecies conservation.

It has been suggested (Paek et al - PMID: 28388415) that LMBRD2 is a potential regulator of β2 adrenoreceptor signalling through involvement in GPCR signalling.

► Kaplanis et al (2020 - https://doi.org/10.1101/797787) in a dataset of 31058 parent-offspring trios (WES) previously identified 3 individuals with developmental disorder, harboring c.1448G>A - p.Arg483His. These individuals (1 from the DDD study, and 2 GeneDx patients) appear in Decipher. [ https://decipher.sanger.ac.uk/ddd/research-variant/40e17c78cc9655a6721006fc1e0c98db/overview ]. The preprint by Kaplanis et al is cited by Malhotra et al, with Arg483His reported in 6 patients overall in both studies.
Sources: Literature
Intellectual disability - microarray and sequencing v3.256 PISD Arina Puzriakova reviewed gene: PISD: Rating: ; Mode of pathogenicity: None; Publications: 31263216, 30858161, 30488656, 3561949; Phenotypes: Liberfarb syndrome, 618889; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.255 PIBF1 Arina Puzriakova reviewed gene: PIBF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26167768, 29695797, 30858804; Phenotypes: Joubert syndrome 33, 617767; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.255 TAF1C Konstantinos Varvagiannis gene: TAF1C was added
gene: TAF1C was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TAF1C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TAF1C were set to 32779182
Phenotypes for gene: TAF1C were set to Global developmental delay; Intellectual disability; Spasticity; Strabismus; Seizures; Abnormality of nervous system morphology
Penetrance for gene: TAF1C were set to Complete
Review for gene: TAF1C was set to AMBER
Added comment: Knuutinen et al (2020 - PMID: 32779182) report on 2 individuals from 2 consanguineous families, homozygous for TAF1C missense variants.

Both presented with an early onset neurological phenotype with severe global DD, ID (2/2 - moderate and profound), spasticity (2/2), ophthalmic findings (strabismus 2/2, nystagmus 1/2). Epilepsy, abnormal brain MRI (cerebral and cerebellar atrophy and white matter hyperintensities) as well and additional findings were reported in one (always the same individual).

Following a normal CMA, exome in the first case revealed a homozygous missense SNV (NM_005679.3:c.1165C>T / p.Arg389Cys) supported by in silico predictions. mRNA and protein levels were substantially reduced in fibroblasts from this subject. Only the patient and parents were tested for the variant but not 3 unaffected sibs (fig1).

The second individual was homozygous for another missense variant (p.Arg405Cys) also supported by in silico predictions. The girl was the single affected person within the family with an unaffected sib and parents heterozygous for the variant. Several other unaffected relatives in the extended pedigree were either carriers for this variant or homozygous for the wt allele.

TAF1C encodes the TATA-box binding protein associated factor (TAF) RNA polymerase I subunit.

RNA polymerase I (Pol I) transcribes genes to produce rRNA. For Pol I to initiate transcription, two transcription factors are required : UBF (upstream binding factor encoded by UBTF) and SL1 (selectivity factor 1). The latter is formed by TBP (TATA-binding protein) and 3 Pol I-specific TBP-associated factors (TAFs).

A recurrent de novo missense variant in UBTF (encoding the other Pol I transcription factor) causes a disorder with highly similar features. The specific variant acts through a gain-of-function mechanism (and not by LoF which appears to apply for TAF1C based on expression data).

The authors hypothesize that altered Pol I activity and resulting ribosomal stress could cause the microcephaly and leukodystrophy (both reported in 1 - the same - individual).

As a result, TAF1C may be considered for inclusion in the ID panel with amber rating pending further evidence.
Sources: Literature
Intellectual disability - microarray and sequencing v3.246 PDP1 Arina Puzriakova reviewed gene: PDP1: Rating: ; Mode of pathogenicity: None; Publications: 15855260, 19184109, 31392110; Phenotypes: Pyruvate dehydrogenase phosphatase deficiency, 608782; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.239 MADD Konstantinos Varvagiannis reviewed gene: MADD: Rating: GREEN; Mode of pathogenicity: None; Publications: 28940097, 29302074, 32761064; Phenotypes: Global developmental delay / Intellectual disability / Seizures, Global developmental delay / Intellectual disability / Seizures / Abnormality of the endocrine system / Exocrine pancreatic insufficiency / Constipation / Diarrhea / Anemia / Thrombocytopenia / Abnormality of the autonomic nervous system; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.237 AFF3 Sarah Leigh reviewed gene: AFF3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.226 PJA1 Zornitza Stark reviewed gene: PJA1: Rating: AMBER; Mode of pathogenicity: None; Publications: 32530565; Phenotypes: Intellectual disability, trigonocephaly; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.226 SCAF4 Zornitza Stark reviewed gene: SCAF4: Rating: GREEN; Mode of pathogenicity: None; Publications: 32730804; Phenotypes: intellectual disability, seizures, behavioral abnormalities; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.226 PIGQ Konstantinos Varvagiannis reviewed gene: PIGQ: Rating: GREEN; Mode of pathogenicity: None; Publications: 32588908, 24463883, 25558065, 31148362; Phenotypes: Epileptic encephalopathy, early infantile, 77 (MIM #618548); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.225 EIF2AK2 Arina Puzriakova reviewed gene: EIF2AK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32197074; Phenotypes: Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome, 618877; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.224 FARSB Arina Puzriakova reviewed gene: FARSB: Rating: AMBER; Mode of pathogenicity: None; Publications: 29573043, 29979980, 30014610; Phenotypes: Rajab interstitial lung disease with brain calcifications, 613658; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.223 IREB2 Arina Puzriakova reviewed gene: IREB2: Rating: ; Mode of pathogenicity: None; Publications: 30915432, 31243445; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.222 CHD1 Arina Puzriakova reviewed gene: CHD1: Rating: ; Mode of pathogenicity: None; Publications: 28866611; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.221 PAM16 Arina Puzriakova reviewed gene: PAM16: Rating: ; Mode of pathogenicity: None; Publications: 24786642, 27354339; Phenotypes: Spondylometaphyseal dysplasia, Megarbane-Dagher-Melike type, 613320; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.220 NDUFA2 Arina Puzriakova reviewed gene: NDUFA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18513682, 28857146, 32154054; Phenotypes: Mitochondrial complex I deficiency, nuclear type 13, 618235; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.219 NDUFAF1 Arina Puzriakova reviewed gene: NDUFAF1: Rating: ; Mode of pathogenicity: None; Publications: 17557076, 21931170, 24963768; Phenotypes: Mitochondrial complex I deficiency, nuclear type 11, 618234; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.219 NARS Konstantinos Varvagiannis changed review comment from: [Please note that HGNC Approved Gene Symbol for this gene is NARS1]

Manole et al (2020 - PMID: 32738225) provide evidence that both biallelic and monoallelic (de novo) pathogenic NARS1 variants cause a neurodevelopmental disorder. In total 32 individuals from 21 families are reported, with biallelic variants identified in individuals from 13 families and de novo in 8 families.

Similar features were reported for AR/AD occurrences of the disorder and included of microcephaly (90% - most often primary), epilepsy (23/32 or 74% - variable semiology incl. partial/myoclonic/generalized tonic-clonic seizures), DD and ID (as a universal feature), abnormal tone in several (hypotonia/spasticity), ataxia, demyelinating peripheral neuropathy (in 3 or more for each inheritance mode - or a total of 25%). Some individuals had dysmorphic features.

NARS1 encodes an aminoacyl-tRNA synthetase (ARS) [asparaginyl-tRNA synthetase 1]. Aminoacyl-tRNA synthetases constitute a family of enzymes catalyzing attachment of amino-acids to their cognate tRNAs. As the authors comment, mutations in genes encoding several other ARSs result in neurological disorders ranging from peripheral neuropathy to severe multi-systemic NDD. Dominant, recessive or both modes for inheritance for mutations in the same gene (e.g. AARS1, YARS1, MARS1, etc) have been reported.

Some variants were recurrent, e.g. the c.1600C>T / p.Arg534* which occurred in 6 families as a de novo event or c.1633C>T p.Arg545Cys (homozygous in 6 families). 3 different variants were reported to have occured de novo (c.965G>T - p.Arg322Leu, c.1525G>A - p.Gly509Ser, p.Arg534*) with several other variants identified in hmz/compound htz individuals. A single SNV (c.1067A>C - p.Asp356Ala) was suggested to be acting as modifier and pathogenic only when in trans with a severe variant. [NM_004539.4 used as RefSeq for all].

The authors provide several lines of evidence for a partial loss-of-function effect (e.g. reduction in mRNA expression, enzyme levels and activity in fibroblasts or iNPCs) underlying pathogenicity of the variants identified in individuals with biallelic variants. A gain-of-function (dominant-negative) effect is proposed for de novo variants (such effect also demonstrated for the p.Arg534* in a zebrafish model).

As also Manole et al suggest, NARS1 can be considered for inclusion in gene panels for DD/ID, epilepsy and/or demyelinating neuropathy.
Sources: Literature; to: [Please note that HGNC Approved Gene Symbol for this gene is NARS1]

Manole et al (2020 - PMID: 32738225) provide evidence that both biallelic and monoallelic (de novo) pathogenic NARS1 variants cause a neurodevelopmental disorder. In total 32 individuals from 21 families are reported, with biallelic variants identified in individuals from 13 families and de novo in 8 families.

Similar features were reported for AR/AD occurrences of the disorder and included microcephaly (90% - most often primary), epilepsy (23/32 or 74% - variable semiology incl. partial/myoclonic/generalized tonic-clonic seizures), DD and ID (as a universal feature), abnormal tone in several (hypotonia/spasticity), ataxia, demyelinating peripheral neuropathy (in 3 or more for each inheritance mode - or a total of 25%). Some individuals had dysmorphic features.

NARS1 encodes an aminoacyl-tRNA synthetase (ARS) [asparaginyl-tRNA synthetase 1]. Aminoacyl-tRNA synthetases constitute a family of enzymes catalyzing attachment of amino-acids to their cognate tRNAs. As the authors comment, mutations in genes encoding several other ARSs result in neurological disorders ranging from peripheral neuropathy to severe multi-systemic NDD. Dominant, recessive or both modes for inheritance for mutations in the same gene (e.g. AARS1, YARS1, MARS1, etc) have been reported.

Some variants were recurrent, e.g. the c.1600C>T / p.Arg534* which occurred in 6 families as a de novo event or c.1633C>T p.Arg545Cys (homozygous in 6 families). 3 different variants were reported to have occured de novo (c.965G>T - p.Arg322Leu, c.1525G>A - p.Gly509Ser, p.Arg534*) with several other variants identified in hmz/compound htz individuals. A single SNV (c.1067A>C - p.Asp356Ala) was suggested to be acting as modifier and pathogenic only when in trans with a severe variant. [NM_004539.4 used as RefSeq for all].

The authors provide several lines of evidence for a partial loss-of-function effect (e.g. reduction in mRNA expression, enzyme levels and activity in fibroblasts or iNPCs) underlying pathogenicity of the variants identified in individuals with biallelic variants. A gain-of-function (dominant-negative) effect is proposed for de novo variants (such effect also demonstrated for the p.Arg534* in a zebrafish model).

As also Manole et al suggest, NARS1 can be considered for inclusion in gene panels for DD/ID, epilepsy and/or demyelinating neuropathy.
Sources: Literature
Intellectual disability - microarray and sequencing v3.219 NARS Konstantinos Varvagiannis gene: NARS was added
gene: NARS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NARS was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NARS were set to 32738225
Phenotypes for gene: NARS were set to Abnormal muscle tone; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Ataxia; Abnormality of the face; Demyelinating peripheral neuropathy
Penetrance for gene: NARS were set to Complete
Review for gene: NARS was set to GREEN
Added comment: [Please note that HGNC Approved Gene Symbol for this gene is NARS1]

Manole et al (2020 - PMID: 32738225) provide evidence that both biallelic and monoallelic (de novo) pathogenic NARS1 variants cause a neurodevelopmental disorder. In total 32 individuals from 21 families are reported, with biallelic variants identified in individuals from 13 families and de novo in 8 families.

Similar features were reported for AR/AD occurrences of the disorder and included of microcephaly (90% - most often primary), epilepsy (23/32 or 74% - variable semiology incl. partial/myoclonic/generalized tonic-clonic seizures), DD and ID (as a universal feature), abnormal tone in several (hypotonia/spasticity), ataxia, demyelinating peripheral neuropathy (in 3 or more for each inheritance mode - or a total of 25%). Some individuals had dysmorphic features.

NARS1 encodes an aminoacyl-tRNA synthetase (ARS) [asparaginyl-tRNA synthetase 1]. Aminoacyl-tRNA synthetases constitute a family of enzymes catalyzing attachment of amino-acids to their cognate tRNAs. As the authors comment, mutations in genes encoding several other ARSs result in neurological disorders ranging from peripheral neuropathy to severe multi-systemic NDD. Dominant, recessive or both modes for inheritance for mutations in the same gene (e.g. AARS1, YARS1, MARS1, etc) have been reported.

Some variants were recurrent, e.g. the c.1600C>T / p.Arg534* which occurred in 6 families as a de novo event or c.1633C>T p.Arg545Cys (homozygous in 6 families). 3 different variants were reported to have occured de novo (c.965G>T - p.Arg322Leu, c.1525G>A - p.Gly509Ser, p.Arg534*) with several other variants identified in hmz/compound htz individuals. A single SNV (c.1067A>C - p.Asp356Ala) was suggested to be acting as modifier and pathogenic only when in trans with a severe variant. [NM_004539.4 used as RefSeq for all].

The authors provide several lines of evidence for a partial loss-of-function effect (e.g. reduction in mRNA expression, enzyme levels and activity in fibroblasts or iNPCs) underlying pathogenicity of the variants identified in individuals with biallelic variants. A gain-of-function (dominant-negative) effect is proposed for de novo variants (such effect also demonstrated for the p.Arg534* in a zebrafish model).

As also Manole et al suggest, NARS1 can be considered for inclusion in gene panels for DD/ID, epilepsy and/or demyelinating neuropathy.
Sources: Literature
Intellectual disability - microarray and sequencing v3.219 ZNF407 Konstantinos Varvagiannis gene: ZNF407 was added
gene: ZNF407 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ZNF407 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ZNF407 were set to 24907849; 32737394; 23195952
Phenotypes for gene: ZNF407 were set to Global developmental delay; Intellectual disability
Penetrance for gene: ZNF407 were set to unknown
Review for gene: ZNF407 was set to AMBER
Added comment: You may consider inclusion of this gene probably with amber rating (or green if the evidence for biallelic variants is considered sufficient).

Biallelic variants:

- Kambouris et al. (2014 - PMID: 24907849) described 2 brothers with severe DD and ID, born to first cousin parents. Homozygosity mapping, following other non-diagnostic investigations (incl. aCGH), revealed 4 major homozygosity intervals. Exome sequencing in one identified 5 variants within these intervals, ZNF407 (c.5054C>G, p.Ser1685Trp) being the best candidate, supported also by segregation studies. The authors commented that zinc finger proteins act as transcriptional regulators, with mutations in genes encoding for other zinc finger proteins interfering with normal brain development.

- Zahra et al. (2020 - PMID: 32737394) report on 7 affected individuals (from 3 families) homozygous or compound heterozygous for ZNF407 variants. Features included hypotonia, DD and ID (in all) and variable occurrence of short stature (6/6), microcephaly (in at least 5), behavioural, visual problems and deafness. Linkage analysis in the first family revealed a 4.4 Mb shared homozygosity region and exome (30x) revealed a 3-bp duplication, confirmed by Sanger sequencing and segregating with the disease (NM_001146189:c.2814_2816dup, p.Val939dup). Affected subjects from the 2 other families were each found to be homozygous (c.2405G>T) or compound heterozygous (c.2884C>G, c.3642G>C) for other variants. Segregation was compatible in all families. Other studies were not performed. The authors comment than only the 3-bp duplication fulfilled ACMG criteria for classification as LP, the other variants being all formally classified as VUS (also due to in silico predictions predicting a LB effect). In addition, while several features such as DD/ID and short stature appeared to be frequent among all patients reported, Zahra et all comment that there was partial clinical overlap with the sibs described by Kambouris et al (additional variants?).


Monoallelic disruption of ZNF407:

- Ren et al (2013 - PMID: 23195952) described an 8 y.o. boy with ID and ASD. The boy was found to harbor a de novo translocation between chromosomes 3 and 18 [46,XY,t(3;18)(p13;q22.3)]. Array CGH did not reveal any P/LP CNV. Delineation of the breakpoints (FISH, long-range PCR) revealed that the chr18 breakpoint disrupted intron 3 of ZNF407 (isoform 1) with the other breakpoint within a gene-free region of exon 3. There was a loss of 4-8 nt in chr18 and 2-6 in chr3. Sequencing of ZNF407 did not reveal additional variants. RNA isolation in blood followed by RT-PCR studied expression of all 3 ZNF407 isoforms (the intronic region being shared by isoforms 1 and 2). Expression of isoform 1 was shown to be significantly reduced compared to controls. Isoform 2 was undetectable (in blood) while isoform 3 expression was similar to controls. Sequencing of 105 additional patients with similar clinical presentation (ID & ASD) revealed 2 further individuals with de novo missense variants.

- Based on the discussion by Kambouris et al (PMID: 24907849 - cited literature not here reviewed) ZNF407 may be deleted in patients with congenital aural atresia due to deletion of a critical region of 18q22.3 (though TSHZ1 is responsible for this phenotype) or 18q- although such deletions span several other genes (cited PMID: 16639285). In one case the breakpoint was shown to be disrupting ZNF407 (cited PMID: 24092497).

- The denovo db and Decipher (research variant tab) list few individuals with de novo ZNF407 SNVs although these do not seem to allow conclusions.

https://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=ZNF407
https://decipher.sanger.ac.uk/search/ddd-research-variants/results?q=znf407
Sources: Literature
Intellectual disability - microarray and sequencing v3.219 MAPK1 Konstantinos Varvagiannis gene: MAPK1 was added
gene: MAPK1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MAPK1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MAPK1 were set to 32721402
Phenotypes for gene: MAPK1 were set to Global developmental delay; Intellectual disability; Behavioral abnormality; Growth delay; Abnormality of the face; Abnormality of the neck; Abnormality of the cardiovascular system; Abnormality of the skin
Penetrance for gene: MAPK1 were set to unknown
Mode of pathogenicity for gene: MAPK1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: MAPK1 was set to GREEN
Added comment: Motta et al (2020 - PMID: 32721402) report on 7 unrelated individuals harboring de novo missense MAPK1 pathogenic variants.

The phenotype corresponded to a neurodevelopmental disorder and - as the authors comment - consistently included DD, ID , behavioral problems. Postnatal growth delay was observed in approximately half. Hypertelorism, ptosis, downslant of palpebral fissures, wide nasal bridge as low-set/posteriorly rotated ears were among the facial features observed (each in 3 or more subjects within this cohort). Together with short/webbed neck and abnormalities of skin (lentigines / CAL spots) and growth delay these led to clinical suspicion of Noonan s. or disorder of the same pathway in some. Congenital heart defects (ASD, mitral valve insufficiency, though not cardiomyopathy) occurred in 4/7. Bleeding diathesis and lymphedema were reported only once.

MAPK1 encodes the mitogen-activated protein kinase 1 (also known as ERK2) a serine/threonine kinase of the RAS-RAF-MEK-(MAPK/)ERK pathway.

MAPK1 de novo variants were identified in all individuals following trio exome sequencing (and extensive previous genetic investigations which were non-diagnostic).

The distribution of variants, as well as in silico/vitro/vivo studies suggest a GoF effect (boosted signal through the MAPK cascade. MAPK signaling also upregulated in Noonan syndrome).

The authors comment that screening of 267 additional individuals with suspected RASopathy (without mutations in previously implicated genes) did not reveal other MAPK1 variants.

Overall this gene can be considered for inclusion in the ID panel with green rating.
Sources: Literature
Intellectual disability - microarray and sequencing v3.218 NCAPH Arina Puzriakova gene: NCAPH was added
gene: NCAPH was added to Intellectual disability. Sources: Literature
watchlist tags were added to gene: NCAPH.
Mode of inheritance for gene: NCAPH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NCAPH were set to 27737959
Phenotypes for gene: NCAPH were set to Microcephaly 23, primary, autosomal recessive, 617985
Added comment: Associated with Microcephaly 23 in OMIM and a possible gene for microcephaly in G2P.

PMID: 27737959 (2016) - A homozygous missense variant in NCAPH (c.728C>T, p.Pro243Leu) was detected in a 42-year-old male with microcephaly (OFC -4.2 SD) and moderate ID. Functional studies indicated that although the variant did not affect cellular protein levels, it disrupted condensin-dependent mitotic chromosome integrity, providing supporting evidence for pathogenicity. Biallelic variants in other genes encoding subunits of the two condensin complexes result in a similar phenotype.
Sources: Literature
Intellectual disability - microarray and sequencing v3.216 NCAPG2 Arina Puzriakova reviewed gene: NCAPG2: Rating: AMBER; Mode of pathogenicity: None; Publications: 30609410; Phenotypes: Khan-Khan-Katsanis syndrome, 618460; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.215 NCAPD2 Arina Puzriakova reviewed gene: NCAPD2: Rating: AMBER; Mode of pathogenicity: None; Publications: 27737959, 28097321, 31056748; Phenotypes: Microcephaly 21, primary, autosomal recessive, 617983; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.214 HADHB Arina Puzriakova reviewed gene: HADHB: Rating: AMBER; Mode of pathogenicity: None; Publications: 12754706, 19699128; Phenotypes: Trifunctional protein deficiency, 609015; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.212 VPS51 Arina Puzriakova reviewed gene: VPS51: Rating: AMBER; Mode of pathogenicity: None; Publications: 30624672, 31207318; Phenotypes: Pontocerebellar hypoplasia, type 13, 618606; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.211 LRRC32 Arina Puzriakova reviewed gene: LRRC32: Rating: RED; Mode of pathogenicity: None; Publications: 30976112; Phenotypes: Global developmental delay, Speech delay, Hypotonia, Cleft palate, Proliferative retinopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.209 LAMB2 Arina Puzriakova reviewed gene: LAMB2: Rating: AMBER; Mode of pathogenicity: None; Publications: 15367484, 17256789; Phenotypes: Pierson syndrome, 609049; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.209 TUBB2A Arina Puzriakova reviewed gene: TUBB2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 32571897; Phenotypes: Cortical dysplasia, complex, with other brain malformations 5, 615763; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.209 NGLY1 Eleanor Williams reviewed gene: NGLY1: Rating: ; Mode of pathogenicity: None; Publications: 32259258; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.209 SETD1B Arina Puzriakova reviewed gene: SETD1B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.209 EEF1A2 Eleanor Williams reviewed gene: EEF1A2: Rating: ; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 32160274; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.207 IFT27 Arina Puzriakova reviewed gene: IFT27: Rating: AMBER; Mode of pathogenicity: None; Publications: 24488770, 30761183, 29588463; Phenotypes: Bardet-Biedl syndrome 19, 615996; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.206 HNMT Arina Puzriakova reviewed gene: HNMT: Rating: AMBER; Mode of pathogenicity: None; Publications: 26206890; Phenotypes: Intellectual disability, Mental retardation, 616739; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.205 GNE Arina Puzriakova reviewed gene: GNE: Rating: AMBER; Mode of pathogenicity: None; Publications: 32053088, 29923088, 10356312, 11326336, 11486897, 27142465; Phenotypes: Sialuria, 269921; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.204 EXOSC8 Arina Puzriakova reviewed gene: EXOSC8: Rating: AMBER; Mode of pathogenicity: None; Publications: 24989451; Phenotypes: Pontocerebellar hypoplasia type 1C, 616081; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.204 DSCR3 Arina Puzriakova Added comment: Comment on list classification: Currently not associated with any phenotype in OMIM or G2P. Variants only found in one family - additional cases required to validate pathogenicity.
Intellectual disability - microarray and sequencing v3.202 ATP6AP1 Arina Puzriakova reviewed gene: ATP6AP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 27231034; Phenotypes: Immunodeficiency, 300972, Hepatopathy, Intellectual disability, Cutis laxa, Epilepsy; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability - microarray and sequencing v3.201 PDE10A Arina Puzriakova reviewed gene: PDE10A: Rating: AMBER; Mode of pathogenicity: None; Publications: 27058446; Phenotypes: Dyskinesia, limb and orofacial, infantile-onset, 616921; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.201 SMARCA2 Konstantinos Varvagiannis reviewed gene: SMARCA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32694869; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.201 MORC2 Konstantinos Varvagiannis gene: MORC2 was added
gene: MORC2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MORC2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MORC2 were set to https://doi.org/10.1016/j.ajhg.2020.06.013
Phenotypes for gene: MORC2 were set to Charcot-Marie-Tooth disease, axonal, type 2Z, MIM #616688
Penetrance for gene: MORC2 were set to unknown
Mode of pathogenicity for gene: MORC2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: MORC2 was set to GREEN
Added comment: The current review is based on a recent report by Sacoto et al (2020 - https://doi.org/10.1016/j.ajhg.2020.06.013).

While several previous studies focused on the phenotype of axonal motor and senory neuropathy in individuals with heterozygous MORC2 pathogenic variants (Charcot-Marie-Tooth disease, axonal, type 2Z, MIM #616688) some of them presented among others with hypotonia, muscle weakness, intellectual disability, microcephaly or hearing loss [refs provided by Sacoto et al - learning disabilities (in some patients) also listed in OMIM's clinical synopsis].

Sacoto et al present a cohort of 20 individuals having genetic testing for developmental delay or growth failure (with a single one for a diagnosis of sensorimotor neuropathy).

Overlapping features included DD, ID (18/20 - mild to severe), short stature (18/20), microcephaly (15/20) and variable craniofacial dysmorphisms. The authors comment that features suggestive of neuropathy (weakness, hyporeflexia, abnormal EMG/NCS) were frequent but not the predominant complaint. EMG/NCS abnormalities were abnormal in 6 out of 10 subjects investigated in this cohort. Other findings included brain MRI abnormalities (12/18 - in 5/18 Leigh-like lesions), hearing loss (11/19) and pigmentary retinopathy in few (5).

Affected subjects were found to harbor in all cases missense variants in the ATPase module of MORC2 [residues 1 to 494 - NM_001303256.1 - the module consists of an ATPase domain (aa 1-265), a transducer S5-like domain (266-494) and a coiled-coiled domain (CC1 - aa 282-361)].

Variants had occured mostly as de novo events although inheritance from a similarly affected parent was also reported.

Some of them were recurring within this cohort and/or the literature eg. c.79G>A/p.Glu27Lys (x5), c.260C>T/p.Ser87Leu (x2), c.394C>T/p.Arg132Cys (4x), c.1164C>G/p.Ser388Arg (x2), c.1181A>G/p.Tyr394Cys (x3).

MORC2 encodes an ATPase involved in chromatin remodeling, DNA repair and transcriptional regulation. Chromatin remodeling and epigenetic silencing by MORC2 is mediated by the HUSH (Human Silencing Hub) complex. Functional studies (MORC2-knockout HeLa cells harboring a HUSH-sensitive GFP reporter were transduced with wt or mt MORC2 followed by measurement of reporter repression) supported the deleterious effect of most variants known at the time (hyperactivation of HUSH-mediating silencing, in line with previous observations).

Overall this gene can be considered for inclusion in the ID panel with green rating. Also other gene panels (e.g. for short stature, microcephaly, hearing loss, pigmentary retinopathy, etc) if it meets the respective criteria for inclusion.
Sources: Literature
Intellectual disability - microarray and sequencing v3.201 HIST1H4J Arina Puzriakova Added comment: Comment on list classification: Amber rating as additional cases are required to validate pathogenicity, but added to watchlist.
Intellectual disability - microarray and sequencing v3.200 HIST1H4J Arina Puzriakova reviewed gene: HIST1H4J: Rating: AMBER; Mode of pathogenicity: None; Publications: 31804630; Phenotypes: Microcephaly, Intellectual disability, Dysmorphic facial features, Growth delay; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.199 ADAMTS10 Arina Puzriakova reviewed gene: ADAMTS10: Rating: AMBER; Mode of pathogenicity: None; Publications: 15368195, 18567016, 19836009; Phenotypes: Weill-Marchesani syndrome, 277600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.193 KCNN3 Arina Puzriakova Added comment: Comment on mode of pathogenicity: Gain-of-function variants identified in all patients, reported to date.
Intellectual disability - microarray and sequencing v3.193 KCNN3 Arina Puzriakova Mode of pathogenicity for gene: KCNN3 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability - microarray and sequencing v3.183 LZTFL1 Arina Puzriakova reviewed gene: LZTFL1: Rating: GREEN; Mode of pathogenicity: ; Publications: 22510444, 23692385; Phenotypes: Bardet-Biedl syndrome 17, 615994; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.183 LYRM7 Arina Puzriakova reviewed gene: LYRM7: Rating: GREEN; Mode of pathogenicity: ; Publications: 24014394, 26912632, 28694194; Phenotypes: Mitochondrial complex III deficiency, nuclear type 8, 615838; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.183 LIPT1 Arina Puzriakova reviewed gene: LIPT1: Rating: GREEN; Mode of pathogenicity: ; Publications: 24341803, 29681092, 31042466, 24256811, 27247813; Phenotypes: Lipoyltransferase 1 deficiency, 616299; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.183 KLF7 Arina Puzriakova reviewed gene: KLF7: Rating: GREEN; Mode of pathogenicity: ; Publications: 29251763; Phenotypes: Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.183 KCNN3 Arina Puzriakova reviewed gene: KCNN3: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype -please provide details in the comments; Publications: 31155282; Phenotypes: Zimmermann-Laband syndrome 3, 618658; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.183 GPC4 Arina Puzriakova reviewed gene: GPC4: Rating: GREEN; Mode of pathogenicity: ; Publications: 30982611; Phenotypes: Keipert syndrome, 301026; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability - microarray and sequencing v3.183 IQSEC3 Arina Puzriakova reviewed gene: IQSEC3: Rating: RED; Mode of pathogenicity: ; Publications: 31130284; Phenotypes: Intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.183 EIF2AK1 Arina Puzriakova reviewed gene: EIF2AK1: Rating: RED; Mode of pathogenicity: ; Publications: 32197074; Phenotypes: Leukoencephalopathy, motor delay, spasticity, and dysarthria syndrome, 618878, ADHD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.183 EIF2A Arina Puzriakova reviewed gene: EIF2A: Rating: RED; Mode of pathogenicity: ; Publications: 31130284; Phenotypes: Intellectual disability, Seizures, ASD; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.183 DNM1L Arina Puzriakova reviewed gene: DNM1L: Rating: GREEN; Mode of pathogenicity: ; Publications: 27145208, 30767894, 30711678, 26931468, 27328748, 27301544, 26604000, 26992161; Phenotypes: Epileptic encephalopathy, 614388, Global developmental delay, Cerebral atrophy, Microcephaly; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.183 ATAD1 Arina Puzriakova reviewed gene: ATAD1: Rating: GREEN; Mode of pathogenicity: ; Publications: 28180185, 29390050, 29659736; Phenotypes: Encephalopathy, Progressive hypertonia, Seizures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.183 ADD3 Arina Puzriakova reviewed gene: ADD3: Rating: GREEN; Mode of pathogenicity: ; Publications: 23836506, 29768408; Phenotypes: Cerebral palsy, spastic quadriplegic, 617008, Intellectual disability, Microcephaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.181 ASTN1 Arina Puzriakova reviewed gene: ASTN1: Rating: AMBER; Mode of pathogenicity: None; Publications: 26539891, 27431290, 29706646; Phenotypes: Intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.174 PTPN23 Eleanor Williams Phenotypes for gene: PTPN23 were changed from Developmental epileptic encephalopathy with hypomyelination and brain atrophy; Intellectual disability; Severe developmental delay, to Developmental epileptic encephalopathy with hypomyelination and brain; Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity MIM#618890 atrophy; Intellectual disability; Severe developmental delay,
Intellectual disability - microarray and sequencing v3.170 CNPY3 Konstantinos Varvagiannis gene: CNPY3 was added
gene: CNPY3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CNPY3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CNPY3 were set to 29394991; 30237576
Phenotypes for gene: CNPY3 were set to Epileptic encephalopathy, early infantile, 60 (MIM 617929)
Penetrance for gene: CNPY3 were set to Complete
Review for gene: CNPY3 was set to GREEN
Added comment: Biallelic CNPY3 mutations cause Epileptic encephalopathy, early infantile, 60 (MIM 617929).

The phenotype including among others hypotonia, intractable seizures, DD and ID has been first reported by Mutoh et al (2018 - PMID: 29394991) in 3 subjects from 2 families. Evidence was provided for the role of the gene (incl. mouse model) and pathogenicity of the identified variants (resulting in LoF).

Another subject with similar features of hypotonia, DD, intractable epilepsy, feeding problems has been described briefly by Maddirevula et al (2019 - PMID: 30237576).
Sources: Literature
Intellectual disability - microarray and sequencing v3.170 KIF21B Konstantinos Varvagiannis gene: KIF21B was added
gene: KIF21B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: KIF21B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KIF21B were set to 32415109
Phenotypes for gene: KIF21B were set to Global developmental delay; Intellectual disability; Abnormality of brain morphology; Microcephaly
Penetrance for gene: KIF21B were set to unknown
Mode of pathogenicity for gene: KIF21B was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: KIF21B was set to GREEN
Added comment: Asselin et al (2020 - PMID: 32415109) report on 4 individuals with KIF21B pathogenic variants. DD/ID (borderline intellectual functioning to severe ID) was a feature in all. Variable other findings included brain malformations (CCA) and microcephaly. 3 missense variants and a 4-bp insertion were identified, in 3 cases as de novo events while in a single subject the variant was inherited from the father who was also affected. The authors provide evidence for a role of KIF21B in the regulation of processes involved in cortical development and deleterious effect of the missense variants impeding neuronal migration and kinesin autoinhibition. Phenotypes specific to variants (e.g. CCA or microcephaly) were recapitulated in animal models. Missense variants are thought to exert a gain-of-function effect. As commented on, the 4-bp duplication (/frameshift) variant might not be pathogenic. In blood sample from the respective individual, RT-qPCR analysis suggested that haploinsufficiency (NMD) applies. Although Kif21b haploinsufficiency in mice was shown to lead to impaired neuronal positioning, the gene might partially tolerate LoF variants as also suggested by 28 such variants in gnomAD. Homozygous Kif21b ko mice display severe morphological abnormalities, partial loss of commissural fibers, cognitive deficits and altered synaptic transmission (several refs to previous studies provided by the authors).
Sources: Literature
Intellectual disability - microarray and sequencing v3.170 TMEM106B Konstantinos Varvagiannis gene: TMEM106B was added
gene: TMEM106B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TMEM106B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TMEM106B were set to 29186371; 29444210; 32595021
Phenotypes for gene: TMEM106B were set to Leukodystrophy, hypomyelinating, 16 (MIM #617964)
Penetrance for gene: TMEM106B were set to Complete
Mode of pathogenicity for gene: TMEM106B was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: TMEM106B was set to GREEN
Added comment: 6 unrelated individuals with Leukodystrophy, hypomyelinating, 16 (MIM #617964) due to a recurrent TMEM106B variant have been reported to date in the literature (Simons et al 2017 - PMID: 29186371, Yan et al 2018 - PMID: 29444210, Ikemoto et al 2020 - PMID: 32595021).

While a 3 y.o. female described by Yan et al had DD (eg sitting at 9m, walking at 25m) with normal cognitive functioning, and a 38 y.o. female had borderline intellectual functioning (IQ 76), 4 affected individuals had ID. Among them, a 19 y.o. male with severe ID was also found to harbor a second de novo possibly damaging USP7 variant. Seizures have been reported in 2 unrelated subjects. [Clinical features are also summarized in table 1 - Ikemoto et al].

All harbored NM_001134232.2(TMEM106B):c.754G>A (p.Asp252Asn) which in almost all cases occurred as a de novo event. In a single case this variant was inherited from a mosaic parent with mild DD in infancy but normal cognition (reported by Simons et al).

As discussed by Ito et al (2018 - PMID: 30643851) the encoded protein is a structural component of the lysosomal membrane, playing a role on lysosome acidification. Acidity of the lysosome mediates multiple aspects of lysosomal function. Ito et al, using patient-derived fibroblasts assessed mRNA and protein levels. These were unaltered compared with controls. While TMEM106B had been previously shown to affect lysosome number, morphology and acidification, Ito et al demonstrated increased number of lysosomes in patient cells as well as impaired acidification compared to controls. As commented lysosomes are required for generation of myelin.

Recurrence of this missense variant, the presence of pLoF TMEM106B variants in gnomAD as well as the phenotypically normal Tmem106b null mice suggest that this variant may have a gain-of-function or dominant negative effect.

Genes for other forms of hypomyelinating lipodystrophy (incl. PLP1) have green rating in the ID panel.

Overall TMEM106B can be considered for the ID panel with green rating and the epilepsy panel with amber rating.
Sources: Literature
Intellectual disability - microarray and sequencing v3.170 TBC1D2B Konstantinos Varvagiannis gene: TBC1D2B was added
gene: TBC1D2B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TBC1D2B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D2B were set to 32623794
Phenotypes for gene: TBC1D2B were set to Global developmental delay; Intellectual disability; Seizures; Gingival overgrowth; Behavioral abnormality; Abnormality of the mandible; Abnormality of brain morphology; Abnormality of the eye; Hearing abnormality
Penetrance for gene: TBC1D2B were set to Complete
Review for gene: TBC1D2B was set to AMBER
Added comment: Harms et al (2020 - PMID: 32623794) report on 3 unrelated individuals with biallelic pLoF TBC1D2B variants.

Features included cognitive impairment (mild ID in one case, regression at the age of 12y in another, hypotonia and delayed milestones in a third aged 8m), seizures (3/3 - variable age of onset) and/or gingival overgrowth (2/3 - prior to initiation of AEDs). Other findings included behavioral abnormalities, mandibular anomalies, abnormal brain imaging and ophthalmologic or (rarely) audiometric evaluations.

All were born to non-consanguineous couples and additional investigations were performed in some.

Variants were identified by WES or trio WGS, with Sanger confirmation/compatible segregation analyses.

In line with the pLoF variants, mRNA studies in fibroblasts from 2 unrelated affected individuals demonstrated significantly reduced (~80-90%) TBC1C2D mRNA levels compared to controls, restored following cycloheximide treatment. Protein was absent in patient fibroblasts.

TBC-domain containing GTPase activating proteins are known as key regulators of RAB GTPase activity. TBC1D2B was shown to colocalize with RAB5-positive endocytic vesicles. CRISPR/Cas9-mediated ko of TBC1D2B in HeLa cells suggested a role in EGF receptor endocytosis and decreased cell viability of TBC1D2B-deficient HeLa cells upon serum deprivation.

Genes encoding other TBC domain-containg GTPase-activating proteins, e.g. TBC1D7 and TBC1D20, TBC1D24 are associated with recessive neurodevelopmental disorders (with ID and/or seizures) and the pathophysiological defect in TBC1D2B-related disorder (deficit in vesicle trafficking and/or cell survival) is proposed to be similar to that of TBC1D24.

Overall this gene can be considered for inclusion with amber/green rating in the ID panel and green in epilepsy panel.
Sources: Literature
Intellectual disability - microarray and sequencing v3.170 CCDC174 Konstantinos Varvagiannis gene: CCDC174 was added
gene: CCDC174 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CCDC174 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC174 were set to 26358778
Phenotypes for gene: CCDC174 were set to Hypotonia, infantile, with psychomotor retardation - IHPMR, 616816
Penetrance for gene: CCDC174 were set to Complete
Mode of pathogenicity for gene: CCDC174 was set to Other
Review for gene: CCDC174 was set to AMBER
Added comment: Biallelic pathogenic CCDC174 variants cause Hypotonia, infantile, with psychomotor retardation - IHPMR (MIM 616816).

Volodarsky et al [2015 - PMID: 26358778] describe 6 children from 2 unrelated families with - among others - severe hypotonia, psychomotor delay and abducens nerve palsy. All affected subjects were homozygous for a stoploss variant. Evidence from functional studies/animal model is provided supporting the role of the gene in this phenotype.

Overall this gene can be considered for inclusion in the ID panel with amber rating (2 families, single founder variant, consistent phenotype, supportive studies) pending further reports.
Sources: Literature
Intellectual disability - microarray and sequencing v3.167 SBF1 Sarah Leigh reviewed gene: SBF1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.157 ADARB1 Arina Puzriakova reviewed gene: ADARB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32220291; Phenotypes: Neurodevelopmental disorder with hypotonia, microcephaly, and seizures, 618862; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.157 SETD1A Sarah Leigh reviewed gene: SETD1A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.156 GNAI2 Arina Puzriakova reviewed gene: GNAI2: Rating: AMBER; Mode of pathogenicity: None; Publications: 31036916, 27787898; Phenotypes: Syndromic developmental disorder; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.153 NRROS Sarah Leigh reviewed gene: NRROS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.153 FEM1B Arina Puzriakova reviewed gene: FEM1B: Rating: RED; Mode of pathogenicity: None; Publications: 31036916; Phenotypes: Global developmental delay; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.151 NOVA2 Sarah Leigh Phenotypes for gene: NOVA2 were changed from Intellectual disability; autism; hypotonia; spasticity; ataxia to Neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities 618859
Intellectual disability - microarray and sequencing v3.124 COG4 Sarah Leigh reviewed gene: COG4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.123 MCM3AP Eleanor Williams reviewed gene: MCM3AP: Rating: GREEN; Mode of pathogenicity: None; Publications: 32202298; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.109 SLC1A1 Sarah Leigh reviewed gene: SLC1A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.80 COG4 Zornitza Stark reviewed gene: COG4: Rating: GREEN; Mode of pathogenicity: None; Publications: 31949312, 30290151, 19494034, 21185756; Phenotypes: Saul-Wilson syndrome, OMIM #618150, Congenital disorder of glycosylation, type IIj, OMIM #613489; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.80 TTC5 Zornitza Stark reviewed gene: TTC5: Rating: GREEN; Mode of pathogenicity: None; Publications: 29302074, 32439809; Phenotypes: Central hypotonia, Global developmental delay, Intellectual disability, Abnormality of nervous system morphology, Microcephaly, Abnormality of the face, Behavioral abnormality, Abnormality of the genitourinary system; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.76 KAT8 Rebecca Foulger Mode of pathogenicity for gene: KAT8 was changed from None to Other
Intellectual disability - microarray and sequencing v3.68 TRAPPC4 Rebecca Foulger Phenotypes for gene: TRAPPC4 were changed from Feeding difficulties; Progressive microcephaly; Intellectual disability; Seizures; Spastic tetraparesis; Abnormality of the face; Scoliosis; Cortical visual impairment; Hearing impairment to Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy, 618741
Intellectual disability - microarray and sequencing v3.62 PTRHD1 Helen Brittain reviewed gene: PTRHD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.62 TMX2 Eleanor Williams Phenotypes for gene: TMX2 were changed from Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormal cortical gyration to Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormal cortical gyration; Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730
Intellectual disability - microarray and sequencing v3.39 CUL3 Konstantinos Varvagiannis reviewed gene: CUL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 32341456; Phenotypes: Global developmental delay, Intellectual disability, Seizures, Abnormality of cardiovascular system morphology, Abnormality of the palate, Pseudohypoaldosteronism, type IIE - MIM #614496; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.35 UGDH Konstantinos Varvagiannis gene: UGDH was added
gene: UGDH was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: UGDH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UGDH were set to 32001716
Phenotypes for gene: UGDH were set to Epileptic encephalopathy, early infantile, 84 - MIM #618792
Penetrance for gene: UGDH were set to Complete
Review for gene: UGDH was set to GREEN
Added comment: Hengel et al (2020 - PMID: 32001716) report on 36 individuals with biallelic UGDH pathogenic variants.

The phenotype corresponded overall to a developmental epileptic encephalopathy with hypotonia, feeding difficulties, severe global DD, moderate or commonly severe ID in all. Hypotonia and motor disorder (incl. spasticity, dystonia, ataxia, chorea, etc) often occurred prior to the onset of seizures. A single individual did not present seizures and 2 sibs had only seizures in the setting of fever.

Affected subjects were tested by exome sequencing and UGDH variants were the only/best candidates for the phenotype following also segregation studies. Many were compound heterozygous or homozygous (~6 families were consanguineous) for missense variants and few were compound heterozygous for missense and pLoF variants. There were no individuals with biallelic pLoF variants identified. Parental/sib studies were all compatible with AR inheritance mode.

UGDH encodes the enzyme UDP-glucose dehydrogenase which converts UDP-glucose to UDP-glucuronate, the latter being a critical component of the glycosaminoglycans, hyaluronan, chondroitin sulfate, and heparan sulfate [OMIM].

Patient fibroblast and biochemical assays suggested a LoF effect of variants leading to impairment of UGDH stability, oligomerization or enzymatic activity (decreased UGDH-catalyzed reduction of NAD+ to NADH / hyaluronic acid production which requires UDP-glucuronate).

Attempts to model the disorder using an already developped zebrafish model (for a hypomorphic LoF allele) were unsuccessful as fish did not exhibit seizures spontaneously or upon induction with PTZ.

Modelling of the disorder in vitro using patient-derived cerebral organoids demonstrated smaller organoids due to reduced number of proliferating neural progenitors.
Sources: Literature
Intellectual disability - microarray and sequencing v3.35 YIF1B Konstantinos Varvagiannis gene: YIF1B was added
gene: YIF1B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: YIF1B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YIF1B were set to 32006098
Phenotypes for gene: YIF1B were set to Central hypotonia; Failure to thrive; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Spasticity; Abnormality of movement
Penetrance for gene: YIF1B were set to Complete
Review for gene: YIF1B was set to GREEN
Added comment: AlMuhaizea et al (2020 - PMID: 32006098) report on the phenotype of 6 individuals (from 5 families) with biallelic YIF1B truncating variants.

Affected subjects presented hypotonia, failure to thrive, microcephaly (5/6), severe global DD and ID (as evident from best motor/language milestones achieved - Table S1) as well as features suggestive of a motor disorder (dystonia/spasticity/dyskinesia). Seizures were reported in 2 unrelated individuals (2/6). MRI abnormalities were observed in some with thin CC being a feature in 3.

Variable initial investigations were performed including SNP CMA, MECP2, microcephaly / neurotransmitter disorders gene panel testing did not reveal P/LP variants.

YIF1B variants were identified in 3 families within ROH. Following exome sequencing, affected individuals were found to be homozygous for truncating variants (4/5 families being consanguineous). The following 3 variants were identified (NM_001039672.2) : c.186dupT or p.Ala64fs / c.360_361insACAT or p.Gly121fs / c.598G>T or p.Glu200*.

YIF1B encodes an intracellular transmembrane protein.

It has been previously demonstrated that - similarly to other proteins of the Yip family being implicated in intracellular traffic between the Golgi - Yif1B is involved in the anterograde traffic pathway. Yif1B KO mice demonstrate a disorganized Golgi architecture in pyramidal hippocampal neurons (Alterio et al 2015 - PMID: 26077767). The rat ortholog interacts with serotonin receptor 1 (5-HT1AR) with colocalization of Yif1BB and 5-HT1AR in intermediate compartment vesicles and involvement of the former in intracellular trafficing/modulation of 5-HT1AR transport to dendrites (PMID cited: 18685031).

Available mRNA and protein expression data (Protein Atlas) suggest that the gene is widely expressed in all tissues incl. neuronal cells. Immunochemistry data from the Human Brain Atlas also suggest that YIF1B is found in vesicles and localized to the Golgi apparatus. Immunohistochemistry in normal human brain tissue (cerebral cortex) demonstrated labeling of neuronal cells (Human Protein Atlas).

Functional/network analysis of genes co-regulated with YIF1B based on available RNAseq data, suggest enrichement in in genes important for nervous system development and function.

Please consider inclusion in other panels that may be relevant (e.g. microcephaly, etc).
Sources: Literature
Intellectual disability - microarray and sequencing v3.35 TNRC6B Konstantinos Varvagiannis reviewed gene: TNRC6B: Rating: GREEN; Mode of pathogenicity: None; Publications: 32152250, 28135719, 25363768, 27479843, 28959963, 25228304; Phenotypes: Global developmental delay, Intellectual disability, Autistic behavior; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v3.31 CDK19 Zornitza Stark reviewed gene: CDK19: Rating: GREEN; Mode of pathogenicity: None; Publications: 32330417; Phenotypes: Intellectual disability, epileptic encephalopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.31 CACNB4 Zornitza Stark reviewed gene: CACNB4: Rating: AMBER; Mode of pathogenicity: None; Publications: 32176688; Phenotypes: Intellectual disability, epilepsy, movement disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.29 NRROS Zornitza Stark gene: NRROS was added
gene: NRROS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NRROS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NRROS were set to 32100099; 32197075
Phenotypes for gene: NRROS were set to neurodegeneration; intracranial calcification; epilepsy
Review for gene: NRROS was set to GREEN
Added comment: Normal development or mild developmental delay until onset of regression around age of 1 concurrent with epilepsy
Biallelic LOF mutations with functional evidence of pathogenicity reported in 6 unrelated families. Suggest also add to Epilepsy panel, possibly others.
Sources: Literature
Intellectual disability - microarray and sequencing v3.29 NOVA2 Zornitza Stark gene: NOVA2 was added
gene: NOVA2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NOVA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NOVA2 were set to 32197073
Phenotypes for gene: NOVA2 were set to Intellectual disability; autism; hypotonia; spasticity; ataxia
Review for gene: NOVA2 was set to GREEN
gene: NOVA2 was marked as current diagnostic
Added comment: Six individuals with de novo frameshift variants resulting in C-terminal extension suggesting partial LoF as mechanism.
Sources: Literature
Intellectual disability - microarray and sequencing v3.24 NUP188 Zornitza Stark reviewed gene: NUP188: Rating: GREEN; Mode of pathogenicity: None; Publications: 32021605, 28726809, 32275884; Phenotypes: microcephaly, ID, cataract, structural brain abnormalities, hypoventilation; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.23 SCAMP5 Sarah Leigh changed review comment from: Comment on list classification: Not associated with phenotype in OMIM (last edited on 10/06/2014) or in Gen2Phen. Two variants have been identified in three unrelated cases (one monoallelic, one biallelic). Supportive functional studies have been reported.
It would appear that the two variants reported so far in this gene result in differing mode of pathogenicity and phenotypic features. With heterozygous c.538G>T, p.Gly180Trp seeming to have a dominant-negative effect resulting in autistic spectrum disorder, intellectual disability and seizures. While homozygous c.271C>T, p.R91W seems to have a loss of function effect resulting in early onset epilepsy and Parkinson’s disease. This may be due to different functional domains of the mature protein being altered.; to: Comment on list classification: Not associated with phenotype in OMIM (last edited on 10/06/2014) or in Gen2Phen. Two variants have been identified in three unrelated cases (one monoallelic, one biallelic). Supportive functional studies have been reported.
It would appear that the two variants reported so far in this gene result in differing mode of pathogenicity and phenotypic features. With heterozygous c.538G>T, p.Gly180Trp seeming to have a dominant-negative effect resulting in autistic spectrum disorder, intellectual disability and seizures. While homozygous c.271C>T, p.R91W seems to have a loss of function effect resulting in early onset epilepsy and Parkinson’s disease. This may be due to different functional domains of the mature protein being altered.
Based on this evidence, SCAMP5 is rated as Amber, with a Watchlist tag. This status may change if further cases are reported.
Intellectual disability - microarray and sequencing v3.23 SCN8A Sarah Leigh Added comment: Comment on mode of pathogenicity: Based on report in PMID 31625145, reporting biallelic loss of function SCN8A variants in three cases in two families with severe developmental and epileptic encephalopathy. This differs from the previosly reported gain of function monoallelic variants (PMID 24194747;22365152).
Intellectual disability - microarray and sequencing v3.23 SCN8A Sarah Leigh Mode of pathogenicity for gene: SCN8A was changed from to Other
Intellectual disability - microarray and sequencing v3.19 SCAMP5 Sarah Leigh Added comment: Comment on mode of pathogenicity: Heterozygous c.538G>T, p.Gly180Trp seeming to have a dominant-negative effect resulting in autistic spectrum disorder, intellectual disability and seizures. While homozygous c.271C>T, p.R91W seems to have a loss of function effect resulting in early onset epilepsy and Parkinson’s disease.
Intellectual disability - microarray and sequencing v3.19 SCAMP5 Sarah Leigh Mode of pathogenicity for gene: SCAMP5 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Other
Intellectual disability - microarray and sequencing v3.18 SCAMP5 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM (last edited on 10/06/2014) or in Gen2Phen. Two variants have been identified in three unrelated cases (one monoallelic, one biallelic). Supportive functional studies have been reported.
It would appear that the two variants reported so far in this gene result in differing mode of pathogenicity and phenotypic features. With heterozygous c.538G>T, p.Gly180Trp seeming to have a dominant-negative effect resulting in autistic spectrum disorder, intellectual disability and seizures. While homozygous c.271C>T, p.R91W seems to have a loss of function effect resulting in early onset epilepsy and Parkinson’s disease. This may be due to different functional domains of the mature protein being altered.
Intellectual disability - microarray and sequencing v3.15 RNF13 Sarah Leigh reviewed gene: RNF13: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.3 SLC5A6 Zornitza Stark reviewed gene: SLC5A6: Rating: GREEN; Mode of pathogenicity: None; Publications: 31754459, 27904971, 31392107; Phenotypes: Developmental delay, epilepsy, neurodegeneration; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 RARS Zornitza Stark reviewed gene: RARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 31814314; Phenotypes: Leukodystrophy, hypomyelinating, 9 (# 616140); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 CXorf56 Zornitza Stark reviewed gene: CXorf56: Rating: GREEN; Mode of pathogenicity: None; Publications: 29374277, 31822863; Phenotypes: Mental retardation, X-linked 107, MIM# 301013; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.3 RUNX2 Zornitza Stark reviewed gene: RUNX2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cleidocranial dysplasia, MIM# 119600; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.3 RSPO4 Zornitza Stark reviewed gene: RSPO4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Anonychia congenita, MIM# 206800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 RSPH3 Zornitza Stark reviewed gene: RSPH3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 32, MIM# 616481; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 RSPH1 Zornitza Stark reviewed gene: RSPH1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 24, MIM# 615481; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 RPS19 Zornitza Stark reviewed gene: RPS19: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Diamond-Blackfan anemia 1, MIM#105650; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.3 RPGRIP1 Zornitza Stark reviewed gene: RPGRIP1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cone-rod dystrophy 13, MIM# 608194, Leber congenital amaurosis 6, MIM# 613826; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 RPE65 Zornitza Stark reviewed gene: RPE65: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Leber congenital amaurosis 2, MIM# 204100, Retinitis pigmentosa 20, MIM# 613794, Retinitis pigmentosa 87 with choroidal involvement, MIM# 618697; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 ROBO3 Zornitza Stark reviewed gene: ROBO3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Gaze palsy, familial horizontal, with progressive scoliosis, 1 607313; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 RNF13 Zornitza Stark reviewed gene: RNF13: Rating: GREEN; Mode of pathogenicity: None; Publications: 30595371; Phenotypes: Epileptic encephalopathy, early infantile, 73, MIM# 618379; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.3 RHEB Zornitza Stark reviewed gene: RHEB: Rating: GREEN; Mode of pathogenicity: None; Publications: 29051493; Phenotypes: Intellectual disability, Macrocephaly; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.3 RETREG1 Zornitza Stark reviewed gene: RETREG1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuropathy, hereditary sensory and autonomic, type IIB, MIM# 613115; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 MYO5B Zornitza Stark reviewed gene: MYO5B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Microvillus inclusion disease, MIM# 251850; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 MYH9 Zornitza Stark reviewed gene: MYH9: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss, MIM# 155100; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.3 MYH8 Zornitza Stark reviewed gene: MYH8: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Trismus-pseudocamptodactyly syndrome, MIM# 158300; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.3 MYH6 Zornitza Stark reviewed gene: MYH6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Sick sinus syndrome 3} 614090 3 Atrial septal defect 3, MIM# 614089, Cardiomyopathy, dilated, 1EE, MIM# 613252, Cardiomyopathy, hypertrophic, 14, MIM# 613251; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.3 MTHFS Zornitza Stark reviewed gene: MTHFS: Rating: GREEN; Mode of pathogenicity: None; Publications: 30031689, 31844630, 22303332; Phenotypes: Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination, 618367; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.3 MSX2 Zornitza Stark reviewed gene: MSX2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Craniosynostosis 2, MIM# 604757, Parietal foramina 1, MIM# 168500, Parietal foramina with cleidocranial dysplasia, MIM# 168550; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.3 MSX1 Zornitza Stark reviewed gene: MSX1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ectodermal dysplasia 3, Witkop type 189500, Orofacial cleft 5 608874, Tooth agenesis, selective, 1, with or without orofacial cleft 106600; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.3 MPV17 Zornitza Stark reviewed gene: MPV17: Rating: GREEN; Mode of pathogenicity: None; Publications: 22593919; Phenotypes: Mitochondrial DNA depletion syndrome 6 (hepatocerebral type), OMIM #256810; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.3 MNX1 Zornitza Stark reviewed gene: MNX1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Currarino syndrome, OMIM #176450; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.3 MN1 Zornitza Stark reviewed gene: MN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31834374, 31839203; Phenotypes: Intellectual disability, dysmophic features, rhombencephalosynapsis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.3 MMP13 Zornitza Stark reviewed gene: MMP13: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Metaphyseal anadysplasia 1, MIM# 602111, Metaphyseal dysplasia, Spahr type, MIM# 250400, Spondyloepimetaphyseal dysplasia, Missouri type, MIM# 602111; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 MGP Zornitza Stark reviewed gene: MGP: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Keutel syndrome, MIM# 245150; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 MFSD2A Zornitza Stark reviewed gene: MFSD2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 26005865, 26005868, 24828044; Phenotypes: Microcephaly 15, primary, autosomal recessive, MIM# 616486; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 MFRP Zornitza Stark reviewed gene: MFRP: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Microphthalmia, isolated 5, MIM# 611040; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 METTL5 Zornitza Stark reviewed gene: METTL5: Rating: GREEN; Mode of pathogenicity: None; Publications: 29302074, 31564433; Phenotypes: Intellectual developmental disorder, autosomal recessive 72, MIM# 618665; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.3 MESP2 Zornitza Stark reviewed gene: MESP2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spondylocostal dysostosis 2, autosomal recessive, MIM# 608681; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 MC2R Zornitza Stark reviewed gene: MC2R: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Glucocorticoid deficiency, due to ACTH unresponsiveness, MIM# 202200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 MATN3 Zornitza Stark reviewed gene: MATN3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spondyloepimetaphyseal dysplasia 608728, {Osteoarthritis susceptibility 2} 140600, Epiphyseal dysplasia, multiple, 5 607078; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 MAPRE2 Zornitza Stark reviewed gene: MAPRE2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26637975; Phenotypes: Symmetric circumferential skin creases, congenital, 2, MIM# 616734; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 MAPK10 Zornitza Stark reviewed gene: MAPK10: Rating: RED; Mode of pathogenicity: None; Publications: 23329067, 16249883; Phenotypes: Intellectual disability, seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.3 MAP3K1 Zornitza Stark reviewed gene: MAP3K1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: 46XY sex reversal 6, MIM# 613762; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.3 MAP1B Zornitza Stark reviewed gene: MAP1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 31317654, 30150678, 30214071; Phenotypes: Intellectual disability, seizures, PVNH, dysmorphic features; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.3 MADD Zornitza Stark reviewed gene: MADD: Rating: GREEN; Mode of pathogenicity: None; Publications: 28940097; Phenotypes: Intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.3 NUP107 Zornitza Stark reviewed gene: NUP107: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Galloway-Mowat syndrome 7, MIM# 618348, Nephrotic syndrome, type 11, MIM# 616730; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.3 NR5A1 Zornitza Stark reviewed gene: NR5A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: 46XY sex reversal 3, 612965, Premature ovarian failure 7, 612964, Adrenocortical insufficiency, Spermatogenic failure 8, 613957; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.3 NR2F2 Zornitza Stark reviewed gene: NR2F2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital heart defects, multiple types, 4, MIM# 615779; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.3 NPR2 Zornitza Stark reviewed gene: NPR2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Acromesomelic dysplasia, Maroteaux type, MIM# 602875, Epiphyseal chondrodysplasia, Miura type MIM#615923, Short stature with nonspecific skeletal abnormalities 616255; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 NPHS1 Zornitza Stark reviewed gene: NPHS1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Nephrotic syndrome, type 1, MIM# 256300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 NPHP4 Zornitza Stark reviewed gene: NPHP4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Nephronophthisis 4, MIM# 606966, Senior-Loken syndrome 4, MIM# 606996; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 NPHP3 Zornitza Stark reviewed gene: NPHP3: Rating: GREEN; Mode of pathogenicity: None; Publications: 18371931; Phenotypes: Meckel syndrome 7, MIM# 267010; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 NOTCH2 Zornitza Stark reviewed gene: NOTCH2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Alagille syndrome 2, MIM#610205, Hajdu-Cheney syndrome, MIM#102500; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.3 NOG Zornitza Stark reviewed gene: NOG: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Brachydactyly, type B2, MIM# 611377, Multiple synostoses syndrome 1, MIM# 186500, Stapes ankylosis with broad thumbs and toes, MIM# 184460, Symphalangism, proximal, 1A, MIM# 185800, Tarsal-carpal coalition syndrome, MIM# 186570; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.3 NODAL Zornitza Stark reviewed gene: NODAL: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Heterotaxy, visceral, 5, MIM# 270100; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.3 NMNAT1 Zornitza Stark reviewed gene: NMNAT1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Leber congenital amaurosis 9, MIM# 608553; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 NKX3-2 Zornitza Stark reviewed gene: NKX3-2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spondylo-megaepiphyseal-metaphyseal dysplasia, MIM# 613330; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 NHP2 Zornitza Stark reviewed gene: NHP2: Rating: AMBER; Mode of pathogenicity: None; Publications: 18523010, 31985013; Phenotypes: Dyskeratosis congenita, autosomal recessive 2, MIM# 613987, Høyeraal-Hreidarsson syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 NHEJ1 Zornitza Stark reviewed gene: NHEJ1: Rating: RED; Mode of pathogenicity: None; Publications: 16439204; Phenotypes: Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 NGF Zornitza Stark reviewed gene: NGF: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuropathy, hereditary sensory and autonomic, type V, MIM# 608654; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 NEK1 Zornitza Stark reviewed gene: NEK1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Short-rib thoracic dysplasia 6 with or without polydactyly, MIM# 263520; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 NEDD4L Zornitza Stark reviewed gene: NEDD4L: Rating: GREEN; Mode of pathogenicity: None; Publications: 27694961; Phenotypes: Periventricular nodular heterotopia 7, MIM#617201; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.3 ZNF335 Zornitza Stark reviewed gene: ZNF335: Rating: GREEN; Mode of pathogenicity: None; Publications: 23178126, 27540107, 29652087; Phenotypes: Microcephaly 10, primary, autosomal recessive, OMIM #615095; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 ZNF148 Zornitza Stark reviewed gene: ZNF148: Rating: GREEN; Mode of pathogenicity: None; Publications: 27964749; Phenotypes: Global developmental delay, absent or hypoplastic corpus callosum, and dysmorphic facies, 617260; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.3 ZMPSTE24 Zornitza Stark reviewed gene: ZMPSTE24: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Mandibuloacral dysplasia with type B lipodystrophy, MIM# 608612, Restrictive dermopathy, lethal, MIM# 275210; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 ZIC3 Zornitza Stark reviewed gene: ZIC3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Heterotaxy, visceral, 1, X-linked 306955, Congenital heart defects, nonsyndromic, 1, X-linked, 306955, VACTERL association, X-linked, 314390; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability - microarray and sequencing v3.3 ZIC1 Zornitza Stark reviewed gene: ZIC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26340333, 30391508; Phenotypes: Structural brain anomalies with impaired intellectual development and craniosynostosis, OMIM #618736; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.3 XYLT1 Zornitza Stark reviewed gene: XYLT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24581741, 22711505, 23982343; Phenotypes: Desbuquois dysplasia 2, OMIM# 615777; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 XPC Zornitza Stark reviewed gene: XPC: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Xeroderma pigmentosum, group C, MIM# 278720; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 WRAP53 Zornitza Stark reviewed gene: WRAP53: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Dyskeratosis congenita, autosomal recessive 3, OMIM# 613988; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 WNT7A Zornitza Stark reviewed gene: WNT7A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Fuhrmann syndrome, MIM# 228930, Ulna and fibula, absence of, with severe limb deficiency, MIM# 276820; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 WNT5A Zornitza Stark reviewed gene: WNT5A: Rating: AMBER; Mode of pathogenicity: None; Publications: 17256787; Phenotypes: Robinow syndrome, autosomal dominant 1, OMIM# 180700; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.3 WNT3 Zornitza Stark reviewed gene: WNT3: Rating: RED; Mode of pathogenicity: None; Publications: 14872406; Phenotypes: Tetra-amelia syndrome 1, MIM# 273395; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.3 WNT10B Zornitza Stark reviewed gene: WNT10B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Split-hand/foot malformation 6, MIM#225300; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.3 WNT1 Zornitza Stark reviewed gene: WNT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26671912; Phenotypes: Osteogenesis imperfecta, type XV, OMIM# 615220; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 WFS1 Zornitza Stark reviewed gene: WFS1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Wolfram syndrome 1, MIM# 222300, Wolfram-like syndrome, autosomal dominant, MIM# 614296; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 WDR35 Zornitza Stark reviewed gene: WDR35: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.3 WDR34 Zornitza Stark reviewed gene: WDR34: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.3 WDR19 Zornitza Stark reviewed gene: WDR19: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Short-rib thoracic dysplasia 5 with or without polydactyly, OMIM #614376, Nephronophthisis 13, OMIM #614377, Senior-Loken syndrome 8, OMIM#616307; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 VSX2 Zornitza Stark reviewed gene: VSX2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Microphthalmia with coloboma 3, MIM# 610092, Microphthalmia, isolated 2, MIM# 610093; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 VAMP1 Zornitza Stark reviewed gene: VAMP1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Myasthenic syndrome, congenital, 25, MIM# 618323; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 UVSSA Zornitza Stark reviewed gene: UVSSA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: UV-sensitive syndrome 3 614640; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 USP7 Zornitza Stark reviewed gene: USP7: Rating: GREEN; Mode of pathogenicity: None; Publications: 30679821; Phenotypes: ID, Autism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.3 USP18 Zornitza Stark reviewed gene: USP18: Rating: GREEN; Mode of pathogenicity: None; Publications: 31940699, 12833411, 27325888; Phenotypes: Pseudo-TORCH syndrome 2, OMIM #617397; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 USB1 Zornitza Stark reviewed gene: USB1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Poikiloderma with neutropenia, MIM# 604173; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 UROS Zornitza Stark reviewed gene: UROS: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Porphyria, congenital erythropoietic, MIM# 263700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 UGT1A1 Zornitza Stark reviewed gene: UGT1A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Crigler-Najjar syndrome, type I, OMIM #218800, Crigler-Najjar syndrome, type II, OMIM #606785; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 UGP2 Zornitza Stark reviewed gene: UGP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31820119; Phenotypes: Epileptic encephalopathy, intellectual disability, microcephaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 TYRP1 Zornitza Stark reviewed gene: TYRP1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Albinism, oculocutaneous, type III, 203290; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 TYR Zornitza Stark reviewed gene: TYR: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Albinism, oculocutaneous, type IA, 203100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 TXNL4A Zornitza Stark reviewed gene: TXNL4A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Burn-McKeown syndrome, MIM# 608572; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 TUBA8 Zornitza Stark reviewed gene: TUBA8: Rating: RED; Mode of pathogenicity: None; Publications: 19896110, 31481326, 28388629; Phenotypes: Cortical dysplasia, complex, with other brain malformations 8, MIM# 613180; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 TSHR Zornitza Stark reviewed gene: TSHR: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypothyroidism, congenital, nongoitrous, 1, MIM# 275200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 TRPV4 Zornitza Stark reviewed gene: TRPV4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.3 TRPS1 Zornitza Stark reviewed gene: TRPS1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Trichorhinophalangeal syndrome, type I (MIM 190350), Trichorhinophalangeal syndrome, type III (MIM 190351); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.3 TRPM3 Zornitza Stark reviewed gene: TRPM3: Rating: GREEN; Mode of pathogenicity: None; Publications: 31278393; Phenotypes: Intellectual disability, epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.3 TRPM1 Zornitza Stark reviewed gene: TRPM1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Night blindness, congenital stationary (complete), 1C, autosomal recessive, MIM# 613216; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 TRIP11 Zornitza Stark reviewed gene: TRIP11: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Achondrogenesis, type IA, MIM# 200600, Osteochondrodysplasia, MIM# 184260; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.3 TRIM32 Zornitza Stark reviewed gene: TRIM32: Rating: RED; Mode of pathogenicity: None; Publications: 16606853; Phenotypes: Bardet-Biedl syndrome 11, MIM# 615988; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 TRAPPC4 Zornitza Stark reviewed gene: TRAPPC4: Rating: GREEN; Mode of pathogenicity: None; Publications: 31794024; Phenotypes: intellectual disability, epilepsy, spasticity, microcephaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 TRAPPC2 Zornitza Stark reviewed gene: TRAPPC2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spondyloepiphyseal dysplasia tarda, MIM# 313400; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability - microarray and sequencing v3.3 TRAK1 Zornitza Stark reviewed gene: TRAK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28940097, 28364549, 29846532; Phenotypes: Epileptic encephalopathy, early infantile, 68, MIM# 618201; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 TP63 Zornitza Stark reviewed gene: TP63: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ADULT syndrome, OMIM #103285, Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM #604292, Hay-Wells syndrome, OMIM #106260, Limb-mammary syndrome, OMIM #603543, Orofacial cleft 8, OMIM #618149, Rapp-Hodgkin syndrome, OMIM #129400, Split-hand/foot malformation 4, OMIM #605289; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.3 SPOP Zornitza Stark gene: SPOP was added
gene: SPOP was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SPOP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPOP were set to 32109420
Phenotypes for gene: SPOP were set to Intellectual disability; dysmorphism; microcephaly; macrocephaly
Mode of pathogenicity for gene: SPOP was set to Other
Review for gene: SPOP was set to GREEN
gene: SPOP was marked as current diagnostic
Added comment: Seven individuals reported with de novo missense variants in this gene. Gain-of-function variants associated with microcephaly whereas dominant-negative variants associated with macrocephaly.
Sources: Literature
Intellectual disability - microarray and sequencing v3.3 TMPRSS6 Zornitza Stark reviewed gene: TMPRSS6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Iron-refractory iron deficiency anemia 206200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 TMEM126B Zornitza Stark reviewed gene: TMEM126B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial complex I deficiency, nuclear type 29, MIM# 618250; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 TINF2 Zornitza Stark reviewed gene: TINF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 1404302, 18252230, 21477109; Phenotypes: Revesz syndrome, MIM# 268130; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.3 TGFB3 Zornitza Stark reviewed gene: TGFB3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Arrhythmogenic right ventricular dysplasia 1, MIM# 107970, Loeys-Dietz syndrome 5, MIM# 615582; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.3 TGFB2 Zornitza Stark reviewed gene: TGFB2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Loeys-Dietz syndrome 4, MIM# 614816; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.3 TGFB1 Zornitza Stark reviewed gene: TGFB1: Rating: AMBER; Mode of pathogenicity: None; Publications: 29483653; Phenotypes: Inflammatory bowel disease, immunodeficiency, and encephalopathy, MIM# 618213; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 TET3 Zornitza Stark reviewed gene: TET3: Rating: GREEN; Mode of pathogenicity: None; Publications: 31928709; Phenotypes: Intellectual disability, dysmorphic features, abnormal growth, movement disorders; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 TEK Zornitza Stark reviewed gene: TEK: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Glaucoma 3, primary congenital, E , MIM#617272, Venous malformations, multiple cutaneous and mucosal, MIM# 600195; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.3 TCTN3 Zornitza Stark reviewed gene: TCTN3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22883145, 25118024, 26092869; Phenotypes: Joubert syndrome 18, OMIM #614815, Orofaciodigital syndrome IV, OMIM #258860; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.3 TCF12 Zornitza Stark reviewed gene: TCF12: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Craniosynostosis 3, MIM# 615314; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.3 TBXAS1 Zornitza Stark reviewed gene: TBXAS1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ghosal hematodiaphyseal syndrome, MIM# 231095; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 TBX5 Zornitza Stark reviewed gene: TBX5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Holt-Oram syndrome, MIM# 142900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.3 TBX4 Zornitza Stark reviewed gene: TBX4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Amelia, posterior, with pelvic and pulmonary hypoplasia syndrome, MIM# 601360, Ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertension, MIM# 147891; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 TBX3 Zornitza Stark reviewed gene: TBX3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ulnar-mammary syndrome, MIM# 181450; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.3 TBX22 Zornitza Stark reviewed gene: TBX22: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Abruzzo-Erickson syndrome, MIM# 302905, Cleft palate with ankyloglossia, MIM# 303400; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability - microarray and sequencing v3.3 TBX20 Zornitza Stark reviewed gene: TBX20: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Atrial septal defect 4, MIM# 611363; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.3 TBX15 Zornitza Stark reviewed gene: TBX15: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cousin syndrome, MIM# 260660; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 TANC2 Zornitza Stark reviewed gene: TANC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31616000; Phenotypes: Intellectual disability, autism, epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.3 TAB2 Zornitza Stark reviewed gene: TAB2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital heart defects, nonsyndromic, 2, MIM# 614980; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.3 SUZ12 Zornitza Stark reviewed gene: SUZ12: Rating: GREEN; Mode of pathogenicity: None; Publications: 31736240, 30019515, 28229514; Phenotypes: Intellectual disability, Overgrowth; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.3 STT3A Zornitza Stark reviewed gene: STT3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 23842455, 30701557, 28424003; Phenotypes: Congenital disorder of glycosylation, type Iw, OMIM #615596; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 STS Zornitza Stark reviewed gene: STS: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.3 STAT1 Zornitza Stark reviewed gene: STAT1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.3 STAR Zornitza Stark reviewed gene: STAR: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Lipoid adrenal hyperplasia, MIM# 201710; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 SRY Zornitza Stark reviewed gene: SRY: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.3 SPEG Zornitza Stark reviewed gene: SPEG: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Centronuclear myopathy 5, OMIM #615959; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 SPAG1 Zornitza Stark reviewed gene: SPAG1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 28, MIM# 615505; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 SOX17 Zornitza Stark reviewed gene: SOX17: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Vesicoureteral reflux 3, MIM# 613674; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.3 RASA1 Zornitza Stark reviewed gene: RASA1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Capillary malformation-arteriovenous malformation 1, MIM# 608354; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.3 SNX27 Zornitza Stark reviewed gene: SNX27: Rating: GREEN; Mode of pathogenicity: None; Publications: 25894286, 31721175, 21300787, 23524343; Phenotypes: intellectual disability, seizures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 SMCHD1 Zornitza Stark reviewed gene: SMCHD1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Bosma arhinia microphthalmia syndrome, OMIM #603457, Fascioscapulohumeral muscular dystrophy 2, digenic, OMIM #158901; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.3 DDC Lothar Schlueter reviewed gene: DDC: Rating: GREEN; Mode of pathogenicity: None; Publications: 28100251, 30952622, 30689738, 25597765, 24788355; Phenotypes: Aromatic L-amino acid decarboxylase deficiency 608643, floppy child, dystonia, hypotonia, developmental delay, oculogyric crisis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 SKIV2L Zornitza Stark reviewed gene: SKIV2L: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Trichohepatoenteric syndrome 2, MIM# 614602; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 SIX5 Zornitza Stark reviewed gene: SIX5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Branchiootorenal syndrome 2 610896; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.3 SIX1 Zornitza Stark reviewed gene: SIX1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Branchiootic syndrome 3, MIM# 608389, Deafness, autosomal dominant 23, MIM# 605192; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.3 SH3PXD2B Zornitza Stark reviewed gene: SH3PXD2B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Frank-ter Haar syndrome, MIM# 249420; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 SEC23B Zornitza Stark reviewed gene: SEC23B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ?Cowden syndrome 7 616858, Dyserythropoietic anemia, congenital, type II 224100; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 SCN1B Zornitza Stark reviewed gene: SCN1B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Epileptic encephalopathy, early infantile, 52, MIM#617350; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.3 SCN11A Zornitza Stark reviewed gene: SCN11A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuropathy, hereditary sensory and autonomic, type VII, MIM#615548; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.3 SCARF2 Zornitza Stark reviewed gene: SCARF2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Van den Ende-Gupta syndrome, MIM# 600920; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 SCAMP5 Zornitza Stark reviewed gene: SCAMP5: Rating: GREEN; Mode of pathogenicity: Other; Publications: 31439720; Phenotypes: Intellectual disability, seizures, autism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.3 SBDS Zornitza Stark reviewed gene: SBDS: Rating: RED; Mode of pathogenicity: None; Publications: 19906387; Phenotypes: Shwachman-Diamond syndrome, MIM#260400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 SALL4 Zornitza Stark reviewed gene: SALL4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Duane-radial ray syndrome, MIM# 607323; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.3 SOX3 Zornitza Stark reviewed gene: SOX3: Rating: AMBER; Mode of pathogenicity: None; Publications: 29175558, 30125608, 12428212, 15800844; Phenotypes: Mental retardation, X-linked, with isolated growth hormone deficiency, MIM#300123, Panhypopituitarism, X-linked, MIM#312000; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability - microarray and sequencing v3.3 PUM1 Zornitza Stark reviewed gene: PUM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29474920, 25768905; Phenotypes: Spinocerebellar ataxia 47, MIM#617931; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.3 PSAT1 Zornitza Stark reviewed gene: PSAT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 26960553, 17436247, 25152457; Phenotypes: Phosphoserine aminotransferase deficiency, MIM# 610992, Neu-Laxova syndrome 2, MIM# 616038; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 PRSS56 Zornitza Stark reviewed gene: PRSS56: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Microphthalmia, isolated 6, MIM# 613517; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 PROP1 Zornitza Stark reviewed gene: PROP1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Pituitary hormone deficiency, combined, 2, MIM# 262600; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.3 PRKAR1A Zornitza Stark reviewed gene: PRKAR1A: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Acrodysostosis 1, with or without hormone resistance, MIM# 101800; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.3 PRDM12 Zornitza Stark reviewed gene: PRDM12: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuropathy, hereditary sensory and autonomic, type VIII, MIM# 616488; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.3 PPA2 Zornitza Stark reviewed gene: PPA2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Sudden cardiac failure, infantile, MIM# 617222; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.1 POLR1D Zornitza Stark reviewed gene: POLR1D: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Treacher Collins syndrome 2, MIM# 613717; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1 POLR1C Zornitza Stark reviewed gene: POLR1C: Rating: GREEN; Mode of pathogenicity: None; Publications: 26151409; Phenotypes: Leukodystrophy, hypomyelinating, 11, MIM# 616494; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1 POLD1 Zornitza Stark reviewed gene: POLD1: Rating: RED; Mode of pathogenicity: None; Publications: 31449058; Phenotypes: Intellectual disability, immunodeficiency, Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome, MIM#615381; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1 POC1B Zornitza Stark reviewed gene: POC1B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cone-rod dystrophy 20 615973; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1 PNPT1 Zornitza Stark reviewed gene: PNPT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Combined oxidative phosphorylation deficiency 13, MIM#614932; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1 PMS2 Zornitza Stark reviewed gene: PMS2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Mismatch repair cancer syndrome, MIM# 276300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.1 PLOD2 Zornitza Stark reviewed gene: PLOD2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Bruck syndrome 2 609220; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 PKHD1 Zornitza Stark reviewed gene: PKHD1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Polycystic kidney disease 4, with or without hepatic disease 263200; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 PKD1L1 Zornitza Stark reviewed gene: PKD1L1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Heterotaxy, visceral, 8, autosomal, MIM# 617205; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 PITX3 Zornitza Stark reviewed gene: PITX3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Anterior segment dysgenesis 1, multiple subtypes, MIM# 107250, cataract; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.0 PITX2 Zornitza Stark reviewed gene: PITX2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Axenfeld-Rieger syndrome, type 1, MIM# 180500; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.0 PIK3R1 Zornitza Stark reviewed gene: PIK3R1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: SHORT syndrome, MIM#269880; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.0 PIK3C2A Zornitza Stark reviewed gene: PIK3C2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 31034465; Phenotypes: Oculoskeletodental syndrome, 618440; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 PGM1 Zornitza Stark reviewed gene: PGM1: Rating: RED; Mode of pathogenicity: None; Publications: 24499211; Phenotypes: Congenital disorder of glycosylation, type It, MIM# 614921; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 PET100 Zornitza Stark reviewed gene: PET100: Rating: GREEN; Mode of pathogenicity: None; Publications: 24462369, 25293719, 31406627; Phenotypes: Mitochondrial complex IV deficiency, MIM# 220110; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.0 PDE6G Zornitza Stark reviewed gene: PDE6G: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Retinitis pigmentosa 57 613582; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 PAX9 Zornitza Stark reviewed gene: PAX9: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Tooth agenesis, selective, 3 604625; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 PAX3 Zornitza Stark reviewed gene: PAX3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Craniofacial-deafness-hand syndrome, MIM#122880, Waardenburg syndrome, type 1, MIM#193500, Waardenburg syndrome, type 3, MIM#148820; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.0 PAPSS2 Zornitza Stark reviewed gene: PAPSS2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Brachyolmia 4 with mild epiphyseal and metaphyseal changes, MIM# 612847; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 OXR1 Zornitza Stark reviewed gene: OXR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31785787; Phenotypes: Intellectual disability, seizures, cerebellar atrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.0 OTULIN Zornitza Stark reviewed gene: OTULIN: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Autoinflammation, panniculitis, and dermatosis syndrome, MIM# 617099; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 OTOGL Zornitza Stark reviewed gene: OTOGL: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Deafness, autosomal recessive 84B, MIM# 614944; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 LTBP3 Zornitza Stark reviewed gene: LTBP3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Dental anomalies and short stature 601216, Geleophysic dysplasia 3 617809; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 LTBP2 Zornitza Stark reviewed gene: LTBP2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Weill-Marchesani syndrome 3, recessive, MIM# 614819, Glaucoma 3, primary congenital, MIM# 613086, Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma, MIM# 251750; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 LSS Zornitza Stark reviewed gene: LSS: Rating: GREEN; Mode of pathogenicity: None; Publications: 30723320; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 LRRC6 Zornitza Stark reviewed gene: LRRC6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 19, MIM# 614935; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 LRP4 Zornitza Stark reviewed gene: LRP4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cenani-Lenz syndactyly syndrome, MIM# 212780, Sclerosteosis 2, MIM# 614305; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 LMX1B Zornitza Stark reviewed gene: LMX1B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 LMNA Zornitza Stark reviewed gene: LMNA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 LIAS Zornitza Stark reviewed gene: LIAS: Rating: GREEN; Mode of pathogenicity: None; Publications: 24334290, 22152680; Phenotypes: Hyperglycinemia, lactic acidosis, and seizures, MIM#614462; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.0 LHX4 Zornitza Stark reviewed gene: LHX4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 LHX3 Zornitza Stark reviewed gene: LHX3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Pituitary hormone deficiency, combined, 3, MIM# 221750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 LGI4 Zornitza Stark reviewed gene: LGI4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Arthrogryposis multiplex congenita, neurogenic, with myelin defect, MIM#617468; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 LFNG Zornitza Stark reviewed gene: LFNG: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 LEMD3 Zornitza Stark reviewed gene: LEMD3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 LDB3 Zornitza Stark reviewed gene: LDB3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 LAS1L Zornitza Stark reviewed gene: LAS1L: Rating: GREEN; Mode of pathogenicity: None; Publications: 25644381, 25644381; Phenotypes: Wilson-Turner syndrome, MIM# 309585; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.0 KLHL40 Zornitza Stark reviewed gene: KLHL40: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Nemaline myopathy 8, autosomal recessive 615348; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 KLF1 Zornitza Stark reviewed gene: KLF1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 KIT Zornitza Stark reviewed gene: KIT: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.0 KIRREL3 Zornitza Stark reviewed gene: KIRREL3: Rating: RED; Mode of pathogenicity: None; Publications: 19012874; Phenotypes: Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.0 KIF22 Zornitza Stark reviewed gene: KIF22: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spondyloepimetaphyseal dysplasia with joint laxity, type 2 603546; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 KDM6B Zornitza Stark reviewed gene: KDM6B: Rating: GREEN; Mode of pathogenicity: None; Publications: 31124279; Phenotypes: Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.0 KDM3B Zornitza Stark reviewed gene: KDM3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 30929739; Phenotypes: Intellectual disability, short stature; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.0 KCTD1 Zornitza Stark reviewed gene: KCTD1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 KCNQ1 Zornitza Stark reviewed gene: KCNQ1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 KCNMA1 Zornitza Stark reviewed gene: KCNMA1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 27567911, 29545233, 26195193, 31427379; Phenotypes: Cerebellar atrophy, developmental delay, and seizures, MIM# 617643, Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, MIM#609446; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.0 KCNK4 Zornitza Stark reviewed gene: KCNK4: Rating: GREEN; Mode of pathogenicity: None; Publications: 30290154; Phenotypes: Facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth syndrome 618381; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.0 KCND3 Zornitza Stark reviewed gene: KCND3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinocerebellar ataxia 19, MIM#607346; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.0 KCNC3 Zornitza Stark reviewed gene: KCNC3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinocerebellar ataxia 13, MIM#605259; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.0 KBTBD13 Zornitza Stark reviewed gene: KBTBD13: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Nemaline myopathy 6, autosomal dominant, MIM# 609273; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.0 KAT8 Zornitza Stark reviewed gene: KAT8: Rating: GREEN; Mode of pathogenicity: None; Publications: 31794431; Phenotypes: Intellectual disability, seizures, autism, dysmorphic features; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.0 JAK3 Zornitza Stark reviewed gene: JAK3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 JAGN1 Zornitza Stark reviewed gene: JAGN1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neutropenia, severe congenital, 6, autosomal recessive 616022; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 JAG1 Zornitza Stark reviewed gene: JAG1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Alagille syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.0 IRF6 Zornitza Stark reviewed gene: IRF6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 IQSEC1 Zornitza Stark reviewed gene: IQSEC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31607425; Phenotypes: Intellectual developmental disorder with short stature and behavioral abnormalities, MIM# 618687; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.0 SCN4A Zornitza Stark reviewed gene: SCN4A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Hyperkalemic periodic paralysis, type 2, MIM# 170500, Hypokalemic periodic paralysis, type 2, MIM# 613345, Myasthenic syndrome, congenital, 16, MIM# 614198, Myotonia congenita, atypical, acetazolamide-responsive 608390, Paramyotonia congenita 168300; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 INPPL1 Zornitza Stark reviewed gene: INPPL1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Opsismodysplasia, MIM# 258480; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 IMPAD1 Zornitza Stark reviewed gene: IMPAD1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Chondrodysplasia with joint dislocations, GPAPP type, MIM# 614078; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 IL11RA Zornitza Stark reviewed gene: IL11RA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Craniosynostosis and dental anomalies, MIM# 614188; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 IHH Zornitza Stark reviewed gene: IHH: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Acrocapitofemoral dysplasia, MIM# 607778, Brachydactyly, type A1, MIM# 112500; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 IGF2 Zornitza Stark reviewed gene: IGF2: Rating: RED; Mode of pathogenicity: None; Publications: 31544945, 26154720; Phenotypes: Growth restriction, severe, with distinctive facies, MIM#616489; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 IFT80 Zornitza Stark reviewed gene: IFT80: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 IFT122 Zornitza Stark reviewed gene: IFT122: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 IFITM5 Zornitza Stark reviewed gene: IFITM5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 HYLS1 Zornitza Stark reviewed gene: HYLS1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Hydrolethalus syndrome, MIM#236680; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 HYDIN Zornitza Stark reviewed gene: HYDIN: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 HYAL1 Zornitza Stark reviewed gene: HYAL1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 HSPG2 Zornitza Stark reviewed gene: HSPG2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Schwartz-Jampel syndrome, type 1, MIM#255800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 HSF4 Zornitza Stark reviewed gene: HSF4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 HSD3B7 Zornitza Stark reviewed gene: HSD3B7: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 HR Zornitza Stark reviewed gene: HR: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 HPSE2 Zornitza Stark reviewed gene: HPSE2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 HPS1 Zornitza Stark reviewed gene: HPS1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 HPGD Zornitza Stark reviewed gene: HPGD: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 HOXD13 Zornitza Stark reviewed gene: HOXD13: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 HOXC13 Zornitza Stark reviewed gene: HOXC13: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 HOXA13 Zornitza Stark reviewed gene: HOXA13: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 HNF4A Zornitza Stark reviewed gene: HNF4A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 HMGCS2 Zornitza Stark reviewed gene: HMGCS2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: HMG-CoA synthase-2 deficiency, MIM# 605911; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 HADH Zornitza Stark reviewed gene: HADH: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: 3-hydroxyacyl-CoA dehydrogenase deficiency, MIM#231530, Hyperinsulinemic hypoglycemia, familial, 4, MIM#609975; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 GUCY2C Zornitza Stark reviewed gene: GUCY2C: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 GRM6 Zornitza Stark reviewed gene: GRM6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 GRIA1 Zornitza Stark reviewed gene: GRIA1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.0 GRHL3 Zornitza Stark reviewed gene: GRHL3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 GPSM2 Zornitza Stark reviewed gene: GPSM2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Chudley-McCullough syndrome, MIM#604213; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 GPR179 Zornitza Stark reviewed gene: GPR179: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 GOT2 Zornitza Stark reviewed gene: GOT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31422819; Phenotypes: Epileptic encephalopathy, early infantile, 82, MIM# 618721; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.0 GNAI3 Zornitza Stark reviewed gene: GNAI3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 HDAC4 Zornitza Stark reviewed gene: HDAC4: Rating: AMBER; Mode of pathogenicity: None; Publications: 24715439, 20691407, 31209962; Phenotypes: Brachydactyly mental retardation syndrome, Brachydactyly without intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.0 GLMN Zornitza Stark reviewed gene: GLMN: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 GLE1 Zornitza Stark reviewed gene: GLE1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 GJB1 Zornitza Stark reviewed gene: GJB1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Charcot-Marie-Tooth neuropathy, X-linked dominant, 1, MIM#302800; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 GJA8 Zornitza Stark reviewed gene: GJA8: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 GJA3 Zornitza Stark reviewed gene: GJA3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 GJA1 Zornitza Stark reviewed gene: GJA1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Atrioventricular septal defect 3, MIM#600309, Craniometaphyseal dysplasia, autosomal recessive, MIM#218400, Erythrokeratodermia variabilis et progressiva 3, MIM#617525, Hypoplastic left heart syndrome 1, MIM#241550, Oculodentodigital dysplasia, MIM#164200, Oculodentodigital dysplasia, autosomal recessive, MIM#257850, Palmoplantar keratoderma with congenital alopecia, MIM#104100, Syndactyly, type III, MIM# 186100; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 GHR Zornitza Stark reviewed gene: GHR: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Growth hormone insensitivity, partial, MIM#604271, Laron dwarfism, MIM#262500; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 GDF6 Zornitza Stark reviewed gene: GDF6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 GDF5 Zornitza Stark reviewed gene: GDF5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 GBA2 Zornitza Stark reviewed gene: GBA2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 46, autosomal recessive, MIM#614409; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 GATA6 Zornitza Stark reviewed gene: GATA6: Rating: GREEN; Mode of pathogenicity: None; Publications: 22158542; Phenotypes: Pancreatic agenesis and congenital heart defects, MIM#600001; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.0 GATA4 Zornitza Stark reviewed gene: GATA4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 GATA2 Zornitza Stark reviewed gene: GATA2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 GAS8 Zornitza Stark reviewed gene: GAS8: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 GALK1 Zornitza Stark reviewed gene: GALK1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 GAA Zornitza Stark reviewed gene: GAA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 FZD6 Zornitza Stark reviewed gene: FZD6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 FYCO1 Zornitza Stark reviewed gene: FYCO1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 FXN Zornitza Stark reviewed gene: FXN: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 FTL Zornitza Stark reviewed gene: FTL: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodegeneration with brain iron accumulation 3, MIM#606159, Hyperferritinemia-cataract syndrome, MIM#600886, L-ferritin deficiency, dominant and recessive, MIM#615604; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 FRY Zornitza Stark reviewed gene: FRY: Rating: AMBER; Mode of pathogenicity: None; Publications: 31487712, 27457812, 21937992; Phenotypes: Intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 FOXN1 Zornitza Stark reviewed gene: FOXN1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 FOXF1 Zornitza Stark reviewed gene: FOXF1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 FOXE3 Zornitza Stark reviewed gene: FOXE3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 FOXE1 Zornitza Stark reviewed gene: FOXE1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 FOXC2 Zornitza Stark reviewed gene: FOXC2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 FOXC1 Zornitza Stark reviewed gene: FOXC1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 FLVCR1 Zornitza Stark reviewed gene: FLVCR1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ataxia, posterior column, with retinitis pigmentosa, MIM#609033; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 FLT4 Zornitza Stark reviewed gene: FLT4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 FLNB Zornitza Stark reviewed gene: FLNB: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 FKBP14 Zornitza Stark reviewed gene: FKBP14: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 FHL1 Zornitza Stark reviewed gene: FHL1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 FGF3 Zornitza Stark reviewed gene: FGF3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Deafness, congenital with inner ear agenesis, microtia, and microdontia, MIM#610706; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 FGF14 Zornitza Stark reviewed gene: FGF14: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinocerebellar ataxia 27, MIM# 609307; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.0 FGF10 Zornitza Stark reviewed gene: FGF10: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.0 FDFT1 Zornitza Stark reviewed gene: FDFT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29909962; Phenotypes: Squalene synthase deficiency, MIM#618156; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.0 FBXW4 Zornitza Stark reviewed gene: FBXW4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 FBP1 Zornitza Stark reviewed gene: FBP1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 FBN1 Zornitza Stark reviewed gene: FBN1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 FAR1 Zornitza Stark reviewed gene: FAR1: Rating: AMBER; Mode of pathogenicity: None; Publications: 25439727; Phenotypes: Peroxisomal fatty acyl-CoA reductase 1 disorder, MIM#616154; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 FAM20A Zornitza Stark reviewed gene: FAM20A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 FAM161A Zornitza Stark reviewed gene: FAM161A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 FAAH2 Zornitza Stark reviewed gene: FAAH2: Rating: RED; Mode of pathogenicity: None; Publications: 25885783; Phenotypes: Neuropsychiatric disorder; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability - microarray and sequencing v3.0 FA2H Zornitza Stark reviewed gene: FA2H: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 EYA1 Zornitza Stark reviewed gene: EYA1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 EXT2 Zornitza Stark reviewed gene: EXT2: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: Seizures, scoliosis, and macrocephaly syndrome, MIM#616682; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.0 EVC2 Zornitza Stark reviewed gene: EVC2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ellis-van Creveld syndrome, MIM#225500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 EVC Zornitza Stark reviewed gene: EVC: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ellis-van Creveld syndrome, MIM#225500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 ERMARD Zornitza Stark reviewed gene: ERMARD: Rating: RED; Mode of pathogenicity: None; Publications: 24056535, 27087860; Phenotypes: Periventricular nodular heterotopia 6, MIM#615544; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.0 ERF Zornitza Stark reviewed gene: ERF: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Chitayat syndrome, MIM#617180, Craniosynostosis 4, MIM#600775; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 ERCC4 Zornitza Stark reviewed gene: ERCC4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Xeroderma pigmentosum, group F, MIM#278760, XFE progeroid syndrome, MIM# 610965; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 EOGT Zornitza Stark reviewed gene: EOGT: Rating: RED; Mode of pathogenicity: None; Publications: 31368252; Phenotypes: Adams-Oliver syndrome 4, MIM#615297; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 ENPP1 Zornitza Stark reviewed gene: ENPP1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 ELN Zornitza Stark reviewed gene: ELN: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Supravalvar aortic stenosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.0 ATAD3A Zornitza Stark reviewed gene: ATAD3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 32004445; Phenotypes: Harel-Yoon syndrome 617183; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.0 EDNRA Zornitza Stark reviewed gene: EDNRA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Mandibulofacial dysostosis with alopecia, MIM# 616367; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 EDA Zornitza Stark reviewed gene: EDA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 ECEL1 Zornitza Stark reviewed gene: ECEL1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 DYNC2H1 Zornitza Stark reviewed gene: DYNC2H1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Short-rib thoracic dysplasia 3 with or without polydactyly, MIM#613091; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 DVL1 Zornitza Stark reviewed gene: DVL1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Robinow syndrome, autosomal dominant 2 616331; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 DSTYK Zornitza Stark reviewed gene: DSTYK: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 DSPP Zornitza Stark reviewed gene: DSPP: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 DPM3 Zornitza Stark reviewed gene: DPM3: Rating: RED; Mode of pathogenicity: None; Publications: 19576565, 28803818, 30931530, 31469168; Phenotypes: Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 15 612937; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 DNM1L Zornitza Stark gene: DNM1L was added
gene: DNM1L was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: DNM1L was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: DNM1L were set to Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1, MIM#614388
Mode of pathogenicity for gene: DNM1L was set to Other
Review for gene: DNM1L was set to GREEN
gene: DNM1L was marked as current diagnostic
Added comment: Dominant and recessive disease described depending on domain affected; dominant negative effect of heterozygous missense variants. LoF/LoF or LoF/missense for AR variants.
Sources: Expert list
Intellectual disability - microarray and sequencing v3.0 DNAAF4 Zornitza Stark reviewed gene: DNAAF4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 DNAAF3 Zornitza Stark reviewed gene: DNAAF3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 DMP1 Zornitza Stark reviewed gene: DMP1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 DLL4 Zornitza Stark reviewed gene: DLL4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 DLL3 Zornitza Stark reviewed gene: DLL3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 DLL1 Zornitza Stark reviewed gene: DLL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31353024; Phenotypes: Intellectual disability, autism, seizures, variable brain abnormalities, scoliosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.0 DENND5A Zornitza Stark reviewed gene: DENND5A: Rating: GREEN; Mode of pathogenicity: None; Publications: 27431290, 27866705; Phenotypes: Epileptic encephalopathy, early infantile, 49 617281; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 DDOST Zornitza Stark reviewed gene: DDOST: Rating: RED; Mode of pathogenicity: None; Publications: 22305527; Phenotypes: Congenital disorder of glycosylation, type Ir, MIM# 614507; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 DDB2 Zornitza Stark reviewed gene: DDB2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 DCC Zornitza Stark reviewed gene: DCC: Rating: RED; Mode of pathogenicity: None; Publications: 31697046; Phenotypes: Agenesis of the corpus callosum; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.0 CYP7B1 Zornitza Stark reviewed gene: CYP7B1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 5A, autosomal recessive, MIM# 270800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 CYP2U1 Zornitza Stark reviewed gene: CYP2U1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 56, autosomal recessive, MIM#615030; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 CYP1B1 Zornitza Stark reviewed gene: CYP1B1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 CTSK Zornitza Stark reviewed gene: CTSK: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 CTSF Zornitza Stark reviewed gene: CTSF: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ceroid lipofuscinosis, neuronal, 13, Kufs type, MIM#615362; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 CTNS Zornitza Stark reviewed gene: CTNS: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 CRYGD Zornitza Stark reviewed gene: CRYGD: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 CRYBB3 Zornitza Stark reviewed gene: CRYBB3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 CRYBB2 Zornitza Stark reviewed gene: CRYBB2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 CRYBB1 Zornitza Stark reviewed gene: CRYBB1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 CRYBA1 Zornitza Stark reviewed gene: CRYBA1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 CRYAA Zornitza Stark reviewed gene: CRYAA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 CRX Zornitza Stark reviewed gene: CRX: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 COMP Zornitza Stark reviewed gene: COMP: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 COL9A3 Zornitza Stark reviewed gene: COL9A3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 COL9A2 Zornitza Stark reviewed gene: COL9A2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 COL9A1 Zornitza Stark reviewed gene: COL9A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 COL6A1 Zornitza Stark reviewed gene: COL6A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 COL4A4 Zornitza Stark reviewed gene: COL4A4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 COL4A3 Zornitza Stark reviewed gene: COL4A3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 COL2A1 Zornitza Stark reviewed gene: COL2A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 COL1A1 Zornitza Stark reviewed gene: COL1A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 COL18A1 Zornitza Stark reviewed gene: COL18A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Knobloch syndrome, type 1, MIM#267750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 COL11A1 Zornitza Stark reviewed gene: COL11A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Stickler syndrome, type II, MIM# 604841; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.0 COL10A1 Zornitza Stark reviewed gene: COL10A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Metaphyseal chondrodysplasia, Schmid type, MIM# 156500; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 CLDN19 Zornitza Stark reviewed gene: CLDN19: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypomagnesemia 5, renal, with ocular involvement, MIM# 248190; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 CLCN7 Zornitza Stark reviewed gene: CLCN7: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Osteopetrosis; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 CIB2 Zornitza Stark reviewed gene: CIB2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Deafness, autosomal recessive 48, MIM# 609439, Usher syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 CHUK Zornitza Stark reviewed gene: CHUK: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cocoon syndrome, MIM# 613630; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 CHSY1 Zornitza Stark reviewed gene: CHSY1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Temtamy preaxial brachydactyly syndrome 605282; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 CHST3 Zornitza Stark reviewed gene: CHST3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spondyloepiphyseal dysplasia with congenital joint dislocations, MIM# 143095; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 CHRNG Zornitza Stark reviewed gene: CHRNG: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Escobar syndrome, MIM# 265000, Multiple pterygium syndrome, lethal type, MIM# 253290; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 CHRDL1 Zornitza Stark reviewed gene: CHRDL1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Megalocornea 1, X-linked, MIM# 309300; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability - microarray and sequencing v3.0 CHM Zornitza Stark reviewed gene: CHM: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Choroideremia, MIM# 303100; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability - microarray and sequencing v3.0 CHD1 Zornitza Stark gene: CHD1 was added
gene: CHD1 was added to Intellectual disability. Sources: Expert list
Mode of inheritance for gene: CHD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHD1 were set to 28866611
Phenotypes for gene: CHD1 were set to Pilarowski-Bjornsson syndrome, MIM#617682
Mode of pathogenicity for gene: CHD1 was set to Other
Review for gene: CHD1 was set to GREEN
gene: CHD1 was marked as current diagnostic
Added comment: Six unrelated individuals with heterozygous variants reported. Possible dominant negative mechanism: reported variants are missense, and an individual with a deletion did not have a neurological phenotype.
Sources: Expert list
Intellectual disability - microarray and sequencing v3.0 CEP104 Zornitza Stark reviewed gene: CEP104: Rating: GREEN; Mode of pathogenicity: None; Publications: 26477546; Phenotypes: Joubert syndrome 25, MIM# 616781; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 CDH3 Zornitza Stark reviewed gene: CDH3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ectodermal dysplasia, ectrodactyly, and macular dystrophy 225280, Hypotrichosis, congenital, with juvenile macular dystrophy 601553; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 CDH23 Zornitza Stark reviewed gene: CDH23: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Deafness, Usher syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 CDH2 Zornitza Stark reviewed gene: CDH2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31585109; Phenotypes: Intellectual disability, corpus callosum abnormalities, congenital abnormalities; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.0 CCT5 Zornitza Stark reviewed gene: CCT5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuropathy, hereditary sensory, with spastic paraplegia, MIM# 256840; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 CCNO Zornitza Stark reviewed gene: CCNO: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 29, MIM# 615872; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 CCDC65 Zornitza Stark reviewed gene: CCDC65: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 27, MIM# 615504; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 CCDC40 Zornitza Stark reviewed gene: CCDC40: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 15, MIM# 613808; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 CCDC114 Zornitza Stark reviewed gene: CCDC114: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 20, MIM# 615067; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 CCDC103 Zornitza Stark reviewed gene: CCDC103: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 17, MIM# 614679; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 CARS2 Zornitza Stark reviewed gene: CARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30139652; Phenotypes: Combined oxidative phosphorylation deficiency 27, MIM#616672; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 EBP Zornitza Stark reviewed gene: EBP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Chondrodysplasia punctata, X-linked dominant MIM#302960, Conradi-Hunermann syndrome, MEND syndrome, MIM#300960; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.0 CACNA2D2 Zornitza Stark reviewed gene: CACNA2D2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebellar atrophy with seizures and variable developmental delay, MIM#618501; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.0 CA5A Zornitza Stark reviewed gene: CA5A: Rating: RED; Mode of pathogenicity: None; Publications: 26913920; Phenotypes: Hyperammonemia due to carbonic anhydrase VA deficiency, MIM# 615751; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 C8orf37 Zornitza Stark reviewed gene: C8orf37: Rating: ; Mode of pathogenicity: None; Publications: 26854863, 27008867; Phenotypes: Bardet-Biedl syndrome 21, MIM#617406; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 C4orf26 Zornitza Stark reviewed gene: C4orf26: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Amelogenesis imperfecta, type IIA4, MIM# 614832; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 C2orf71 Zornitza Stark reviewed gene: C2orf71: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Retinitis pigmentosa 54 613428; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 C2CD3 Zornitza Stark reviewed gene: C2CD3: Rating: GREEN; Mode of pathogenicity: None; Publications: 30097616, 27094867, 26477546, 24997988,; Phenotypes: Orofaciodigital syndrome XIV, MIM# 615948; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.0 C19orf12 Zornitza Stark reviewed gene: C19orf12: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodegeneration with brain iron accumulation 4, MIM#614298; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 BMPR1B Zornitza Stark reviewed gene: BMPR1B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Acromesomelic dysplasia, Demirhan type MIM#609441, Brachydactyly, type A1, D, MIM#616849, Brachydactyly, type A2, MIM# 112600; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 BMPER Zornitza Stark reviewed gene: BMPER: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Diaphanospondylodysostosis, MIM# 608022; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 BICD2 Zornitza Stark reviewed gene: BICD2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinal muscular atrophy, lower extremity-predominant, 2A, autosomal dominant, MIM#615290; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.0 BHLHA9 Zornitza Stark reviewed gene: BHLHA9: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Syndactyly, mesoaxial synostotic, with phalangeal reduction, MIM# 609432; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 BGN Zornitza Stark reviewed gene: BGN: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Meester-Loeys syndrome, MIM# 300989, Spondyloepimetaphyseal dysplasia, X-linked, MIM#300106; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability - microarray and sequencing v3.0 BFSP2 Zornitza Stark reviewed gene: BFSP2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cataract 12, multiple types, MIM# 611597; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.0 BCORL1 Zornitza Stark reviewed gene: BCORL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24123876, 30941876; Phenotypes: Shukla-Vernon syndrome, MIM# 301029; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.0 B9D1 Zornitza Stark reviewed gene: B9D1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24886560, 21493627; Phenotypes: Joubert syndrome 27, MIM#617120, Meckel syndrome 9, MIM#614209; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.0 ATP8B1 Zornitza Stark reviewed gene: ATP8B1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cholestasis, benign recurrent intrahepatic, MIM# 243300, Cholestasis, intrahepatic, of pregnancy, 1, MIM#147480, Cholestasis, progressive familial intrahepatic 1, MIM# 211600; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 ATP6V1B1 Zornitza Stark reviewed gene: ATP6V1B1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Renal tubular acidosis with deafness 267300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 ATP1A2 Zornitza Stark reviewed gene: ATP1A2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Alternating hemiplegia of childhood 1, MIM# 104290; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.0 ARHGEF6 Zornitza Stark reviewed gene: ARHGEF6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: MENTAL RETARDATION X-LINKED TYPE 46; Mode of inheritance: None
Intellectual disability - microarray and sequencing v3.0 ANKH Zornitza Stark reviewed gene: ANKH: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Craniometaphyseal dysplasia, MIM#123000; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.0 ALG9 Zornitza Stark reviewed gene: ALG9: Rating: GREEN; Mode of pathogenicity: None; Publications: 28932688; Phenotypes: Congenital disorder of glycosylation, type Il, MIM#608776; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 ALDOB Zornitza Stark reviewed gene: ALDOB: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Fructose intolerance, hereditary, MIM# 229600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 AHCY Zornitza Stark reviewed gene: AHCY: Rating: ; Mode of pathogenicity: None; Publications: 31957987, 27671891, 30121674, 28779239; Phenotypes: Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, MIM#613752; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 AGPS Zornitza Stark reviewed gene: AGPS: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Rhizomelic chondrodysplasia punctata, type 3, MIM#600121; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 AGL Zornitza Stark reviewed gene: AGL: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Glycogen storage disease IIIa, MIM# 232400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 AFG3L2 Zornitza Stark reviewed gene: AFG3L2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic ataxia 5, autosomal recessive, MIM#614487; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 ADGRG6 Zornitza Stark reviewed gene: ADGRG6: Rating: RED; Mode of pathogenicity: None; Publications: 30549416; Phenotypes: Lethal congenital contracture syndrome 9, OMIM #616503; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 ADCY5 Zornitza Stark reviewed gene: ADCY5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Dyskinesia, familial, with facial myokymia, MIM#606703; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.0 ACADSB Zornitza Stark reviewed gene: ACADSB: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: 2-methylbutyrylglycinuria, MIM# 610006; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 ABCC6 Zornitza Stark reviewed gene: ABCC6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Arterial calcification, generalized, of infancy, 2, MIM#614473, Pseudoxanthoma elasticum, MIM#264800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v3.0 ABAT Zornitza Stark reviewed gene: ABAT: Rating: GREEN; Mode of pathogenicity: None; Publications: 10407778, 20052547, 27596361, 28411234,; Phenotypes: GABA-transaminase deficiency, MIM#613163; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v3.0 SUPT16H Konstantinos Varvagiannis gene: SUPT16H was added
gene: SUPT16H was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SUPT16H was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SUPT16H were set to http://dx.doi.org/10.1136/jmedgenet-2019-106193
Phenotypes for gene: SUPT16H were set to Global developmental delay; Intellectual disability; Abnormality of the corpus callosum
Penetrance for gene: SUPT16H were set to Complete
Review for gene: SUPT16H was set to AMBER
Added comment: Bina et al (2020 - http://dx.doi.org/10.1136/jmedgenet-2019-106193) report on 4 unrelated individuals with heterozygous SNVs affecting SUPT16H as well as 1 further with microdeletion spanning this gene.

The phenotype consisted of DD with subsequent ID in a subset of them (ages of the cohort: 2y-14y), autistic features in few, abnormalities of the corpus callosum (for 3 with available MRI images), variable gastrointestinal problems in some, and possibly minor dysmorphic features.

SUPT16H encodes a subunit of the FACT (facilitates chromatin transcription) complex, a chromatin-specific factor required for transcription elongation as well as for DNA replication and repair (OMIM citing Belotserkovskaya et al. 2003 - PMID: 12934006). The 2 subunits of the complex [Spt16 (encoded by SUPT16H) and SSRP1] are essential for histone regulation. As the authors note, Spt16 interacts with the histone dimer H2A-H2B during transcription to allow RNA polymerase access to previously coiled DNA [cited PMIDs : 9489704, 10421373 / A recent study by Liu et al 2019 (PMID: 31775157) appears highly relevant].

SUPT16H has a Z-score of 5.1 in gnomAD and a pLI of 1 (%HI of 22.56 in Decipher).

SNVs :
4 de novo missense SNVs were identified following exome sequencing (NM_007192.3:c.484A>G or I162V / L432P / N571S / R734W), all absent from gnomAD and mostly predicted to be deleterious (I162V predicted benign, tolerated, disease-causing by PolyPhen2, SIFT, MutationTaster respectively and had a CADD score of 13.61). Prior work-up for these individuals (incl. CMA in some / MS-MLPA for Angelman s. in 1 / metabolic investigations) had (probably) not revealed an apparent cause, with small CNVs inherited from healthy parents (a 4q13.3 dup / 20q13.2 del - coordinates not provided).

There were no studies performed for the identified variants.

CNVs :
A 5th individual reported by Bina et al was found to harbor a 2.05 Mb 14q11.2 deletion spanning SUPT16H. The specific deletion also spanned CHD8 while the same individual harbored also a 30.17 Mb duplication of 18p11.32q12.1.

CNVs spanning SUPT16H reported to date, also span the (very) proximal CHD8. [Genomic coordinates (GRCh38) for SUPT16H and CHD8 as provided by OMIM : 14:21,351,471-21,384,018 / 14:21,385,198-21,456,122]. Haploinsufficiency of CHD8 is associated with a distinctive syndrome with overgrowth and ID (Douzgou et al 2019 - PMID: 31001818). The phenotype of SUPT16H-CHD8 duplications is discussed in other studies/reviews. [Smol et al 2020 - PMID: 31823155 / Smyk et al 2016 - PMID: 26834018].

Animal models were not commented on by Bina et al (possibly not available for mouse : http://www.informatics.jax.org/marker/MGI:1890948 / https://www.mousephenotype.org/data/genes/MGI:1890948 ).
Sources: Literature
Intellectual disability - microarray and sequencing v3.0 TET3 Konstantinos Varvagiannis gene: TET3 was added
gene: TET3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TET3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: TET3 were set to https://doi.org/10.1016/j.ajhg.2019.12.007
Phenotypes for gene: TET3 were set to Global developmental delay; Intellectual disability; Macrocephaly; Growth abnormality; Seizures; Autistic behavior; Abnormality of movement; Abnormality of the face
Penetrance for gene: TET3 were set to Complete
Review for gene: TET3 was set to GREEN
Added comment: Beck et al (2020 - DOI: https://doi.org/10.1016/j.ajhg.2019.12.007) report on individuals with monoallelic de novo or biallelic pathogenic TET3 variants.

For both inheritance modes (AR/AD) DD/ID were among the observed features (mild-severe - individuals from families 2, 4 and 6 for whom presence of ID was not commented, relevance to the current panel is suggested from the developmental milestones in the supplement. One individual presented DD without ID). Other features included hypotonia (in 8), ASD/autistic features (in 5), seizures (2 unrelated subjects for each inheritance mode). Postnatal growth abnormalities were observed in many, in most cases involving head size (with/without abnormal stature) and few presented abnormal prenatal growth. Variable movement disorders were observed in some. Some facial features appeared to be more common (eg. long face, tall forehead, etc).

Most were referred for their DD. Extensive prior genetic investigations had (mostly) come out normal (with possible contribution of a 16p11.2 dup in an individual with monoallelic variant or a 16q22 dup in another with biallelic TET3 variants). Monoallelic / biallelic variants in all subjects were identified following exome sequencing.

TET3 encodes a methylcytosine dioxygenase (the TET family consisting of 3 enzymes, TET1, TET2, TET3). These enzymes are involved in DNA demethylation through a series of reactions beginning with the conversion of 5-methyl cytosine [5mc] to 5-hydromethylcytosine [5hmC].

5 individuals from 3 families (1/3 consanguineous) harbored biallelic missense variants. 5 different missense variants were observed. Heterozygous parents appeared to be mildly affected (eg. having learning difficulties, etc).

6 individuals from 5 families harbored monoallelic variants [3 truncating (of which 2 localizing in the last exon), 2 missense SNVs]. In one family the variant was inherited from a similarly affected parent. In all other cases the variant had occured de novo. No additional TET3 variants were identified, with the limitations of WES.

All missense mutations, whether observed in individuals with biallelic or monoallelic variants, were located within the catalytic domain or - for a single variant (NM_001287491.1:c.2254C>T / p.Arg752Cys) - adjacent to it.

Functional studies were carried out only for (all) missense variants observed in individuals with biallelic variants. Conversion of 5mC to 5hmC is the first step in DNA demethylation. In HEK293 cells overexpressing either wt or variants, production of 5hmc was measured. 4/5 missense variants evaluated demonstrated a defect in converting 5mC to 5hmC, Arg752Cys being an exception (as also predicted by its localization).

DD/ID and abnormal growth are also features of disorders of the epigenetic machinery (DNA methylation machinery, histone machinery, chromatin remodelers, other chromatin-associated proteins). Similarly to TET3, both monoallelic and biallelic variants in KDM5B, encoding for another component of the epigenetic machinery, have been identified in individuals with ID.

Mouse models discussed by the authors [several Refs provided though not here reviewed] : The gene has been shown to be highly expressed in oocytes, zygotes and neurons and to play a role in demethylation of the paternal genome after fertilization. (From the MGI: 'mice inheriting a null allele from a germ cell conditional null mother display impaired reprogramming of the paternal genome resulting in reduced embryo viability'). Beck et al also note that Tet3 inhibition or depletion in differentiated neurons can impact synaptic function [PMIDs cited: 25915473, 24757058, 26711116].
Sources: Literature
Intellectual disability - microarray and sequencing v3.0 RNF113A Konstantinos Varvagiannis reviewed gene: RNF113A: Rating: GREEN; Mode of pathogenicity: None; Publications: 25612912, 31880405, 31793730, 29133357, 30506991, 15256591, 24026126, 23555887; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability - microarray and sequencing v3.0 MTHFS Konstantinos Varvagiannis changed review comment from: Biallelic pathogenic MTHFS variants cause Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination (# 618367).

The gene encodes 5,10-Methenyltetrahydrofolate synthetase which catalyzes conversion of 5-formyltetrahydrofolate (5-FTHF or folinic acid) to 5,10-methenyltetrahydrofolate (5,10-MTHF).

At least 3 unrelated individuals have been reported. The phenotype appears to be relevant to both epilepsy and ID gene panels and the role of variants/the gene supported by enzymatic activity studies, 5-FTHF accumulation, 5,10-MTHF levels (low/low-normal), the role of folate metabolism pathway overall and some supporting (metabolic) evidence from the mouse model.
---
Rodan et al (2018 - PMID: 30031689) reported on 2 individuals both presenting with microcephaly, severe global DD, epilepsy, progressive spasticity and cerebral hypomyelination upon MRI imaging. Short stature was also feature in both.

The 1st patient was an 8-year-old male who following exome sequencing was found to harbor 2 missense variants each inherited from a carrier parent. (NM_006441.3:c.434G>A / p.R145Q and c.107T>C / p.L36P). A further AFG3L2 indel was not felt to fit with his phenotype (and the onset of the related disorder appears to occur later).

Previous investigations included extensive metabolic testing, CMA, Angelman syndrome methylation analysis, GFAP, POLG1, TYMP sequencing, mitochondrial genome analysis and an XL-ID gene panel (further suggesting relevance of this gene to the current panel) were all non-diagnostic.

CSF 5-MTHF levels were initially on the low-normal range, subsequently found to be decreased (upon folinic acid supplementation) and later normalized upon use of another regimen.

MTHFS activity was measured in control fibroblasts as well as fibroblasts from this individual, with the latter demonstrating no enzyme activity. Accumulation (30x elevation) of 5-FTHF (the substrate of MTHFS) was demonstrated in patient fibroblasts.

The 2nd patient was a 11-year-old male with similar features incl. global DD (standing/walking/single words at/after 4 years of age, limited vocabulary and articulation upon last examination).

Extensive metabolic work-up as well as genetic testing for an epilepsy panel, vanishing white matter disease gene panel, mitochondrial genome as well as specific gene sequencing (LAMA2, POLR3A, POLR3B) were all non-diagnostic. Trio exome revealed 2 MTHFS variants in trans configuration (c.484C>T / p.Q162X and c.434G>A / p.R145Q).
---
Romero et al (2019 - PMID: 31844630) reported on a 4-year-old female with congenital microcephaly, severe global DD (nonverbal/nonambulatory at the age of 4), spasticity, epilepsy and cerebral hypomyelination.

Extensive investigations prior to exome sequencing revealed macrocytic anemia, decreased CSF 5-MTHF and elevated neopterin, 2 CNVs of uncertain significance upon CMA with additional long ROH on chr15. Methylation studies were negative. The child was homozygous for c.220C>T / p.R74X (RefSeq is probably NM_006441.3. MTHFS lies on chr15. The parents were unrelated but came from the same town). There were no other candidate variants from the exome analysis.

Both articles discuss extensively the role of the folate metabolism pathway overall in nucleic acid synthesis, AA metabolism, neurotransmitter synthesis, methylation as well as 5-FTHF / 5,10-MTHF in particular in myelin stabilization and DNA synthesis (eg. according to Romero et al. a defect in MTHFS would impair myelin production and also lead to decreased myelin stability).
---
A book chapter cited by Rodan et al (in N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases - DOI: 10.1007/978-3-642-40337-8_10) included limited details on a patient with 'MTHFS gene mutation'. This individual had early speech delay, seizures beginning in infancy, ID, autistic features, recurrent infections and was found to have very low CSF 5-MTHF levels. [Details in p169 and table 10.6 - p173].
---
In a mouse model reported by Field et al (2011 - PMID: 22303332), Mthfs was disrupted through insertion of a gene trap vector between the first 2 exons. Heterozygous [Mthfs(gt/+)] mice were fertile and viable. Mthfs protein levels were slightly but not statistically significantly reduced in tissues measured. No homozygous embryos were recovered following intercrosses of heterozygous mice, suggesting that Mthfs is an essential gene. Mouse embryonic fibroblasts from heterozygous mice [Mthfs (gt/+)] exhibited reduced de novo purine biosynthesis, but did not exhibit altered de novo thymidylate biosynthesis. Plasma folate levels were altered in heterozygous mice on a standard (/control) diet.
Sources: Literature; to: Biallelic pathogenic MTHFS variants cause Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination (# 618367).

The gene encodes 5,10-Methenyltetrahydrofolate synthetase which catalyzes conversion of 5-formyltetrahydrofolate (5-FTHF or folinic acid) to 5,10-methenyltetrahydrofolate (5,10-MTHF).

At least 3 unrelated individuals have been reported. The phenotype appears to be relevant to both epilepsy and ID gene panels and the role of variants/the gene supported by enzymatic activity studies, 5-FTHF accumulation, 5,10-MTHF levels (low/low-normal), the role of folate metabolism pathway overall and some supporting (metabolic) evidence from the mouse model.
---
Rodan et al (2018 - PMID: 30031689) reported on 2 individuals both presenting with microcephaly, severe global DD, epilepsy, progressive spasticity and cerebral hypomyelination upon MRI imaging. Short stature was also feature in both.

The 1st patient was an 8-year-old male who following exome sequencing was found to harbor 2 missense variants each inherited from a carrier parent. (NM_006441.3:c.434G>A / p.R145Q and c.107T>C / p.L36P). A further AFG3L2 indel was not felt to fit with his phenotype (and the onset of the related disorder appears to occur later).

Previous investigations included extensive metabolic testing, CMA, Angelman syndrome methylation analysis, GFAP, POLG1, TYMP sequencing, mitochondrial genome analysis and an XL-ID gene panel (further suggesting relevance of this gene to the current panel) were all non-diagnostic.

CSF 5-MTHF levels were initially on the low-normal range, subsequently found to be decreased (upon folinic acid supplementation) and later normalized upon use of another regimen.

MTHFS activity was measured in control fibroblasts as well as fibroblasts from this individual, with the latter demonstrating no enzyme activity. Accumulation (30x elevation) of 5-FTHF (the substrate of MTHFS) was demonstrated in patient fibroblasts.

The 2nd patient was a 11-year-old male with similar features incl. global DD (standing/walking/single words at/after 4 years of age, limited vocabulary and articulation upon last examination).

Extensive metabolic work-up as well as genetic testing for an epilepsy panel, vanishing white matter disease gene panel, mitochondrial genome as well as specific gene sequencing (LAMA2, POLR3A, POLR3B) were all non-diagnostic. Trio exome revealed 2 MTHFS variants in trans configuration (c.484C>T / p.Q162X and c.434G>A / p.R145Q).
---
Romero et al (2019 - PMID: 31844630) reported on a 4-year-old female with congenital microcephaly, severe global DD (nonverbal/nonambulatory at the age of 4), spasticity, epilepsy and cerebral hypomyelination.

Extensive investigations prior to exome sequencing revealed macrocytic anemia, decreased CSF 5-MTHF and elevated neopterin, 2 CNVs of uncertain significance upon CMA with additional long ROH on chr15. Methylation studies were negative. The child was homozygous for c.220C>T / p.R74X (RefSeq is probably NM_006441.3. MTHFS lies on chr15. The parents were unrelated but came from the same town). There were no other candidate variants from the exome analysis.

Both articles discuss extensively the role of the folate metabolism pathway overall in nucleic acid synthesis, AA metabolism, neurotransmitter synthesis, methylation as well as 5-FTHF / 5,10-MTHF in particular in myelin stabilization and DNA synthesis (eg. according to Romero et al. a defect in MTHFS would impair myelin production and also lead to decreased myelin stability).
---
A book chapter cited by Rodan et al (in N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases - DOI: 10.1007/978-3-642-40337-8_10) included limited details on a patient with 'MTHFS gene mutation'. This individual had early speech delay, seizures beginning in infancy, ID, autistic features, recurrent infections and was found to have very low CSF 5-MTHF levels. [Details in p169 and table 10.6 - p173].
---
In a mouse model reported by Field et al (2011 - PMID: 22303332), Mthfs was disrupted through insertion of a gene trap vector between the first 2 exons. Heterozygous [Mthfs(gt/+)] mice were fertile and viable. Mthfs protein levels were slightly but not statistically significantly reduced in tissues measured. No homozygous embryos were recovered following intercrosses of heterozygous mice, suggesting that Mthfs is an essential gene. Mouse embryonic fibroblasts from heterozygous mice [Mthfs (gt/+)] exhibited reduced de novo purine biosynthesis, but did not exhibit altered de novo thymidylate biosynthesis. Plasma folate levels were altered in heterozygous mice on a standard (/control) diet.

[Please consider inclusion in other possibly relevant panels e.g. for metabolic disorders]
Sources: Literature
Intellectual disability - microarray and sequencing v3.0 MTHFS Konstantinos Varvagiannis gene: MTHFS was added
gene: MTHFS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MTHFS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTHFS were set to 30031689; 31844630; 22303332; https://doi.org/10.1007/978-3-642-40337-8_10
Phenotypes for gene: MTHFS were set to Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination, 618367
Penetrance for gene: MTHFS were set to Complete
Review for gene: MTHFS was set to GREEN
Added comment: Biallelic pathogenic MTHFS variants cause Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination (# 618367).

The gene encodes 5,10-Methenyltetrahydrofolate synthetase which catalyzes conversion of 5-formyltetrahydrofolate (5-FTHF or folinic acid) to 5,10-methenyltetrahydrofolate (5,10-MTHF).

At least 3 unrelated individuals have been reported. The phenotype appears to be relevant to both epilepsy and ID gene panels and the role of variants/the gene supported by enzymatic activity studies, 5-FTHF accumulation, 5,10-MTHF levels (low/low-normal), the role of folate metabolism pathway overall and some supporting (metabolic) evidence from the mouse model.
---
Rodan et al (2018 - PMID: 30031689) reported on 2 individuals both presenting with microcephaly, severe global DD, epilepsy, progressive spasticity and cerebral hypomyelination upon MRI imaging. Short stature was also feature in both.

The 1st patient was an 8-year-old male who following exome sequencing was found to harbor 2 missense variants each inherited from a carrier parent. (NM_006441.3:c.434G>A / p.R145Q and c.107T>C / p.L36P). A further AFG3L2 indel was not felt to fit with his phenotype (and the onset of the related disorder appears to occur later).

Previous investigations included extensive metabolic testing, CMA, Angelman syndrome methylation analysis, GFAP, POLG1, TYMP sequencing, mitochondrial genome analysis and an XL-ID gene panel (further suggesting relevance of this gene to the current panel) were all non-diagnostic.

CSF 5-MTHF levels were initially on the low-normal range, subsequently found to be decreased (upon folinic acid supplementation) and later normalized upon use of another regimen.

MTHFS activity was measured in control fibroblasts as well as fibroblasts from this individual, with the latter demonstrating no enzyme activity. Accumulation (30x elevation) of 5-FTHF (the substrate of MTHFS) was demonstrated in patient fibroblasts.

The 2nd patient was a 11-year-old male with similar features incl. global DD (standing/walking/single words at/after 4 years of age, limited vocabulary and articulation upon last examination).

Extensive metabolic work-up as well as genetic testing for an epilepsy panel, vanishing white matter disease gene panel, mitochondrial genome as well as specific gene sequencing (LAMA2, POLR3A, POLR3B) were all non-diagnostic. Trio exome revealed 2 MTHFS variants in trans configuration (c.484C>T / p.Q162X and c.434G>A / p.R145Q).
---
Romero et al (2019 - PMID: 31844630) reported on a 4-year-old female with congenital microcephaly, severe global DD (nonverbal/nonambulatory at the age of 4), spasticity, epilepsy and cerebral hypomyelination.

Extensive investigations prior to exome sequencing revealed macrocytic anemia, decreased CSF 5-MTHF and elevated neopterin, 2 CNVs of uncertain significance upon CMA with additional long ROH on chr15. Methylation studies were negative. The child was homozygous for c.220C>T / p.R74X (RefSeq is probably NM_006441.3. MTHFS lies on chr15. The parents were unrelated but came from the same town). There were no other candidate variants from the exome analysis.

Both articles discuss extensively the role of the folate metabolism pathway overall in nucleic acid synthesis, AA metabolism, neurotransmitter synthesis, methylation as well as 5-FTHF / 5,10-MTHF in particular in myelin stabilization and DNA synthesis (eg. according to Romero et al. a defect in MTHFS would impair myelin production and also lead to decreased myelin stability).
---
A book chapter cited by Rodan et al (in N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases - DOI: 10.1007/978-3-642-40337-8_10) included limited details on a patient with 'MTHFS gene mutation'. This individual had early speech delay, seizures beginning in infancy, ID, autistic features, recurrent infections and was found to have very low CSF 5-MTHF levels. [Details in p169 and table 10.6 - p173].
---
In a mouse model reported by Field et al (2011 - PMID: 22303332), Mthfs was disrupted through insertion of a gene trap vector between the first 2 exons. Heterozygous [Mthfs(gt/+)] mice were fertile and viable. Mthfs protein levels were slightly but not statistically significantly reduced in tissues measured. No homozygous embryos were recovered following intercrosses of heterozygous mice, suggesting that Mthfs is an essential gene. Mouse embryonic fibroblasts from heterozygous mice [Mthfs (gt/+)] exhibited reduced de novo purine biosynthesis, but did not exhibit altered de novo thymidylate biosynthesis. Plasma folate levels were altered in heterozygous mice on a standard (/control) diet.
Sources: Literature
Intellectual disability - microarray and sequencing v3.0 PUM1 Konstantinos Varvagiannis commented on gene: PUM1: 5 unrelated individuals with de novo pathogenic PUM1 variants have been reported in the literature. DD (5/5), ID (4/5 - relevant severity to the current panel), seizures (4/4 - absence/tonic-clonic, abnormal EEG) and variable other features (incl. facial dysmorphism, ataxia, cryptorchidism) appear to be part of the phenotype. 9 individuals with deletions spanning PUM1 and proximal genes presented similar features.

[1] PMID: 29474920 - Gennarino et al (2018)
[2] PMID: 30903679 - Bonnemason-Carrere et al (2019)
[3] PMID: 31859446 - Voet et al (2019) [with review of the literature]

SNVs in relevant individuals were identified by exome sequencing and were in all cases de novo.

Arg1147Trp was a recurrent variant reported in 3 unrelated subjects with ID and seizures (Refs 1,2,3 / NM_001020658.1:c.3439C>T). A nonsense variant was reported in an additional one with DD, ID, seizures and additional features (c.2509C>T / p.Arg837* - Ref3). One individual with a de novo missense variant (c.3416G>A / p.Arg1139Trp) with DD and ataxia, though without ID was reported in Ref1.

Details on 9 individuals with 0.3 - 5.6 Mb deletions spanning PUM1 and other genes are provided in Ref1. Features also included DD, ID, seizures, ataxia, etc.

Extensive initial investigations were reported for individuals in Refs 2 and 3 (various investigations incl. karyotype, SNP-array, targeted sequencing of OPHN1, KANSL1 or of a small panel of ID genes, biopsies and/or metabolic work-up) to rule out alternative causes. These only revealed a likely benign CNV and a GRIA3 SNV of uncertain significance in the case of an individual harboring the recurrent Arg1147Trp variant [Ref2].

Role of the gene (from OMIM):
Pumilio proteins, such as PUM1, negatively regulate gene expression by repressing translation of mRNAs to which they bind (Lee et al., 2016). A clinically significant PUM1 target is ataxin (ATXN1; 601556), mutation in which causes spinocerebellar ataxia-1 (SCA1; 601556).

Variant studies:
- Arg1147Trp was shown to be associated with normal PUM1 mRNA levels, but reduced (to ~43%) PUM1 protein levels in patient fibroblasts. ATXN1 mRNA and protein levels, as well as protein and/or mRNA levels of other PUM1 targets were shown to be increased (Ref1).
- In Ref1, in vitro transfection assays with wt or mt PUM1 were performed in HEK293T cells to evaluate repression of ATXN1 and E2F3. While overexpression of wt and Arg1147Trp were able to reduce ATXN1 and E2F3 levels, Arg1139Trp was not able to repress ATXN1 or E2F3.
- Upon overexpression in mouse hippocampal neurons, PUM1 missense mutations (among others Arg1139Trp and Arg1147Trp) were shown to alter neuronal morphology.

Overall haploinsufficiency is the proposed mechanism for the disorder for which the acronym PADDAS is used (Pumilio1-associated developmental disability, ataxia and seizure).

Milder mutations reducing PUM1 levels by 25% are associated with adult-onset ataxia without ID (PRCA or Pumilio1-related cerebellar ataxia) [Ref1].

Mouse models:
The role of PUM1 was first suggested in mouse models where Pum1 mutations were shown to lead to a SCA1-like phenotype (PMID cited : 12086639 - Watase et al 2002) further shown to be caused by increased Atxn1 mRNA and protein levels (PMID cited : 25768905 - Gennarino et al 2015).
The mouse model seems to recapitulate several of the features observed in affected individuals : Pum1 homozygous ko mice display among others hyperactivity, progressive cerebellar signs, spontaneous seizures as also observed in affected individuals (PMID cited : 25768905 - Gennarino et al 2015). Cryptorchidism was observed in 2 patients similar to testicular hypoplasia reported in Pum1 ko mice (PMID cited : 22342750 - Chen et al 2012).
- Heterozygous mice were evaluated in Ref1 with 69% or 75% exhibiting spontaneous seizures by the end of 30 or 35 wks respectively, with abnormal EEG activity already by 16 wks.

Additional individuals with PUM1 variants and a relevant phenotype of ID with or without seizures have been reported as part of the DDD study or as external submissions to Decipher and ClinVar :

https://decipher.sanger.ac.uk/search?q=PUM1#research-variants/results [ DDD4K.01387 participant ]
https://decipher.sanger.ac.uk/search?q=pum1#consented-patients/results [ external submission(s) ]
https://www.ncbi.nlm.nih.gov/clinvar/variation/431110/ [ splice-site variant in an individual with ID submitted prior to the 1st publication on the disorder ]
Intellectual disability - microarray and sequencing v3.0 DLL1 Konstantinos Varvagiannis gene: DLL1 was added
gene: DLL1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DLL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DLL1 were set to 31353024
Phenotypes for gene: DLL1 were set to Global developmental delay; Intellectual disability; Morphological abnormality of the central nervous system; Seizures; Behavioral abnormality; Autism; Scoliosis
Penetrance for gene: DLL1 were set to unknown
Review for gene: DLL1 was set to GREEN
Added comment: Heterozygous DLL1 pathogenic variants cause Neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures (# 618709).

Fischer-Zirnsak et al (2019 - PMID: 31353024) reported on 15 affected individuals from 12 unrelated families.

Most common features included DD/ID (12/14), ASD (6/14 - belonging to 6 families) or other behavioral abnormalities, seizures (6/14 - from 6 unrelated families) and various brain MRI abnromalities. As commented by OMIM (based on the same ref) "Cognitive function ranges from severely impaired to the ability to attend schools with special assistance". Among other features, scoliosis was observed in 4. The authors could not identify a distinctive facial gestalt.

Variable initial investigations (where discussed/performed - also suggesting relevance to the current panel) included CMA, FMR1, FLNA, mitochondrial DNA analysis and metabolic work-up but had not revealed an alternative cause.

The DLL1 variants were identified by WES (with the exception of a 122-kb microdeletion spanning DLL1 and FAM120B detected by CMA). Nonsense, frame-shift, splice-site variants in positions predicted to result to NMD were identified in most. One individual was found to harbor a missense variant (NM_005618.3:c.536G>T / p.Cys179Phe) and another the aforementioned microdeletion.

The variant in several individuals had occurred as a de novo event. In 2 families, it was inherited from an also affected parent (an unaffected sib was non-carrier) while in 3 families parental studies were not possible/complete.

In frame insertion of 4 residues was demonstrated for a splice site variant, from LCLs of the corresponding individual. For another individual, material was unavailable for mRNA studies. The missense variant affected a cysteine (of the DSL domain) conserved in all Notch ligands while AA changes affecting the same position of JAG1 (another Notch ligand) have been described in patients with Alagille s.

Based on the variants identified and reports of deletions spanning DLL1 in the literature, haploinsufficiency is the proposed underlying mechanism. The gene has also a pLI of 1 and %HI of 4.65.

DLL1 encodes the Delta-like canonical Notch ligand 1. Notch signaling is an established pathway for brain morphogenesis. Previous in vivo and in vitro studies have demonstrated the role of DLL1 in CNS. The gene is highly expressed in neuronal precursor cells during embryogenesis. Expression of Dll1 (and other molecules of the Notch signalling pathway) in an oscillatory/sustained pattern and cell-cell interactions important for this pathway have been demonstrated to play a role in neuronal differentiation. [Most discussed by Fischer-Zirnsak et al with several refs provided / also Gray et al., 1999 - PMID: 10079256 & OMIM].

Animal models as summarized by the authors:
[Mouse] Loss of Dll1 in mice has been shown to increase neuronal differentiation, cause CNS hyperplasia and increased number of neurons (PMIDs cited: 9109488, 12397111, 20081190). Reduced Dll1 expression was associated with scoliosis and mild vertebral defects (cited PMIDs: 19562077, 14960495, 22484060 / among others Dll1 haploinsufficiency and dominant negative models studied). Scoliosis and vertebral segmentation defects were features in 4 and 1 individual, respectively in the cohort of 15.
[Zebrafish] Homozygous mutations in dlA, the zebrafish ortholog, disrupted the Delta-Notch signaling and led to patterning defects in the hindbrain and overproduction of neurons (cited: 15366005).

Please consider inclusion in other possibly relevant panels e.g. for ASD.
Sources: Literature
Intellectual disability - microarray and sequencing v3.0 TFE3 Konstantinos Varvagiannis reviewed gene: TFE3: Rating: GREEN; Mode of pathogenicity: Other; Publications: 30595499, 31833172, https://doi.org/10.1126/scisignal.aax0926; Phenotypes: Global developmental delay, Intellectual disability, Abnormality of skin pigmentation, Coarse facial features, Seizures; Mode of inheritance: Other
Intellectual disability - microarray and sequencing v3.0 MN1 Konstantinos Varvagiannis gene: MN1 was added
gene: MN1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MN1 were set to 31834374; 31839203; 15870292
Phenotypes for gene: MN1 were set to Central hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Hearing impairment; Abnormality of facial skeleton; Craniosynostosis; Abnormality of the face; Abnormality of the cerebellum; Abnormality of the corpus callosum; Polymicrogyria
Penetrance for gene: MN1 were set to Complete
Review for gene: MN1 was set to GREEN
Added comment: Two studies by Mak et al (2019 - PMID: 31834374 / Ref1) and Miyake et al (2019 - PMID: 31839203 / Ref2) provide sufficient evidence for heterozygous MN1 C-terminal truncating variants (predicted to escape NMD - localizing within the last nucleotides of exon 1 or in exon 2) being associated with a distinctive phenotype and DD and ID among the features.

Mak et al also discuss on the phenotype of individuals with variants causing N-terminal truncation or with MN1 deletions (discussed at the end of this review).

Overlapping features for C-terminal truncating variants included hypotonia, feeding difficulties, global DD and ID, hearing loss, cranial shape defects (/craniosynostosis in few), highly suggestive/distinctive facial features (eg. frontal bossing, hypertelorism, downslanting palpebral-fissures, shallow orbits, short upturned nose, low-set/posteriorly rotated/dysplastic ears, etc) and brain MRI abnormalities (eg. rhomboencephalosynapsis or cerebellar dysplasia, polymicrogyria, dysplastic CC).

The majority of the affected individuals were investigated by WES/WGS with a single one tested by targeted MN1 Sanger sequencing due to highly suggestive features. Variable previous investigations incl. CMA in several, gene panel testing (Rasopathies, hearing loss, craniofacial panels, FMR1, etc) and metabolic work were normal in most. In a single case a likely pathogenic ACSL4 also explained part of the phenotype (Ref2). In the majority of these individuals, the variant had occured as a de novo event. Two sibs had inherited the truncating variant from a milder affected mosaic parent. A parental sample was not available for an additional individual.

p.(Arg1295*) or NM_002430.2:c.3883C>T was a recurrent variant, seen in several individuals and in both studies.

Several lines of evidence are provided for the MN1 variants and the role of the gene including:
- For few individuals for whom cell lines were available, variants were shown to escape NMD by cDNA/RT-PCR/RNA-seq [Ref1 & 2].
- The gene has a high expression in fetal brain [Ref2 / fig S2]
- MN1 (* 156100 - MN1 protooncogene, transcriptional regulator) has been proposed to play a role in cell proliferation and shown to act as transcription cofactor (increasing its transactivation capacity in synergy with coactivators EP300 and RAC3) [Discussion and Refs provided in Ref2].
- In vitro studies suggested increased protein stability (upon transfection of wt/mut constructs in HEK293T cells), enhanced MN1 aggregation in nuclei (when wt/mut GFP-tagged MN1 was expressed in HeLa cells), increased inhibitory effect on cell growth (MG63 cells - role of MN1 in cell proliferation discussed above) and retained transactivation activity (upon transient MN1 overexpression of wt/mt MN1 in HEK293T cells) for the variants. These seem to support a gain-of-function effect for the C-terminal truncating variants [Ref2].
- The truncating variants are proposed to raise the fraction of Intrinsically disordered regions (IDRs = regions without fixed tertiary structure) probably contributing to the above effects [Ref2].
- Expression of FLAG-tagged MN1 wt/mut MN1 followed by immunoprecipitation and mass spectrometry analysis (mCAT-Hela cells), provided evidence that MN1 is involved in transcriptional regulation: a. through binding ZBTB24 and RING1 E3 ubiquitin ligase (with mutant MN1 displaying impaired interaction with ZBTB24 and no binding to RING1) and/or b. through interaction with DNA-binding transcription factors PBX1 and PKNOX1. Proper MN1 degradation is proposed to mediate precise transcriptional regulation. [Ref2]
- Transcriptome analysis in LCLs from an affected individual suggested dysregulation of genes relevant to neuronal development (eg. LAMP, ITGA, etc) and GO analysis suggested enrichment for pathways possibly linked to the observed phenotypes [Ref2].
- Discussed in both Refs1/2, homozygous Mn1-ko mice display abnormal skull bone development and die at/shortly after birth as a result of cleft palate. Heterozygous Mn1-ko mice display hypoplastic membranous bones of the cranial skeleton and cleft palate (CP), the latter with incomplete penetrance [Meester-Smoor et al 2005 - PMID: 15870292]. This is thus compatible with the cranial shape defects observed in C-terminal truncations (while CP has been reported in gene deletions, bifid uvula was reported once in C-terminal and N-terminal truncating variants, in the latter case with submucous CP).
-----
The phenotype of other MN1 variants is discussed by Mak et al (Ref1) :
- 3 individuals with MN1 N-terminal truncating variants (eg. Ser179*, Pro365Thrfs*120, Ser472*) presented speech delay, mild conductive hearing loss and facial features different from C-terminal truncations. None of these individuals had significant ID.
- Microdeletions: One individual (#27) with 130 kb deletion harboring only MN1, presented microcephaly, DD and ID and mildly dysmorphic facial features. Deletions spanning MN1 and other genes (eg a 1.17 Mb deletion in ind. #28) and relevant cases from the literature reviewed, with mild DD/ID, variable palatal defects and/or facial dysmorphisms (distinct from the C-terminal truncating variants) among the frequent findings.

[Please consider inclusion in other possibly relevant gene panels eg. for hearing loss (conductive/sensorineural in 16/20 reported by Mak et al) or craniosynostosis, etc].
Sources: Literature
Intellectual disability - microarray and sequencing v3.0 CXorf56 Konstantinos Varvagiannis gene: CXorf56 was added
gene: CXorf56 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: CXorf56 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: CXorf56 were set to 29374277; 31822863
Phenotypes for gene: CXorf56 were set to ?Mental retardation, X-linked 107, 301013
Penetrance for gene: CXorf56 were set to unknown
Review for gene: CXorf56 was set to AMBER
Added comment: Verkerk et al (2018 - PMID: 29374277) reported on a three-generation family with five males and one female presenting mild non-syndromic ID. Segregation was compatible with X-linked inheritance.

Multipoint linkage analysis with XL microsatellite markers demonstrated a linkage peak at Xq23-24 with LOD score of 3.3. Haplotype analysis and utilization of additional STR markers allowed narrowing to a region of 7.6 Mb containing 92 genes.

WGS in 3 affected males (spanning 3 generations) and 1 unaffected male and application of relevant filters for rare protein affecting variants within this region - present only in affected but absent in the unaffected individual - suggested a CXorf56 frameshift variant in exon 2 [NM_022101.3:c.159_160insTA / p.(Asp54*)] as the only relevant for this phenotype.

Sanger sequencing was performed for 25 family members with all 5 affected males and 1 affected female harboring this insertion and 8 unaffected females (also) shown to be carriers.

X-chromosome inactivation studies demonstrated that unaffected females had skewed inactivation (76-93%) of the variant allele, while the single affected female did not have a skewed XCI pattern (54%).

In EBV-transformed lymphoblasts grown with/without cycloheximide, mRNA levels were shown to be significantly lower in the affected female compared to unaffected ones (and corrected upon treatment with cycloheximide). mRNA levels were also significantly lower in cell lines from an affected male, with expression showing significant increase after treatment with cycloheximide. These results confirmed that nonsense-mediated decay applies.

The variant was absent from ExAC (where CXorf56 has a pLI of 0.93) and 188 healthy Dutch individuals.

The function of CXorf56 is not known. The gene appears to be expressed in brain and a (broad) range of other tissues [ https://gtexportal.org/home/gene/CXORF56 ].

Immunostaining in 8-week old murine brain, showed that the protein is present in the nucleus and cell soma of most neurons in brain cortex and cerebellum. Upon transfection of human CXorf56 cDNA in mouse primary hippocampal neurons, the protein localized in the nucleus, dendrites (co-localizing with Map2) and dendritic spines. As the authors note, the latter may suggest a role in synaptic function.

Overexpression in HEK293T cells demonstrated predominantly nuclear localization.

Mouse : Based on MGI (and an article by Cox et al. - PMID: 20548051 / both cited by the authors) male chimeras hemizygous for a gene trapped allele have abnormal midbrain-hindbrain boundary morphology, decreased forebrain size, while a subset hemizygous for a different gene trapped allele show growth delay [ http://www.informatics.jax.org/marker/MGI:1924894 ].

-----

Rocha et al (2019 - PMID: 31822863) report on 9 affected individuals with mild to severe ID belonging to 3 unrelated families. Additional features in this cohort - observed in some - included abnormal reflexes, fine tremor, seizures (in 3), abnormal gait, etc.

In the 1st family, 3 males presented with (severe/severe/moderate) ID and 2 females with mild ID. Following a normal CMA and FMR1 testing, trio plus exome sequencing revealed a CXorf56 in-frame deletion [NM_022101.3:c.498_503del / p.(Glu167_Glu168del)]. Sanger sequencing in 9 members, confirmed presence of the variant in one unaffected mother, all her affected sons (2) and daughers(2) and an affected grandson and absence in 2 remaining unaffected daughters. Skewing of XCI was seen in blood cells from affected females (97 and 83%) while the unaffected mother had complete inactivation of the carrier X-chromosome. The authors commented that even minor reductions in CXorf56 (suggested by XCI in affected females) may be detrimental and/or that inactivation for this gene may be different than that of AR gene (which was studied instead) or in other tissues.

In family 2, an affected mother (with learning difficulties) and her 2 sons - the most severely affected presenting moderate ID - harbored a frameshift variant [c.303_304delCTinsACCC / p.(Phe101Leufs*20)].

A male with ID belonging to a 3rd family, for which no further information was available, was found to harbor the c.498_503del variant (also discussed above) as a de novo event.

It has been commented that individuals with Xq24 deletions spanning CXorf56 present with ID, although (all) such deletions reported in the literature also span the neighboring UBE2A gene, associated with Mental retardation, X-linked syndromic, Nascimento-type (MIM #300860).

-----

In OMIM, the CXorf56-related phenotype is ?Mental retardation, X-linked 107 (# 301013), based only on the report by Verkerk et al.

This gene is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc).

-----

Overall, CXorf56 can be considered for inclusion in the ID panel either with amber (function of the gene unknown, skewed XCI also in affected females in the 2nd reference) or with green rating (several individuals from 4 families, compatible segregation studies and females presenting a milder phenotype than males or unaffected, LOD score in the 1st report, studies confirming lower mRNA levels and NMD, gene expressed in human brain, expression in mouse brain cortex and cerebellum, evidence from transfection studies in mouse hippocampal neurons).

[Note : penetrance was here set to unknown / It was complete for males, incomplete for females].
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability - microarray and sequencing v3.0 UGP2 Konstantinos Varvagiannis gene: UGP2 was added
gene: UGP2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: UGP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UGP2 were set to 31820119
Phenotypes for gene: UGP2 were set to Seizures; Global developmental delay; Intellectual disability; Feeding difficulties; Abnormality of vision; Abnormality of the face
Penetrance for gene: UGP2 were set to Complete
Review for gene: UGP2 was set to GREEN
Added comment: Perenthaler et al. (2019 - PMID: 31820119) provide evidence that homozygosity for a variant abolishing the start codon of the UGP2 transcript (NM_001001521.1) encoding the predominant (short) protein isoform in brain, leads to a severe epileptic encephalopathy.

This variant (chr2:64083454A>G / NM_001001521.1:c.1A>G - p.?) is also predicted to result in a substitution of a methionine at position 12 by a valine of the longer UGP2 transcript (NM_006759.3:c.34A>G - p.Met12Val).

The 2 isoforms differ only by 11 amino acids at the N-terminal and are otherwise expected to be functionally equivalent.

The authors provide details on 22 individuals from 15 families (some of which consanguineous).

Features included intractable seizures (in all), absence of developmental milestones (in all), progressive microcephaly, visual impairment. The authors reported also presence of somewhat similar facial features. Some of these individuals passed away early.

Previous work-up in several of them (incl. SNP-array, gene panel testing and metabolic investigations) had not revealed any abnormality, apart from ROH in some individuals. In all cases, the homozygous UGP2 SNV was the only P/LP variant for the neurodevelopmental phenotype following exome/genome sequencing. Segregation studies in affected/unaffected family members were compatible.

Families came from the Netherlands (but mostly from) India, Pakistan and Iran. Presence of a region of homozygosity shared between individuals from different families suggested that the variant might represent a mutation that originated several generations ago (in the area of Balochistan). The variant is present 15x in gnomAD, only in heterozygous state (in Asian mostly, reported once in Ashkenazi Jewish or Europeans) [ https://gnomad.broadinstitute.org/variant/2-64083454-A-G ].

UGP2 encodes UDP-glucose pyrophosphorylase which is an essential enzyme in sugar metabolism, catalyzing conversion of glucose-1-phosphate to UDP-glucose. UDP-glucose, in turn, serves as precursor for production of glycogen by glycogen synthase.

The authors provide several lines of evidence for a the role of the gene in the CNS as well as for the deleterious effect of the specific variant :
- In patient fibroblasts total UGP2 levels were not signifficantly different compared to parent / control fibroblasts, the longer isoform being upregulated (and stable) when the shorter is missing. Immunocytochemistry demonstrated similar localization of UGP2 in the case of mutant or wt cells. Enzymatic activity (/capacity to produce UDP-glucose) was similar between homozygous mut, heterozygous and wt fibroblasts.
- In H9-derived neural stem cells, Western Blot, RT-PCR and qRT-PCR suggested that the short isoform is the predominant one. (In embryonic stem cells, or fibroblasts the ratio between short and long isoform was lower).
- Analysis of RNA-seq data from human fetal tissues suggested that the short isoform is the predominant in brain.
- UGP2 was detected upon immunohistochemistry in fetal brain tissues from first to third trimester of pregnancy while Western Blot confirmed preferential expression of the shorter isoform.
- Homozygous embryonic (ESC) or neural stem cells (NSC) for the variant (knock-in/KI) or for a frameshift variant (knock-out/KO) were generated. Study of NSCs demonstrated reduced total UGP2 protein expression upon Western Blot in the case of KI cells and depleted in KO ones. Transcriptome analysis did not show major transcriptome alterations in KI/KO ESCs compared to wt. In NSC KI/KO cells transcriptome alterations were observed compared to wt with upregulation among others of genes for synaptic processes and genes implicated in epilepsy.
- The absence of UGP2 was shown to result in reduced ability of KO/KI NSCs to produce UDP-glucose, reduced capacity to synthesize glycogen under hypoxia (rescued in the case of KO cells by overexpression of wt or long isoform), defects of protein glycosylation as well as in increased unfolded protein response (/susceptibility to ER stress). These alterations are commented to be possibly implicated in pathogenesis of epilepsy, progressive microcephaly, etc.
- A CRISPR-Cas9 zebrafish model leading with loss of ugp2a and hypomorphic ugp2b (the zebrafish homologs of UGP2) demonstrated abnormal behavior, reduced eye movements and increased frequency/duration of movements upon stimulation with a potent convulsant (suggestive of increased seizure susceptibility).
- UGP knockout in drosophila is lethal while flies compound heterozygous for hypomorphic alleles are viable but show a movement defects due to altered synaptogenesis secondary to glycosylation defects (cited PMID: 27466186).
- The authors make speculations as for the occurrence of a single variant (and not others) eg. absence of UGP2 (in the case of LoF variants affecting both isoforms) would possibly be incompatible with life, Met12Val being tolerable for the long transcript not affecting stability/enzymatic activity (which may not be the case for other substitutions affecting Met12), etc.
Sources: Literature
Intellectual disability - microarray and sequencing v3.0 SUZ12 Konstantinos Varvagiannis changed review comment from: ID can be a feature in individuals heterozygous for SUZ12 pathogenic variants. 13 affected individuals (from 12 families) have been reported:

[1] PMID 28229514 (Imagawa et al, 2017) : 1 individual
[2] PMID 30019515 (Imagawa et al, 2018) : 2 further unrelated subjects
[3] PMID 31736240 (Cyrus et al, 2019) : 10 additional subjects (from 9 families)

Reviewed by Cyrus et al, features observed in more than half of the (13) affected individuals included prenatal and/or postnatal overgrowth (in some only prenatal, others only postnatal, others did not manifest overgrowth at all), some suggestive facial features (eg. prominent forehead, hypertelorism, downslanting palpebral fissures, round face, broad/low nasal bridge), DD and ID (the latter in 7/13, in most cases mild), advanced bone age, musculoskeletal abnormalities and cryptorchidism. Less frequent features included brain MRI abnormalities (eg. CC hypoplasia/agenesis, etc.), umbilical hernias, respiratory abnormalities, cardiac anomalies (in one).

All were diagnosed with WES/WGS/panel testing, with few having additional findings upon this or prior testing (eg. CNVs/SNVs).

SUZ12 encodes one of the 4 core proteins of the PRC2 complex (the 3 other being encoded by EZH1/2, EED and RBBP4/7). The complex has a methyltransferase activity, catalyzing addition of up to 3 methyl groups on histone 3 at lysine residue 27 (H3K27), leading to chromatin compaction and further to gene silencing.

Mutations in genes encoding 2 other core components of the PRC2 complex - namely EZH2 and EED - cause Weaver and Cohen-Gibson syndrome with overlapping phenotype incl. overgrowth, advanced bone age, craniofacial features and DD/ID.

The SET domain of EZH1/2 and EED as well as the VEFS domain of SUZ12 are contributing to the catalytic activity.

SUZ12 variants reported to date include missense and pLoF variants (frameshift, nonsense, splice site ones) predicted to disrupt or eliminate the VEFS-box domain [almost all missense within this domain with the exception of one proximal to it (Arg535Gln) / pLoF causing truncation prior or within this domain (Arg654Ter might be an exception)] {NP_056170.2}.

Variants either occurred de novo or were inherited (~1/3), on some occasions from a mildly affected parent. Parental mosaicism has also been reported (eg. in ref1, and one or possibly two additional families in ref3).

Some preliminary assumptions on possible genotype-phenotype correlations (for overgrowth and ID related to missense/pLoF variants) are discussed in ref3.

SUZ12 is also be deleted in some patients with NF1 deletion (and a diagnosis of neurofibromatosis type 1). Deletion of SUZ12 has been proposed to contribute to the phenotype of these individuals (eg. overgrowth, cognitive development, facial features). [Discussed in ref1].

Functional studies have been carried out only in the first report (ref1) and demonstrated decreased trimethylation of H3K27 in the case of a missense variant. Overall a partial loss-of-function mechanism has been proposed for the variants.

Mouse models: A study by Pasini et al (PMID: 15385962) did not report phenotypic differences between wt and heterozygous Suz12 knockout mice (gene-trap vector) as for size, morphology and fertility. Total knockout resulted in embryonic lethality, significant growth retardation and several developmental defects. Loss of Suz12 was shown to result in absence of di- and tri-methylated H3K27 in the ko embryos. In another study cited (Miro et al - PMID: 19535498) heterozygous mice (replacement of exons 12-16 with a lacZ gene and neo cassette) displayed variable CNS defects with incomplete penetrance.

The role of the PRC2 complex and the phenotypes related to mutations in genes encoding its core components, are discussed in PMID: 31724824 (also by Cyrus et al, 2019).

SUZ12 is not associated with any phenotype in OMIM. In G2P it is included in the DD panel associated with Weaver-like overgrowth syndrome (disease confidence : confirmed). The gene is also included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx).
Sources: Literature; to: ID can be a feature in individuals heterozygous for SUZ12 pathogenic variants. 13 affected individuals (from 12 families) have been reported:

[1] PMID 28229514 (Imagawa et al, 2017) : 1 individual
[2] PMID 30019515 (Imagawa et al, 2018) : 2 further unrelated subjects
[3] PMID 31736240 (Cyrus et al, 2019) : 10 additional subjects (from 9 families)

Reviewed by Cyrus et al, features observed in more than half of the (13) affected individuals included prenatal and/or postnatal overgrowth (in some only prenatal, others only postnatal, others did not manifest overgrowth at all), some suggestive facial features (eg. prominent forehead, hypertelorism, downslanting palpebral fissures, round face, broad/low nasal bridge), DD and ID (the latter in 7/13, in most cases mild), advanced bone age, musculoskeletal abnormalities and cryptorchidism. Less frequent features included brain MRI abnormalities (eg. CC hypoplasia/agenesis, etc.), umbilical hernias, respiratory abnormalities, cardiac anomalies (in one).

All were diagnosed with WES/WGS/panel testing, with few having additional findings upon this or prior testing (eg. CNVs/SNVs).

SUZ12 encodes one of the 4 core proteins of the PRC2 complex (the 3 other being encoded by EZH1/2, EED and RBBP4/7). The complex has a methyltransferase activity, catalyzing addition of up to 3 methyl groups on histone 3 at lysine residue 27 (H3K27), leading to chromatin compaction and further to gene silencing.

Mutations in genes encoding 2 other core components of the PRC2 complex - namely EZH2 and EED - cause Weaver and Cohen-Gibson syndrome with overlapping phenotype incl. overgrowth, advanced bone age, craniofacial features and DD/ID.

The SET domain of EZH1/2 and EED as well as the VEFS domain of SUZ12 are contributing to the catalytic activity.

SUZ12 variants reported to date include missense and pLoF variants (frameshift, nonsense, splice site ones) predicted to disrupt or eliminate the VEFS-box domain [almost all missense within this domain with the exception of one proximal to it (Arg535Gln) / pLoF causing truncation prior or within this domain (Arg654Ter might be an exception)] {NP_056170.2}.

Variants either occurred de novo or were inherited (~1/3), on some occasions from a mildly affected parent. Parental mosaicism has also been reported (eg. in ref1, and one or possibly two additional families in ref3).

Some preliminary assumptions on possible genotype-phenotype correlations (for overgrowth and ID related to missense/pLoF variants) are discussed in ref3.

SUZ12 may also be deleted in some patients with NF1 deletion (and a diagnosis of neurofibromatosis type 1). Deletion of SUZ12 has been proposed to contribute to the phenotype of these individuals (eg. overgrowth, cognitive development, facial features). [Discussed in ref1].

Functional studies have been carried out only in the first report (ref1) and demonstrated decreased trimethylation of H3K27 in the case of a missense variant. Overall a partial loss-of-function mechanism has been proposed for the variants.

Mouse models: A study by Pasini et al (PMID: 15385962) did not report phenotypic differences between wt and heterozygous Suz12 knockout mice (gene-trap vector) as for size, morphology and fertility. Total knockout resulted in embryonic lethality, significant growth retardation and several developmental defects. Loss of Suz12 was shown to result in absence of di- and tri-methylated H3K27 in the ko embryos. In another study cited (Miro et al - PMID: 19535498) heterozygous mice (replacement of exons 12-16 with a lacZ gene and neo cassette) displayed variable CNS defects with incomplete penetrance.

The role of the PRC2 complex and the phenotypes related to mutations in genes encoding its core components, are discussed in PMID: 31724824 (also by Cyrus et al, 2019).

SUZ12 is not associated with any phenotype in OMIM. In G2P it is included in the DD panel associated with Weaver-like overgrowth syndrome (disease confidence : confirmed). The gene is also included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx).
Sources: Literature
Intellectual disability - microarray and sequencing v3.0 SUZ12 Konstantinos Varvagiannis changed review comment from: ID can be a feature in individuals heterozygous for SUZ12 pathogenic variants. 13 affected individuals (from 12 families) have been reported:

[1] PMID 28229514 (Imagawa et al, 2017) : 1 individual
[2] PMID 30019515 (Imagawa et al, 2018) : 2 further unrelated subjects
[3] PMID 31736240 (Cyrus et al, 2019) : 10 newly diagnosed subjects (from 9 families)

Reviewed by Cyrus et al, features observed in more than half of the (13) affected individuals included prenatal and/or postnatal overgrowth (in some only prenatal, others only postnatal, others did not manifest overgrowth at all), some suggestive facial features (eg. prominent forehead, hypertelorism, downslanting palpebral fissures, round face, broad/low nasal bridge), DD and ID (the latter in 7/13, in most cases mild), advanced bone age, musculoskeletal abnormalities and cryptorchidism. Less frequent features included brain MRI abnormalities (eg. CC hypoplasia/agenesis, etc.), umbilical hernias, respiratory abnormalities, cardiac anomalies (in one).

All were diagnosed with WES/WGS/panel testing, with few having additional findings upon this or prior testing (eg. CNVs/SNVs).

SUZ12 encodes one of the 4 core proteins of the PRC2 complex (the 3 other being encoded by EZH1/2, EED and RBBP4/7). The complex has a methyltransferase activity, catalyzing addition of up to 3 methyl groups on histone 3 at lysine residue 27 (H3K27), leading to chromatin compaction and further to gene silencing.

Mutations in genes encoding 2 other core components of the PRC2 complex - namely EZH2 and EED - cause Weaver and Cohen-Gibson syndrome with overlapping phenotype incl. overgrowth, advanced bone age, craniofacial features and DD/ID.

The SET domain of EZH1/2 and EED as well as the VEFS domain of SUZ12 are contributing to the catalytic activity.

SUZ12 variants reported to date include missense and pLoF variants (frameshift, nonsense, splice site ones) predicted to disrupt or eliminate the VEFS-box domain [almost all missense within this domain with the exception of one proximal to it (Arg535Gln) / pLoF causing truncation prior or within this domain (Arg654Ter might be an exception)] {NP_056170.2}.

Variants either occurred de novo or were inherited (~1/3), on some occasions from a mildly affected parent. Parental mosaicism has also been reported (eg. in ref1, and one or possibly two additional families in ref3).

Some preliminary assumptions on possible genotype-phenotype correlations (for overgrowth and ID related to missense/pLoF variants) are discussed in ref3.

SUZ12 is also be deleted in some patients with NF1 deletion (and a diagnosis of neurofibromatosis type 1). Deletion of SUZ12 has been proposed to contribute to the phenotype of these individuals (eg. overgrowth, cognitive development, facial features). [Discussed in ref1].

Functional studies have been carried out only in the first report (ref1) and demonstrated decreased trimethylation of H3K27 in the case of a missense variant. Overall a partial loss-of-function mechanism has been proposed for the variants.

Mouse models: An study by Pasini et al (PMID: 15385962) did not report phenotypic differences between wt and heterozygous Suz12 knockout mice (gene-trap vector) as for size, morphology and fertility. Total knockout resulted in embryonic lethality, significant growth retardation and several developmental defects. Loss of Suz12 was shown to result in absence of di- and tri-methylated H3K27 in the ko embryos. In another study cited (Miro et al - PMID: 19535498) heterozygous mice (replacement of exons 12-16 with a lacZ gene and neo cassette) displayed variable CNS defects with incomplete penetrance.

The role of the PRC2 complex and the phenotypes related to mutations in genes encoding its core components, are discussed in PMID: 31724824 (also by Cyrus et al, 2019).

SUZ12 is not associated with any phenotype in OMIM. In G2P it is included in the DD panel associated with Weaver-like overgrowth syndrome (disease confidence : confirmed). The gene is also included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx).
Sources: Literature; to: ID can be a feature in individuals heterozygous for SUZ12 pathogenic variants. 13 affected individuals (from 12 families) have been reported:

[1] PMID 28229514 (Imagawa et al, 2017) : 1 individual
[2] PMID 30019515 (Imagawa et al, 2018) : 2 further unrelated subjects
[3] PMID 31736240 (Cyrus et al, 2019) : 10 additional subjects (from 9 families)

Reviewed by Cyrus et al, features observed in more than half of the (13) affected individuals included prenatal and/or postnatal overgrowth (in some only prenatal, others only postnatal, others did not manifest overgrowth at all), some suggestive facial features (eg. prominent forehead, hypertelorism, downslanting palpebral fissures, round face, broad/low nasal bridge), DD and ID (the latter in 7/13, in most cases mild), advanced bone age, musculoskeletal abnormalities and cryptorchidism. Less frequent features included brain MRI abnormalities (eg. CC hypoplasia/agenesis, etc.), umbilical hernias, respiratory abnormalities, cardiac anomalies (in one).

All were diagnosed with WES/WGS/panel testing, with few having additional findings upon this or prior testing (eg. CNVs/SNVs).

SUZ12 encodes one of the 4 core proteins of the PRC2 complex (the 3 other being encoded by EZH1/2, EED and RBBP4/7). The complex has a methyltransferase activity, catalyzing addition of up to 3 methyl groups on histone 3 at lysine residue 27 (H3K27), leading to chromatin compaction and further to gene silencing.

Mutations in genes encoding 2 other core components of the PRC2 complex - namely EZH2 and EED - cause Weaver and Cohen-Gibson syndrome with overlapping phenotype incl. overgrowth, advanced bone age, craniofacial features and DD/ID.

The SET domain of EZH1/2 and EED as well as the VEFS domain of SUZ12 are contributing to the catalytic activity.

SUZ12 variants reported to date include missense and pLoF variants (frameshift, nonsense, splice site ones) predicted to disrupt or eliminate the VEFS-box domain [almost all missense within this domain with the exception of one proximal to it (Arg535Gln) / pLoF causing truncation prior or within this domain (Arg654Ter might be an exception)] {NP_056170.2}.

Variants either occurred de novo or were inherited (~1/3), on some occasions from a mildly affected parent. Parental mosaicism has also been reported (eg. in ref1, and one or possibly two additional families in ref3).

Some preliminary assumptions on possible genotype-phenotype correlations (for overgrowth and ID related to missense/pLoF variants) are discussed in ref3.

SUZ12 is also be deleted in some patients with NF1 deletion (and a diagnosis of neurofibromatosis type 1). Deletion of SUZ12 has been proposed to contribute to the phenotype of these individuals (eg. overgrowth, cognitive development, facial features). [Discussed in ref1].

Functional studies have been carried out only in the first report (ref1) and demonstrated decreased trimethylation of H3K27 in the case of a missense variant. Overall a partial loss-of-function mechanism has been proposed for the variants.

Mouse models: A study by Pasini et al (PMID: 15385962) did not report phenotypic differences between wt and heterozygous Suz12 knockout mice (gene-trap vector) as for size, morphology and fertility. Total knockout resulted in embryonic lethality, significant growth retardation and several developmental defects. Loss of Suz12 was shown to result in absence of di- and tri-methylated H3K27 in the ko embryos. In another study cited (Miro et al - PMID: 19535498) heterozygous mice (replacement of exons 12-16 with a lacZ gene and neo cassette) displayed variable CNS defects with incomplete penetrance.

The role of the PRC2 complex and the phenotypes related to mutations in genes encoding its core components, are discussed in PMID: 31724824 (also by Cyrus et al, 2019).

SUZ12 is not associated with any phenotype in OMIM. In G2P it is included in the DD panel associated with Weaver-like overgrowth syndrome (disease confidence : confirmed). The gene is also included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx).
Sources: Literature
Intellectual disability - microarray and sequencing v3.0 SUZ12 Konstantinos Varvagiannis gene: SUZ12 was added
gene: SUZ12 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SUZ12 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SUZ12 were set to 28229514; 30019515; 31736240; 15385962; 19535498; 31724824
Phenotypes for gene: SUZ12 were set to Overgrowth; Global developmental delay; Intellectual disability; Accelerated skeletal maturation; Abnormality of the skeletal system; Abnormality of the genitourinary system; Abnormality of the corpus callosum; Abnormality of the respiratory system; Abnormality of the abdominal wall
Penetrance for gene: SUZ12 were set to unknown
Review for gene: SUZ12 was set to GREEN
Added comment: ID can be a feature in individuals heterozygous for SUZ12 pathogenic variants. 13 affected individuals (from 12 families) have been reported:

[1] PMID 28229514 (Imagawa et al, 2017) : 1 individual
[2] PMID 30019515 (Imagawa et al, 2018) : 2 further unrelated subjects
[3] PMID 31736240 (Cyrus et al, 2019) : 10 newly diagnosed subjects (from 9 families)

Reviewed by Cyrus et al, features observed in more than half of the (13) affected individuals included prenatal and/or postnatal overgrowth (in some only prenatal, others only postnatal, others did not manifest overgrowth at all), some suggestive facial features (eg. prominent forehead, hypertelorism, downslanting palpebral fissures, round face, broad/low nasal bridge), DD and ID (the latter in 7/13, in most cases mild), advanced bone age, musculoskeletal abnormalities and cryptorchidism. Less frequent features included brain MRI abnormalities (eg. CC hypoplasia/agenesis, etc.), umbilical hernias, respiratory abnormalities, cardiac anomalies (in one).

All were diagnosed with WES/WGS/panel testing, with few having additional findings upon this or prior testing (eg. CNVs/SNVs).

SUZ12 encodes one of the 4 core proteins of the PRC2 complex (the 3 other being encoded by EZH1/2, EED and RBBP4/7). The complex has a methyltransferase activity, catalyzing addition of up to 3 methyl groups on histone 3 at lysine residue 27 (H3K27), leading to chromatin compaction and further to gene silencing.

Mutations in genes encoding 2 other core components of the PRC2 complex - namely EZH2 and EED - cause Weaver and Cohen-Gibson syndrome with overlapping phenotype incl. overgrowth, advanced bone age, craniofacial features and DD/ID.

The SET domain of EZH1/2 and EED as well as the VEFS domain of SUZ12 are contributing to the catalytic activity.

SUZ12 variants reported to date include missense and pLoF variants (frameshift, nonsense, splice site ones) predicted to disrupt or eliminate the VEFS-box domain [almost all missense within this domain with the exception of one proximal to it (Arg535Gln) / pLoF causing truncation prior or within this domain (Arg654Ter might be an exception)] {NP_056170.2}.

Variants either occurred de novo or were inherited (~1/3), on some occasions from a mildly affected parent. Parental mosaicism has also been reported (eg. in ref1, and one or possibly two additional families in ref3).

Some preliminary assumptions on possible genotype-phenotype correlations (for overgrowth and ID related to missense/pLoF variants) are discussed in ref3.

SUZ12 is also be deleted in some patients with NF1 deletion (and a diagnosis of neurofibromatosis type 1). Deletion of SUZ12 has been proposed to contribute to the phenotype of these individuals (eg. overgrowth, cognitive development, facial features). [Discussed in ref1].

Functional studies have been carried out only in the first report (ref1) and demonstrated decreased trimethylation of H3K27 in the case of a missense variant. Overall a partial loss-of-function mechanism has been proposed for the variants.

Mouse models: An study by Pasini et al (PMID: 15385962) did not report phenotypic differences between wt and heterozygous Suz12 knockout mice (gene-trap vector) as for size, morphology and fertility. Total knockout resulted in embryonic lethality, significant growth retardation and several developmental defects. Loss of Suz12 was shown to result in absence of di- and tri-methylated H3K27 in the ko embryos. In another study cited (Miro et al - PMID: 19535498) heterozygous mice (replacement of exons 12-16 with a lacZ gene and neo cassette) displayed variable CNS defects with incomplete penetrance.

The role of the PRC2 complex and the phenotypes related to mutations in genes encoding its core components, are discussed in PMID: 31724824 (also by Cyrus et al, 2019).

SUZ12 is not associated with any phenotype in OMIM. In G2P it is included in the DD panel associated with Weaver-like overgrowth syndrome (disease confidence : confirmed). The gene is also included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx).
Sources: Literature
Intellectual disability - microarray and sequencing v2.1143 AFF3 Konstantinos Varvagiannis changed review comment from: Voisin et al. (2019 - https://doi.org/10.1101/693937) report on 10 individuals with de novo missense AFF3 variants affecting a 9-amino-acid sequence (degron) important for the protein's degradation and summarize the phenotype of an additional individual previously described by Steichen-Gersdorf et al. (2008 - PMID: 18616733) with a 500 kb affecting only AFF3 (LAF4) and removing also this sequence.

The phenotype of missense variants consisted of kidney anomalies, mesomelic dysplasia, seizures, hypertrichosis, intellectual disability and pulmonary problems and was overlapping with that of the deletion. [10 of 11 subjects exhibited severe developmental epileptic encephalopathy].

9 probands harbored missense variants affecting the codon 258 while one individual had a variant affecting codon 260 [c.772G>T or p.Ala258Ser (x2), c.772G>A or p.Ala258Thr (x6), c.773C>T or p.Ala258Val (x1) and c.779T>G or p.(Val260Gly) (x1) - NM_001025108.1 / NP_001020279.1]. The deletion removed exons 4-13.

AFF1-4 are ALF transcription factor paralogs, components of the transcriptional super elongation complex regulating expression of genes involved in neurogenesis and development.

Using HEK293T cells expressing FLAG-tagged AFF3 (and AFF4) wt or mutants, accumulation of mutated forms was shown upon immunoblot.

Aff3+/- and/or -/- mice exhibit skeletal defects. These were more pronounced in homozygous mice which demonstrated also some elements in favor of kidney dysfunction and/or metabolic deregulation and possible neurological dysfunction (signs of impaired hearing and diminished grip strength). Homozygous mice had CNS anomalies (enlarged lateral ventricles and decreased corpus callosum size) similar to some affected individuals, although these were not observed in another Aff3-/- model. Knock-in mice modeling the microdeletion and the Ala258Thr variant displayed lower mesomelic limb deformities and early lethality respectively [cited PMIDs : 21677750, 25660031, knock-in model was part of the present study].

Accumulation of the protein in zebrafish (by overexpression of the human wt AFF3 mRNA), led to morphological defects.

Reanalysis of transcriptome data from previously generated HEK293T cell lines knocked down for AFF2, AFF3 and AFF4 by shRNAs (study) suggested that these transcription factors are not redundant.

Finally, CHOPS syndrome (#616368) due to mutations of AFF4 also leading to increased protein stability presents a partially overlapping phenotype (incl. cognitive impairment) to that of AFF3.
----
Shimizu et al. (8/2019 - PMID: 31388108) describe an additional individual with de novo AFF3 missense variant. The phenotype overlaps with that summarized by Voisin et al. incl. mesomelic dysplasia with additional skeletal anomalies, bilateral kidney hypoplasia and severe DD at the age of 2.5 years. Seizures and pulmonary problems were not observed. Although a different RefSeq is used the variant is among those also reported by Voisin et al. [NM_002285.2:c.697G>A (p.Ala233Thr) corresponding to NM_001025108.1:c.772G>A (p.Ala258Thr)].
----
In G2P, AFF3 is associated with Skeletal dysplasia with severe neurological disease (disease confidence : probable / ID and seizures among the assigned phenotypes). There is no associated phenotype in OMIM.
Some diagnostic laboratories include AFF3 in their ID panel (eg. among the many co-authors' affiliations GeneDx and Victorian Clinical Genetics - which was already listed as source for AFF3 in the current panel).
----
As a result this gene can be considered for upgrade to green (relevant phenotype and severity, sufficient cases, evidence for accumulation similar to AFF4, animal models, etc) or amber (pending publication of the article).

[Review modified to add additional reference/case report]; to: Voisin et al. (2019 - https://doi.org/10.1101/693937) report on 10 individuals with de novo missense AFF3 variants affecting a 9-amino-acid sequence (degron) important for the protein's degradation and summarize the phenotype of an additional individual previously described by Steichen-Gersdorf et al. (2008 - PMID: 18616733) with a 500 kb deletion affecting only AFF3 (LAF4) and removing also this sequence.

The phenotype of missense variants consisted of kidney anomalies, mesomelic dysplasia, seizures, hypertrichosis, intellectual disability and pulmonary problems and was overlapping with that of the deletion. [10 of 11 subjects exhibited severe developmental epileptic encephalopathy].

9 probands harbored missense variants affecting the codon 258 while one individual had a variant affecting codon 260 [c.772G>T or p.Ala258Ser (x2), c.772G>A or p.Ala258Thr (x6), c.773C>T or p.Ala258Val (x1) and c.779T>G or p.(Val260Gly) (x1) - NM_001025108.1 / NP_001020279.1]. The deletion removed exons 4-13.

AFF1-4 are ALF transcription factor paralogs, components of the transcriptional super elongation complex regulating expression of genes involved in neurogenesis and development.

Using HEK293T cells expressing FLAG-tagged AFF3 (and AFF4) wt or mutants, accumulation of mutated forms was shown upon immunoblot.

Aff3+/- and/or -/- mice exhibit skeletal defects. These were more pronounced in homozygous mice which demonstrated also some elements in favor of kidney dysfunction and/or metabolic deregulation and possible neurological dysfunction (signs of impaired hearing and diminished grip strength). Homozygous mice had CNS anomalies (enlarged lateral ventricles and decreased corpus callosum size) similar to some affected individuals, although these were not observed in another Aff3-/- model. Knock-in mice modeling the microdeletion and the Ala258Thr variant displayed lower mesomelic limb deformities and early lethality respectively [cited PMIDs : 21677750, 25660031, knock-in model was part of the present study].

Accumulation of the protein in zebrafish (by overexpression of the human wt AFF3 mRNA), led to morphological defects.

Reanalysis of transcriptome data from previously generated HEK293T cell lines knocked down for AFF2, AFF3 and AFF4 by shRNAs (study) suggested that these transcription factors are not redundant.

Finally, CHOPS syndrome (#616368) due to mutations of AFF4 also leading to increased protein stability presents a partially overlapping phenotype (incl. cognitive impairment) to that of AFF3.
----
Shimizu et al. (8/2019 - PMID: 31388108) describe an additional individual with de novo AFF3 missense variant. The phenotype overlaps with that summarized by Voisin et al. incl. mesomelic dysplasia with additional skeletal anomalies, bilateral kidney hypoplasia and severe DD at the age of 2.5 years. Seizures and pulmonary problems were not observed. Although a different RefSeq is used the variant is among those also reported by Voisin et al. [NM_002285.2:c.697G>A (p.Ala233Thr) corresponding to NM_001025108.1:c.772G>A (p.Ala258Thr)].
----
In G2P, AFF3 is associated with Skeletal dysplasia with severe neurological disease (disease confidence : probable / ID and seizures among the assigned phenotypes). There is no associated phenotype in OMIM.
Some diagnostic laboratories include AFF3 in their ID panel (eg. among the many co-authors' affiliations GeneDx and Victorian Clinical Genetics - which was already listed as source for AFF3 in the current panel).
----
As a result this gene can be considered for upgrade to green (relevant phenotype and severity, sufficient cases, evidence for accumulation similar to AFF4, animal models, etc) or amber (pending publication of the article).

[Review modified to add additional reference/case report]
Intellectual disability - microarray and sequencing v2.1136 FA2H Rebecca Foulger Added comment: Comment on list classification: Upgraded from Amber to Green based on Green review by Alistair Pagnamenta: PMID:31135052 analysed a cohort of 19 cases with biallelic FA2H variants. Phenotype includes spastic paraplegia associated with ID: mild cognitive deficits were noted from childhood in 93% of cases, and were considered progressive in all but two cases.
Intellectual disability - microarray and sequencing v2.1135 TRAPPC4 Konstantinos Varvagiannis gene: TRAPPC4 was added
gene: TRAPPC4 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TRAPPC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC4 were set to 31794024
Phenotypes for gene: TRAPPC4 were set to Feeding difficulties; Progressive microcephaly; Intellectual disability; Seizures; Spastic tetraparesis; Abnormality of the face; Scoliosis; Cortical visual impairment; Hearing impairment
Penetrance for gene: TRAPPC4 were set to Complete
Review for gene: TRAPPC4 was set to GREEN
Added comment: Van Bergen et al. (2019 - PMID: 31794024) report on 7 affected individuals from 3 famillies (only 1 of which consanguineous), all homozygous for a TRAPPC4 splicing variant.

Overlapping features included feeding difficulties, progressive microcephaly, severe to profound developmental disability (7/7 - DD also prior to the onset of seizures / regression also reported in 3), epilepsy (7/7 - onset in the first year), spastic quadriparesis. Other findings in some/few incl. scoliosis, cortical visual and hearing impairment. Some facial features were shared (eg. bitemporal narrowing, long philtrum, open mouth with thin tented upper lip, pointed chin, etc). Brain imaging demonstrated abnormalities in those performed (among others cerebral with/without cerebellar atrophy).

Work-up prior to exome sequencing was normal (highly variable incl. metabolic testing, CMA, MECP2, CDKL5, mitochondrial depletion studies, etc).

Exome of affected individuals (and parents +/- affected sibs in some families) revealed a homozygous TRAPPC4 splicing variant [NM_016146.5:c.454+3A>G / chr11:g.118890966A>G (hg19)]. Sanger sequencing confirmed variant in affecteds, heterozygosity in parents and compatible genotypes with disease status in sibs/other members.

Families were of Caucasian/Turkish and French-Canadian ethnicities. SNP array to compare haplotypes between affecteds in 2 families did not reveal a shared haplotype (/founder effect) and the variant is present in gnomAD (68/281054 - no hmz) in many populations (European/Asian/African/Latino) [https://gnomad.broadinstitute.org/variant/11-118890966-A-G].

mRNA studies in fibroblasts from an affected individual confirmed the splicing defect (2 RT-PCR products corresponding to wt and a shorter due to skipping of exon 3, the latter further confirmed by Sanger sequencing. The shorter transcript is not present in controls). qPCR revealed that the normal transript in patient fibroblasts was present at 6% of the level observed in control fibroblasts (or 54% in the case of a heterozygote parent compared to controls).

Western blot in patient fibroblasts, revealed presence of full-length protein in significantly reduced levels compared to fibroblasts from carrier parents or controls. There was no band using an antibody targeting the N-terminal region of the protein prior to exon 3, suggesting that NMD applies (skipping of ex3 is also predicted to lead to frameshift).

TRAPPC4 encodes one of the core proteins of the TRAPP complex. Use of different accessory proteins leads to formation of 2 distinct complexes (TRAPPII / III). The complex has an important role in intracellular trafficking. Both TRAPPII & TRAPPIII have a function in the secretory pathway, while complex III has a role also in autophagy. Core proteins are important for the complex stability. The TRAPP complex serves as a GEF for Ypt/Rab GTPases [several refs in article].

Mutations in genes for other proteins of the complex lead to neurodevelopmental disorders with associated ID ('TRAPPopathies' used by the authors / TRAPPC12, C6B, C9 green in the current panel).

Western blot suggested that levels of other TRAPP subunits (TRAPPC2 or C12) under denaturing conditions, although PAGE/size exclusion chromatography suggested that the levels of fully-assembled TRAPP complexes were lower in affected individuals.

Studies in patient fibroblasts showed a secretory defect (between ER, Golgi and the plasma membrane) which was restored upon lentiviral transduction with wt TRAPPC4 construct. Basal and starvation-induced autophagy were also impaired in patient fibroblasts (increased LC3 marker and LC3-positive structures / impaired co-localization with lysosomes) partly due to defective autophagosome formation (/sealing).

TRAPPC4 is the human orthologue of the yeast Trs23. In a yeast model of reduced Trs23 (due to temperature instability) the authors demonstrated impaired assembly of the TRAPP core. The yeast model recapitulated the autophagy as well as well as the secretory defect observed in patient fibroblasts.
Sources: Literature
Intellectual disability - microarray and sequencing v2.1135 SNX27 Konstantinos Varvagiannis gene: SNX27 was added
gene: SNX27 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SNX27 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNX27 were set to 25894286; 31721175; 21300787; 23524343
Phenotypes for gene: SNX27 were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures
Penetrance for gene: SNX27 were set to Complete
Review for gene: SNX27 was set to GREEN
gene: SNX27 was marked as current diagnostic
Added comment: Evidence from 2 publications suggests that DD, ID and seizures are part of the phenotype of individuals with biallelic SNX27 pathogenic variants :
---------
Damseh, Danson et al (2015 - PMID: 25894286) first reported on a consanguineous family with 4 affected sibs, homozygous for an SNX27 pathogenic variant. Features incl. hypotonia soon after birth, failure to thrive, severely delayed psychomotor development with no milestone acquisition, occurrence of myoclonic seizures with 3 individuals deceased early. Exome sequencing in one revealed a few candidate variants, with an SNX27 frameshift one [NM_030918.6:c.515_516del - p.(His172Argfs*6) / absent from ExAC] being the only retained following Sanger segregation studies. Using fibroblasts from an affected individual, Western blot with an antibody which would also bind prior to the truncation site, was consistent with dramatically reduced/absent SNX27 truncated mutant protein. Protein levels of VPS35, a component of the retromer responsible for direct cargo binding (not mediated by a cargo adaptor as SNX27), were normal.
---------
Parente et al (2019 - PMID: 31721175) reported on a 13-year-old male with motor and language delay, ADHD, ID (kindergarten academic level at the age of 13) and seizures with onset at the age of 9 years (GTC, with abnormal EEG and postical SV tachycardia). Variable physical findings were reported. White matter hyperintesities were noted upon initial brain MRI (but were less marked in subsequent ones). Initial genetic testing (Alexander's disease, CMA, FMR1) was normal. Exome revealed compound heterozygosity for 2 SNX27 variants (NM_030918.5/NM_001330723.1 both apply c.510C>G - p.Tyr170* and c.1295G>A - p.Cys432Tyr) each inherited from healthy carrier parents. There were no other potentially causative variants. A parental history of - isolated - late onset seizures was reported (so this individual may not be considered for the seizure phenotype here).

The authors also reported on a further 31-year old affected male. This individual had infantile hypotonia, poor eye contact with subsequent significant DD, seizures (febrile/afebrile T-C with onset at the age of 14m) and ID estimated in the severe range. Variable - though somewhat different - physical findings were reported. Initial work-up included basic metabolic testing, standard karyotype, FISH for 15q11 and subtelomeric regions and PHF6 genetic testing - all normal. Exome (and subsequent Sanger confirmation/parental studies) revealed compound heterozygosity for a missense and a frameshift variant (c.989G>A / p.Arg330His and c.782dupT / p.Leu262Profs*6 same in NM_001330723.1, NM_030918.6).
---------
SNX27 encodes sorting nexin 27, a cargo adaptor for the retromer. The latter is a multi-protein complex essential for regulating the retrieval and recycling of transmembrane cargos from endosomes to the trans-Golgi network or the plasma membrane [Lucas et al 2016 - PMID: 27889239 / McNally et al 2018 - PMID: 30072228].

As summarized by Parente et al, the encoded protein by regulating composition of the cell surface influences several processes eg. neuronal excitability, synaptic plasticity, Wnt signaling etc. It has been shown to interact with surface receptors and their ligands including GIRK channels, 5-HT4, ionotropic glutamate receptors (incl. NMDA- and AMPA-type receptors) and mGluR5 [several refs. provided].

Knockout of Snx27 in mice resulted in embryonic lethality (16% hmz of the 25% expected), severe postnatal growth retardation and death within the first 3 weeks. Snx27(+/-) mice have normal neuroanatomy but exhibit cognitive deficits (in learning and memory) and defects in synaptic function/plasticity with reduced amounts of NMDA and AMPA receptors (Cai et al - PMID: 21300787, Wang et al - PMID: 23524343).
---------
The gene is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx) and a current primary ID gene in SysID. There is no associated phenotype in OMIM/G2P.
Sources: Literature
Intellectual disability - microarray and sequencing v2.1135 FA2H Alistair Pagnamenta reviewed gene: FA2H: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31135052, 20104589; Phenotypes: HSP, ID, Seizures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v2.1135 SLC5A6 Konstantinos Varvagiannis changed review comment from: SLC5A6 encodes the sodium dependent multivitamin transporter (SMVT), a transporter of biotin, pantothenate and lipoate. The transporter has a major role in vitamin uptake in the digestive system (among others is the sole transporter for intestinal uptake of biotin which is not synthesized and but must be obtained from exogenous sources) as well as transport across the blood-brain barrier (SMVT being responsible for 89% of biotin transport) [several refs provided by Subramanian et al and Byrne et al].

4 affected individuals from 3 families have been reported.

Subramanian et al (2017 - PMID: 27904971) et al reported on a girl with feeding difficulties and failure to thrive (requiring nasogastric tube placement), microcephaly, DD (at 15m developmental age corresponding to 6m with features suggestive of spastic cerebral palsy), occurrence of multiple infections, osteoporosis and pathologic bone fractures. MRIs suggested brain atrophy, thin CC and hypoplasia of the pons. Metabolic (AA, OA) investigations and array-CGH were normal. Whole exome sequencing revealed presence of a missense (Arg123Leu - RefSeq not provided) and a nonsense (Arg94Ter) SLC5A6 variant. Serum biotin was normal although - at the time - the child was on parenteral and G-T nutrition. Following administration of biotin, pantothenic acid and lipoic acid the child demonstrated among others improved motor and verbal skills, head growth and normalization of immunoglobulin levels. Transfection of mutants in human derived intestinal HuTu-80 cells and brain U87 cells was carried out and a 3H-biotin assay showed no induction in biotin uptake confirming impaired functionality of the transporter. While wt protein displayed normal expression/membrane localization, Arg94Ter was poorly expressed with ectopic localization (cytoplasm). Arg123Leu was retained predominantly intracellularly, probably in the ER as was further supported by colocalization with DsRed-ER. Evidence from the literature is provided that deficiencies of the specific vitamins explain the clinical features (DD, microcephaly, immunological defect, osteopenia, etc).

Schwantje et al (2019 - PMID: 31392107) described a girl with severe feeding problems, vomiting with blood (suspected Mallory-Weiss syndrome), poor weight gain and delayed gross motor development. The child presented an episode of gastroenteritis associated with reduced consciousness, circulatory insufficiency and metabolic derangement (hypoglycemia, severe metabolic acidosis, hyperammonemia, mild lactate elevation, ketonuria). Investigations some months prior to the admission (?) were suggestive of a metabolic disorder due to elevated plasma C3-carnitine, C5-OH-carnitine and elevated urinary excretion of 3-OH-isovaleric acid (biotinidase deficiency was considered in the DD but enzymatic activity was only marginally decreased). Biotin supplementation was initiated. Trio-exome sequencing (at 3yrs) demonstrated compound heterozygosity for 2 frameshift variants [NM_021095.2:c.422_423del / p.(Val141Alafs*34) and c.1865_1866del]. Following this result, increase of biotin supplementation and introduction of pantothenic acid, GI symptoms (incl. chronic diarrhea) resolved and the child displayed improved appetite and growth, yet a stable motor delay. The authors cite previous studies of conditional ko mice, displaying intestinal mucosal abnormalities and growth defects (similar to the child's problems), prevented by biotin and pantothenic acid supplementation.

Byrne et al (2019 - PMID: 31754459) reported on a sibling pair with severe motor/speech developmental regression following a plateau (at 12m and 14m), development of ataxia and dyskinetic movements (both), seizures (one). Feeding difficulties, reflux and failure to thrive required N-G/gastrostomy feeding while both presented GI hemorrhage (in the case of the older sib, lethal). Other features in the youngest sib included brain MRI abnormalities (cerebral/cerebellar atrophy, thin CC, etc) and IgG deficiency. Biochemical, single-gene testing and mtDNA sequencing were not diagnostic. Exome in one, revealed presence of a frameshift [c.422_423del as above] and a missense variant (Arg400Thr). Sanger sequencing confirmed variants in both sibs and heterozygosity in parents. HeLa cells transfected with empty vector, wt or mut expression constructs confirmed significantly decreased 3H-biotin uptake for mut constructs compared to wt (and similar to empty vector). Parenteral triple vitamin replacement at the age of ~7 years resulted in improved overall condition, regain of some milestones, attenuation of vomiting, and resolution of peripheral neuropathy. Seizure were well-controlled (as was the case before treatment) despite persistence of epileptiform discharges. Again the authors cite studies of conditional (intestine-specific) SLC5A6 ko mice, with those viable (~1/3) demonstrating growth retardation, decreased boned density and GI abnormalities (similar to affected individuals). The phenotype could be rescued by oversupplementation of biotin and pantothenic acid (PMIDs cited: 23104561, 29669219).

[Please consider inclusion in other relevant panels eg. metabolic disorders]
Sources: Literature; to: SLC5A6 encodes the sodium dependent multivitamin transporter (SMVT), a transporter of biotin, pantothenate and lipoate. The transporter has a major role in vitamin uptake in the digestive system (among others is the sole transporter for intestinal uptake of biotin which is not synthesized but must be obtained from exogenous sources) as well as transport across the blood-brain barrier (SMVT being responsible for 89% of biotin transport) [several refs provided by Subramanian et al and Byrne et al].

4 affected individuals from 3 families have been reported.

Subramanian et al (2017 - PMID: 27904971) et al reported on a girl with feeding difficulties and failure to thrive (requiring nasogastric tube placement), microcephaly, DD (at 15m developmental age corresponding to 6m with features suggestive of spastic cerebral palsy), occurrence of multiple infections, osteoporosis and pathologic bone fractures. MRIs suggested brain atrophy, thin CC and hypoplasia of the pons. Metabolic (AA, OA) investigations and array-CGH were normal. Whole exome sequencing revealed presence of a missense (Arg123Leu - RefSeq not provided) and a nonsense (Arg94Ter) SLC5A6 variant. Serum biotin was normal although - at the time - the child was on parenteral and G-T nutrition. Following administration of biotin, pantothenic acid and lipoic acid the child demonstrated among others improved motor and verbal skills, head growth and normalization of immunoglobulin levels. Transfection of mutants in human derived intestinal HuTu-80 cells and brain U87 cells was carried out and a 3H-biotin assay showed no induction in biotin uptake confirming impaired functionality of the transporter. While wt protein displayed normal expression/membrane localization, Arg94Ter was poorly expressed with ectopic localization (cytoplasm). Arg123Leu was retained predominantly intracellularly, probably in the ER as was further supported by colocalization with DsRed-ER. Evidence from the literature is provided that deficiencies of the specific vitamins explain the clinical features (DD, microcephaly, immunological defect, osteopenia, etc).

Schwantje et al (2019 - PMID: 31392107) described a girl with severe feeding problems, vomiting with blood (suspected Mallory-Weiss syndrome), poor weight gain and delayed gross motor development. The child presented an episode of gastroenteritis associated with reduced consciousness, circulatory insufficiency and metabolic derangement (hypoglycemia, severe metabolic acidosis, hyperammonemia, mild lactate elevation, ketonuria). Investigations some months prior to the admission (?) were suggestive of a metabolic disorder due to elevated plasma C3-carnitine, C5-OH-carnitine and elevated urinary excretion of 3-OH-isovaleric acid (biotinidase deficiency was considered in the DD but enzymatic activity was only marginally decreased). Biotin supplementation was initiated. Trio-exome sequencing (at 3yrs) demonstrated compound heterozygosity for 2 frameshift variants [NM_021095.2:c.422_423del / p.(Val141Alafs*34) and c.1865_1866del]. Following this result, increase of biotin supplementation and introduction of pantothenic acid, GI symptoms (incl. chronic diarrhea) resolved and the child displayed improved appetite and growth, yet a stable motor delay. The authors cite previous studies of conditional ko mice, displaying intestinal mucosal abnormalities and growth defects (similar to the child's problems), prevented by biotin and pantothenic acid supplementation.

Byrne et al (2019 - PMID: 31754459) reported on a sibling pair with severe motor/speech developmental regression following a plateau (at 12m and 14m), development of ataxia and dyskinetic movements (both), seizures (one). Feeding difficulties, reflux and failure to thrive required N-G/gastrostomy feeding while both presented GI hemorrhage (in the case of the older sib, lethal). Other features in the youngest sib included brain MRI abnormalities (cerebral/cerebellar atrophy, thin CC, etc) and IgG deficiency. Biochemical, single-gene testing and mtDNA sequencing were not diagnostic. Exome in one, revealed presence of a frameshift [c.422_423del as above] and a missense variant (Arg400Thr). Sanger sequencing confirmed variants in both sibs and heterozygosity in parents. HeLa cells transfected with empty vector, wt or mut expression constructs confirmed significantly decreased 3H-biotin uptake for mut constructs compared to wt (and similar to empty vector). Parenteral triple vitamin replacement at the age of ~7 years resulted in improved overall condition, regain of some milestones, attenuation of vomiting, and resolution of peripheral neuropathy. Seizure were well-controlled (as was the case before treatment) despite persistence of epileptiform discharges. Again the authors cite studies of conditional (intestine-specific) SLC5A6 ko mice, with those viable (~1/3) demonstrating growth retardation, decreased boned density and GI abnormalities (similar to affected individuals). The phenotype could be rescued by oversupplementation of biotin and pantothenic acid (PMIDs cited: 23104561, 29669219).

[Please consider inclusion in other relevant panels eg. metabolic disorders]
Sources: Literature
Intellectual disability - microarray and sequencing v2.1135 SLC5A6 Konstantinos Varvagiannis gene: SLC5A6 was added
gene: SLC5A6 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SLC5A6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC5A6 were set to 27904971; 31392107; 31754459; 23104561; 29669219
Phenotypes for gene: SLC5A6 were set to Feeding difficulties; Failure to thrive; Global developmental delay; Developmental regression; Intellectual disability; Seizures; Microcephaly; Cerebral atrophy; Abnormality of the corpus callosum; Vomiting; Chronic diarrhea; Gastrointestinal hemorrhage; Abnormal immunoglobulin level; Osteopenia; Abnormality of metabolism/homeostasis
Penetrance for gene: SLC5A6 were set to Complete
Review for gene: SLC5A6 was set to GREEN
Added comment: SLC5A6 encodes the sodium dependent multivitamin transporter (SMVT), a transporter of biotin, pantothenate and lipoate. The transporter has a major role in vitamin uptake in the digestive system (among others is the sole transporter for intestinal uptake of biotin which is not synthesized and but must be obtained from exogenous sources) as well as transport across the blood-brain barrier (SMVT being responsible for 89% of biotin transport) [several refs provided by Subramanian et al and Byrne et al].

4 affected individuals from 3 families have been reported.

Subramanian et al (2017 - PMID: 27904971) et al reported on a girl with feeding difficulties and failure to thrive (requiring nasogastric tube placement), microcephaly, DD (at 15m developmental age corresponding to 6m with features suggestive of spastic cerebral palsy), occurrence of multiple infections, osteoporosis and pathologic bone fractures. MRIs suggested brain atrophy, thin CC and hypoplasia of the pons. Metabolic (AA, OA) investigations and array-CGH were normal. Whole exome sequencing revealed presence of a missense (Arg123Leu - RefSeq not provided) and a nonsense (Arg94Ter) SLC5A6 variant. Serum biotin was normal although - at the time - the child was on parenteral and G-T nutrition. Following administration of biotin, pantothenic acid and lipoic acid the child demonstrated among others improved motor and verbal skills, head growth and normalization of immunoglobulin levels. Transfection of mutants in human derived intestinal HuTu-80 cells and brain U87 cells was carried out and a 3H-biotin assay showed no induction in biotin uptake confirming impaired functionality of the transporter. While wt protein displayed normal expression/membrane localization, Arg94Ter was poorly expressed with ectopic localization (cytoplasm). Arg123Leu was retained predominantly intracellularly, probably in the ER as was further supported by colocalization with DsRed-ER. Evidence from the literature is provided that deficiencies of the specific vitamins explain the clinical features (DD, microcephaly, immunological defect, osteopenia, etc).

Schwantje et al (2019 - PMID: 31392107) described a girl with severe feeding problems, vomiting with blood (suspected Mallory-Weiss syndrome), poor weight gain and delayed gross motor development. The child presented an episode of gastroenteritis associated with reduced consciousness, circulatory insufficiency and metabolic derangement (hypoglycemia, severe metabolic acidosis, hyperammonemia, mild lactate elevation, ketonuria). Investigations some months prior to the admission (?) were suggestive of a metabolic disorder due to elevated plasma C3-carnitine, C5-OH-carnitine and elevated urinary excretion of 3-OH-isovaleric acid (biotinidase deficiency was considered in the DD but enzymatic activity was only marginally decreased). Biotin supplementation was initiated. Trio-exome sequencing (at 3yrs) demonstrated compound heterozygosity for 2 frameshift variants [NM_021095.2:c.422_423del / p.(Val141Alafs*34) and c.1865_1866del]. Following this result, increase of biotin supplementation and introduction of pantothenic acid, GI symptoms (incl. chronic diarrhea) resolved and the child displayed improved appetite and growth, yet a stable motor delay. The authors cite previous studies of conditional ko mice, displaying intestinal mucosal abnormalities and growth defects (similar to the child's problems), prevented by biotin and pantothenic acid supplementation.

Byrne et al (2019 - PMID: 31754459) reported on a sibling pair with severe motor/speech developmental regression following a plateau (at 12m and 14m), development of ataxia and dyskinetic movements (both), seizures (one). Feeding difficulties, reflux and failure to thrive required N-G/gastrostomy feeding while both presented GI hemorrhage (in the case of the older sib, lethal). Other features in the youngest sib included brain MRI abnormalities (cerebral/cerebellar atrophy, thin CC, etc) and IgG deficiency. Biochemical, single-gene testing and mtDNA sequencing were not diagnostic. Exome in one, revealed presence of a frameshift [c.422_423del as above] and a missense variant (Arg400Thr). Sanger sequencing confirmed variants in both sibs and heterozygosity in parents. HeLa cells transfected with empty vector, wt or mut expression constructs confirmed significantly decreased 3H-biotin uptake for mut constructs compared to wt (and similar to empty vector). Parenteral triple vitamin replacement at the age of ~7 years resulted in improved overall condition, regain of some milestones, attenuation of vomiting, and resolution of peripheral neuropathy. Seizure were well-controlled (as was the case before treatment) despite persistence of epileptiform discharges. Again the authors cite studies of conditional (intestine-specific) SLC5A6 ko mice, with those viable (~1/3) demonstrating growth retardation, decreased boned density and GI abnormalities (similar to affected individuals). The phenotype could be rescued by oversupplementation of biotin and pantothenic acid (PMIDs cited: 23104561, 29669219).

[Please consider inclusion in other relevant panels eg. metabolic disorders]
Sources: Literature
Intellectual disability - microarray and sequencing v2.1134 CNOT3 Konstantinos Varvagiannis reviewed gene: CNOT3: Rating: GREEN; Mode of pathogenicity: None; Publications: 28135719, 31201375, 24121232; Phenotypes: Intellectual developmental disorder with speech delay, autism, and dysmorphic facies, MIM 618672; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.1129 PNPT1 Konstantinos Varvagiannis changed review comment from: Biallelic PNPT1 pathogenic variants cause Combined oxidative phosphorylation deficiency 13 (MIM 614932). Despite phenotypic variability - common to disorders resulting from mitochondrial dysfunction - DD and ID of relevant severity to the current panel have been reported in several individuals published in the literature. Seizures may also be observed.

Rius et al (2019 - PMID: 31752325) provide an overview of 24 affected individuals (7 new and 17 from previous studies). Neurodevelopmental features are summarized in fig.1 and additional details are provided in the supplement. Based on this review, seizures were present in 7 individuals (of the 18 for whom this information was available).

PNPT1 encodes the mitochondrial polynucleotide phosphorylase, involved in the import of nuclear-encoded RNA to mitochondria. Loss of its activity has been shown to result in combined respiratory chain deficiency. However, as discussed by Rius et al and previous articles as well, OXPHOS studies in affected individuals may be normal or suggestive of only mild impairement due to tissue specificity and different assay methods used (eg. spectrophotometric vs dipstick activity assays). The same applies to lactate which was normal or mildly elevated in some affected individuals.

Missense, pLoF function variants as well as a synonymous one leading to aberrant splicing (NM_033109.4:c.1818T>G) have been reported.

Overall, this gene might be considered for upgrade to green rating.; to: Biallelic PNPT1 pathogenic variants cause Combined oxidative phosphorylation deficiency 13 (MIM 614932). Despite phenotypic variability - common to disorders resulting from mitochondrial dysfunction - DD and ID of relevant severity to the current panel have been reported in several individuals published in the literature. Seizures may also be observed.

Rius et al (2019 - PMID: 31752325) provide an overview of 24 affected individuals (7 new and 17 from previous studies). Neurodevelopmental features are summarized in fig.1 and additional details are provided in the supplement. Based on this review, seizures were present in 7 individuals (of the 18 for whom this information was available).

PNPT1 encodes the mitochondrial polynucleotide phosphorylase, involved in the import of nuclear-encoded RNA to mitochondria. Loss of its activity has been shown to result in combined respiratory chain deficiency. However, as discussed by Rius et al and previous articles as well, OXPHOS studies in affected individuals may be normal or suggestive of only mild impairment due to tissue specificity and different assay methods used (eg. spectrophotometric vs dipstick activity assays). The same applies to lactate which was normal or mildly elevated in some affected individuals.

Missense, pLoF function variants as well as a synonymous one leading to aberrant splicing (NM_033109.4:c.1818T>G) have been reported.

Overall, this gene might be considered for upgrade to green rating.
Intellectual disability - microarray and sequencing v2.1129 PNPT1 Konstantinos Varvagiannis reviewed gene: PNPT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31752325; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v2.1127 ZNF292 Catherine Snow reviewed gene: ZNF292: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v2.1123 AP1B1 Catherine Snow reviewed gene: AP1B1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v2.1122 FDFT1 Catherine Snow reviewed gene: FDFT1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v2.1122 TMX2 Konstantinos Varvagiannis edited their review of gene: TMX2: Added comment: A recent report by Vandervore, Schot et al. following the previous review (Am J Hum Genet. 2019 Nov 12 - PMID: 31735293), provides further evidence that biallelic TMX2 mutations cause malformations of cortical development, microcephaly, DD and ID and epilepsy.

As a result this gene should probably be considered for inclusion in the ID/epilepsy panels with green rating.

Overall, 14 affected subjects from 10 unrelated families are reported in the aforementioned study. The majority had severe DD/ID (failure to achieve milestones, absent speech/ambulation and signs of cerebral palsy) with few having a somewhat milder impairment. 12 (of the 14) presented with epilepsy (spasms, myoclonic seizures, focal seizures with/without generalization or generalized tonic-clonic seizures) with onset most often in early infancy. Upon brain MRI (in 12 individuals), 5 presented polymicrogyria, 2 others pachygyria, 4 with brain atrophy, etc.

All individuals were found to harbor biallelic TMX2 mutations by exome sequencing while previous investigations in several had ruled out alternative causes (infections, metabolic or chromosomal anomalies). Missense variants, an in-frame deletion as well as pLoF (stopgain/frameshift) variants were reported. [NM_015959.3 used as ref below].

The effect of variants was supported by mRNA studies, eg. RT-qPCR/allele specific RT-qPCR. The latter proved reduced expression for a frameshift variant (c.391dup / p.Leu131Profs*6) most likely due to NMD. Total mRNA levels were also 23% lower in an individual compound htz for a missense variant and a stopgain one localized in the last exon (c.757C>T / p.Arg253*). As for the previously reported c.614G>A (p.Arg205Gln), affecting the last nucleotide of exon 6, total mRNA in skin fibroblasts from a homozygous individual was not significantly decreased. RNA-Seq however demonstrated the presence of 4 different transcripts (roughly 25% each), one representing the regular mRNA, one with intron 6 retention (also present at low levels in healthy individuals), one with loss of 11 nucleotides within exon 6 and a fourth one due to in-frame skipping of exon 6.

*To the best of my understanding :

Thioredoxin (TRX)-related transmembrane proteins (TMX) belong to the broader family of oxidoreductases of protein disulfide isomerase (PDI) having an important role in protein folding.

Study of the data from the Allen Human Brain Atlas suggest relevant fetal expression also increasing during postnatal life.

As RNA-seq was carried out for 2 individuals, GO analysis suggested that the most deregulated clusters of genes are implicated in post-translational protein modifications (as would be expected for PDIs), membranes and synapse while pathway analysis suggested that relevant categories were inhibited eg. nervous system development/function and cell growth/proliferation/survival.

Upon transfection of HEK293T cells, exogenous TMX2 was shown to co-localize with calnexin (CNX) to the (ER) mitochondria-associated-membrane. Mass-spectrometry based analysis of co-immunoprecipitated proteins confirmed interaction with CNX but also other regulators of calcium homeostasis, mitochondrial membrane components and respiratory chain NADH dehydrogenase.

Study of the mitochondrial activity of TMX2-deficient fibroblasts suggested reduced respiratory reserve capacity, compensated by increased glycolytic activity.

TMX2 occurs in both reduced and oxidized monomeric form. It also forms (homo)dimers with the ratio of dimers/monomers increasing under conditions of oxidative stress. Variant TMX2 increased propensity to form dimers, thus mimicking increased oxidative state. This was observed under stress but also under native conditions.

---------; Changed rating: GREEN
Intellectual disability - microarray and sequencing v2.1119 IQSEC1 Catherine Snow reviewed gene: IQSEC1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31607425; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v2.1117 SVBP Catherine Snow reviewed gene: SVBP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, 618569; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v2.1115 KCNT2 Ivone Leong Added comment: Comment on mode of pathogenicity: Variants have gain-of-function effect.
Intellectual disability - microarray and sequencing v2.1115 KCNT2 Ivone Leong Mode of pathogenicity for gene: KCNT2 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability - microarray and sequencing v2.1102 DMXL2 Konstantinos Varvagiannis changed review comment from: This gene can be considered for upgrade to green rating (ID and epilepsy with >=4 relevant individuals/families/variants and >=2 studies, role of the protein, effect of variants in most cases demonstrated, phenotypic similarities with other disorders affecting autophagy, some evidence from animal models, etc).

Rare heterozygous variants disrupting DMXL2 (intragenic losses/gains, SNVs, CNVs affecting also additional genes) have been reported in individuals with variable neurodevelopmental disorders (ASD and ID) or psychiatric phenotypes [Costain et al. 2019 - PMID: 30732576 - summarized in Table 1]. (Highly) variable expressivity and possibly incomplete penetrance were proposed in the respective study. As a result evidence for ID/seizures due to monoallelic variants appears to be relatively limited.

DD, ID and (probably) epilepsy appear however to be features in several individuals with biallelic pathogenic variants as summarized in the studies below.

OMIM recently added a relevant entry with the DMXL2-associated phenotypes being the following:
- Epileptic encephalopathy, early infantile, 81; EIEE81 - 618663 (AD) [based on refs 2,3]
- ?Deafness, autosomal dominant 71 - 617605 (AD) [DD/ID/seizures are not part of the phenotype]
- ?Polyendocrine-polyneuropathy syndrome - 616113 (AR) [based on ref1]

DMXL2 is not associated with any phenotype in G2P. In SysID it is listed as a candidate ID gene based on the report by Tata et al (ref1). This gene is included in some gene panels for ID.

[1] Tata el al. (2014 - PMID: 25248098) reported on 3 sibs born to consanguineous Senegalese parents, presenting with a progressive endocrine and neurodevelopmental disorder. Features incl. incomplete puberty, central hypothyroidism, abnormal glucose regulation, moderate ID (3/3) and peripheral polyneuropathy. Seizures were not part of the phenotype. Linkage analysis suggested 2 candidate regions on chromosomes 13 and 15 with a LOD score of 2.5. High throughput sequencing of genes within these regions (~500) in an affected member and parent revealed a 15 bp in-frame deletion of DMXL2 (NM_015263.4:c.5827_5841del / p.Asp1943_Ser1947del). Sanger sequencing of other affected and unaffected members supported AR inheritance. RT-qPCR demonstrated that DMXL2 mRNA levels in blood lymphocytes were significantly lower in homozygous patients compared to heterozygous or wt family members or controls. The authors demonstrated that the encoded protein (rabconnectin-3a) is a synaptic protein (expressed in exocytosis vesicles) at the ends of axons of GnRH producing neurons. Neuron-specific deletion of one allele in mice resulted in delayed puberty and very low fertility. Adult mice had lower number of GnRH neurons in hypothalamus. siRNA-mediated downregulation of Dmxl2 expression in an insulin-secreting cell line resulted in only slight insulin secretion in response to augmenting concentrations of glucose, providing evidence of involvement of the protein in control of regulated insulin secretion.
-----------
[2] Maddirevula et al. (2019 - PMID: 30237576) reported briefly on a 36 months old boy, born to consanguineous parents, homozygous for a frameshift DMXL2 variant [individual 17-3220 | NM_001174117.1:c.4349_4350insTTACATGA or p.(Glu1450Aspfs*23)]. Features included focal seizures (onset at the age of 3m) with subsequent global DD, absent eye contact, cerebral atrophy and macrocephaly. This individual was identified following re-evaluation of exome data in a database of ~1550 exomes specifically for homozygous variants that would have been classified earlier as LP/P if the respective gene had sufficient evidence for association with a disorder. The family was not reported to have other affected members. As the authors noted, the boy was not known to have the multi-endocrine abnormalities reported by Tata et al. There are no additional information provided (eg. on confirmation of variants, etc).
-----------
[3] Esposito et al. (2019 - PMID: 31688942) report on 3 sibling pairs (all 3 families unrelated) with biallelic DMXL2 mutations and summarize previous evidence on the gene and the DMXL2-related phenotypes.

All presented a highly similar phenotype of Ohtahara syndrome (seizures with onset in the first days of life, tonic/myoclonic/occasionaly focal, burst-suppression upon EEG), profound DD/ID, quadriparesis, sensorineural hearing loss and presence of dysmorphic features. Sibs from 2 families presented evidence of peripheral polyneuropathy. Early brain MRIs revealed thin CC and hypomyelination in all, with later scans suggestive of gray and white matter shrinkage with leukoencephalopathy. None achieved developmental skills following birth with 5/6 deceased by the age of 9 years.

Exome sequencing revealed biallelic DMXL2 variants in all, with compatible parental segregation studies (NM_015263.3):
- Fam1 (2 sibs) : c.5135C>T (p.Ala1712Val) in trans with c.4478C>G (p.Ser1493*)
- Fam2 (2 sibs) : homozygosity for c.4478C>A (p.Ser1493*)
- Fam3 (2 sibs) : homozygosity for c.7518-1G>A

Heterozygous parents (aged 39-59) did not exhibit hearing impairment [report of a single multigenerational family by Chen et al (2017 - PMID: 27657680) where a heterozygous missense variant segregated with hearing loss - respective OMIM entry: ?Deafness, autosomal dominant 71 - 617605].

In patients' fibroblasts, effect of the variants on mRNA/protein expression was demonstrated with mRNA expressed only in a patient from family 1, and degraded/absent for the 2 stopgain SNVs affecting codon 1493. Skipping of ex31 leading to frameshift/introduction of a PTC was shown for the splice variant (p.Trp2508Argfs*4 secondary to c.7518-1G>A). Protein was also absent upon western-blot.

DMXL2 encodes a vesicular protein, DmX-Like protein 2 or rabconnectin-3a (cited Tata et al).

The gene is expressed in brain ( https://www.gtexportal.org/home/gene/DMXL2 ).

As Esposito et al comment, it is known to regulate the trafficking and activity of v-ATPase the latter having a role in acidifying intracellular organelles and promoting endosomal maturation (cited PMIDs : 25248098, 19758563, 22875945, 24802872).

In line with this, staining of patients' fibroblasts using the acidotropic dye LysoTracker demonstrated increased signal, reversed by re-expression of DMXL2 protein. Overall an acidic shift in pH with impairment of lysosomal structures and function was suggested. The authors provided additional evidence for altered lysosomal function and associated autophagy with accumulation of autophagy receptors (eg p62) and substrates (polyubiquitinated proteins). Vacuolization and accumulation of atypical fusion-like structures was shown upon ultrastractural analysis.

shRNA-mediated downregulation/silencing of Dmxl2 in mouse hippocampal neurons resulted also in altered lysosomal structures and defective autophagy. The neurons exhibited impaired neurite elongation and synapse formation.

The authors suggest similarities with Vici syndrome, where biallelic EPG5 mutations result in autophagic defects and clinical manifestations of DD/ID/epilepsy.

Dmxl2 homozygous ko mice display embryonic lethality with heterozygous mice displaying macrocephaly and corpus callosum dysplasia (cited PMIDs: 25248098, 30735494) .; to: This gene can be considered for upgrade to green rating (ID and epilepsy with >=4 relevant individuals/families/variants and >=2 studies, role of the protein, effect of variants in most cases demonstrated, phenotypic similarities with other disorders affecting autophagy, some evidence from animal models, etc).

Rare heterozygous variants disrupting DMXL2 (intragenic losses/gains, SNVs, CNVs affecting also additional genes) have been reported in individuals with variable neurodevelopmental disorders (ASD and ID) or psychiatric phenotypes [Costain et al. 2019 - PMID: 30732576 - summarized in Table 1]. (Highly) variable expressivity and possibly incomplete penetrance were proposed in the respective study. As a result evidence for ID/seizures due to monoallelic variants appears to be relatively limited.

DD, ID and (probably) epilepsy appear however to be features in several individuals with biallelic pathogenic variants as summarized in the studies below.

OMIM recently added a relevant entry with the DMXL2-associated phenotypes being the following:
- Epileptic encephalopathy, early infantile, 81; EIEE81 - 618663 (AR) [based on refs 2,3]
- ?Deafness, autosomal dominant 71 - 617605 (AD) [DD/ID/seizures are not part of the phenotype]
- ?Polyendocrine-polyneuropathy syndrome - 616113 (AR) [based on ref1]

DMXL2 is not associated with any phenotype in G2P. In SysID it is listed as a candidate ID gene based on the report by Tata et al (ref1). This gene is included in some gene panels for ID.

[1] Tata el al. (2014 - PMID: 25248098) reported on 3 sibs born to consanguineous Senegalese parents, presenting with a progressive endocrine and neurodevelopmental disorder. Features incl. incomplete puberty, central hypothyroidism, abnormal glucose regulation, moderate ID (3/3) and peripheral polyneuropathy. Seizures were not part of the phenotype. Linkage analysis suggested 2 candidate regions on chromosomes 13 and 15 with a LOD score of 2.5. High throughput sequencing of genes within these regions (~500) in an affected member and parent revealed a 15 bp in-frame deletion of DMXL2 (NM_015263.4:c.5827_5841del / p.Asp1943_Ser1947del). Sanger sequencing of other affected and unaffected members supported AR inheritance. RT-qPCR demonstrated that DMXL2 mRNA levels in blood lymphocytes were significantly lower in homozygous patients compared to heterozygous or wt family members or controls. The authors demonstrated that the encoded protein (rabconnectin-3a) is a synaptic protein (expressed in exocytosis vesicles) at the ends of axons of GnRH producing neurons. Neuron-specific deletion of one allele in mice resulted in delayed puberty and very low fertility. Adult mice had lower number of GnRH neurons in hypothalamus. siRNA-mediated downregulation of Dmxl2 expression in an insulin-secreting cell line resulted in only slight insulin secretion in response to augmenting concentrations of glucose, providing evidence of involvement of the protein in control of regulated insulin secretion.
-----------
[2] Maddirevula et al. (2019 - PMID: 30237576) reported briefly on a 36 months old boy, born to consanguineous parents, homozygous for a frameshift DMXL2 variant [individual 17-3220 | NM_001174117.1:c.4349_4350insTTACATGA or p.(Glu1450Aspfs*23)]. Features included focal seizures (onset at the age of 3m) with subsequent global DD, absent eye contact, cerebral atrophy and macrocephaly. This individual was identified following re-evaluation of exome data in a database of ~1550 exomes specifically for homozygous variants that would have been classified earlier as LP/P if the respective gene had sufficient evidence for association with a disorder. The family was not reported to have other affected members. As the authors noted, the boy was not known to have the multi-endocrine abnormalities reported by Tata et al. There are no additional information provided (eg. on confirmation of variants, etc).
-----------
[3] Esposito et al. (2019 - PMID: 31688942) report on 3 sibling pairs (all 3 families unrelated) with biallelic DMXL2 mutations and summarize previous evidence on the gene and the DMXL2-related phenotypes.

All presented a highly similar phenotype of Ohtahara syndrome (seizures with onset in the first days of life, tonic/myoclonic/occasionaly focal, burst-suppression upon EEG), profound DD/ID, quadriparesis, sensorineural hearing loss and presence of dysmorphic features. Sibs from 2 families presented evidence of peripheral polyneuropathy. Early brain MRIs revealed thin CC and hypomyelination in all, with later scans suggestive of gray and white matter shrinkage with leukoencephalopathy. None achieved developmental skills following birth with 5/6 deceased by the age of 9 years.

Exome sequencing revealed biallelic DMXL2 variants in all, with compatible parental segregation studies (NM_015263.3):
- Fam1 (2 sibs) : c.5135C>T (p.Ala1712Val) in trans with c.4478C>G (p.Ser1493*)
- Fam2 (2 sibs) : homozygosity for c.4478C>A (p.Ser1493*)
- Fam3 (2 sibs) : homozygosity for c.7518-1G>A

Heterozygous parents (aged 39-59) did not exhibit hearing impairment [report of a single multigenerational family by Chen et al (2017 - PMID: 27657680) where a heterozygous missense variant segregated with hearing loss - respective OMIM entry: ?Deafness, autosomal dominant 71 - 617605].

In patients' fibroblasts, effect of the variants on mRNA/protein expression was demonstrated with mRNA expressed only in a patient from family 1, and degraded/absent for the 2 stopgain SNVs affecting codon 1493. Skipping of ex31 leading to frameshift/introduction of a PTC was shown for the splice variant (p.Trp2508Argfs*4 secondary to c.7518-1G>A). Protein was also absent upon western-blot.

DMXL2 encodes a vesicular protein, DmX-Like protein 2 or rabconnectin-3a (cited Tata et al).

The gene is expressed in brain ( https://www.gtexportal.org/home/gene/DMXL2 ).

As Esposito et al comment, it is known to regulate the trafficking and activity of v-ATPase the latter having a role in acidifying intracellular organelles and promoting endosomal maturation (cited PMIDs : 25248098, 19758563, 22875945, 24802872).

In line with this, staining of patients' fibroblasts using the acidotropic dye LysoTracker demonstrated increased signal, reversed by re-expression of DMXL2 protein. Overall an acidic shift in pH with impairment of lysosomal structures and function was suggested. The authors provided additional evidence for altered lysosomal function and associated autophagy with accumulation of autophagy receptors (eg p62) and substrates (polyubiquitinated proteins). Vacuolization and accumulation of atypical fusion-like structures was shown upon ultrastractural analysis.

shRNA-mediated downregulation/silencing of Dmxl2 in mouse hippocampal neurons resulted also in altered lysosomal structures and defective autophagy. The neurons exhibited impaired neurite elongation and synapse formation.

The authors suggest similarities with Vici syndrome, where biallelic EPG5 mutations result in autophagic defects and clinical manifestations of DD/ID/epilepsy.

Dmxl2 homozygous ko mice display embryonic lethality with heterozygous mice displaying macrocephaly and corpus callosum dysplasia (cited PMIDs: 25248098, 30735494) .
Intellectual disability - microarray and sequencing v2.1102 DMXL2 Konstantinos Varvagiannis reviewed gene: DMXL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25248098, 30237576, 31688942; Phenotypes: Epileptic encephalopathy, early infantile, 81, MIM 618663, ?Polyendocrine-polyneuropathy syndrome, MIM 616113; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.1098 ZNF292 Konstantinos Varvagiannis gene: ZNF292 was added
gene: ZNF292 was added to Intellectual disability. Sources: Radboud University Medical Center, Nijmegen,Literature
Mode of inheritance for gene: ZNF292 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZNF292 were set to 31723249; 29904178
Phenotypes for gene: ZNF292 were set to Intellectual disability; Autism; Attention deficit hyperactivity disorder; Abnormality of the face; Abnormal muscle tone; Abnormality of nervous system morphology; Growth abnormality; Feeding difficulties; Abnormality of the skeletal system; Abnormality of the cardiovascular system; Microcephaly; Seizures
Penetrance for gene: ZNF292 were set to Incomplete
Review for gene: ZNF292 was set to GREEN
gene: ZNF292 was marked as current diagnostic
Added comment: Mirzaa et al. (2019 - PMID: 31723249) report on 28 individuals (from 27 families) with putatively pathogenic ZNF292 variants.

Main features consisted of DD and ID (27/28 - mild in 40%, moderate in 22%, severe in 11%) with or without ASD and ADHD. A single individual had no evidence of ID but had speech delay and ASD at the age of 6. Additional features (by diminishing order of frequency) included presence of non-specific dysmorphic features (~45%), abnormal tone, brain MRI abnormalities, growth failure, feeding difficulties, skeletal and cardiac anomalies, microcephaly and epilepsy (~11%).

As the authors comment, ZNF292 encodes a zinc finger protein, acting as a transcription factor.

Evidence is provided that gene has high expression in the developing human brain, with its expression being higher in prenatal development and diminishing postnatally. Znf292 is also expressed in adult mouse brain (highest in hippocampus/Purkinje cells).

Variants were identified by exome or targeted panel sequencing (targeted capture/molecular inversion probes). Previous investigations (eg. aCGH, analysis of relevant genes) had probably ruled out alternative causes in most with few having VUS or possibly relevant additional variants (eg. a KDM5C stopgain variant in a male).

24 putatively pathogenic variants were observed in this cohort, all predicting LoF (stopgain, frameshift or splice variants). All were de novo with the exception of one family where the variant was inherited from an affected parent. Almost all were absent from gnomAD and had CADD scores > 35.

Most variants lied within the last and largest exon that encodes a DNA binding domain. RT-PCR on RNA from 2 individuals harboring such variants confirmed that NMD does not apply. This exon however represents ~88% of the total coding length so the distribution of variants in this (NMD escaping) region was consistent with what would also be expected by chance.

ZNF292 has a pLI of 1 in gnomAD. Manual review of some relevant LoF variants in gnomAD suggested that they represent false positive calls.

As a result, the effect of variants is not clear although haploinsufficiency is still possible based also on phenotype of (larger) deletions spanning this gene (cited: Engwerda et al - PMID: 29904178 / The study focuses on deletions of the broader 6q. A possible role of ZNF292 is discussed as autism was present in 4/10 individuals with deletions encompassing this gene).

Based on the aforementioned cohort with one individual being diagnosed with mild ID only as an adult and/or presence of 5 pLoF variants in gnomAD the authors propose that some variants may be incompletely penetrant or associated with only mild features.

Finally, 15 additional individuals (belonging to 12 families) harbored variants for which pathogenicity was suspected (but could not be concluded) due to insufficient phenotypic information, lack of sufficient parental studies or missense variants. In this cohort variants were mostly pLoF, while 3 individuals (incl. 2 sibs) had a de novo missense SNV.
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Other studies were not here reviewed as some of the individuals reported were published previously in larger cohorts.
------
There is no associated phenotype in OMIM / G2P. SysID includes this gene among the candidate ID ones.
ZNF292 is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc and GeneDx).
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Overall ZNF292 could be added to the ID panel probably with green (or amber) rating.

[Please consider inclusion in other possibly relevant panels eg. autism, epilepsy]
Sources: Radboud University Medical Center, Nijmegen, Literature
Intellectual disability - microarray and sequencing v2.1098 CNOT2 Konstantinos Varvagiannis gene: CNOT2 was added
gene: CNOT2 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: CNOT2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CNOT2 were set to 31512373; 31145527; 28135719; 28159701; 30768759; 21505450; 18076123; 22247066
Phenotypes for gene: CNOT2 were set to Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies, MIM 618608
Penetrance for gene: CNOT2 were set to unknown
Review for gene: CNOT2 was set to GREEN
gene: CNOT2 was marked as current diagnostic
Added comment: Heterozygous pathogenic CNOT2 variants cause Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies (MIM 618608 - recently added disorder in OMIM). Larger 12q15 deletions, spanning CNOT2 have been reported in patients with similar phenotype.

Relevant individuals - most discussed below - include 2 patients with truncating de novo mutation, 1 with de novo intragenic deletion, few with small deletions spanning also 2-3 additional proximal genes and others with larger 12q15 deletions encompassing CNOT2 and several other genes.

Overall the phenotype - summarized by Uehara et al. (Ref1 - below) - seems to consist of language delay, mild motor delay (in most), some suggestive facial features (upslanted palpebral fissures, anteverted nares, thin upper lip and micrognathia). Nasal speech has also been reported in some individuals.

As commented by Uehara et al. (Ref1), CNOT2 (CCR4-NOT transcription complex subunit 2) is a member of the carbon catabolite repressor 4 complex (CCR4-NOT), the latter having an important role in deadenylation of mRNA and global mRNA expression. Disruption of the complex - which can be caused by loss of one of its components - results in various human disorders incl. neural diseases. siRNA CNOT2 depletion has been shown to induce CCR4-NOT disruption (cited PMIDs: 16284618, 29438013, 31006510, 21299754).

The type of variants (truncating, intragenic deletion, larger deletions) and the highly overlapping phenotypes in the respective patients suggest happloinsufficiency as the underlying mechanism. CNOT2 has also a pLI of 1 in gnomAD (o/e =0.06) and a %HI in Decipher of 4.39.

The gene appears to have relevant expression (https://www.proteinatlas.org/ENSG00000111596-CNOT2/tissue).
Animal models have not been discussed (or phenotypes possibly not sufficiently studied - MGI for Cnot2 : http://www.informatics.jax.org/marker/MGI:1919318).

CNOT2 is not associated with any phenotype in G2P. It is listed among the ID candidate genes in SysID.
This gene is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc).

Overall CNOT2 could be considered for inclusion in the ID panel with amber (DD although outcome is not known, presumed dysfunction of the CCR4-NOT complex, variant studies or animal models not available) or green rating (sufficient cases and variants, consistent phenotype).
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Individuals with CNOT2-only disruption:
[1] PMID: 31512373 (Uehara et al., 2019) - A 6 y.o. male investigated for hypotonia, feeding problems, DD (speech and motor), macrocephaly (+3 SD) and some possibly suggestive facial/other features was found to harbor a de novo stopgain variant (NM_001199302.1: c.946A>T, p.Lys316Ter) after trio exome sequencing. The variant and its de novo occurrence were confirmed by Sanger sequencing. NMD was the predicted effect (variant in ex11 of 21 / effect not further studied). Previous metabolic work-up and chromosomal testing had not revealed an alternative diagnosis.
[2] PMID: 31145527 (Alesi et al. 2019) - A 13 y.o. boy with hypotonia, failure to thrive, DD and following a specific schooling program for children with learning difficulties is reported. The authors comment on the facial phenotype (incl. upslanted p-f, anteverted nares, etc). Other features included valvular/supravalvular pulm. stenosis, mid aortic insufficiency, renal anomalies/failure, skeletal anomalies. Speech was nasal. CMA revealed an 85-kb 12q15 deletion spanning only CNOT2 (exons 3-15). Real-time PCR in proband and parents confirmed the variant and its de novo occurrence.
[3] PMID: 28135719 (DDD study, 2017) - An individual with developmental disorder and a de novo (validated) frameshift variant was identified [DDD4K.00807 - NM_014515.5:c.1158del / p.(L387Sfs*3)]. Phenotype in Decipher incl. abnormality of head/neck, nervous, skeletal system and growth. [https://decipher.sanger.ac.uk/ddd/research-variant/16b4f7866652f08e25a194f65535b4c5#overview].

Individuals with disruption of additional proximal genes due to CNVs:
[4] PMID: 28159701 (Alesi et al. 2017) - The authors report on a 29 y.o. individual with history of DD, learning difficulties, ID (WAIS-R IQ of 48 at the age of 17 y), some dysmorphic facial features. Additional features incl. recurrent infections, nasal voice as well as skeletal anomalies. CMA revealed a 742 kb microdeletion spanning CNOT2, KCNMB4 and PTPRB. Real-time PCR confirmed deletion and it's de novo occurrence in the proband.
[5] PMID: 30768759 (Uehara et al. 2019) - A female investigated among others for global DD (walking/1st words at 24m), mild ID, submucosal cleft palate with some distinctive facial features (upslanted p-f, micrognathia, etc) was found to harbor a 1.32-Mb deletion of 12q15 encompassing CNOT2 and 14 other genes. Given the phenotypic resemblance to patients with 12q15 deletions, the previously defined smallest region of overlap (ref 4,6), the LoF SNV in Decipher the authors suggested that CNOT2 is the critical gene for the phenotype of 12q15 deletion syndrome.

Larger deletions defining the smallest region of overlap
[6] PMID: 21505450 (Vergult et al. 2011) - 3 patients with de novo microdeletions of ~ 2.5 Mb in size with a 1.34 MB common region of overlap are reported. Learning diability, DD, nasal speech and hypothyroidism were among the common features.
[7] PMID: 18076123 (Schluth et al. 2008) - A girl with large (~10 Mb) de novo deletion of 12q15 - q21.2 identified by BAC array was described. The phenotype consisted of hypotonia, DD, moderate ID, growth delay and facial dysmorphic features.
[8] PMID: 22247066 (Lopez et al. 2012) - A patient with ID and features of Floating-Harbor syndrome was found to harbor a 4.7 Mb de novo 12q15-q21.1 deletion spanning CNOT2 and 18 additional genes.
[..]
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability - microarray and sequencing v2.1098 TMX2 Konstantinos Varvagiannis gene: TMX2 was added
gene: TMX2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TMX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMX2 were set to 31586943; 31270415
Phenotypes for gene: TMX2 were set to Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormal cortical gyration
Penetrance for gene: TMX2 were set to Complete
Review for gene: TMX2 was set to AMBER
Added comment: PMID: 31586943 - Ghosh et al. 2019 - reported on 8 individuals from 4 consanguineous families from the Middle East and Central Asia, all with a phenotype of DD/ID, seizures and microcephaly with lissencephaly (microlissencephaly is the term applying to the combination of two) upon brain MRI.

All patients were investigated by exome sequencing and the variant localized within a region of ROH which was common to all 4 families. All were homozygous for a TMX2 missense variant (NM_001144012.2:c.500G>A or p.Arg167Gln / NM_015959.4:c.614G>A p.Arg205Gln or hg38 - Chr11:g.57739039G>A). The variant was considered to be the best candidate, upon review of all other homozygous ones.

Sanger sequencing confirmed homozygosity for the variant in affected subjects, with additional compatible segregation studies including parents in all families as well as unaffected sibs (in two families).

Despite presence of the same mutation in all, several proximal to this variant SNPs did not appear to be shared among the families studied, thus suggesting that the variant had arisen within different haplotype blocks.

The authors comment that the variant was not previously identified in public databases. (The variant seems to correspond to rs370455806, present in 10 htz individuals in gnomAD, as well as in the GME database [GME Genotype Count 992:0:1 (hmz?) | Allele Count: 2,1984] . GME includes primarily - although not necessarily - healthy individuals).

This SNV affecting the last nucleotide of an exon of several transcripts (correct ref. is NM_001144012.2 as appears in the supplement / using NM_001347898.1 as in the fig./text the variant would lie within an intron), an eventual splicing effect was studied. mRNA transcript levels were assessed following RT-PCR using different sets of primers. There was no evidence of novel splice isoforms but mRNA levels were reduced compared to controls (15-50% in affected individuals, to a lesser level in carriers). This led to the hypothesis that NMD of an aberrantly spliced mRNA might apply, although this was not proven.

TMX2 encodes a protein disulfide isomerase (PDI). PDIs are transmembrane ER proteins which have a critical role in protein folding (PMID cited: 12670024). There were no relevant studies carried out in the article.

As for animal models, the authors comment that mice homozygous for null mutations display preweaning lethality with complete penetrance.(http://www.informatics.jax.org/diseasePortal/popup?isPhenotype=true&markerID=MGI:1914208&header=mortality/aging).
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Previously, Schot el al. (ESHG Conference 2018 Oral Presentation - Mutations in the thioredoxin related gene TMX2 cause primary microcephaly, polymicrogyria and severe neurodegeneration with impaired mitochondrial energy metabolism - available in PMID: 31270415 / https://www.nature.com/articles/s41431-019-0407-4 ) reported on 7 individuals from 5 unrelated families with biallelic TMX2 mutations. A newborn with microcephaly, polymicrogyria who died of refractory epilepsy, was compound heterozygous for 2 TMX2 variants. 6 additional individuals (from 4 unrelated families) with similar phenotype were found to harbor biallelic TMX2 mutations. It was commented that TMX2 is enriched in mitochondria-associated membrane of the ER with a role in ER stress protection and regulation of neuronal apoptosis. In line with this, fibroblasts from 2 unrelated patients showed secondary OXPHOS deficiency and increased glycolytic activity (the latter possibly as a compensatory mechanism).
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There is no associated phenotype in OMIM/G2P/SysID.
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Overall this gene could be considered for inclusion in the ID/epilepsy panel probably with amber (/red) rating pending further evidence.
Sources: Literature
Intellectual disability - microarray and sequencing v2.1098 NSF Konstantinos Varvagiannis gene: NSF was added
gene: NSF was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NSF was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NSF were set to 31675180
Phenotypes for gene: NSF were set to Seizures; EEG with burst suppression; Global developmental delay; Intellectual disability
Penetrance for gene: NSF were set to unknown
Mode of pathogenicity for gene: NSF was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: NSF was set to AMBER
Added comment: Suzuki et al. (2019 - PMID: 31675180) report on 2 unrelated individuals with de novo missense NSF variants. Overall the phenotype corresponded to an early infantile epileptic encephalopathy. The first patient developed vomiting and tonic seizures immediately after birth, with burst-suppression pattern upon EEG. Trio exome sequencing, followed by Sanger sequencing of proband and parents, revealed a de novo missense variant (NM_006178.3:c.1375G>A / p.Ala459Thr), absent from public databases and predicted in silico to be deleterious (CADD score of 30). The girl died 36 days after birth due to respiratory failure. Another subject, having necessitated mechanical ventilation due to absence of spontaneous respiration after birth, developed myoclonic seizures. EEG showed a burst-suppression pattern. At the age of 3, she was noted to have persistence of seizures and profound ID. Trio exome sequencing identified a missense NSF variant (c.1688C>T / p.Pro563Leu) also confirmed and shown to be de novo by Sanger sequencing. Again the variant was absent from public datasets and had a CADD score of 34. While expression of wt NSF allele in the developing eye of Drosophila had no effect, expression of mutants severely affected eye development - suggesting a dominant negative effect. NSF encodes a homo-hexameric AAA ATPase, which is recruited by SNAPs (Soluble NSF Attachment Proteins) - and the latter by SNAREs (SNAP REceptors) - thus having a role in vesicular transport and membrane fusion. There is currently no associated phenotype in OMIM/G2P. Overall, this gene could be considered for inclusion probably with amber/red rating pending further evidence (eg. additional work-up or alternative causes/explanations not discussed).
Sources: Literature
Intellectual disability - microarray and sequencing v2.1098 WDFY3 Konstantinos Varvagiannis reviewed gene: WDFY3: Rating: GREEN; Mode of pathogenicity: None; Publications: 27008544, 31327001, 25198012, 28191889; Phenotypes: ?Microcephaly 18, primary, autosomal dominant - MIM 617520; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.1098 SCAMP5 Konstantinos Varvagiannis gene: SCAMP5 was added
gene: SCAMP5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SCAMP5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SCAMP5 were set to 31439720; 20071347
Phenotypes for gene: SCAMP5 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology; Behavioral abnormality
Penetrance for gene: SCAMP5 were set to unknown
Mode of pathogenicity for gene: SCAMP5 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: SCAMP5 was set to AMBER
Added comment: PMID: 31439720 (Hubert et al. 2019) reported on 2 unrelated individuals with severe ID, seizures behavioral and brain MRI abnormalities (white matter hyperintensity and mesial temporal sclorosis), both harboring the same missense SCAMP5 mutation as a de novo event (NM_001178111.1:c.538G>T or p.Gly180Trp).

Previously aCGH +/- metabolic workup were non diagnostic.

The occurrence of the same de novo variant in both as well as the similar presentation (incl. MRI images) suggested SCAMP5 as the most probable candidate gene, despite presence of few other variants in both.

SCAMP5 is highly expressed in brain (https://www.proteinatlas.org/ENSG00000198794-SCAMP5) and previous studies have suggested a role in synaptic vesicle trafficking (PMIDs cited: 29562188, 25057210, etc).

Cultured skin fibroblasts from affected individuals failed to express SCAMP5.

Scamp is the Drosophila orthologue, with previous studies having demonstrated that mutants display defects in climbing, olfactory-assisted memory and susceptibility to heat induced seizures (PMIDs cited: 25478561, 19144841). Expression of the Scamp Gly302Trp variant in Drosophila ('equivalent' to the SCAMP5 Gly180Trp) revealed strongly reduced levels for the variant compared with wt upon Western Blot, either due to reduced expression or due to increased turnover. Overall the effect of Gly302Trp expression was similar to Scamp knockdown by RNAi (eg. rough eye phenotype, reduced ability to climb the walls of a graded tube after tapping, less/no flies reaching adult stage) but significantly different compared to wt.

As a result, a dominant-negative effect was presumed.
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PMID: 20071347 (Castermans et al. 2010) is cited as a previous report of a relevant affected individual. In this study a 40 y.o. male with early DD, mild ID (IQ of 63) and ASD was found to harbor a de novo apparently balanced t(1;15) translocation affecting CLIC4 and PPCDC (both not associated with ID). [1-Mb resolution aCGH revealed no relevant CNVs].

Studies were however focused on SCAMP5 given that the gene is located downstream of / proximal to PPCDC, has brain-enriched expression as well as involvement in synaptic trafficking and demonstrated:
- Less than 50% expression upon quantitative RT-PCR in patients leukocytes, compared to control.
- Silencing and overexpression of Scamp5 in mouse β-TC3 cells resulted in increased and suppressed respectively secretion of large dense-core vesicles (LDCVs).
- Given conservation of some components involved in secretion of dense core granules (DCGs) in platelets and LDCVs in neuronal cells, study of patient platelets - where SCAMP5 was confirmed to be expressed - suggested an altered pattern of DCGs.
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SCAMP5 is not associated with any phenotype in OMIM/G2P/SysID and not commonly included in gene panels for ID.
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Overall, this gene could be considered for inclusion in the ID and epilepsy panels probably with amber (# of unrelated individuals, 1 recurrent de novo variant and 1 regulatory effect, gene expressed in brain with a role in synaptic vesicle trafficking) or red rating (pending further evidence).
Sources: Literature
Intellectual disability - microarray and sequencing v2.1098 FAM160B1 Konstantinos Varvagiannis gene: FAM160B1 was added
gene: FAM160B1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FAM160B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM160B1 were set to 27431290; 31353455
Phenotypes for gene: FAM160B1 were set to Central hypotonia; Global developmental delay; Intellectual disability; Abnormality of the face
Penetrance for gene: FAM160B1 were set to Complete
Review for gene: FAM160B1 was set to AMBER
Added comment: Anazi et al. (2017 - PMID: 27431290) in a study of 337 subjects with ID, reported on a consanguineous family (15DG2696) with 3 affected sibs. The proband, a 7 y.o. boy had hypotonia, DD, mild ID (IQ of 69), some facial dysmorphic features as well as increased skin elasticity and joint hypermobility. Initial investigations included metabolic testing for OA and CDGs, FMR1 and aCGH. A 4 y.o. sister and a 3 y.o. brother of the proband had similar presentation of DD. Exome sequencing, autozygosity mapping and segregation studies suggested a FAM160B1 hmz missense SNV as the likely causal variant (NM_001135051.1:c.248T>C or p.Leu83Pro). There were no other candidate variants. As the encoded protein has a yet unknown function, with uncertain in silico 3D modeling, the authors speculated disruption of helices affecting fold/(ligand binding) function as the underlying effect of this variant.

Mavioğlu et al. (2019 - PMID: 31353455) reported on a 38 y.o. female with history of motor and language delay, severe ID, ataxia, behavioral abrnormalities as well as some dysmorphic features. This individual was born to consanguineous parents (2nd cousins). There was history of a deceased, similarly affected sib. Initial investigations included metabolic work-up (plasma AA, urinary OA) and karyotyping. SNP genotyping in the family (parents, affected sib, 3 unaffected sibs) and multipoint linkage analysis for AR inheritance, yielded a maximum LOD score of 2.15. Selection of homozygous regions unique to the patient (but not present in unaffected sibs) did not suggest any known ID gene. Exome sequencing of the proband, with analysis of the variants in candidate regions revealed a homozygous stopgain SNV (NM_020940.4:c.115G>T or p.Glu39*) as the best candidate variant (with few others not considered to be relevant). FAM160B1 has a pLI of 1, LoF variants in public databases have MAFs below 0.000034 with no recorded homozygotes. In silico predictions suggested a deleterious effect (CADD score of 40, etc). The previous report by Anazi and fulfilment of the ACMG criteria for its classification of this variant as pathogenic led to its consideration as causal of the patient's phenotype.

Study of the expression of the 2 isoforms of the gene (isoform1: NM_020940, 2:NM_001135051) revealed that the first is ubiquitously expressed and the second only in testes. [To my understanding the 2 isoforms seem to differ only in their last exon, the 2 reported variants affecting both isoforms - http://genome.ucsc.edu/cgi-bin/hgTracks?db=hg19&lastVirtModeType=default&lastVirtModeExtraState=&virtModeType=default&virtMode=0&nonVirtPosition=&position=chr10%3A116577123%2D116663023&hgsid=777553295_dPP9DgaheaF82gTRTfZO6XS5lEzA ]

The function of this gene remains unknown. Animal models/phenotypes are probably not available.

There is no associated phenotype in OMIM/G2P. SysID lists FAM160B1 as a candidate ID gene.
FAM160B1 is not commonly included in gene panels for ID offered by diagnostic laboratories.

As a result this gene can be considered for inclusion in the current panel probably with amber (2 families/variants, variable ID as a feature) or red rating pending further evidence (given the partial phenotypic overlap, unknown function of the gene, variants not further studied, no animal models).
Sources: Literature
Intellectual disability - microarray and sequencing v2.1098 PCYT2 Konstantinos Varvagiannis gene: PCYT2 was added
gene: PCYT2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PCYT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCYT2 were set to 31637422
Phenotypes for gene: PCYT2 were set to Global developmental delay; Developmental regression; Intellectual disability; Spastic paraparesis; Seizures; Spastic tetraparesis; Cerebral atrophy; Cerebellar atrophy
Penetrance for gene: PCYT2 were set to Complete
Review for gene: PCYT2 was set to GREEN
Added comment: Vaz et al. (2019 - PMID: 31637422 - DDD study among the co-authors) report on 5 individuals - from 4 families - with biallelic PCYT2 mutations.

The phenotype corresponded to a complex hererditary paraplegia with global DD, regression (4/5), ID (mild in 3/5, severe in 2/5), spastic para-/tetraparesis, epilepsy (5/5 - variable onset 2-16 yrs - focal or tonic-clonic seizures) and progressive cerebral and cerebellar atrophy.

Exome sequencing in all revealed biallelic PCYT2 variants, confirmed with Sanger s. in probands and their parents (NM_001184917.2 - corresponding to the canonical transcript used as Ref below):
- P1 (Fam1) : 2 missense SNVs in trans configuration, c.730C>T or p.His244Tyr and c.920C>T or p.Pro307Leu
- P2 (Fam2 - consanguineous of White British origin), P3 (Fam3 - Consanguineous of Turkish origin), P4,5 (Fam4 - consanguineous, unspecified origin) : homozygosity for c.1129C>T or p.Arg377Ter) affecting the last exon of 8/12 transcripts, including the canonical one.

Individuals with the same genotype displayed variable degrees of ID (eg P3 - severe / P2, P4,5 - mild ID).

For sibs in Fam4, homozygosity for a missense SACS variant led to consideration of the respective disorder (AR spastic ataxia of Charlevoix-Saguenay) though the variant was predicted to be tolerated in silico and notably the MRI images not suggestive.

All variants were absent from / had extremely low AF in public databases, with no homozygotes.

Posphatidylethanolamine (PE) is a membrane lipid, particularly enriched in human brain (45% of phospholypid fraction). PE is synthesized either via the CDP-ethanolamine pathway or by decarboxylation of phosphatidylserine in mitochondria. PCYT2 encodes CTP:phosophoethanolamine cytidyltransferase (ET) which is an ubiquitously expressed rate-limiting enzyme for PE biosynthesis in the former pathway.

In silico, the 2 missense variants - localizing in the CTP catalytic domain 2 - were predicted to be damaging, as well as to affect protein stability.

Fibroblasts of 3 patients (P1, P2, P3) representing all variants were studied:
- Enzymatic activity was shown to be significantly reduced (though not absent) compared to controls. Abnormalities were noted upon Western Blot incl. absence in all 3 patients studied of one of the 2 bands normally found in controls (probably representing the longer isoform), reduced intensity in all 3 of another band probably corresponding to a shorter isoform, and presence of an additional band of intermediate molec. mass in patients with the truncating variant.
- RT-PCR on mRNA from patient fibroblasts did not reveal (significant) reduction compared to controls.
- Lipidomic profile of patient fibroblasts was compatible with the location of the block in the phospholipid biosynthesis pathway and different from controls.

The lipidomic profile had similarities with what has been reported for EPT1 deficiency, the enzyme directly downstream of ET. The SELENO1-related phenotype (/EPT1 deficiency) is also highly overlapping.

CRISPR-Cas9 was used to generate pcyt2 partial or complete knockout (ko) zebrafish, targeting either the final (ex13) or another exon (ex3) respectively. mRNA expression was shown to be moderately reduced in the first case and severely reduced/absent in the second, compared to wt. Similarly, complete-ko (ex3) led to significantly lower survival, with impaired though somewhat better survival of partial-ko (ex13) zebrafish.

Complete knockout of Pcyt2 in mice is embryonically lethal (PMID cited: 17325045) while heterozygous mice develop features of metabolic syndrome (PMID cited: 22764088).

Given lethality in knockout zebrafish / mice and the residual activity (15-20%) in patient fibroblasts, the variants reported were thought to be hypomorphic and complete loss of function possibly incompatible with life.

PCYT2 is not associated with any phenotype in OMIM/G2P/SysID and not commonly included in gene panels for ID.

As a result this gene could included in the ID / epilepsy panels with green (~/>3 indiv/fam/variants with the nonsense found in different populations, consistent phenotype, lipidomics, in silico/in vitro/in vivo evidence) or amber rating.

[Please consider inclusion in other possibly relevant panels eg. for metabolic disorders, etc].
Sources: Literature
Intellectual disability - microarray and sequencing v2.1098 PDE6D Konstantinos Varvagiannis gene: PDE6D was added
gene: PDE6D was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PDE6D was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDE6D were set to 24166846; 30423442
Phenotypes for gene: PDE6D were set to ?Joubert syndrome 22 - MIM 615665
Penetrance for gene: PDE6D were set to Complete
Review for gene: PDE6D was set to AMBER
gene: PDE6D was marked as current diagnostic
Added comment: Thomas et al. (2014 - PMID: 24166846) reported on a consanguineous Pakistani family with 3 members presenting variable polydactyly, brain anomalies (incl. molar tooth sign), microphthalmia/coloboma with retinal disease, renal hypoplasia suggestive of Joubert syndrome.

Genotyping with a SNP array identified a unique 17-Mb region of homozygosity on chr2 with LOD score of 2.6. The region contained 208 genes, of which 15 present in ciliary gene databases. A homozygous splicing variant appeared to be the only relevant, PDE6D being a ciliary gene within this region [NM_002601.4:c.140-1G>A]. Status of all affected members, parents and 2 unaffected sibs was verified with Sanger sequencing.

PDE6D encodes a phosphodiesterase that binds to prenyl groups and has a critical role in ciliogenesis (Humbert et al. - PMID: 23150559 and OMIM).
Several lines of evidence provided support a role for PDE6D and the reported variants :
- Study of PDE6D expression during human embryogenesis suggests ubiquitous localization and highest levels in organs affected in ciliopathies (CNS, kidney tubules, respiratory tract epitherlial cells).
- RT-PCR of mRNA from control/patient fibroblasts and sequencing confirmed the splicing defect leading to an in-frame deletion of exon 3.
- Wt and mutant protein both localized in the basal body of primary cilia (patient/control fibroblasts). Cilia in both cases had normal morphology.
- Experiments in RPE cells confirmed that INPP5E (involved in Joubert/MORM syndrome) interacts (/is probably a cargo of) PDE6D, a process dependent on prenylation.
- Exon 3 deletion was confirmed to disrupt PDE6D binding to INPP5E.
- Analysis by immunofluoresence of INPP5E localization using control/patient fibroblasts and renal tissue showed absence of INPP5E from primary cilia in the case of patient cells (but not controls) suggesting that PDE6D is important for trafficking INPP5E to the cilium.
- Previous study in mice suggested altered photoreceptor physiology in Pde6d (-/-) animals, resulting in a slowly progressing rod/cone dystrophy. The effect was however limited to the eye. (PMID cited : 17496142 - Zhang et al., 2007).
- Morpholino knockdown of pde6d resulted in pericardial edema, eye abnormalities (microphthalmia and disorganized retinal cell layers) and kidney morphogenesis defects (distended, blocked pronephric openings and proximal tubule cysts). Edema was rescued upon coinjection of morpholino with wt (but not mutant) mRNA. Similarly coinjection led to complete or partial rescue of eye development in the case of wt and mutant mRNA respectively supporting pathogenicity and (partial) loss-of-function effect for the variant.
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Mégarbané et al. (2019 - PMID: 30423442) reported on an affected 6 month-old boy born to Lebanese first-cousin parents. Features included hypotonia, developmental delay, microcephaly, oculomotor apraxia, postaxial polydactyly of hands and feet and presence of a molar tooth sign upon brain MRI. Renal and retinal anomalies were absent (also given his age). Exome sequencing revealed homozygosity for a frameshift PDE6D variant [NM_002601.3:c.367_368insG or p.(Leu123Cysfs*13)]. Sanger sequencing confirmed presence of the variant in the proband and carrier status of the parents. The variant affected the penultimate exon (note : present in only this longest transcript) and was not predicted to trigger NMD but rather lead to elimination of a highly conserved PDZ-interaction domain.
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The phenotype associated with biallelic PDE6D variants in OMIM is ?Joubert syndrome 22 - MIM 615665 based only on the 1st report ('delayed psychomotor development' among the features). There is no relevant entry in G2P. PDE6D is listed as a Current primary (/confirmed) ID gene in SysID (the aforementioned PMIDs cited).

This gene is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx).
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Overall PDE6D could be considered for inclusion in the ID panel probably with amber rating (2 families/variants, DD but outcome otherwise unknown - evidence for the the gene causing JS seems however sufficient).
Sources: Literature
Intellectual disability - microarray and sequencing v2.1098 NTNG2 Konstantinos Varvagiannis gene: NTNG2 was added
gene: NTNG2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NTNG2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NTNG2 were set to 31372774; 31668703
Phenotypes for gene: NTNG2 were set to Central hypotonia; Global developmental delay; Intellectual disability; Behavioral abnormality; Microcephaly; Seizures
Penetrance for gene: NTNG2 were set to Complete
Review for gene: NTNG2 was set to GREEN
Added comment: [1] Abu-Libdeh et al. (2019 - PMID: 31372774) reported 8 individuals from 4 unrelated consanguineous families of Arab Muslim origin, all homozygous for NM_032536.3:c.376dup - p.(Ser126PhefsTer241). Common features included hypotonia, failure to achieve milestones and developmental stagnation without regression during the first year (~9m) of life and severe ID. Minimal purposeful hand use (grasping and bringing objects to mouth), hand stereotypies and bruxism were also observed. Microcephaly and impaired growth were almost universal (with the exception of 2 having an OFC at ~10% percentile). Relevant previous investigations were normal in all and included MECP2, SMN1, aCGH, metabolic testing, etc. The variant was identified by exome in all, and Sanger confirmed with compatible segregation studies in parents and sibs. The variant was found within a shared haplotype of ~4.35 Mb, probably due to a founder effect.

[2] Dias et al. (2019 - PMID: 31668703) described 16 individuals from 7 unrelated families from Iran, Mexico, Turkey, Egypt and Bangladesh. Parents were known to be consanguineous or shown to be distantly related. All patients were homozygous for missense variants private to each family (7 variants) identified following exome sequencing. Shared features incl. hypotonia, GDD, severe to profound ID and behavioral anomalies incl. autistic features/stereotypies (most), screaming/laughing spells (most), bruxism. Microcephaly (5/14), growth below average/FTT and GI problems were also observed.

Epilepsy was reported in 5 individuals belonging to 4 different families in these 2 studies (5/24 overall / 4 variants).

Netrin-G2, the encoded protein, is bound to the plasma membrane by GPI-anchors. Netrins-G2 and G1 (another member of the Netrin-G subfamily) are enriched in presynaptic terminals. Interaction with their cognate Netrin-G ligand trans-synaptic partners / receptors (NGL2, NGL1 respectively) has been shown to promote axon outgrowth, induce and maintain excitatory synapse formation. Complementary and non-overlapping expression in the developping and mature CNS has been shown for Netrin-G2/1 in mice (several references provided by Abu-Libdeh / Dias).

Variant effect : The frameshift variant was not studied by Abu-Libdeh et al. Variants in the 2nd ref. were all missense, displayed no-specific localization and were suggested to affect protein stability and/or expression at the cell surface as 4/7 involved loss or addition of cystein residues (possibly creating unpaired cysteins) and 2 of the remaining 3 were predicted to affect the hydrophobic core. In line with this, overexpression of wt/variant constructs in HeLa cells demonstrated substantially decreased cell surface expression for all variants.

Mouse models/phenotypes : Dias et al. showed that siRNA-mediated Ntng2 knockdown in N2a cells led to significant reduction in neurite number and length. Studied previously, Ntng2 knockout mice display impaired learning, memory, visual and motor functioning (PMID cited : 26746425).

NTNG2 is not associated with any phenotype in OMIM/G2P. SysID lists it among the candidate ID genes, citing PMID: 29302074 (not here reviewed & NTNG2 not in the main text).

Overall this gene can be considered for inclusion in the ID panel probably as green (>3 individuals/families/variants, consistent phenotype in both reports, role of the gene, in silico and in vitro studies, animal model, etc) or amber.

[Please consider inclusion in other panels if relevant eg. ASD panel (many individuals having autistic / Rett-like features or epilepsy) or epilepsy (>3 individuals/families/variants although most families were also consanguineous)]
Sources: Literature
Intellectual disability - microarray and sequencing v2.1098 AP1B1 Konstantinos Varvagiannis gene: AP1B1 was added
gene: AP1B1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: AP1B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP1B1 were set to 31630788; 31630791
Phenotypes for gene: AP1B1 were set to Failure to thrive; Abnormality of the skin; Hearing abnormality; Abnormality of copper homeostasis; Global developmental delay; Intellectual disability
Penetrance for gene: AP1B1 were set to Complete
Review for gene: AP1B1 was set to AMBER
Added comment: Boyden et al. (2019 - PMID: 31630788) and Alsaif et al (2019 - PMID: 31630791) report on the phenotype related to biallelic AP1B1 mutations.

Common features included failure to thrive, ichthyosis (with variable palmoplantar keratoderma/erythroderma/abnormal hair) and hearing loss. Each study focused on different additional features eg. thrombocytopenia or photophobia in all individuals reported by Boyden et al, while Alsaif et al. focused on abnormal copper metabolism (low plasma copper and ceruloplasmin) observed in all 3 affected individuals and enteropathy/hepatopathy observed in 2 sibs.

DD was observed in all 3 individuals (2 families) reported by Alsaif et al. and patient 424 reported by Boyden et al. ID was noted in all individuals of relevant age (2 from 2 families) in the study by Alsaif. Boyden commented that ID is not part of the phenotype. The adult (424) - despite his early DD - was noted to have normal intellect and had graduated college. The other patient (1325) was last followed up at 11 months (still DD was not reported).

AP1B1 encodes one of the large subunits (β1) of the adaptor protein complex 1. Each of the AP complexes is a heterotetramer composed of two large (one of γ, α, δ, ε and β1-β4 for AP-1 to AP-4 respectively), one medium (μ1-μ4) and one small (σ1-σ4) adaptin subunit. The complex is involved in vesicle-mediated transport.

Variants were confirmed in probands and carrier parents (NM_001127.3):
Boyden Pat424 (33y) : c.430T>C (p.Cys144Arg) in trans with c.2335delC (p.Leu779Serfs*26)
Boyden Pat1325 (11m) [consanguineous Ashkenazi Jewish family] : homozygosity for c.2374G>T (p.Glu792*)
Alsaif sibs P1,P2 (4y4m, 1y5m) [consanguineous - Pakistani origin] : homozygous for a chr22 75 kb deletion spanning only the promoter and ex1-2 of AP1B1
Alsaif P3 (4y6m) [consanguineous - Saudi origin] : homozygous for a c.38-1G>A

Variant / additional studies :
22q 75-kb deletion: PCR deletion mapping and Sanger delineated the breakpoints of the 22q12.2 del to chr22:29758984-29815476 (hg?). Complete absence of transcript upon RT-PCR (mRNA from fibrolasts).
Splicing variant (c.38-1G>A): RT-PCR confirmed replacement of the normal transcript by an aberrant harboring a 1 bp deletion (r.40del).
Stopgain variant (c.2374G>T): Western blot demonstrated loss of AP1B1 (and marked reduction also for AP1G1) in cultured keratinocytes of the homozygous patient.

Loss-of-function is the effect predicted by variants. Vesicular defects were observed in keratinocytes of an affected individual (homozygous for the nonsense variant). Rescue of these vesicular defects upon transduction with wt AP1B1 lentiviral construct confirmed the LoF effect. [Boyden et al.]

ATP7A and ATP7B, two copper transporters, have been shown to depend on AP-1 for their trafficking. Similar to MEDNIK syndrome, caused by mutations in AP1S1 and having an overlapping phenotype with AP1B1 (also including hypocupremia and hypoceruloplasminemia), fibroblasts from 2 affected individuals (from different families) demonstrated abnormal ATP7A trafficking. [Alsaif et al.]

Proteomic analysis of clathrin coated vesicles (2 ind from 2 fam) demonstrated that AP1B1 was the only AP1/AP2 CCV component consistently reduced in 2 individuals (from 2 families). [Alsaif et al.]

Boyden et al. provided evidence for abnormal differentiation and proliferation in skin from an affected individual. In addition E-cadherin and β-catenin were shown to be mislocalized in keratinocytes from this affected individual.

Loss of ap1b1 in zebrafish is not lethal but lead to auditory defects (/vestibular deficits). The inner ears appear to develop normally, although there is progressive degeneration of ear epithelia. There are no behavioral/neurological phenotypes listed for mouse models. [ http://www.informatics.jax.org/marker/MGI:1096368 ].

AP1B1 is not associated with any phenotype in OMIM/G2P/SysID.

Overall this gene could be considered for inclusion in the ID panel probably with amber rating.
Sources: Literature
Intellectual disability - microarray and sequencing v2.1098 FDFT1 Konstantinos Varvagiannis gene: FDFT1 was added
gene: FDFT1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FDFT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FDFT1 were set to 29909962
Phenotypes for gene: FDFT1 were set to Profound global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology; Cortical visual impairment; Abnormality of the skin; Abnormality of the face
Penetrance for gene: FDFT1 were set to Complete
Review for gene: FDFT1 was set to AMBER
Added comment: Biallelic pathogenic FDFT1 variants cause Squalene synthase deficiency (MIM 618156). 3 individuals from 2 families (and 3 variants) have been reported. DD, ID and seizures are part of the phenotype (3/3). The metabolic profile observed is specific and highly suggestive of disruption of the cholesterol biosynthesis pathway (at the specific level) while the clinical presentation is similar to other disorders of the pathway (SLO). The effect of 2 variants has been studied in detail (in one case mis-splicing demonstrated and in the other regulatory effect). Overall, this gene could be considered for inclusion in the ID/epilepsy panel with amber rating. As the gene is currently present only in the DDG2P panel, please consider adding it to relevant ones (eg. IEMs, undiagnosed metabolic disorders, etc). [Details provided below].
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Coman et al. (2018 - PMID: 29909962) reported on 3 relevant individuals from 2 unrelated families.

The phenotype consisted of seizures (3/3 - neonatal onset - generalized), profound DD (ID can be inferred from the description in the supplement), variable brain MRI abnormalities (white matter loss, hypoplastic CC), cortical visual impairment, dry skin with photosensitivity as well facial dysmorphic features. Male subjects presented genital anomalies (cryptorchidism/hypospadias).

FDFT1 encodes squalene synthase, the enzyme which catalyzes conversion of farnesyl-pyrophosphate to squalene - the first specific step in cholesterol biosynthesis.

A specific pattern of metabolites was observed in all, similar to a pattern previously observed in animal models/humans treated with squalene synthase inhibitor or upon loading with farnesol (in animals). Overall the pattern was suggestive of a cholesterol biosynthesis defect at the level of squalene synthase as suggested by increased total farnesol levels (farnesyl-pyrophosphate + free farnesol), reduced/normal squalene, low plasma cholesterol as well as other metabolites.

Clinical features also resembled those observed in Smith-Lemli-Opitz syndrome (another disorder of cholesterol biosynthesis).

WES was carried out in affected individuals and their parents and revealed for sibs of the first family, compound heterozygosity for a maternally inherited 120-kb deletion spanning exons 6-10 of FDFT1 and CTSB and a paternally inherited FDFT1 variant in intron 8 (TC deletion/AG insertion). Variant studies for the latter included:
- Minigene splice assay demonstrating retention of 22 bp in intron 8.
- Partial splicing defect with both nl and mis-spliced cDNA (patient fibroblasts)
- Reduced protein levels in lymphoblasts/fibroblasts from both sibs upon Western blot.
Contribution of the CTSB deletion was considered unlikely (carrier mother was unaffected).

As for the 2nd family, WES data allowed identification of a homozygous deep-intronic (although this is transcript-specific) 16-bp deletion in the proband. Parents were carriers. For the specific variant :
- cDNA studies failed to detect 3 (of 10) isoforms which are normally present in control fibroblasts. Eventual NMD (which would be predicted if the deletion resulted in splicing defect) was eliminated given the absent effect of cyclohexamide addition, thus suggesting a regulatory effect.
- Given a predicted promoter/enhancer effect of the deleted region, a luciferase assay performed, suggested that the sequence had promoter capacity, with the construct containing the 16-bp deletion showing reduced promoter activity.

Fdft1 knockout mice demonstrate embryonic lethality around mid-gestation while they exhibit severe growth retardation and defective neural tube closure.

In G2P FDFT1 is associated with 'Defect in Cholesterol Biosynthesis' (confidence:possible/biallelic/LoF). The gene belongs to the Current primary ID gene group of SysID. It is not commonly included in gene panels for ID offered by diagnostic laboratories.
Sources: Literature
Intellectual disability - microarray and sequencing v2.1098 IQSEC1 Konstantinos Varvagiannis gene: IQSEC1 was added
gene: IQSEC1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: IQSEC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IQSEC1 were set to 31607425
Phenotypes for gene: IQSEC1 were set to Central hypotonia; Global developmental delay; Intellectual disability; Behavioral abnormality; Short stature
Penetrance for gene: IQSEC1 were set to Complete
Review for gene: IQSEC1 was set to AMBER
Added comment: Ansar et al. (2019 - PMID: 31607425) reported on 5 individuals with biallelic IQSEC1 variants.

Common features included hypotonia, DD, speech impairment, severe ID, behavioral problems as well as short stature. Early-onset seizures were observed in 3 sibs (for whom there was also a paternal family history of seizures).

These subjects belonging to 2 consanguineous families from Pakistan and S. Arabia were found to harbor homozygous missense variants private to each family (Fam1: NM_001134382.2:c.1028C>T or p.Thr354Met following SNP genotyping of several members and exome of the proband | Fam2: c.962G>A or p.Arg321Gln following exome in 2 affected members). Sanger confirmation and study of parents (+/- sibs) were compatible.

The homozygous variant was the only candidate in the 1st family (also following exclusion of other causes of ID/short stature), and most likely/compatible with the patient's phenotype in the 2nd.

As the authors note, IQSEC1-3 encode guanine exchange factors (GEFs) for the ARF family of GTPases. IQSEC2 is a known XLID gene, while biallelic IQSEC3 mutations in ID have been recently reported (PMID: 31130284), all presenting phenotypic similarities (ID, short stature, speech defect).

Previous studies cited had shown that IQSEC1 & 2 are concentrated at the postsynaptic density of glutamatergic synapses in mammalian brain, playing a role in actin-dependent processes incl. AMPA receptor trafficing at synapses (all refs in article).

Drosophila model: The ortholog of IQSEC1, 2 and 3 is schizo and the phenotype associated with its loss is a growth cone guidance defect through dysregulation of the Slit-Robo pathway (all refs in article). The authors studied overexpression of either reference IQSEC1 cDNA or variant cDNAs in wt flies, the former only being toxic/lethal. Loss of schizo was also embryonically lethal but was partially rescued by expression of reference IQSEC1 cDNA. Expression of cDNA for the 2 variants did not rescue lethality. As a result LoF appears to be the underlying effect of both variants. The authors provided evidence that schizo is localized in glia and neurons at various stages of development and is important for proper axon guidance in both CNS and PNS. In Drosophila, schizo is also localized in photoreceptors and RNAi-mediated knockdown resulted in severely impaired sight (also observed in 1 patient).

Mouse model: Through generation of Iqsec1-floxed mice, it was demonstrated that targeted depletion of Iqsec1 in the cortex resulted in increased density/immature morphology of dendritic spines.

IQSEC1 is not associated with any phenotype in OMIM / G2P / SysID and not commonly included in gene panels for ID.

As a result, this gene could be considered for inclusion in the ID panel as probably as amber (2 families/variants).
Sources: Literature
Intellectual disability - microarray and sequencing v2.1095 TAOK1 Ellen McDonagh reviewed gene: TAOK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31230721; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v2.1092 SVBP Alistair Pagnamenta reviewed gene: SVBP: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31363758, 30607023; Phenotypes: brain abnormalities, microcephaly, intellectual disability, delayed gross motor development, spasticity, delayed speech development; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v2.1082 PMPCB Catherine Snow reviewed gene: PMPCB: Rating: GREEN; Mode of pathogenicity: None; Publications: 29576218; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v2.1082 PCDH12 Catherine Snow Phenotypes for gene: PCDH12 were changed from intellectual disability; microcephaly; epilepsy; perithalamic hyperechogenicity; periventricular hyperechogenicity; midbrain abnormalities; hypothalamic abnormalities to intellectual disability; microcephaly; epilepsy; perithalamic hyperechogenicity; periventricular hyperechogenicity; midbrain abnormalities; hypothalamic abnormalities; Microcephaly, seizures, spasticity, and brain calcification, 251280
Intellectual disability - microarray and sequencing v2.1079 CDH2 Catherine Snow reviewed gene: CDH2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v2.1076 TANC2 Rebecca Foulger changed review comment from: Comment on list classification: Updated rating from Red to Amber based on PMID:31616000 2019 article suggested by Andrea Haworth. Sufficient unrelated cases (19/20) with an ID/DD phenotype but the pathogenicity of the variants has not yet been verified. Therefore Amber with 'watchlist' tag is appropriate pending functional studies.; to: Comment on list classification: Updated rating from Red to Amber based on PMID:31616000 2019 article suggested by Andrea Haworth. Sufficient unrelated cases (19/20) with an ID/DD phenotype but the pathogenicity of the variants has not yet been verified. Not yet associated with a disorder in Gene2Phenotype or OMIM. Currently only 1 paper, therefore Amber with 'watchlist' tag is appropriate pending functional studies.
Intellectual disability - microarray and sequencing v2.1076 TANC2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Amber based on PMID:31616000 2019 article suggested by Andrea Haworth. Sufficient unrelated cases (19/20) with an ID/DD phenotype but the pathogenicity of the variants has not yet been verified. Therefore Amber with 'watchlist' tag is appropriate pending functional studies.
Intellectual disability - microarray and sequencing v2.1064 FBXW11 Catherine Snow reviewed gene: FBXW11: Rating: GREEN; Mode of pathogenicity: None; Publications: 31402090, 16865294; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v2.1062 TDP2 Konstantinos Varvagiannis gene: TDP2 was added
gene: TDP2 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: TDP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TDP2 were set to 24658003; 30109272; 31410782
Phenotypes for gene: TDP2 were set to Spinocerebellar ataxia, autosomal recessive 23, 616949)
Penetrance for gene: TDP2 were set to unknown
Review for gene: TDP2 was set to GREEN
gene: TDP2 was marked as current diagnostic
Added comment: Biallelic pathogenic TGP2 variants cause Spinocerebellar ataxia, autosomal recessive 23 (MIM 616949). At least 6 affected individuals from 4 families have been reported, in all cases homozygous for LoF variants (3 different). ID, epilepsy and ataxia are consistent features of the disorder.

TDP2 encodes a phosphodiesterase that is required for efficient repair of double strand breaks (DSBs) produced by abortive topoisomerase II (TOP2) activity.

The gene is expressed in fetal and adult human brain.

Evidence at the variant level (mRNA, protein levels) and additional studies for impairment of TOP2-induced DSB repair support a role.

Animal models (primarily mice) reproduce the DSB repair defect, provide some histopathological evidence, show transcriptional dysregulation of genes (in line with the role of TOP2 in transcription). They have however failed to reproduce relevant neurological phenotypes.

Published studies are summarized below.

TDP2 is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc and GeneDx). There is no associated phenotype in G2P. TDP2 is listed among the current primary ID genes in SysID.

Overall, this gene could be considered for inclusion in the ID and epilepsy panels probably as green (>=3 patients/families/variants, relevant ID and seizures in all, expression in brain, mRNA/protein levels tested, impaired activity) or amber (absence of neurological phenotypes in mouse model).
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[1] - PMID: 24658003 (Gómez-Herreros et al. 2014):
Reports 3 individuals from a consanguineous Irish family. Features included seizures (onset by 2m, 6m and 12y), ID (3/3) and ataxia (3/3).

A splicing variant (NM_016614.3:c.425+1G>A) was found in a 9.08-Mb region of homozygosity shared by all. A further ZNF193 missense variant localizing in the same region was thought unlikely to contribute to the phenotype (evidence also provided in subsequent study).

The effect of the specific variant was proven by abnormal mRNA size, lower mRNA levels due to NMD (corrected upon cyclohexamide treatment), loss of TDP2 protein upon WB, loss of protein activity in lymphoblastoid cells from affected individuals, decreased repair of DSBs and increased cell death upon addition of etoposide (which promotes TOP2 abortive activity).

The authors report very briefly on a further patient (from Egypt), with ID, 'reports of fits' and ataxia. This individual, with also affected sibs, was homozygous LoF (c.413_414delinsAA / p.Ser138*). Again, the authors were not able to detect TDP2 activity in blood from this subject.

As also commented:
- TDP2 has relevant expression in human (particularly adult) brain.
- Mouse model : Tdp2 is expressed in relevant tissues, absence of Tdp2 activity was observed in neural tissue of mice homoyzgous for an ex1-3 del, with impairment of DSB repair. The authors were unable to detect a neurological phenotype with behavioral analyses, preliminary assesment of seizure propensity. Mice did not show developmental defects. Histopathology however, revealed ~25% reduction in the density of interneurons in cerebellum (a 'hallmark of DSB repair' and associated with seizures and ataxia). Transcription of several genes was shown to be disregulated.
- Knockdown in zebrafish appears to affect left-right axis detremination (cited PMID: 18039968).

[2] - PMID: 30109272 (Zagnoli-Vieira et al. 2018):
A 6 y.o. male with seizures (onset by 5m), hypotonia, DD and ID, microcephaly and some additional clinical features and testing (ETC studies on muscle biopsy, +lactate, +(lactate/pyruvate) ratio) which could be suggestive of mitochondrial disorder. This individual from the US was homozygous for the c.425+1G>A variant but lacked the ZNF193 one (despite a shared haplotype with the Irish patients). Again absence of the protein was shown upon WB in patient fibroblasts, also supported by its activity. Complementation studies restored the DSB repair defect. The defect was specific to TOP2-induced DSBs as suggested by hypersensitivity to etoposide but not to ionizing radiation. CRISPR/Cas9 generated mutant human A549 cells demonstrated abnormal DSB repair. Fibroblasts / edited A549 cells failed to show mitochondrial defects (which were noted in muscle).

[3] - PMID: 31410782 (Ciaccio et al. 2019):
A girl born to consanguineous Italian parents, presented with moderate/severe ID, seizures (onset at 12y) and - among others - gait ataxia, tremor and dysmetria. MRI at the age of 12, demonstrated cerebellar atrophy (although previous exams were N). WES revealed a homozygous nonsense variant (c.400C>T / p.Arg134Ter) for which each parent was found to be carrier. Previous investigations included aCGH, NGS testing for epilepsy and metabolic testing.
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability - microarray and sequencing v2.1062 PCDH12 Konstantinos Varvagiannis reviewed gene: PCDH12: Rating: ; Mode of pathogenicity: None; Publications: 27164683, 28804758, 29556033, 30178464, 30459466, 18477666; Phenotypes: Microcephaly, seizures, spasticity, and brain calcification, 251280; Mode of inheritance: None; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.1062 NKAP Konstantinos Varvagiannis reviewed gene: NKAP: Rating: GREEN; Mode of pathogenicity: None; Publications: DOI: 10.1016/j.ajhg.2019.09.009; Phenotypes: Global developmental delay, Intellectual disability, Tall stature, Scoliosis, Pectus excavatum, Pectus carinatum, Arachnodactyly, Camptodactyly, Abnormality of the cardiovascular system, Abnormality of the genitourinary system, Abnormality of the face, Obesity; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability - microarray and sequencing v2.1062 APC2 Konstantinos Varvagiannis gene: APC2 was added
gene: APC2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: APC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: APC2 were set to 31585108; 25753423; 19759310; 22573669
Phenotypes for gene: APC2 were set to Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system
Penetrance for gene: APC2 were set to Complete
Review for gene: APC2 was set to GREEN
gene: APC2 was marked as current diagnostic
Added comment: Probably 14 individuals from 9 families (8 consanguineous) with biallelic APC2 LoF variants have been reported.

ID and brain abnormalities were features in all, although the presentation was quite different between sibs in the first report (PMID: 25753423 - mild/mod ID, ventriculomegaly and CC anomalies, macrocephaly with variable height, Sotos-like facial features) and 12 subsequently described patients (PMID: 31585108 - severe ID, P>A lissencephaly/CC anomalies/ventriculomegaly/paucity of white matter in (almost) all, gT-C/myoclonic seizures in 8/12 with onset 3m-6y, OFC in the low percentiles).

In all cases relevant alternative diagnoses (eg. macrocephaly/overgrowth syndromes - 1st report, mutations in other lissencephaly genes, metabolic disorders - 2nd) were ruled out.

APC2 encodes Adenomatous polyposis coli protein 2, expressed in the CNS.

All variants reported to date were LoF (stopgain/frameshift/splicing) and were supported by parental-only studies. Mutations in the 1st report as well as 4/8 variants from the 2nd report localized within the last exon (NM_005883.2 / longest of >=3 isoforms), although the 2nd report did not observe obvious genotype-phenotype correlations.

Despite a pLI of 1 in gnomAD, Lee et al. comment that heterozygous carriers did not have any noticeable phenotype. They further note that carriers were not examined by brain MRI, though. 27 heterozygous high-confidence variants appear in individuals in gnomAD. Finally as commented on, APC2 is not mutated in colon cancer.

Animal models: Apc -/- mice displayed disrupted neuronal migration, with defects of lamination of cerebral cortex and cerebellum supporting the observed brain abnormalities. In addition Apc2-deficient mice also presented impaired learning and memory abilities. Extensive additional studies have shown Apc2 co-localization with microtubules affecting their stabilization, distribution along actin fibers (all supporting a role in cytoskeletal organization) and regulation of Rac1 (a Rho GTPase). Generation of Neuro2a cells demonstrated abnormal localization mainly in cell bodies of mutant hAPC2 proteins (due to frameshift in the last exon / deletion of the C-terminal part) - different from wt (neurites, growth cones, cell bodies). The first patient report also provided evidence for Apc2 being a downstream effector of Nsd1, with Nsd1 knockdown brains displaying impaired migration / laminar positioning of cortical neurons (similar to Apc2-/- model) and rescued by forced expression of Apc2.

Relevant articles:
PMIDs: 19759310 and 22573669 (Shintani et al. 2009 & 2012) [mouse model]
PMID: 25753423 (Almuriekhi et al. 2015) [2 individuals + mouse model]
PMID: 31585108 (Lee et al. 2019) [12 individuals from 8 families]
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In OMIM, the APC2-related phenotype is ?Sotos syndrome 3 (MIM 617169 - AR). G2P does not have any associated phenotype for this gene. In SysID, APC2 belongs to the Current primary ID genes.
APC2 is included in gene panels for ID offered by some diagnostic laboratories (eg. Radboudumc, GeneDx).
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Overall, this gene could be considered for inclusion in the ID panel probably as green (>3 individuals/families/variants, highly specific pattern of lissencephaly in 12/14, mouse model supporting migration defects and impaired learning/memory) rather than amber (differences between the 1st and the other families reported as for the OFC and presence of lissencephaly).
Sources: Literature
Intellectual disability - microarray and sequencing v2.1062 CDH2 Konstantinos Varvagiannis changed review comment from: Accogli et al. (2019 - PMID: 31585109) report on 9 individuals with de novo pathogenic CDH2 variants.

Overlapping features included axon pathfinding defects (corpus callosum agenesis/hypoplasia, mirror movements, Duane anomaly), cardiac, ocular and genital anomalies. Neurodevelopmental phenotypes included DD (8/9), ID (2/8 mild and 2/8 moderate, the remaining had either low-average/borderline int. functioning (2), did not present ID (2) or did not have relevant age for evaluation) and ASD (in 2).

CDH2 encodes cadherin-2 (N-cadherin) with high expression in neural tissue. As the authors note, the gene has important role in neural development, incl. proliferation and differentiation of neural progenitor cells, neural tube formation, synaptogenesis, neuronal migration and axon elongation. N-cadherin, similar to other classical cadherins has an extracellular domain with 5 extracellular cadherin (EC) domain repeats that mediate cell adhesion either in cis or in trans (between molecules of the same / different cells).

Mutations in other cadherins have been associated among others with neurodevelopmental disorders (eg. PCDH19, PCDH12, etc).

Variants in all cases were de novo, identified following trio-WES. 7 missense variants (6 of which clustering within the EC4-EC5 linker region or the EC5 domain - calculated p=1.37x10-4) and 2 frameshift ones predicted not to lead to NMD were identified.

One individual had an additional DNM1 variant, formally fulfilling ACMG criteria for pathogenic. The authors however felt that presentation of the specific subject (low-average/borderline int. functioning, absence of seizures and microcephaly) was not compatible with the phenotype of DNM1-encephalopathy .

Missense SNVs within the EC4-EC5 region, were shown to impair cell-cell adhesion by affecting both self-binding and trans adhesion to wt N-cadherin (in L cells studied). This supported a possible dominant-negative effect. A single variant in the EC2 domain - previously shown to be critical for adhesion - was thought to have a similar effect. The authors speculated that truncating variants may also act in a dominant-negative manner (as has been demonstrated for other cadherins) although LoF remains possible.

Cdh2 knockout in mice is embryonically lethal. Mouse with conditional inactivation of Cdh2 in the cerebral cortex leads to cortical disorganization and CCA similar to the human phenotypes (PMIDs cited: 9015265, 17222817). Other animal studies (mouse, zebrafish, chicken, dog, etc) are also cited to link with specific defects.

Heterozygous CDH2 variants affecting the ectodomain have been associated with ARVC (2 variants, one of which segregated with the disorder in a 3-generation family, the other identified in two unrelated families with several affecteds - refs. provided in the article). Cardiac abnormalities were noted in several subjects (incl. electrical activity in 2). [Amber rating of this gene in Arrhythmogenic cardiomyopathy panel].
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The gene is not associated with any phenotype in OMIM / G2P / SysID and not commonly included in panels for ID.
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As a result CDH2 could be considered for inclusion in the ID panel probably as amber (mild/moderate ID in 4/8, uncertainty regarding the underlying effect of some variants or additional phenotypes (ARVC)) or green (>3 individuals/variants/families, ID is a feature and in some cases of moderate degree).
Sources: Literature; to: Accogli et al. (2019 - PMID: 31585109) report on 9 individuals with de novo pathogenic CDH2 variants.

Overlapping features included axon pathfinding defects (corpus callosum agenesis/hypoplasia, mirror movements, Duane anomaly), cardiac, ocular and genital anomalies. Neurodevelopmental phenotypes included DD (8/9), ID (2/8 mild and 2/8 moderate, the remaining had either low-average/borderline int. functioning (2), did not present ID (2) or did not have relevant age for evaluation) and ASD (in 2).

CDH2 encodes cadherin-2 (N-cadherin) with high expression in neural tissue. As the authors note, the gene has important role in neural development, incl. proliferation and differentiation of neural progenitor cells, neural tube formation, synaptogenesis, neuronal migration and axon elongation. N-cadherin, similar to other classical cadherins has an extracellular domain with 5 extracellular cadherin (EC) domain repeats that mediate cell adhesion either in cis or in trans (between molecules of the same / different cells).

Mutations in other cadherins have been associated among others with neurodevelopmental disorders (eg. PCDH19, PCDH12, etc).

Variants in all cases were de novo, identified following trio-WES. 7 missense variants (6 of which clustering within the EC4-EC5 linker region or the EC5 domain - calculated p=1.37x10-4) and 2 frameshift ones predicted not to lead to NMD were identified.

One individual had an additional DNM1 variant, formally fulfilling ACMG criteria for pathogenic. The authors however felt that presentation of the specific subject (low-average/borderline int. functioning, absence of seizures and microcephaly) was not compatible with the phenotype of DNM1-encephalopathy .

Missense SNVs within the EC4-EC5 region, were shown to impair cell-cell adhesion by affecting both self-binding and trans adhesion to wt N-cadherin (in L cells studied). This supported a possible dominant-negative effect. A single variant in the EC2 domain - previously shown to be critical for adhesion - was thought to have a similar effect. The authors speculated that truncating variants may also act in a dominant-negative manner (as has been demonstrated for other cadherins) although LoF remains possible.

Cdh2 knockout in mice is embryonically lethal. Conditional inactivation of Cdh2 in the cerebral cortex leads to cortical disorganization and CCA similar to the human phenotypes (PMIDs cited: 9015265, 17222817). Other animal studies (mouse, zebrafish, chicken, dog, etc) are also cited to link with specific defects.

Heterozygous CDH2 variants affecting the ectodomain have been associated with ARVC (2 variants, one of which segregated with the disorder in a 3-generation family, the other identified in two unrelated families with several affecteds - refs. provided in the article). Cardiac abnormalities were noted in several subjects (incl. electrical activity in 2). [Amber rating of this gene in Arrhythmogenic cardiomyopathy panel].
------
The gene is not associated with any phenotype in OMIM / G2P / SysID and not commonly included in panels for ID.
------
As a result CDH2 could be considered for inclusion in the ID panel probably as amber (mild/moderate ID in 4/8, uncertainty regarding the underlying effect of some variants or additional phenotypes (ARVC)) or green (>3 individuals/variants/families, ID is a feature and in some cases of moderate degree).
Sources: Literature
Intellectual disability - microarray and sequencing v2.1062 CDH2 Konstantinos Varvagiannis gene: CDH2 was added
gene: CDH2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CDH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CDH2 were set to 31585109; 9015265; 17222817
Phenotypes for gene: CDH2 were set to Abnormality of the corpus callosum; Abnormality of neuronal migration; Bimanual synkinesia; Duane anomaly; Abnormality of cardiovascular system; Abnormality of the eye; Abnormality of the genital system; Global developmental delay; Intellectual disability
Penetrance for gene: CDH2 were set to unknown
Review for gene: CDH2 was set to AMBER
Added comment: Accogli et al. (2019 - PMID: 31585109) report on 9 individuals with de novo pathogenic CDH2 variants.

Overlapping features included axon pathfinding defects (corpus callosum agenesis/hypoplasia, mirror movements, Duane anomaly), cardiac, ocular and genital anomalies. Neurodevelopmental phenotypes included DD (8/9), ID (2/8 mild and 2/8 moderate, the remaining had either low-average/borderline int. functioning (2), did not present ID (2) or did not have relevant age for evaluation) and ASD (in 2).

CDH2 encodes cadherin-2 (N-cadherin) with high expression in neural tissue. As the authors note, the gene has important role in neural development, incl. proliferation and differentiation of neural progenitor cells, neural tube formation, synaptogenesis, neuronal migration and axon elongation. N-cadherin, similar to other classical cadherins has an extracellular domain with 5 extracellular cadherin (EC) domain repeats that mediate cell adhesion either in cis or in trans (between molecules of the same / different cells).

Mutations in other cadherins have been associated among others with neurodevelopmental disorders (eg. PCDH19, PCDH12, etc).

Variants in all cases were de novo, identified following trio-WES. 7 missense variants (6 of which clustering within the EC4-EC5 linker region or the EC5 domain - calculated p=1.37x10-4) and 2 frameshift ones predicted not to lead to NMD were identified.

One individual had an additional DNM1 variant, formally fulfilling ACMG criteria for pathogenic. The authors however felt that presentation of the specific subject (low-average/borderline int. functioning, absence of seizures and microcephaly) was not compatible with the phenotype of DNM1-encephalopathy .

Missense SNVs within the EC4-EC5 region, were shown to impair cell-cell adhesion by affecting both self-binding and trans adhesion to wt N-cadherin (in L cells studied). This supported a possible dominant-negative effect. A single variant in the EC2 domain - previously shown to be critical for adhesion - was thought to have a similar effect. The authors speculated that truncating variants may also act in a dominant-negative manner (as has been demonstrated for other cadherins) although LoF remains possible.

Cdh2 knockout in mice is embryonically lethal. Mouse with conditional inactivation of Cdh2 in the cerebral cortex leads to cortical disorganization and CCA similar to the human phenotypes (PMIDs cited: 9015265, 17222817). Other animal studies (mouse, zebrafish, chicken, dog, etc) are also cited to link with specific defects.

Heterozygous CDH2 variants affecting the ectodomain have been associated with ARVC (2 variants, one of which segregated with the disorder in a 3-generation family, the other identified in two unrelated families with several affecteds - refs. provided in the article). Cardiac abnormalities were noted in several subjects (incl. electrical activity in 2). [Amber rating of this gene in Arrhythmogenic cardiomyopathy panel].
------
The gene is not associated with any phenotype in OMIM / G2P / SysID and not commonly included in panels for ID.
------
As a result CDH2 could be considered for inclusion in the ID panel probably as amber (mild/moderate ID in 4/8, uncertainty regarding the underlying effect of some variants or additional phenotypes (ARVC)) or green (>3 individuals/variants/families, ID is a feature and in some cases of moderate degree).
Sources: Literature
Intellectual disability - microarray and sequencing v2.1055 HNRNPR Catherine Snow reviewed gene: HNRNPR: Rating: GREEN; Mode of pathogenicity: None; Publications: 31079900, 26795593; Phenotypes: Intellectual Disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v2.1054 DDX6 Catherine Snow reviewed gene: DDX6: Rating: GREEN; Mode of pathogenicity: None; Publications: 31422817; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v2.1047 KCNMA1 Catherine Snow reviewed gene: KCNMA1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31427379, 31152168; Phenotypes: Cerebellar atrophy, developmental delay, and seizures, 617643; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v2.1047 SMG9 Konstantinos Varvagiannis reviewed gene: SMG9: Rating: GREEN; Mode of pathogenicity: None; Publications: 27018474, 31390136; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.1047 METTL5 Konstantinos Varvagiannis gene: METTL5 was added
gene: METTL5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: METTL5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: METTL5 were set to 29302074; http://doi.org/10.1016/j.ajhg.2019.09.007; https://imgc2019.sciencesconf.org/data/abstract_book_complete.pdf
Phenotypes for gene: METTL5 were set to Delayed speech and language development; Intellectual disability; Microcephaly; Behavioral abnormality
Penetrance for gene: METTL5 were set to Complete
Review for gene: METTL5 was set to GREEN
Added comment: [1] - PMID: 29302074 :
In a WES/WGS study of 404 consanguineous families with two or more offspring affected by ID, Hu et al. identified two sibs homozygous for a METTL5 missense variant [NM_014168:c.182G>A / p.Gly61Asp]. These 2 subjects, born to first cousin parents from Iran, presented with early learning impairment, aggressive behaviour, severe microcephaly (-7SD and -8SD) and ID formally evaluated to be in the severe range. Sanger confirmation of variants and segregation studies were performed for all available and informative members in families participating in the study. In silico predictions were all in favour of a deleterious effect (PolyPhen2, MutationTaster, SIFT, CADD) and the variant was absent from ExAC. The effect of the specific variant was studied in ref. 2 (below).

[2] - DOI: 10.1016/j.ajhg.2019.09.007 :
Richard et al. (2019) reported on 5 additional individuals from 2 consanguineous families. Common phenotype consisted of speech delay, moderate/severe ID (4/4), microcephaly (4/4 - though milder than in the first report), behavioral problems (ADHD, aggressiveness, autistic feat.) and possibly some overlapping facial features (nose and ear abnormalities). 3 sibs from the 1st family, from Pakistan, were homozygous for a frameshift variant (NM_014167.2:c.344_345delGA / p.Arg115Asnfs*19) while sibs from the 2nd family, from Yemen, were homozygous for p.Lys191Valfs*1 (c.571_572delAA). Confirmation and segregation studies supported a role for the variants.

The authors performed additional studies for METTL5 and all 3 variants reported to date, notably:
- Based on RNA-seq data from the Allen Brain Atlas, METTL5 is expressed in the developing and adult human brain (incl. cerebellar cortex, hippocampus and striatum).
- Immunostaining in mouse brain demonstrated ubiquitous expression (postnatal day 30).
- In rat hippocampal neurons, enrichment of METTL5 was found in the soma, the nucleus and pre- and post- synaptic regions.
- Myc-/GFP-tagged METTL5 wt or mutants were transiently expressed in COS7 cells, and were found in the cytoplasm and nucleus. Levels of the 2 frameshift variants were significantly reduced compared with wt, although this was not the case for Gly61Asp.
- Upon transfection of rat hippocampal neurons, METTL5-GFP tagged wt and mt proteins showed similar localicalization in nucleus and dendrites.
- Western blot on HEK293T cells transfected with Myc-METTL5 wt or mt constructs demonstrated decreased amounts for the frameshift (but not the missense) variants while comparison after addition of a proteasome inhibitor or cyclohexamide suggested that this is not probably due to decreased mutant protein - rather than mRNA (NMD) - stability.
- In zebrafish, morpholino knockdown of mettl5 led to reduced head size and head/body ratio (reproducing the microcephaly phenotype) and curved tails. Forebrain and midbrain sizes were also significantly reduced.

Based on the ACMG criteria, Gly61Asp is classified as VUS (PM2, PP1, PP3) and the frameshift ones as pathogenic (PS3, PM2, PM4, PP1, PP3).

The authors comment that METTL5 is an uncharacterized member of the methyltransferase superfamily (of 33 METTL proteins). Variants in other methyltransferase-like genes (mainly METTL23) have been associated with ID, while various histone-/DNA-/tRNA-/rRNA- methyltransferases such as EHMT1, DNMT3A, NSUN2, FTSJ1, etc have been implicated in ID. Given the role of methyltransferases in neurodevelopment and neuroplasticity, homology comparisons suggesting presence of relevant domain in METTL5 and accumulation of the protein in the nucleus, a role as epigenetic regulator is proposed (see also ref. 3).

[3] - Conference abstract by Helmut et al. ["A novel m6A RNA methyltransferase in mammals - characterization of Mettl5 mutant mice in the German Mouse Clinic" - Oral presentation in the 33rd International Mammalian Genome Conference Sept. 2019 - available at : https://imgc2019.sciencesconf.org/data/abstract_book_complete.pdf ]
The group using an in vitro methyltransferase assay, identified METTL5 as a m6A RNA methyltransferase. Generation of Mettl5-knockout mice using the CRISPR/Cas technology, suggested that homozygous mice are subviable, with lower body mass and abnormal growth of nasal bones in half. Homozygous mice were hypoactive and hypoexploratory during an open field test at the age of 8 weeks, while further alterations were observed in neurological functions. Phenotypic deviations were absent or very mild in heterozygous animals. As a result, the mouse model appeared to recapitulate relevant human phenotypes (microcephaly, ID and growth retardation).

----
There is no associated entry in OMIM (neither for the gene nor for a related disorder). G2P does not list any phenotype for this gene, either.

METTL5 is included in the SysID database as a current primary ID gene (cited: 27457812, 28097321 / Given the shared co-authors with the study by Richard et al. as well as the overlapping variants, these articles probably report on the same individuals recently described in more detail).

The gene is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx).
----

Overall, METTL5 could be considered for inclusion in the ID panel probably as green (3 families, 3 variants, segregation, suggested role of the gene, relevant expression patterns, some evidence at the variant-level, zebrafish and mouse models) or amber (underlying effect of Gly61Asp unknown and variant classified as VUS).
Sources: Literature
Intellectual disability - microarray and sequencing v2.1047 CSDE1 Konstantinos Varvagiannis gene: CSDE1 was added
gene: CSDE1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CSDE1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CSDE1 were set to http://doi.org/10.1126/sciadv.aax2166
Phenotypes for gene: CSDE1 were set to Autism; Global developmental delay; Intellectual disability
Penetrance for gene: CSDE1 were set to unknown
Review for gene: CSDE1 was set to GREEN
Added comment: Guo et al. (2019 - DOI: 10.1126/sciadv.aax2166) report on 18 individuals from 18 unrelated families, with heterozygous likely gene disrupting (stopgain/frameshift/spice-site) CSDE1 variants.

Initial sequencing with MIPs found in 3 individuals from an autism cohort (4045 probands), while subsequent targeted sequencing of a larger cohort (autism spectrum/ID network) led to identification of 5 additional relevant individuals and Genematcher/collaborations a further 10 (the latter by WES).

Consistent phenotypes included ASD (10 of 15 formally evaluated), DD (motor: 15/17 - speech: 17/17) and ID (mild to severe in 14 of 16 assessed, in further 2 in the below-average range). Recurrent seizures or epilepsy were reported for 7 of 16 patients. Other variable features were anxiety or ADHD, increased OFC, ocular, hand and MRI anomalies.

The study was mainly focused on LGD variants with p.R123* (NM_001242891.1:c.367C>T) being a reccurrent one, found in 3 families.

8 of these variants were de novo, 8 further inherited (often from a less severely affected parent, although parental neuropsychiatric status was not available for individuals from all 3 groups). In 2 cases inheritance was unknown (only 1 parental sample available).

3 individuals with de novo missense variants were also identified. Features in those individuals also included ASD and/or DD and ID (2/3) [Table S1].

Arguments to support involvement of the CSDE1 variants included the:
- role of the gene encoding an RNA binding protein implicated in neuronal migration/differentiation (cited : 24012837, 29129916),
- statistically significant burden of the variants in the cohorts examined,
- relevant CSDE1 intolerance scores (pLI of 1 and %RVIS of 6.18),
- relevant human (mRNA) / mouse (protein) spatial and temporal expression patterns,
- exclusion of apparent alternative diagnoses to the extent possible in many subjects with CNVs/SNVs/ROH of uncertain significance in very few,
- cosegregation with rather similar neuropsychiatric phenotypes in case of carrier parents,
- enrichment of ASD-related genes (and FMRP targets) among CSDE1-binding targets,
- suppression of Ctnnb1 expression (at the protein level) affecting Wnt/β-catenin signalling,
- effect of knockdown and/or mutants in mouse (shRNA) and Drosophila (mt and siRNA) models affecting synapse formation and synaptic transmission,
- rescue of many of the previous phenotypes by expression of human CSDE1 (mice), expression of stabilized β-Catenin (mice) or RNAi-stable-dUNR (Drosophila) [also supporting LoF as the underlying effect of variants].

CSDE1 is not commonly included in gene panels for ID offered by diagnostic laboratories. There is no associated phenotype in OMIM/G2P.

Overall, this gene could be considered for inclusion in the ID panel probably as green (or amber).
Sources: Literature
Intellectual disability - microarray and sequencing v2.1046 INTS6 Konstantinos Varvagiannis reviewed gene: INTS6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v2.1046 NUP188 Konstantinos Varvagiannis reviewed gene: NUP188: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v2.1046 CPD Konstantinos Varvagiannis reviewed gene: CPD: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v2.1046 CA5A Konstantinos Varvagiannis reviewed gene: CA5A: Rating: RED; Mode of pathogenicity: None; Publications: 26913920, 25834911, 24530203; Phenotypes: Hyperammonemia due to carbonic anhydrase VA deficiency (MIM 615751); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v2.1046 TIMM50 Konstantinos Varvagiannis gene: TIMM50 was added
gene: TIMM50 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: TIMM50 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TIMM50 were set to 27573165; 30190335; 31058414; Serajee et al. (ASHG conference 2015 - abstract Nr. 2299T)
Phenotypes for gene: TIMM50 were set to 3-methylglutaconic aciduria, type IX (MIM 617698)
Penetrance for gene: TIMM50 were set to Complete
Review for gene: TIMM50 was set to GREEN
gene: TIMM50 was marked as current diagnostic
Added comment: Biallelic pathogenic TIMM50 variants cause 3-methylglutaconic aciduria, type IX (MIM 617698).

At least 9 affected individuals from 5 unrelated (but often consanguineous) families of variable origin have been reported (based on a conference abstract and PMIDs : 27573165, 30190335, 31058414).

TIMM50 encodes encodes a subunit of the mitochondrial presequence import machinery called the TIM23 complex. TIMM50 serves as a major receptor in the intermembrane space that binds to proteins on their way to cross the mitochondrial inner membrane (summary by Shahrour et al., 2017 and OMIM).

The highly overlapping patient clinical features [seizures, DD and ID - the latter in all age-appropriate individuals (5 from 3 families - refs 2,4)], metabolic investigations (lactate elevations in many, elevated urinary 3MGA in almost all, variable mitochondrial complex deficiencies in some), additional extensive functional evidence of mitochondrial dysfunction or the similar phenotypes in other types of 3-methylglutaconic aciduria all support a role for the gene.

[AUH- / CLPB- / DNAJC19- / HTRA2- / OPA3- / SERAC1-related methylglutaconic acidurias are all included as relevant disorders in the ID panel, with the respective genes rated green.]

TIMM50 is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc and GeneDx).

The gene is not associated with any phenotype in G2P

As a result this gene could be considered for inclusion/upgrade as green in both ID and epilepsy panels respectively.

---------

[1] - Serajee et al. (ASHG conference 2015 - abstract Nr. 2299T) reported on a patient born to consanguineous parents of South Asian ancestry with intractable epilepsy, microcephaly, DD and spastic quadriplegia. Metabolic investigations revealed increased urinary 3MGA. Two similarly affected sisters with demonstrated increase of 3MGA, were deceased following an infection. WES in the affected child, 2 unaffected sibs and the parents suggested a homozygous missense variant as the likely cause of the disorder in the proband (c.1114G>A / p.G372S - Reference not specified though the variant probably corresponds to ENST00000314349.4 and ClinVar's entry VCV000208697.1 - www.ncbi.nlm.nih.gov/clinvar/variation/208697/).

[2] - Shahroor et al. (2017, PMID: 27573165) reported on 2 consanguineous families, each with 2 affected individuals. Two sibs from the 1st family (of Bedouin origin) presented with seizures (onset at 3m and 4m respectively), DD and ID with slightly elevated plasma lactate and increased urinary 3MGA upon metabolic investigations. Enzymatic activities of mitochondrial complex I-V were carried out for 1 sib and were normal also after normalization for citrate synthase. Following a SNP array, WES was carried out in affected children and their parents. Both sibs were homozygous for a missense SNV [NM_001001563.1:c.755C>T / p.Thr252Met]. Segregation studies - also in 3 unaffected sibs - supported a role for the variant.

Two sibs from the 2nd family (of Muslim origin) presented with seizures (myoclonic jerks at 3m, generalized tonic movements at 2m - respectively) with DD and ID. Urinary 3MGA was elevated for both, with CSF lactate also elevated in one. WES revealed homozygosity for p.Arg217Trp (NM_001001563.1:c.649C>T) and segregation studies in parents and an unaffected sib were again compatible.

The authors could not demonstrate pathogenicity of the variants in a yeast based system although - as also commented on in Ref 4 - the human TIMM50 could not rescue the yeast ΔΤim50 growth defect and global conservation between the two proteins is poor.

[3] - Reyes et al. (2018, PMID: 30190335) reported on one individual with onset of infantile spasms at the age of 2m with hypsarrythmia upon EEG and psychomotor regression. Leigh-like features were noted upon brain MRI. Lactate was elevated in both plasma and CSF. Urinary 3MGA was normal. WES, Sanger confirmation and segregation studies demonstrated compound htz for 2 variants (NM_001001563:c.335C>A or p.S112* and c.569G>C or p.G190A). Functional studies demonstrated among others decrease in all components of the TIM23 complex and decreased mitochondrial membrane potential. Patient fibroblasts grown in glucose had lower levels of all complex II and IV subunits and one complex I subunit (due to the impairment in import system) with decreased mitochondrial respiration and increase in ROS production. Growth in galactose - shifting energy production toward OxPhos - caused massive cell death. The phenotype was rescued/substantially improved following complementation of patient fibroblasts with wt TIMM50.

[4] - Tort et al. (2019, PMID: 31058414) reported on a boy with seizures and ID (diagnosis of West syndrome), Leigh-like MRI anomalies, cardiomyopathy with elevated plasma and CSF lactate and persistent urinary elevation of 3MGA. The proband was found to be compound heterozygous for 2 TIMM50 variants [NM_001001563.5:c.341 G>A (p.Arg114Gln) in trans with c.805 G>A (p.Gly269Ser)] following WES and Sanger confirmation/segregation studies. In patient fibroblasts TIMM50 protein levels were severely reduced upon WB although mRNA levels were similar to control. Muscle biopsy revealed decreased activity of the complexes I-IV, when normalized to the citrate synthase activity. Accumulation of lipidic material in muscle fibers was shown to be associated with mitochondria upon EM. Expression and sublocalization of mitochondria-targeted proteins were not found to be affected in patient fibroblasts. In extracts from muscle biopsy reduced protein levels of SDHA, COX4L and MTCO1 were demonstrated, in line with the disruptions in the activities of the MRC. Mitochondrial morphology and network were shown to be altered in patient fibroblasts. Patient fibroblasts showed marked reduction of max respiratory capacity. Similar reduction was noted in CRISPR/Cas9 generated TIMM50-ko HEK293T cells, but rescued upon transient transfection with a plasmid encoding for wt TIMM50.

(Functional studies better summarized in the respective articles).
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability - microarray and sequencing v2.1033 PAX7 Konstantinos Varvagiannis reviewed gene: PAX7: Rating: RED; Mode of pathogenicity: None; Publications: 31092906; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v2.1033 PAX7 Konstantinos Varvagiannis reviewed gene: PAX7: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v2.1029 PAX7 Louise Daugherty reviewed gene: PAX7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypotonia, Axial hypotonia, Ptosis, Scoliosis, Delayed motor milestones, Myopathy, congenital, progressive, with scoliosis, 618578; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v2.1022 SMARCD1 Cristina Dias reviewed gene: SMARCD1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30879640; Phenotypes: developmental delay, intellectual disability, hypotonia, feeding difficulties, small hands, small feet; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v2.1022 CACNA2D2 Konstantinos Varvagiannis gene: CACNA2D2 was added
gene: CACNA2D2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CACNA2D2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CACNA2D2 were set to 23339110; 24358150; 30410802; 29997391; 31402629; 11487633; 11756448; 4177347; 14660671; 15331424
Phenotypes for gene: CACNA2D2 were set to Cerebellar atrophy with seizures and variable developmental delay (MIM 618501)
Penetrance for gene: CACNA2D2 were set to Complete
Review for gene: CACNA2D2 was set to AMBER
gene: CACNA2D2 was marked as current diagnostic
Added comment: Gene reviewed for the epilepsy panel. Due to the phenotype of EE, with variable GDD (severe in many cases) and/or ID (either specifically commented on or inferred in some cases, although not universal) this gene might also be relevant for the current panel. CACNA2D2 is also included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx) as well as the SysID database. There is no associated phenotype in G2P.

Copied from the epilepsy panel:

Biallelic pathogenic CACNA2D2 variants cause Cerebellar atrophy with seizures and variable developmental delay (MIM 618501).

A recent OMIM update, a subsequent relevant publication by Punatha et al. as well as several additional LP/P variants in ClinVar for the phenotype of epileptic encephalopathy, support possible upgrade to green.

The following affected individuals appear to be relevant [NM_006030.3 used as RefSeq unless otherwise specified]:

[1] Edvardson et al. (PMID: 23339110) - 3 sibs born to consanguineous parents with EIEE, severe GDD / ID (inferred from the descritpion, at least for the oldest one), cerebellar atrophy and movement abnormalities. A CACNA2D2 variant (c.3137T>C / p.Leu1046Pro) was found in affected individuals by SNP-arrays and WES in one of them. Functional studies (reduction in current density of calcium channels in Xenopus laevis oocytes) supported the deleterious effect of the variant. A role of a rare hmz CESLR3 variant could not be ruled out.

[2] Pippucci et al. (PMID: 24358150) - 1 individual born to consanguineous parents, presenting with EE (onset at 1-2 m), severe GDD, cerebellar atrophy and choreiform movements. Homozygosity for a LoF variant (c.1294delA - p.Asn432fs) was found by WES. The role of the variant was further supported by expression studies (80% reduced mRNA levels, protein levels estimated at 3% of control / milder effect in htz parents). The proband was also hmz for a CESLR3 variant. Previous studies incl. 'high-resolution karyotype' and metabolic investigations.

[3] Butler et al. (PMID: 30410802) - A 5 y.o. male, with EE (seizure onset at 7m / GDD) and cerebellar atrophy. Compound heterozygosity for c.782C>T (p.Pro261Leu) and c.3137T>C (p.Leu1046Pro) was demonstrated by WES and supported by segregation studies.

[4] Valence et al. (PMID: 29997391) - Reported on a 20 y.o. male belonging to a cohort of 20 individuals with congenital ataxia, all from consaguineous families. This individual, who had cerebellar atrophy, ataxia, a single episode of febrile seizures and normal cognitive impairment was homozygosity for c.2971G>A (p.Asp991Asn). RT-PCR revealed presence of a normal length transcript as well as an additional, longer one, due to a concurrent splicing effect (activation of a cryptic donor splice site and retention of 4 bases of intronic sequence). Presence of both nl/abn length transcripts was presumed to explain the mild phenotype (variability also commented in OMIM).

[5] Punatha et al. (PMID: 31402629) - 3 affected individuals from 2 consanguineous families presenting with early onset EE (onset 1-7m), GDD/ID, cerebelar atrophy and ataxia. Sibs from the first family were homozygous for c.1778G>C (p.Arg593Pro). An affected 5 y.o. child from the 2nd family was homozygous for c.485_486delAT (p.Tyr162Ter). Mutations were found by WES in regions of AOH.

The following variants - not reported in the literature - have been submitted in ClinVar as LP / P for EE:
[VCV000645106.1] NM_006030.4:c.1389+2T>C - EIEE with suppression bursts - Likely Pathogenic (Invitae)
[VCV000570589.1] NM_006030.4:c.1956_1960del (p.Asn652fs) - EIEE - Pathogenic (Invitae)
[VCV000578284.1] NM_006030.4:c.1555C>T (p.Gln519Ter) - EIEE - Pathogenic (Invitae)
[VCV000653393.1] NM_006030.4:c.851dup (p.Ala286fs) - EIEE with suppression bursts - Pathogenic (Invitae)
[VCV000411003.1] NM_006030.4:c.485_486del (p.Tyr161_Tyr162insTer) - EIEE - Pathogenic (Invitae)

Additional ones have been reported as LP / P although the condition is not specified.
[VCV000620551.1] NM_006030.4:c.1023C>A (p.Cys341Ter) - Likely pathogenic (GeneDx)
[VCV000373439.2] NM_006030.4:c.1846-1G>A - Likely pathogenic (GeneDx)
[VCV000423330.2] NM_006030.4:c.200dup (p.His68fs) - Pathogenic (GeneDx).

The aforementioned laboratories include CACNA2D2 in gene panels for epilepsy (Invitae) and/or ID (GeneDx).

A role for the CACNA2D2 is supported by :
- The highly overlapping features (with the exception of the milder phenotype reported by Valence et al.) incl. early onset of seizures, GDD, cerebellar atrophy in all (9/9 incl. the individual reported by Valence, as evaluated Punatha et al). Ataxia was a feature in many (with movement abnormalities also in the remaining ones).
- The role of the gene encoding the alpha-2-delta-2 auxiliary subunit of high voltage-gated calcium channels. Auxiliary subunits modulate calcium current and channel activation and inactivation kinetics, and may be involved in proper assembly and membrane localization of the channels (summary by Edvardson and OMIM).
- Functional / expression studies for some of the variants (as in Refs 1,2,4).
- Relevant expression patterns (notably in cerebellum) [GTEx project]
- Mouse models recapitulating the human phenotypes (summarized by Edvardson et al) : The 'ducky' mouse model (due to biallelic Cacna2d2 mutations) presenting absence epilepsy, spike-wave seizures and ataxia. Dysgenesis of the cerebellum is among the neuropathological findings (PMIDs cited : 11487633, 11756448, 4177347). The 'entla' mouse model (also AR due to an in-frame duplication) presents also epilepsy and ataxia (PMID : 14660671). Targeted knockout in another mouse model resulted also in ataxic gait, seizure susceptibility and cerebellar anomalies/degeneration (PMID: 15331424).

[Please consider inclusion in other relevant panels eg. for cerebellar anomalies / ataxia].
Sources: Literature
Intellectual disability - microarray and sequencing v2.1022 GABRA2 Konstantinos Varvagiannis changed review comment from: Heterozygous pathogenic GABRA2 variants cause Epileptic encephalopathy, early infantile, 78 (MIM 618557) [new OMIM entry].

At least 8 relevant individuals have been reported to date in the following studies:
- Orenstein et al. (2018 - PMID: 29422393) - 1 individual
- Butler et al. (2018 - PMID: 29961870) - 1 subject
- Maljevic et al. (2019 - PMID: 31032849 - 3 unrelated children as well as 2 affected sibs
- Sanchis-Juan et al. (2019 - bioRxiv / https://doi.org/10.1101/678219) - 1 further patient

In all affected individuals the variants were missense and - in almost all cases - had occurred as de novo events. The 2 sibs reported by Maljevic however, had inherited a missense variant from their unaffected mosaic parent.

Clinical descriptions for individuals from the 3 studies are provided in OMIM and also summarized in the suppl. table 1 by Sanchis-Juan et al. (https://www.biorxiv.org/content/biorxiv/early/2019/06/21/678219/DC2/embed/media-2.xlsx). Seizures, DD and ID (relevant to the current panel) are among the reported features. Functional studies have been performed for most of the variants and are summarized for each one in the OMIM entry for GABRG2 and the aforementioned table as well.

The following variants have been reported (NM_000807.2): c.1003A>C - p.Asn335His (dn) / c.875C>A - Thr292Lys (dn) / c.871C>G - p.Leu291Val (dn) / c.788T>C - p.Met263Thr (dn) / c.851T>C - p.Val284Ala (dn) / c.975C>A - p.Phe325Leu (inherited from mosaic parent) / c.839C>T - p.Pro280Leu (dn - Sanchis-Juan et al).

As commented by Jenkins and Escayg (2019 - PMID: 31032848 / both among the authors of the 1st report) as well as by Sanchis-Juan et al., both loss- and gain- of function effects explain the pathogenicity of the various mutations reported to date. [In gnomAD GABRA2 has a Z-score for missense variants of 3.13 as well as a pLI of 1].
------
GABRA2 is not associated with any phenotype in G2P.
This gene is not commonly included in gene panels for ID offered by diagnostic laboratories.
------
As a result, GABRA2 can be considered for inclusion in the epilepsy and ID panels probably as green (several relevant individuals, several reported variants with supporting functional studies for most, etc.).

[Consider inclusion in other possibly relevant gene panels eg. for ASD which was feature in some patients at relevant age and/or among those evaluated].; to: Heterozygous pathogenic GABRA2 variants cause Epileptic encephalopathy, early infantile, 78 (MIM 618557) [new OMIM entry].

At least 8 relevant individuals have been reported to date in the following studies:
- Orenstein et al. (2018 - PMID: 29422393) - 1 individual
- Butler et al. (2018 - PMID: 29961870) - 1 subject
- Maljevic et al. (2019 - PMID: 31032849 - 3 unrelated children as well as 2 affected sibs
- Sanchis-Juan et al. (2019 - bioRxiv / https://doi.org/10.1101/678219) - 1 further patient

In all affected individuals the variants were missense and - in almost all cases - had occurred as de novo events. The 2 sibs reported by Maljevic however, had inherited a missense variant from their unaffected mosaic parent.

Clinical descriptions for individuals from the 3 studies are provided in OMIM and also summarized, Maljevic - Table 1 (7 patients) and/or in the suppl. table 1 by Sanchis-Juan et al. (8 patients) (https://www.biorxiv.org/content/biorxiv/early/2019/06/21/678219/DC2/embed/media-2.xlsx). Seizures, DD and ID (relevant to the current panel) are among the reported features. Functional studies have been performed for most of the variants and are summarized for each one in the OMIM entry for GABRG2 and the aforementioned table as well.

The following variants have been reported (NM_000807.2): c.1003A>C - p.Asn335His (dn) / c.875C>A - Thr292Lys (dn) / c.871C>G - p.Leu291Val (dn) / c.788T>C - p.Met263Thr (dn) / c.851T>C - p.Val284Ala (dn) / c.975C>A - p.Phe325Leu (inherited from mosaic parent) / c.839C>T - p.Pro280Leu (dn - Sanchis-Juan et al).

As commented by Jenkins and Escayg (2019 - PMID: 31032848 / both among the authors of the 1st report) as well as by Sanchis-Juan et al., both loss- and gain- of function effects explain the pathogenicity of the various mutations reported to date. [In gnomAD GABRA2 has a Z-score for missense variants of 3.13 as well as a pLI of 1].
------
GABRA2 is not associated with any phenotype in G2P.
This gene is not commonly included in gene panels for ID offered by diagnostic laboratories.
------
As a result, GABRA2 can be considered for inclusion in the epilepsy and ID panels probably as green (several relevant individuals, several reported variants with supporting functional studies for most, etc.).

[Consider inclusion in other possibly relevant gene panels eg. for ASD which was feature in some patients at relevant age and/or among those evaluated].
Intellectual disability - microarray and sequencing v2.1022 GABRA2 Konstantinos Varvagiannis reviewed gene: GABRA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29422393, 29961870, 31032849, 31032848, doi.org/10.1101/678219; Phenotypes: Epileptic encephalopathy, early infantile, 78 (MIM 618557); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v2.1022 GABRA2 Konstantinos Varvagiannis gene: GABRA2 was added
gene: GABRA2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: GABRA2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: GABRA2 were set to 29422393; 29961870; 31032849; 31032848; doi.org/10.1101/678219
Phenotypes for gene: GABRA2 were set to Epileptic encephalopathy, early infantile, 78 (MIM 618557)
Penetrance for gene: GABRA2 were set to unknown
Review for gene: GABRA2 was set to GREEN
Added comment: Heterozygous pathogenic GABRA2 variants cause Epileptic encephalopathy, early infantile, 78 (MIM 618557) [new OMIM entry].

At least 8 relevant individuals have been reported to date in the following studies:
- Orenstein et al. (2018 - PMID: 29422393) - 1 individual
- Butler et al. (2018 - PMID: 29961870) - 1 subject
- Maljevic et al. (2019 - PMID: 31032849 - 3 unrelated children as well as 2 affected sibs
- Sanchis-Juan et al. (2019 - bioRxiv / https://doi.org/10.1101/678219) - 1 further patient

In almost all affected individuals, the variants were missense and had occurred as de novo events. The 2 sibs reported by Maljevic however, had inherited a missense variant from their unaffected mosaic parent.

Clinical descriptions for individuals from the 3 studies are provided in OMIM and also summarized in the suppl. table 1 by Sanchis-Juan et al. (https://www.biorxiv.org/content/biorxiv/early/2019/06/21/678219/DC2/embed/media-2.xlsx?download=true). Seizures, DD and ID (relevant to the current panel) are among the reported features. Functional studies have been performed for most of the variants and are summarized for each one in the OMIM entry for GABRG2 and the aforementionned table as well.

The following variants have been reported (NM_000807.2): c.1003A>C - p.Asn335His (dn) / c.875C>A - Thr292Lys (dn) / c.871C>G - p.Leu291Val (dn) / c.788T>C - p.Met263Thr (dn) / c.851T>C - p.Val284Ala (dn) / c.975C>A - p.Phe325Leu (inherited from mosaic parent) / c.839C>T - p.Pro280Leu (dn - Sanchis-Juan et al).

As commented by Jenkins and Escayg (2019 - PMID: 31032848 / both among the authors of the 1st report) as well as by Sanchis-Juan et al., both loss- and gain- of function effects explain the pathogenicity of the various reported (all) missense mutations. [In gnomAD GABRA2 has a Z-score for missense variants of 3.13 as well as a pLI of 1].
------
GABRA2 is not associated with any phenotype in G2P.
This gene is not commonly included in gene panels for ID offered by diagnostic laboratories.
------
As a result, GABRA2 can be considered for inclusion in the epilepsy and ID panels probably as green (several relevant individuals, several reported variants with supporting functional studies for most, etc.).

[Consider inclusion in other possibly relevant gene panels eg. for ASD which was feature in some patients at relevant age and/or among those evaluated].
Sources: Literature
Intellectual disability - microarray and sequencing v2.1022 GABRA5 Konstantinos Varvagiannis reviewed gene: GABRA5: Rating: GREEN; Mode of pathogenicity: None; Publications: 29961870, 31056671; Phenotypes: Epileptic encephalopathy, early infantile, 79 (MIM 618559); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.1022 SLC25A12 Konstantinos Varvagiannis reviewed gene: SLC25A12: Rating: GREEN; Mode of pathogenicity: None; Publications: 31403263, 24515575, 19641205, 27290639, 26633542; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.1021 MED25 Konstantinos Varvagiannis reviewed gene: MED25: Rating: AMBER; Mode of pathogenicity: None; Publications: 30800049, DOI:10.1159/000501114, 25527630, 25792360; Phenotypes: Basel-Vanagait-Smirin-Yosef syndrome (MIM 616449); Mode of inheritance: None; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.1021 MED13 Konstantinos Varvagiannis gene: MED13 was added
gene: MED13 was added to Intellectual disability. Sources: Radboud University Medical Center, Nijmegen,Literature
Mode of inheritance for gene: MED13 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MED13 were set to 29740699
Phenotypes for gene: MED13 were set to Delayed speech and language development; Motor delay; Intellectual disability; Autistic behavior; Attention deficit hyperactivity disorder; Abnormality of the eye; Constipation
Penetrance for gene: MED13 were set to unknown
Review for gene: MED13 was set to AMBER
gene: MED13 was marked as current diagnostic
Added comment: Snijders Blok et al. (2018 - PMID: 29740699) report on 13 individuals with MED13 mutations.

Features included DD with speech difficulties (both universal) and motor delay in some. ID was observed in at least 9/13 and in most cases was in the borderline/mild range (moderate ID reported for 1 individual). Other features were ASD (5/13), ADHD, eye/vision abnormalities and in few individuals obstipation or congenital heart anomalies. Some possibly overlapping facial characteristics were also noted.

MED13 and MED13L are mutually exclusive components of the CDK8 kinase module that regulates the activity of the Mediator complex. The Mediator transmits signals from various transcription factors to RNA polymerase II (Pol II). Reversible binding of the CDK8 kinase controls Mediator - Pol II interaction (prevents Pol II recruitment) and thus acts as a molecular switch in Pol II - mediated transcription. DD and ID are features of the MED13L- and CDK8- related disorders.

3 stopgain, 2 frameshift, 6 missense variants and 1 in-frame deletion were reported. In 11 cases, the variants had occurred as de novo events, while 1 individual had inherited a nonsense variant from a similarly affected mother (unknown inheritance in her case).

Effect of a stopgain variant was studied with similar (total) transcript levels between the affected patient and his parents/controls upon qPCR. Sanger sequencing of cDNA amplicons was suggestive of the presence of an aberrant transcript at ~70% levels relative to the normal transcript. Truncated protein was undetectable by Western Blot in mononuclear blood cells from affected subjects. Total MED13 protein levels were not clearly different when comparing an affected individual with his unaffected parent (?).

Missense variants and the inframe deletion clustered either in the N- or the C-terminal domain, with the N-terminal ones all (T326I, T326del, P327S, P327Q / NM_005121.2 - NP_005112.2) affecting positions of a known phosphodegron sequence, important for the protein's ubiquitination and degradation. Another previously studied variant (T326A) had been shown to prevent degradation. As a result, the variants affecting aa 326-327 might lead to altered (increased) levels of MED13.

The remaining missense variants affected the C-terminal portion (Q2060L, A2064V).

As a result the impact of the different subcategories of variants remains unclear/inconclusive.

MED13 is not associated with any phenotype in OMIM. This gene is part of the DD panel of G2P, associated with "MED13 - Neurodevelopment disorder" (dis. confidence : probable / mutation consequence : LoF / GDD, speech/language delay, ID, autistic behavior among the assigned phenotypes).

MED13 is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc).

ID is part of the phenotype of MED13-related disorder, however as the severity in most individuals - when present - was in the borderline/mild range (not relevant for the present panel) and/or the underlying effect of mutations remains unclear, amber rating can probably be considered for this gene.
Sources: Radboud University Medical Center, Nijmegen, Literature
Intellectual disability - microarray and sequencing v2.1017 GOT2 Catherine Snow reviewed gene: GOT2: Rating: AMBER; Mode of pathogenicity: None; Publications: 31422819; Phenotypes: Global developmental delay, Intellectual disability, Seizures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v2.1015 HNRNPR Konstantinos Varvagiannis changed review comment from: Duijkers et al. (2019 - PMID: 31079900) report on the phenotype of 4 individuals with de novo HNRNPR variants and provide additional information on a previously published case (Helbig et al, 2016 - PMID: 26795593). All 5 were unrelated.

The phenotype consisted of DD (5/5 - moderate to severe in 4 for which this has been commented on), postnatal microcephaly, seizures, brachydactyly, with additional (cardiac, urogenital, etc) anomalies observed in few. Some partially overlapping facial features were also noted.

3 truncating variants as well as a missense one, all localizing within the last exon of the gene (NM_001102398.2 used as ref. although this exon is shared by all transcripts).

HNRNPR encodes heterogeneous nuclear ribonucleoprotein R, which is part of the spliceosome C. The latter functions in the nucleus to process and transport mRNA. Apart from splicing hnRNPs are also involved in other levels of gene regulation (PMID: 27215579). Some hnRNPs have been found in the cytoplasm in stress granules, aggregations of protein, RNAs and stalled initiation complexes that are formed as stress response upon oxidative insult and dissipate upon cessation of this insult.

Western blot in LCLs from affected individuals demonstrated the presence of the truncated protein as well as the full-length and short isoform (as expected by the variant localization).
As the C-terminal part has features of a "prion-like domain" (PrLD), critical for the formation of stress granules in the case of hnRNP-related disorders, comparison of fibroblasts from affected and healthy individuals revealed abnormal persistence of these granules in affected individuals following a recovery period, despite similar formation either at basal levels or under conditions of stress.

In line with a role of hnRNPs in splicing and gene regulation, RNA-Sequencing in fibroblasts from 2 affected individuals revealed abnormal splicing of some genes (eg. HOXA5, HOXB3, LHX9) and significant dysregulation of genes important for the development (upregulation of FOXG1, TBX1, several members of the HOX family and downregulation of LHX9, IRX3, etc) possibly contributing to the patient features.

Helbig et al. provide details on animal studies incl.expression in neural tissues (cerebrum and cerebellum), higher levels of expression early in the development (of both R1/R2 isoforms), etc (extensive discussion in the supplement with several articles cited).

HNRNPR is not associated with any phenotype in OMIM/G2P.

As a result this gene can be considered for inclusion as amber (developmental outcome not commented on sufficiently despite moderate/severe DD in most).
Sources: Literature; to: Duijkers et al. (2019 - PMID: 31079900) report on the phenotype of 4 individuals with de novo HNRNPR variants and provide additional information on a previously published case (Helbig et al, 2016 - PMID: 26795593). All 5 were unrelated.

The phenotype consisted of DD (5/5 - moderate to severe in 4 for which this has been commented on), postnatal microcephaly, seizures, brachydactyly, with additional (cardiac, urogenital, etc) anomalies observed in few. Some partially overlapping facial features were also noted.

3 truncating variants as well as a missense one, all localizing within the last exon of the gene (NM_001102398.2 used as ref. although this exon is shared by all transcripts).

HNRNPR encodes heterogeneous nuclear ribonucleoprotein R, which is part of the spliceosome C. The latter functions in the nucleus to process and transport mRNA. Apart from splicing hnRNPs are also involved in other levels of gene regulation (PMID: 27215579). Some hnRNPs have been found in the cytoplasm in stress granules, aggregations of protein, RNAs and stalled initiation complexes that are formed as stress response upon oxidative insult and dissipate upon cessation of this insult.

Western blot in LCLs from affected individuals demonstrated the presence of the truncated protein as well as the full-length and short isoform (as expected by the variant localization).
As the C-terminal part has features of a "prion-like domain" (PrLD), critical for the formation of stress granules in the case of hnRNP-related disorders, comparison of fibroblasts from affected and healthy individuals revealed abnormal persistence of these granules in affected individuals following a recovery period, despite similar formation either at basal levels or under conditions of stress.

In line with a role of hnRNPs in splicing and gene regulation, RNA-Sequencing in fibroblasts from 2 affected individuals revealed abnormal splicing of some genes (eg. HOXA5, HOXB3, LHX9) and significant dysregulation of genes important for the development (upregulation of FOXG1, TBX1, several members of the HOX family and downregulation of LHX9, IRX3, etc) possibly contributing to the patient features.

Helbig et al. provide details on animal studies incl.expression in neural tissues (cerebrum and cerebellum), higher levels of expression early in the development (of both R1/R2 isoforms), etc (extensive discussion in the supplement with several articles cited).

HNRNPR is not associated with any phenotype in OMIM/G2P.

As a result this gene can be considered for inclusion as amber (developmental outcome not commented on sufficiently despite moderate/severe DD in most) or green.
Sources: Literature
Intellectual disability - microarray and sequencing v2.1015 HNRNPR Konstantinos Varvagiannis gene: HNRNPR was added
gene: HNRNPR was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HNRNPR was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HNRNPR were set to 31079900; 26795593
Phenotypes for gene: HNRNPR were set to Global developmental delay; Intellectual disability; Seizures; Postnatal microcephaly; Short digit
Penetrance for gene: HNRNPR were set to unknown
Review for gene: HNRNPR was set to GREEN
Added comment: Duijkers et al. (2019 - PMID: 31079900) report on the phenotype of 4 individuals with de novo HNRNPR variants and provide additional information on a previously published case (Helbig et al, 2016 - PMID: 26795593). All 5 were unrelated.

The phenotype consisted of DD (5/5 - moderate to severe in 4 for which this has been commented on), postnatal microcephaly, seizures, brachydactyly, with additional (cardiac, urogenital, etc) anomalies observed in few. Some partially overlapping facial features were also noted.

3 truncating variants as well as a missense one, all localizing within the last exon of the gene (NM_001102398.2 used as ref. although this exon is shared by all transcripts).

HNRNPR encodes heterogeneous nuclear ribonucleoprotein R, which is part of the spliceosome C. The latter functions in the nucleus to process and transport mRNA. Apart from splicing hnRNPs are also involved in other levels of gene regulation (PMID: 27215579). Some hnRNPs have been found in the cytoplasm in stress granules, aggregations of protein, RNAs and stalled initiation complexes that are formed as stress response upon oxidative insult and dissipate upon cessation of this insult.

Western blot in LCLs from affected individuals demonstrated the presence of the truncated protein as well as the full-length and short isoform (as expected by the variant localization).
As the C-terminal part has features of a "prion-like domain" (PrLD), critical for the formation of stress granules in the case of hnRNP-related disorders, comparison of fibroblasts from affected and healthy individuals revealed abnormal persistence of these granules in affected individuals following a recovery period, despite similar formation either at basal levels or under conditions of stress.

In line with a role of hnRNPs in splicing and gene regulation, RNA-Sequencing in fibroblasts from 2 affected individuals revealed abnormal splicing of some genes (eg. HOXA5, HOXB3, LHX9) and significant dysregulation of genes important for the development (upregulation of FOXG1, TBX1, several members of the HOX family and downregulation of LHX9, IRX3, etc) possibly contributing to the patient features.

Helbig et al. provide details on animal studies incl.expression in neural tissues (cerebrum and cerebellum), higher levels of expression early in the development (of both R1/R2 isoforms), etc (extensive discussion in the supplement with several articles cited).

HNRNPR is not associated with any phenotype in OMIM/G2P.

As a result this gene can be considered for inclusion as amber (developmental outcome not commented on sufficiently despite moderate/severe DD in most).
Sources: Literature
Intellectual disability - microarray and sequencing v2.1015 DDX6 Konstantinos Varvagiannis gene: DDX6 was added
gene: DDX6 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DDX6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DDX6 were set to 31422817
Phenotypes for gene: DDX6 were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Unsteady gait; Abnormality of the cardiovascular system; Abnormality of the genitourinary system; Abnormality of limbs
Penetrance for gene: DDX6 were set to unknown
Review for gene: DDX6 was set to GREEN
Added comment: Balak et al. (2019 - PMID: 31422817) report on 5 individuals with de novo likely pathogenic DDX6 variants.

Clinical details are provided for 4. Frequent features included hypotonia, DD, ID (4/4), gait instability, cardiac, genitourinary as well anomalies of the extremities.

DDX6 belongs to the DEAD box family of RNA helicases. This helicase is an essential component of processing bodies (P-bodies / PBs), which are mebrane-less organelles involved in storage of mRNAs and proteins related to mRNA decay thus playing an important role in translational repression/post-transcriptional regulation (PMID: 29381060).

All 5 variants had occurred as de novo events, clustered in exon 11 (NM_004397.5) and affected residues 372-373 of the QxxR motif (c.1115A>G or p.His372Arg / c.1118G>A or p.Arg373Gln) or 390-391 of the V motif (c.1168T>C or p.Cys390Arg / c.1171A>C or p.Thr391Pro / c.1172C>T or p.Thr391Ile). The specific motifs (and RecA-2 domain) are involved in RNA binding, helicase activity and protein-partner binding.

Fibroblasts from 2 individuals were studied. Patient cells contained fewer PBs compared to cells from relatives/control-subjects, despite similar amounts of DDX6 protein upon immunobloting. Additional studies suggested that DDX6 variants caused impaired binding of other DDX6 protein partners involved in PB formation / translation repression (eg. LSM14A, 4E-T, etc) thus resulting in defective PB assembly.

Transcriptome analysis in fibroblasts from one affected individual revealed (significant) differential expression of >1000 genes, enriched for genes related to protein translation, ribosome and RNA processing.

As the authors discuss, given the residual PB assembly, haploinsufficiency is favored over a dominant-negative effect which would result in complete suppression of PBs (as sugested by a previous study of a dominant-negative DDX6 variant - PMID cited: 19297524). [In gnomAD, DDX6 has a Z-score for missense variants of 3.78 and a pLI of 1].

DDX6 is not associated with any phenotype in OMIM.
In G2P it is associated with ID (disease confidence : probable / mutations : all missense/in frame).

As a result, this gene can be considered for inclusion in the ID panel as green (sufficient cases, relevant phenotype, functional studies) or amber.
Sources: Literature
Intellectual disability - microarray and sequencing v2.1015 TRAPPC6B Konstantinos Varvagiannis reviewed gene: TRAPPC6B: Rating: GREEN; Mode of pathogenicity: None; Publications: 28626029, 28397838, DOI 10.1055/s-0039-1693664; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.1015 KCNMA1 Konstantinos Varvagiannis reviewed gene: KCNMA1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31427379, 31152168, 27567911; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.1001 AFF3 Rebecca Foulger Mode of pathogenicity for gene: AFF3 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability - microarray and sequencing v2.1000 WDR37 Rebecca Foulger Mode of pathogenicity for gene: WDR37 was changed from None to Other
Intellectual disability - microarray and sequencing v2.996 AFF3 Konstantinos Varvagiannis changed review comment from: Voisin et al. (2019 - https://doi.org/10.1101/693937) report on 10 individuals with de novo missense AFF3 variants affecting a 9-amino-acid sequence (degron) important for the protein's degradation and summarize the phenotype of an additional individual previously described by Steichen-Gersdorf et al. (2008 - PMID: 18616733) with a 500 kb affecting only AFF3 (LAF4) and removing also this sequence.

The phenotype of missense variants consisted of kidney anomalies, mesomelic dysplasia, seizures, hypertrichosis, intellectual disability and pulmonary problems and was overlapping with that of the deletion. [10 of 11 subjects exhibited severe developmental epileptic encephalopathy].

9 probands harbored missense variants affecting the codon 258 while one individual had a variant affecting codon 260 [c.772G>T or p.Ala258Ser (x2), c.772G>A or p.Ala258Thr (x6), c.773C>T or p.Ala258Val (x1) and c.779T>G or p.(Val260Gly) (x1) - NM_001025108.1 / NP_001020279.1]. The deletion removed exons 4-13.

AFF1-4 are ALF transcription factor paralogs, components of the transcriptional super elongation complex regulating expression of genes involved in neurogenesis and development.

Using HEK293T cells expressing FLAG-tagged AFF3 (and AFF4) wt or mutants, accumulation of mutated forms was shown upon immunoblot.

Aff3+/- and/or -/- mice exhibit skeletal defects. These were more pronounced in homozygous mice which demonstrated also some elements in favor of kidney dysfunction and/or metabolic deregulation and possible neurological dysfunction (signs of impaired hearing and diminished grip strength). Homozygous mice had CNS anomalies (enlarged lateral ventricles and decreased corpus callosum size) similar to some affected individuals, although these were not observed in another Aff3-/- model. Knock-in mice modeling the microdeletion and the Ala258Thr variant displayed lower mesomelic limb deformities and early lethality respectively [cited PMIDs : 21677750, 25660031, knock-in model was part of the present study].

Accumulation of the protein in zebrafish (by overexpression of the human wt AFF3 mRNA), led to morphological defects.

Reanalysis of transcriptome data from previously generated HEK293T cell lines knocked down for AFF2, AFF3 and AFF4 by shRNAs (study) suggested that these transcription factors are not redundant.

Finally, CHOPS syndrome (#616368) due to mutations of AFF4 also leading to increased protein stability presents a partially overlapping phenotype (incl. cognitive impairment) to that of AFF3.
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In G2P, AFF3 is associated with Skeletal dysplasia with severe neurological disease (disease confidence : probable / ID and seizures among the assigned phenotypes). There is no associated phenotype in OMIM.
Some diagnostic laboratories include AFF3 in their ID panel (eg. among the many co-authors' affiliations GeneDx and Victorian Clinical Genetics - which was already listed as source for AFF3 in the current panel).
----
As a result this gene can be considered for upgrade to green (relevant phenotype and severity, sufficient cases, evidence for accumulation similar to AFF4, animal models, etc) or amber (pending publication of the article).; to: Voisin et al. (2019 - https://doi.org/10.1101/693937) report on 10 individuals with de novo missense AFF3 variants affecting a 9-amino-acid sequence (degron) important for the protein's degradation and summarize the phenotype of an additional individual previously described by Steichen-Gersdorf et al. (2008 - PMID: 18616733) with a 500 kb affecting only AFF3 (LAF4) and removing also this sequence.

The phenotype of missense variants consisted of kidney anomalies, mesomelic dysplasia, seizures, hypertrichosis, intellectual disability and pulmonary problems and was overlapping with that of the deletion. [10 of 11 subjects exhibited severe developmental epileptic encephalopathy].

9 probands harbored missense variants affecting the codon 258 while one individual had a variant affecting codon 260 [c.772G>T or p.Ala258Ser (x2), c.772G>A or p.Ala258Thr (x6), c.773C>T or p.Ala258Val (x1) and c.779T>G or p.(Val260Gly) (x1) - NM_001025108.1 / NP_001020279.1]. The deletion removed exons 4-13.

AFF1-4 are ALF transcription factor paralogs, components of the transcriptional super elongation complex regulating expression of genes involved in neurogenesis and development.

Using HEK293T cells expressing FLAG-tagged AFF3 (and AFF4) wt or mutants, accumulation of mutated forms was shown upon immunoblot.

Aff3+/- and/or -/- mice exhibit skeletal defects. These were more pronounced in homozygous mice which demonstrated also some elements in favor of kidney dysfunction and/or metabolic deregulation and possible neurological dysfunction (signs of impaired hearing and diminished grip strength). Homozygous mice had CNS anomalies (enlarged lateral ventricles and decreased corpus callosum size) similar to some affected individuals, although these were not observed in another Aff3-/- model. Knock-in mice modeling the microdeletion and the Ala258Thr variant displayed lower mesomelic limb deformities and early lethality respectively [cited PMIDs : 21677750, 25660031, knock-in model was part of the present study].

Accumulation of the protein in zebrafish (by overexpression of the human wt AFF3 mRNA), led to morphological defects.

Reanalysis of transcriptome data from previously generated HEK293T cell lines knocked down for AFF2, AFF3 and AFF4 by shRNAs (study) suggested that these transcription factors are not redundant.

Finally, CHOPS syndrome (#616368) due to mutations of AFF4 also leading to increased protein stability presents a partially overlapping phenotype (incl. cognitive impairment) to that of AFF3.
----
Shimizu et al. (8/2019 - PMID: 31388108) describe an additional individual with de novo AFF3 missense variant. The phenotype overlaps with that summarized by Voisin et al. incl. mesomelic dysplasia with additional skeletal anomalies, bilateral kidney hypoplasia and severe DD at the age of 2.5 years. Seizures and pulmonary problems were not observed. Although a different RefSeq is used the variant is among those also reported by Voisin et al. [NM_002285.2:c.697G>A (p.Ala233Thr) corresponding to NM_001025108.1:c.772G>A (p.Ala258Thr)].
----
In G2P, AFF3 is associated with Skeletal dysplasia with severe neurological disease (disease confidence : probable / ID and seizures among the assigned phenotypes). There is no associated phenotype in OMIM.
Some diagnostic laboratories include AFF3 in their ID panel (eg. among the many co-authors' affiliations GeneDx and Victorian Clinical Genetics - which was already listed as source for AFF3 in the current panel).
----
As a result this gene can be considered for upgrade to green (relevant phenotype and severity, sufficient cases, evidence for accumulation similar to AFF4, animal models, etc) or amber (pending publication of the article).

[Review modified to add additional reference/case report]
Intellectual disability - microarray and sequencing v2.996 GRIA2 Konstantinos Varvagiannis reviewed gene: GRIA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31300657; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v2.996 AFF3 Konstantinos Varvagiannis reviewed gene: AFF3: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: https://doi.org/10.1101/693937, 18616733; Phenotypes: Intellectual disability, Seizures, Abnormality of skeletal morphology, Abnormality of the urinary system, Hypertrichosis, Abnormality of the respiratory system; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.996 WDR37 Konstantinos Varvagiannis reviewed gene: WDR37: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 31327510, 31327508; Phenotypes: Global developmental delay, Intellectual disability, Seizures, Abnormality of the eye, Abnormality of nervous system morphology, Hearing abnormality, Abnormality of the cardiovascular system, Abnormality of the skeletal system, Abnormality of the genitourinary system; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v2.996 WDR37 Konstantinos Varvagiannis gene: WDR37 was added
gene: WDR37 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: WDR37 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: WDR37 were set to 31327510; 31327508
Phenotypes for gene: WDR37 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of the eye; Abnormality of nervous system morphology; Hearing abnormality; Abnormality of the cardiovascular system; Abnormality of the skeletal system; Abnormality of the genitourinary system
Penetrance for gene: WDR37 were set to unknown
Review for gene: WDR37 was set to GREEN
Added comment: Two concurrent publications by Reis et al. and Kanca et al. (2019 - PMIDs: 31327510, 31327508) report on the phenotype of individuals with de novo WDR37 mutations.

The study by Reis et al. provides clinical details on 4 affected individuals, while 5 further are described by Kanca et al.

4 different de novo variants were reported in these individuals who appear to be unrelated in (and between) the 2 studies [NM_014023.3]:
- c.356C>T (p.Ser119Phe) [Reis indiv. 1 - 3y, Kanca proband 3 - 5m2w]
- c.389C>T (p.Thr130Ile) [Reis indiv. 2 - 22m , Kanca proband 5 - 6w]
- c.374C>T (p.Thr125Ile) [Reis indiv. 3 - 8y , Kanca proband 1 - 7y]
- c.386C>G (p.Ser129Cys) [Reis indiv. 4 - unkn age, Kanca probands 2 and 4, 6.5y and 19y]

Common features included DD/ID (severity relevant for the current panel), seizures (9/9), ocular anomalies (corneal opacity/Peters anomaly, coloboma, microphthalmia etc.) and variable brain, hearing, cardiovascular, skeletal and genitourinary anomalies. Some facial and/or other dysmorphic features (incl. excess nuchal skin / webbed neck) were also frequent among affected individuals. Feeding difficulties and growth deficiency were also among the features observed.

The function of WDR37 is not known. Variants demonstrated comparable protein levels and cellular localization compared to wt.

Reis et al. provide evidence using CRISPR-Cas9 mediated genome editing in zebrafish, to introduce the Ser129Cys variant observed in affected individuals as well as novel missense and frameshift variants. Poor growth (similar to the human phenotype) and larval lethality were noted for missense variants. Head size was proportionately small. Ocular (coloboma/corneal) or craniofacial anomalies were not observed. Zebrafish heterozygous for LoF variants survived to adulthood.

Based on these a dominant-negative mechanism was postulated for missense alleles.

RNA-seq analysis in zebrafish showed upregulation of cholesterol biosynthesis pathways (among the most dysregulated ones).

Previous data in mice, suggest a broad expression pattern for Wdr37 with enrichment in ocular and brain tissues, significant associations in homozygous mutant mice for decreased body weight, grip strength, skeletal anomalies and possible increase (p =< 0.05) in ocular (lens/corneal) and other anomalies [BioGPS and International Mouse Phenotyping Consortium cited].

CG12333 loss (the Drosophila WDR37 ortholog) causes increased bang sensitivity in flies (analogous to the human epilepsy phenotype), defects in copulation and grip strength, phenotypes that were rescued by human reference but not variant cDNAs.

As discussed by Kanca et al. based on data from Drosophila and mice, limited phenotypic similarity of CNVs spanning WDR37 and adjacent genes with the reported individuals and the presence of LoF variants in control populations haploinsufficiency appears unlikely. Gain-of-function is also unlikely, as expression of human variants in flies did not exacerbate the observed phenotypes. A dominant-negative effect is again proposed.

WDR37 is not associated with any phenotype in OMIM/G2P.

As a result WDR37 can be considered for inclusion in the ID and epilepsy panels with green (relevant phenotype, sufficient cases, animal models) or amber rating.
Sources: Literature
Intellectual disability - microarray and sequencing v2.995 POU3F3 Catherine Snow reviewed gene: POU3F3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v2.993 SHANK1 Catherine Snow reviewed gene: SHANK1: Rating: RED; Mode of pathogenicity: None; Publications: 30053575, 20868654; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v2.992 PIGB Catherine Snow reviewed gene: PIGB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v2.990 PHF21A Catherine Snow reviewed gene: PHF21A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v2.989 GTF3C3 Catherine Snow reviewed gene: GTF3C3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v2.982 MTO1 Catherine Snow reviewed gene: MTO1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v2.978 UFC1 Catherine Snow Added phenotypes Neurodevelopmental disorder with spasticity and poor growth, 618076 for gene: UFC1
Publications for gene UFC1 were changed from 29868776; 27431290; 30237576 to 30914295
Intellectual disability - microarray and sequencing v2.977 FRMPD4 Catherine Snow reviewed gene: FRMPD4: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v2.975 DLG4 Catherine Snow reviewed gene: DLG4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v2.970 CYP27A1 Catherine Snow reviewed gene: CYP27A1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v2.968 GRIA2 Catherine Snow reviewed gene: GRIA2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v2.965 DEGS1 Rebecca Foulger commented on gene: DEGS1: PMID:30620338: Karsai et al., 2019 identified a homozygous p.Ala280Val variant in DEGS1 in a Turkish patient of consanguineous parents. Both parents and healthy siblings were heterozygous carriers of the variant. Leading symptoms were early-onset developmental delay, movement disorder, progressive spasticity, and epilepsy.
Intellectual disability - microarray and sequencing v2.963 ATN1 Catherine Snow Mode of pathogenicity for gene: ATN1 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability - microarray and sequencing v2.961 ATN1 Catherine Snow reviewed gene: ATN1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v2.953 CTBP1 Chris Buxton reviewed gene: CTBP1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 27094857, 31041561; Phenotypes: intellectual disability, ataxia, hypotonia, tooth enamel defect; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v2.953 DEGS1 Konstantinos Varvagiannis gene: DEGS1 was added
gene: DEGS1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DEGS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DEGS1 were set to 30620337; 30620338; 31186544
Phenotypes for gene: DEGS1 were set to Leukodystrophy hypomyelinating 18, MIM 618404)
Penetrance for gene: DEGS1 were set to Complete
Review for gene: DEGS1 was set to GREEN
Added comment: Several individuals with biallelic pathogenic DEGS1 variants have been reported to date, in the following studies :
[1] Pant et al. 2019 (PMID: 30620337) : 19 patients from 13 unrelated families
[2] Karsai et al. 2019 (PMID: 30620338) : 1 individual
[3] Dolgin et al. 2019 (PMID: 31186544) : 4 individuals belonging to a large consanguineous kindred

As summarized in the first article and OMIM, affected individuals may have very poor psychomotor development, dystonia, spasticity, seizures with hypomyelinating leukodystrophy upon brain imaging and/or progressive atrophy of corpus callosum, thalami and cerebellum. Although a severe form overall was reported for many individuals in the first study, variable severity (eg. mild to severe ID) was reported among individuals belonging to the same kindred in the report by Dolgin et al.

DEGS1 encodes Δ4-dehydroceramide desaturase which catalyzes conversion of dihydroceramide (DhCer) to ceramide (Cer) in the de novo ceramide biosynthetic pathway. Ceramide is the central unit of all sphingolipids, which are components of cellular membranes and play key roles in several processes incl. cell differentiation, neuronal signaling and myelin sheath formation.

Sphingolipid balance is important for the CNS as demonstrated in the case of lysosomal disorders (eg. Gaucher, Niemann Pick, Farber) one enzymatic step away from DEGS1.

Variants of all types (missense, stopgain, frameshift) have been reported with the majority/almost all located in the fatty acid desaturase (FAD) domain.

Extensive studies have been carried out and demonstrated:
- impaired DEGS1 activity in patients' fibroblasts and muscle suggested by increased DhCer/Cer ratio and compatible broader biochemical effects (higher levels of dihydrosphingosine, dihydrosphingomyelins, etc. and lower levels of sphingosine, monohexosylceramides, etc).
- increased ROS production in patient fibroblasts (similar to a Drosophila model of excess DhCer),
- high expression of the gene in child and adult CNS tissues from control individuals (evaluated by RT-qPCR in Ref. 1). A previous study has suggested that DEGS1 expression is upregulated during the 4-9th week of human embryogenesis (PMID cited: 20430792) which may suggest an important role for neural system development.
- decreased expression for some variants either evaluated at the mRNA (RT-qPCR) / protein level (by Western Blot)
- In zebrafish loss of Degs1 resulted in increased DhCer/Cer ratio, locomotor disability and impaired myelination similar to the patients' phenotype. Fingolimod, a sphingosine analog inhibiting Cer synthase (one step prior to DEGS1 in the de novo ceramide biosynthesis pathway, and converting sphingosine to ceramide in the salvage pathway) reduced the DhCer/Cer imbalance, ameliorated the locomotor phenotype and increased the number of myelinating oligodendrocytes in zebrafish, while it reduced the ROS levels in patient fibroblasts.

Previous animal models:
Apart from the zebrafish model (Pant et al.), higher DhCer/Cer ratios have been shown in homozygous Degs1 -/- mice similar to what is also observed in D. melanogaster. As summarized in MGI (and the previous studies as well) "mice homozygous for a knock-out allele exhibit premature death, decreased to absent ceramide levels, decreased body weight, scaly skin, sparse hair, tremors, hematological and blood chemistry abnormalities, decreased bone mineral content and density and decreased liver function." (PMIDs cited: 17339025, 28507162).
----
The respective OMIM entry is Leukodystrophy, hypomyelinating, 18 (#618404). DEGS1 is not associated with any phenotype in G2P.
----
As a result, DEGS1 can be considered for inclusion in the ID and epilepsy panels probably as green (relevant phenotype, sufficient number of individuals, supportive expression and biochemical studies, animal models, etc).
Sources: Literature
Intellectual disability - microarray and sequencing v2.951 POU3F3 Konstantinos Varvagiannis gene: POU3F3 was added
gene: POU3F3 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: POU3F3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: POU3F3 were set to https://doi.org/10.1016/j.ajhg.2019.06.007; 24550763
Phenotypes for gene: POU3F3 were set to Generalized hypotonia; Delayed speech and language development; Global developmental delay; Intellectual disability; Autistic behavior
Penetrance for gene: POU3F3 were set to unknown
Review for gene: POU3F3 was set to GREEN
gene: POU3F3 was marked as current diagnostic
Added comment: Snijders Blok et al. (2019, DOI: https://doi.org/10.1016/j.ajhg.2019.06.007) report on 19 individuals with heterozygous POU3F3 variants.

Features included hypotonia in some, DD/ID (19/19) with impairment in speech and language skills, and autism-like symptoms with formal ASD diagnosis in 7(/19). Epilepsy was reported for 2 individuals. Overlapping facial features were noted among these individuals.

POU3F3 encodes a member of the class III POU family of transcription factors expressed in the central nervous system (Sumiyama et al. 1996, PMID: 8703082 cited in OMIM) and as the authors comment holds a role in regulation of key processes, eg. cortical neuronal migration, upper-layer specification and production and neurogenesis (PMIDs cited: 11859196, 12130536, 22892427, 17141158).

In almost all subjects (17/19) the variant had occurred as a de novo event, while one individual had inherited the variant from a similarly affected parent.

In total 12 nonsense/frameshift variants, 5 missense ones as well as 1 in-frame deletion were identified following (mostly) trio exome sequencing. All variants were absent from gnomAD, with in silico predictions in favour of pathogenicity.

The few missense variants and the in-frame deletion were found either in the POU-specific (NM_006236.2:c.1085G>T / p.Arg362Leu found in 2 subjects) or the POU-homeobox domain (where 2 variants affected the same residue, namely p.Arg407Gly/Leu, the other variant was p.Asn456Ser).

POU3F3 is an intronless gene and as a result truncating variants are not subject to NMD. The gene appears to be intolerant to LoF variants (pLI of 0.89 in gnomAD).

Western blot analysis of YFP-tagged POU3F3 variants (in HEK293 cell lysates) showed that the YFP-fusion proteins were expressed and had the expected molecular weights.

For several truncating variants tested as well as the in-frame deletion, aberrant subcellular localization pattern was demonstrated although this was not the case for 4 missense variants.

In vitro studies were carried out and suggested that POU3F3, as is known to be the case for POU3F2, is able to activate an intronic binding site in FOXP2. Using a luciferase assay, transcriptional activation was severely impaired for truncating variants tested, significantly lower for many missense ones with the exception of those affecting Arg407 in which case luciferase expression was either similar to wt (for Arg407Gly) or even increased in the case of Arg407Leu.

As the authors comment, both loss- and gain- of function mechanisms may underly pathogenicity of variants.

The ability of mutant proteins to form dimers either with wt or themselves was tested. Dimerization capacity was intact for most missense variants but was lost/decreased for truncating variants. The in-frame deletion resulted in impaired dimerization with wt, although homo-dimerization was found to be normal.
---
Dheedene et al. (2014 - PMID: 24550763) had previously reported on a boy with ID. aCGH had demonstrated a de novo 360-kb deletion of 2q12.1 spanning only POU3F3 and MRPS9 the latter encoding a mitochondrial ribosomal protein (which would be most compatible with a - yet undescribed - recessive inheritance pattern / disorder).
---
POU3F3 is not associated with any phenotype in OMIM/G2P.
The gene is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc, among the principal authors of the study).
---
As a result POU3F3 seems to fulfill criteria for inclusion in the current panel probably as green [DD/ID was a universal feature - severity of ID was relevant in 5/10 individuals for whom details were available, functional evidence provided] or amber.
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability - microarray and sequencing v2.948 HK1 Ivone Leong Added comment: Comment on mode of pathogenicity: A gain of function effect is presumed to cause disease.
Intellectual disability - microarray and sequencing v2.948 HK1 Ivone Leong Mode of pathogenicity for gene: HK1 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability - microarray and sequencing v2.938 CTBP1 Konstantinos Varvagiannis changed review comment from: 12 individuals with a recurrent missense variant in CTBP1 have been reported, all summarized in the last article:
- Beck et al. 2016 (PMID: 27094857) : 4 individuals
- Sommerville et al. 2017 (PMID: 28955726) : 1 subject
- Beck et al. 2019 (PMID: 31041561) : 7 further individuals

Features included hypotonia, DD/ID, ataxia and tooth enamel defects. The degree of ID - when present - appeared to be highly variable based at least on the first two reports (3 individuals with severe ID, 1 with borderline-normal intellectual functioning, 1 did not exhibit ID) where this feature was further commented on.

A recurrent missense variant was found in all 12 affected individuals [NM_001328.2:c.1024C>T - p.(Arg342Trp) or NM_001012614.1:c.991C>T - p.(Arg331Trp)]. De novo occurrence this SNV was shown for (almost) all individuals, although in one case maternal sequencing reads were compatible with low-level somatic mosaicism (4/75 reads) not detected by Sanger sequencing. The mother of this individual was phenotypically normal. The variant is absent from gnomAD. Several in silico predictions (SIFT, PolyPhen2, MutationTaster, etc) suggest a deleterious effect.

Given recurrence of this specific variant, and presence of LoF ones in healthy individuals (pLI of 0.98 though in gnomAD) Beck et al. suggested a dominant negative or a gain-of-function effect rather than a loss of function mechanism.

Exclusion of alternative causes: was mainly discussed for the subject reported by Sommerville et al., due to the primary suspicion of a mitochondrial disorder (sequencing and research for mtDNA rearrangements, additional analysis of nuclear genes for mitochondrial disorders).

Expression: CTBP1 encodes C-terminal binding protein 1, with expression among others in brain and cerebellum (https://gtexportal.org/home/gene/CTBP1).

Role and Functional studies:
- The major nuclear isoform of CTBP1 (corresponding to NM_001328.2) and of its paralog CTBP2 function as transcriptional regulators (corepressors). The PLDLS(Pro-Leu-Asp-Leu-Ser)-binding cleft domain where this variant lies, acts as a high-affinity protein-binding interface to recruit DNA-binding repressors and chromatin modifying enzymes (PMID: 17967884).
- In a human glioblastoma cell line interaction of various cofactors with (Flag-tagged) CTBP1 was studied by immunoprecitipation with the Flag antibody and subsequent proteomic (LC-MS) analysis. This demonstrated reduced interaction in the case of R342W (compared to wt) with Zn-finger transcription factors, histone deacetylases, histone methyltransferases, histone H3-K4 demethylase etc. Western blot analyses also revealed reduced interaction of the R342W with several CTBP cofactors.
- RNA-seq analysis in glioblastoma cell line revealed similar overall transcriptional profiles between wt and R342W though multiple RNA species showed significant differences (eg. genes involved in the biological processes of mitotic nuclear division, DNA repair, transcription and regulation of transcription among those that were most upregulated and genes involved in brain development among the most downregulated).
- Patient fibroblasts under conditions of glucose deprivation exhibited strikingly more cell death compared to control fibroblasts. Study of mRNA levels of pro-apoptotic genes by q-RT-PCR revealed that Noxa expression under glucose deprivation vs under normal glucose was 8 to 10-fold enhanced for control fibroblasts, but more than 30-fold enhanced in the case patient fibroblasts. Western blot analyses were also in line with this.
- Mitochondrial dysfunction (probably secondary) with evidence of decreased complex I (and complex IV) activities in skeletal muscle was the case for 2 individuals among multiple patients who had muscle biopsies.

Animal models:
- Beck et al. discuss previously published mouse models where Ctbp1/2 both play overlapping transcriptional roles during development. Homozygous deletion of Ctbp2 is embryonically lethal (>E10.5). Homozygous deletion of Ctbp1 results in viable mice with reduced size and lifespan (Cited: Hildebrand et al. 2002 - PMID: 12101226)
- As commented on by Sommerville et al., Ctbp1 knockout in mouse embryonic fibroblasts resulted in elongated mitochondria, abnormal mitochondrial cristae, diminished ATP and O2 consumption and mitochondrial membrane potential.

----
CTBP1 is associated with Hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome (617915) in OMIM. It is not associated with any phenotype in G2P.
Some diagnostic laboratories (eg. GeneDx participating in the first study and others) include this gene in panels for intellectual disability.
----

As a result, CTBP1 can be added in the current panel probably as green.; to: 12 individuals with a recurrent missense variant in CTBP1 have been reported, all summarized in the last article:
- Beck et al. 2016 (PMID: 27094857) : 4 individuals
- Sommerville et al. 2017 (PMID: 28955726) : 1 subject
- Beck et al. 2019 (PMID: 31041561) : 7 further individuals

Features included hypotonia, DD/ID, ataxia and tooth enamel defects. The degree of ID - when present - appeared to be highly variable based at least on the first two reports (3 individuals with severe ID, 1 with borderline-normal intellectual functioning, 1 did not exhibit ID) where this feature was further commented on.

A recurrent missense variant was found in all 12 affected individuals [NM_001328.2:c.1024C>T - p.(Arg342Trp) or NM_001012614.1:c.991C>T - p.(Arg331Trp)]. De novo occurrence this SNV was shown for (almost) all individuals, although in one case maternal sequencing reads were compatible with low-level somatic mosaicism (4/75 reads) not detected by Sanger sequencing. The mother of this individual was phenotypically normal. The variant is absent from gnomAD. Several in silico predictions (SIFT, PolyPhen2, MutationTaster, etc) suggest a deleterious effect.

Given recurrence of this specific variant, and presence of LoF ones in healthy individuals (pLI of 0.98 though in gnomAD) Beck et al. suggested a dominant negative or a gain-of-function effect rather than a loss of function mechanism.

Exclusion of alternative causes: was mainly discussed for the subject reported by Sommerville et al., due to the primary suspicion of a mitochondrial disorder (sequencing and research for mtDNA rearrangements, additional analysis of nuclear genes for mitochondrial disorders).

Expression: CTBP1 encodes C-terminal binding protein 1, with expression among others in brain and cerebellum (https://gtexportal.org/home/gene/CTBP1).

Role and Functional studies:
- The major nuclear isoform of CTBP1 (corresponding to NM_001328.2) and of its paralog CTBP2 function as transcriptional regulators (corepressors). The PLDLS(Pro-Leu-Asp-Leu-Ser)-binding cleft domain where this variant lies, acts as a high-affinity protein-binding interface to recruit DNA-binding repressors and chromatin modifying enzymes (PMID: 17967884).
- In a human glioblastoma cell line interaction of various cofactors with (Flag-tagged) CTBP1 was studied by immunoprecitipation with the Flag antibody and subsequent proteomic (LC-MS) analysis. This demonstrated reduced interaction in the case of R342W (compared to wt) with Zn-finger transcription factors, histone deacetylases, histone methyltransferases, histone H3-K4 demethylase etc. Western blot analyses also revealed reduced interaction of the R342W with several CTBP cofactors.
- RNA-seq analysis in glioblastoma cell line revealed similar overall transcriptional profiles between wt and R342W though multiple RNA species showed significant differences (eg. genes involved in the biological processes of mitotic nuclear division, DNA repair, transcription and regulation of transcription among those that were most upregulated and genes involved in brain development among the most downregulated).
- Patient fibroblasts under conditions of glucose deprivation exhibited strikingly more cell death compared to control fibroblasts. Study of mRNA levels of pro-apoptotic genes by q-RT-PCR revealed that Noxa expression under glucose deprivation vs under normal glucose was 8 to 10-fold enhanced for control fibroblasts, but more than 30-fold enhanced in the case patient fibroblasts. Western blot analyses were also in line with this.
- Mitochondrial dysfunction (probably secondary) with evidence of decreased complex I (and complex IV) activities in skeletal muscle was the case for 2 individuals among multiple patients who had muscle biopsies.

Animal models:
- Beck et al. discuss previously published mouse models where Ctbp1/2 both play overlapping transcriptional roles during development. Homozygous deletion of Ctbp2 is embryonically lethal (>E10.5). Homozygous deletion of Ctbp1 results in viable mice with reduced size and lifespan (Cited: Hildebrand et al. 2002 - PMID: 12101226)
- As commented on by Sommerville et al., Ctbp1 knockout in mouse embryonic fibroblasts resulted in elongated mitochondria, abnormal mitochondrial cristae, diminished ATP and O2 consumption and mitochondrial membrane potential (Cited: Kim and Youn 2009 - PMID: 19136938).

----
CTBP1 is associated with Hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome (617915) in OMIM. It is not associated with any phenotype in G2P.
Some diagnostic laboratories (eg. GeneDx participating in the first study and others) include this gene in panels for intellectual disability.
----

As a result, CTBP1 can be added in the current panel probably as green.
Intellectual disability - microarray and sequencing v2.938 CTBP1 Konstantinos Varvagiannis reviewed gene: CTBP1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 27094857, 28955726, 31041561; Phenotypes: Hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome (MIM 617915); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.938 CTBP1 Konstantinos Varvagiannis changed review comment from: 12 individuals with a recurrent missense variant in CTBP1 have been reported, all summarized in the last article:
- Beck et al. 2016 (PMID: 27094857) : 4 individuals
- Sommerville et al. 2017 (PMID: 28955726) : 1 subject
- Beck et al. 2019 (PMID: 31041561) : 7 further individuals

Features included hypotonia, DD/ID, ataxia and tooth enamel defects. The degree of ID - when present - appeared to be highly variable based at least on the first two reports (3 individuals with severe ID, 1 with borderline-normal intellectual functioning, 1 did not exhibit ID) where this feature was further commented on.

A recurrent missense variant was found in all 12 affected individuals [NM_001328.2:c.1024C>T - p.(Arg342Trp) or NM_001012614.1:c.991C>T - p.(Arg331Trp)]. De novo occurrence this SNV was shown for (almost) all individuals, although in one case maternal sequencing reads were compatible with low-level somatic mosaicism (4/75 reads) not detected by Sanger sequencing. The mother of this individual was phenotypically normal. The variant is absent from gnomAD. Several in silico predictions (SIFT, PolyPhen2, MutationTaster, etc) suggest a deleterious effect.

Given recurrence of this specific variant, and presence of LoF ones in healthy individuals (pLI of 0.98 though in gnomAD) Beck et al. suggested a dominant negative or a gain-of-function effect rather than a loss of function mechanism.

Exclusion of alternative causes: was mainly discussed for the subject reported by Sommerville et al., due to the primary suspicion of a mitochondrial disorder (sequencing and research for mtDNA rearrangements, additional analysis of nuclear genes for mitochondrial disorders).

Expression: CTBP1 encodes C-terminal binding protein 1, with expression among others in brain and cerebellum (https://gtexportal.org/home/gene/CTBP1 ).

Role and Functional studies:
- The major nuclear isoform of CTBP1 (corresponding to NM_001328.2) and of its paralog CTBP2 function as transcriptional regulators (corepressors). The PLDLS(Pro-Leu-Asp-Leu-Ser)-binding cleft domain where this variant lies, acts as a high-affinity protein-binding interface to recruit DNA-binding repressors and chromatin modifying enzymes (PMID: 17967884).
- In a human glioblastoma cell line interaction of various cofactors with (Flag-tagged) CTBP1 was studied by immunoprecitipation with the Flag antibody and subsequent proteomic (LC-MS) analysis. This demonstrated reduced interaction in the case of R342W (compared to wt) with Zn-finger transcription factors, histone deacetylases, histone methyltransferases, histone H3-K4 demethylase etc. Western blot analyses also revealed reduced interaction of the R342W with several CTBP cofactors.
- RNA-seq analysis in glioblastoma cell line revealed similar overall transcriptional profiles between wt and R342W though multiple RNA species showed significant differences (eg. genes involved in the biological processes of mitotic nuclear division, DNA repair, transcription and regulation of transcription among those that were most upregulated and genes involved in brain development among the most downregulated).
- Patient fibroblasts under conditions of glucose deprivation exhibited strikingly more cell death compared to control fibroblasts. Study of mRNA levels of pro-apoptotic genes by q-RT-PCR revealed that Noxa expression under glucose deprivation vs under normal glucose was 8 to 10-fold enhanced for control fibroblasts, but more than 30-fold enhanced in the case patient fibroblasts. Western blot analyses were also in line with this.
- Mitochondrial dysfunction (probably secondary) with evidence of decreased complex I (and complex IV) activities in skeletal muscle was the case for 2 individuals among multiple patients who had muscle biopsies.

Animal models:
- Beck et al. discuss previously published mouse models where Ctbp1/2 both play overlapping transcriptional roles during development. Homozygous deletion of Ctbp2 is embryonically lethal (>E10.5). Homozygous deletion of Ctbp1 results in viable mice with reduced size and lifespan (Cited: Hildebrand et al. 2002 - PMID: 12101226)
- As commented on by Sommerville et al., Ctbp1 knockout in mouse embryonic fibroblasts resulted in elongated mitochondria, abnormal mitochondrial cristae, diminished ATP and O2 consumption and mitochondrial membrane potential.

----
CTBP1 is associated with Hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome (617915) in OMIM. It is not associated with any phenotype in G2P.
Some diagnostic laboratories (eg. GeneDx participating in the first study and others) include this gene in panels for intellectual disability.
----

As a result, CTBP1 can be added in the current panel probably as green.
Sources: Literature; to: 12 individuals with a recurrent missense variant in CTBP1 have been reported, all summarized in the last article:
- Beck et al. 2016 (PMID: 27094857) : 4 individuals
- Sommerville et al. 2017 (PMID: 28955726) : 1 subject
- Beck et al. 2019 (PMID: 31041561) : 7 further individuals

Features included hypotonia, DD/ID, ataxia and tooth enamel defects. The degree of ID - when present - appeared to be highly variable based at least on the first two reports (3 individuals with severe ID, 1 with borderline-normal intellectual functioning, 1 did not exhibit ID) where this feature was further commented on.

A recurrent missense variant was found in all 12 affected individuals [NM_001328.2:c.1024C>T - p.(Arg342Trp) or NM_001012614.1:c.991C>T - p.(Arg331Trp)]. De novo occurrence this SNV was shown for (almost) all individuals, although in one case maternal sequencing reads were compatible with low-level somatic mosaicism (4/75 reads) not detected by Sanger sequencing. The mother of this individual was phenotypically normal. The variant is absent from gnomAD. Several in silico predictions (SIFT, PolyPhen2, MutationTaster, etc) suggest a deleterious effect.

Given recurrence of this specific variant, and presence of LoF ones in healthy individuals (pLI of 0.98 though in gnomAD) Beck et al. suggested a dominant negative or a gain-of-function effect rather than a loss of function mechanism.

Exclusion of alternative causes: was mainly discussed for the subject reported by Sommerville et al., due to the primary suspicion of a mitochondrial disorder (sequencing and research for mtDNA rearrangements, additional analysis of nuclear genes for mitochondrial disorders).

Expression: CTBP1 encodes C-terminal binding protein 1, with expression among others in brain and cerebellum (https://gtexportal.org/home/gene/CTBP1).

Role and Functional studies:
- The major nuclear isoform of CTBP1 (corresponding to NM_001328.2) and of its paralog CTBP2 function as transcriptional regulators (corepressors). The PLDLS(Pro-Leu-Asp-Leu-Ser)-binding cleft domain where this variant lies, acts as a high-affinity protein-binding interface to recruit DNA-binding repressors and chromatin modifying enzymes (PMID: 17967884).
- In a human glioblastoma cell line interaction of various cofactors with (Flag-tagged) CTBP1 was studied by immunoprecitipation with the Flag antibody and subsequent proteomic (LC-MS) analysis. This demonstrated reduced interaction in the case of R342W (compared to wt) with Zn-finger transcription factors, histone deacetylases, histone methyltransferases, histone H3-K4 demethylase etc. Western blot analyses also revealed reduced interaction of the R342W with several CTBP cofactors.
- RNA-seq analysis in glioblastoma cell line revealed similar overall transcriptional profiles between wt and R342W though multiple RNA species showed significant differences (eg. genes involved in the biological processes of mitotic nuclear division, DNA repair, transcription and regulation of transcription among those that were most upregulated and genes involved in brain development among the most downregulated).
- Patient fibroblasts under conditions of glucose deprivation exhibited strikingly more cell death compared to control fibroblasts. Study of mRNA levels of pro-apoptotic genes by q-RT-PCR revealed that Noxa expression under glucose deprivation vs under normal glucose was 8 to 10-fold enhanced for control fibroblasts, but more than 30-fold enhanced in the case patient fibroblasts. Western blot analyses were also in line with this.
- Mitochondrial dysfunction (probably secondary) with evidence of decreased complex I (and complex IV) activities in skeletal muscle was the case for 2 individuals among multiple patients who had muscle biopsies.

Animal models:
- Beck et al. discuss previously published mouse models where Ctbp1/2 both play overlapping transcriptional roles during development. Homozygous deletion of Ctbp2 is embryonically lethal (>E10.5). Homozygous deletion of Ctbp1 results in viable mice with reduced size and lifespan (Cited: Hildebrand et al. 2002 - PMID: 12101226)
- As commented on by Sommerville et al., Ctbp1 knockout in mouse embryonic fibroblasts resulted in elongated mitochondria, abnormal mitochondrial cristae, diminished ATP and O2 consumption and mitochondrial membrane potential.

----
CTBP1 is associated with Hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome (617915) in OMIM. It is not associated with any phenotype in G2P.
Some diagnostic laboratories (eg. GeneDx participating in the first study and others) include this gene in panels for intellectual disability.
----

As a result, CTBP1 can be added in the current panel probably as green.
Sources: Literature
Intellectual disability - microarray and sequencing v2.938 CTBP1 Konstantinos Varvagiannis gene: CTBP1 was added
gene: CTBP1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CTBP1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CTBP1 were set to 27094857; 28955726; 31041561
Phenotypes for gene: CTBP1 were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Ataxia; Abnormality of dental enamel
Penetrance for gene: CTBP1 were set to unknown
Mode of pathogenicity for gene: CTBP1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: CTBP1 was set to GREEN
gene: CTBP1 was marked as current diagnostic
Added comment: 12 individuals with a recurrent missense variant in CTBP1 have been reported, all summarized in the last article:
- Beck et al. 2016 (PMID: 27094857) : 4 individuals
- Sommerville et al. 2017 (PMID: 28955726) : 1 subject
- Beck et al. 2019 (PMID: 31041561) : 7 further individuals

Features included hypotonia, DD/ID, ataxia and tooth enamel defects. The degree of ID - when present - appeared to be highly variable based at least on the first two reports (3 individuals with severe ID, 1 with borderline-normal intellectual functioning, 1 did not exhibit ID) where this feature was further commented on.

A recurrent missense variant was found in all 12 affected individuals [NM_001328.2:c.1024C>T - p.(Arg342Trp) or NM_001012614.1:c.991C>T - p.(Arg331Trp)]. De novo occurrence this SNV was shown for (almost) all individuals, although in one case maternal sequencing reads were compatible with low-level somatic mosaicism (4/75 reads) not detected by Sanger sequencing. The mother of this individual was phenotypically normal. The variant is absent from gnomAD. Several in silico predictions (SIFT, PolyPhen2, MutationTaster, etc) suggest a deleterious effect.

Given recurrence of this specific variant, and presence of LoF ones in healthy individuals (pLI of 0.98 though in gnomAD) Beck et al. suggested a dominant negative or a gain-of-function effect rather than a loss of function mechanism.

Exclusion of alternative causes: was mainly discussed for the subject reported by Sommerville et al., due to the primary suspicion of a mitochondrial disorder (sequencing and research for mtDNA rearrangements, additional analysis of nuclear genes for mitochondrial disorders).

Expression: CTBP1 encodes C-terminal binding protein 1, with expression among others in brain and cerebellum (https://gtexportal.org/home/gene/CTBP1 ).

Role and Functional studies:
- The major nuclear isoform of CTBP1 (corresponding to NM_001328.2) and of its paralog CTBP2 function as transcriptional regulators (corepressors). The PLDLS(Pro-Leu-Asp-Leu-Ser)-binding cleft domain where this variant lies, acts as a high-affinity protein-binding interface to recruit DNA-binding repressors and chromatin modifying enzymes (PMID: 17967884).
- In a human glioblastoma cell line interaction of various cofactors with (Flag-tagged) CTBP1 was studied by immunoprecitipation with the Flag antibody and subsequent proteomic (LC-MS) analysis. This demonstrated reduced interaction in the case of R342W (compared to wt) with Zn-finger transcription factors, histone deacetylases, histone methyltransferases, histone H3-K4 demethylase etc. Western blot analyses also revealed reduced interaction of the R342W with several CTBP cofactors.
- RNA-seq analysis in glioblastoma cell line revealed similar overall transcriptional profiles between wt and R342W though multiple RNA species showed significant differences (eg. genes involved in the biological processes of mitotic nuclear division, DNA repair, transcription and regulation of transcription among those that were most upregulated and genes involved in brain development among the most downregulated).
- Patient fibroblasts under conditions of glucose deprivation exhibited strikingly more cell death compared to control fibroblasts. Study of mRNA levels of pro-apoptotic genes by q-RT-PCR revealed that Noxa expression under glucose deprivation vs under normal glucose was 8 to 10-fold enhanced for control fibroblasts, but more than 30-fold enhanced in the case patient fibroblasts. Western blot analyses were also in line with this.
- Mitochondrial dysfunction (probably secondary) with evidence of decreased complex I (and complex IV) activities in skeletal muscle was the case for 2 individuals among multiple patients who had muscle biopsies.

Animal models:
- Beck et al. discuss previously published mouse models where Ctbp1/2 both play overlapping transcriptional roles during development. Homozygous deletion of Ctbp2 is embryonically lethal (>E10.5). Homozygous deletion of Ctbp1 results in viable mice with reduced size and lifespan (Cited: Hildebrand et al. 2002 - PMID: 12101226)
- As commented on by Sommerville et al., Ctbp1 knockout in mouse embryonic fibroblasts resulted in elongated mitochondria, abnormal mitochondrial cristae, diminished ATP and O2 consumption and mitochondrial membrane potential.

----
CTBP1 is associated with Hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome (617915) in OMIM. It is not associated with any phenotype in G2P.
Some diagnostic laboratories (eg. GeneDx participating in the first study and others) include this gene in panels for intellectual disability.
----

As a result, CTBP1 can be added in the current panel probably as green.
Sources: Literature
Intellectual disability - microarray and sequencing v2.938 TRPM3 Konstantinos Varvagiannis changed review comment from: Dyment et al. (2019 - https://doi.org/10.1038/s41431-019-0462-x) report on 7 unrelated individuals with a recurrent de novo TRPM3 missense variant [NM_020952.4:c.2509G>A - NP_066003.3:p.(Val837Met)] as well as an additional individual with a further de novo missense variant [c.2810C>A or p.(Pro937Gln) - same ref. sequences].

Overlapping features included hypotonia (7/8 - in one case mixed tone abnormality), DD/ID (8/8 - all individuals at appropriate age - degree relevant), EEG-confirmed epilepsy (7/8). Autism-like features were observed in 4 (out of 6 for whom this information was reported). Other features were noted in a minority (or were private to certain) of these individuals.

Different clinical types of seizures were reported incl. absence, generalized-toni-clonic, infantile spasms as well as subclinical ones. Onset was in infancy or early childhood.

In all individuals the variant was found following trio exome sequencing.

The first variant fulfilled ACMG criteria to be classified as pathogenic due to it's de novo occurrence, prevalence in affected individuals (>=6 affected individuals and in the same time) absence from population databases, in silico predictions in favour of pathogenicity (PS2, PS4_Moderate, PM2, PP3).

The Pro937Gln variant is however classified as a VUS. The subject harboring this variant had an additional de novo variant in another gene (DDB1) not associated with any phenotype, to date.

Several other genetic causes had previously been ruled out for most individuals by other investigations : aCGH was normal in all, FMR1 testing in 6 subjects, genes (PHF6, MECP2, MCT8) or smaller panels for ID (the latter in 3 subjects), mtDNA or testing of nuclear genes for mitochondrial disorders, etc.

TRPM3 encodes transient receptor potential (TRP) cation channel, subfamily M, member 3. TRP channels are a superfamily of gated cation channels sensitive to various physical or chemical stimuli (Clapham 2003 - PMID: 14654832 cited) eg. temperature or pain.

The gene is highly expressed in the brain in humans and other vertebrates (Grimm et al. 2003 - PMID : 12672799 and GTEx - https://gtexportal.org/home/gene/TRPM3).

Animal models : In rat brain, expression is initially restricted to neurons but later - as myelination progresses - shifts to oligodendrocytes (cited : Hoffmann et al. 2010 - PMID: 20163522). Most subjects had normal brain MRI appart from one individual with nonspecific white matter hyperintensities and another with possible mild cerebral volume loss. Trpm3 -/- mice show attenuated nocifensive behavior after heat or dermal injection of pregnenolone sulfate. Heat or pain insensitivity was reported only for 2 individuals.

Functional studies were not carried out, although some hypotheses are proposed following in silico modeling of the TRPM3 variants using an available structure for TRPM7.

As discussed by Dyment et al., happloinsufficiency appears to be unlikely given the presence of LoF variants in ExAC/gnomAD (pLI of 0), some intragenic copy number variants in DGV. In addition, pathogenicity of deletions spanning only TRPM3 or additional proximal genes was not evident in 2 cases:
- In the first case a exon 1-9 deletion was found in 2 brothers with Becker muscular dystrophy due to DMD intragenic duplication and autism/cognitive impairment though the TRPM3 deletion was found also in unaffected family members. The deletion was also found in unaffected relatives. A multiple hit hypothesis was hypothesized for this family. [Pagnamenta et al. 2011 - PMID: 21484199]
- Kuniba et al. [2009 - PMID: 19343044] reported a 1.27-Mb deletion spanning TRPM3, KLF9, SMC5 and MAMDC2 in a patient with Kabuki syndrome working diagnosis. Segregation studies were however not possible. At the time, the molecular etiology of Kabuki syndrome (KMT2D/KDM6A) was not known.
-----
TRPM3 is not associated with any phenotype in OMIM or G2P.
This gene is included in panels for ID offered by some diagnostic laboratories (eg. GeneDx participating in the above study).
-----
As a result, TRPM3 seems to fulfill criteria for inclusion in the ID/epilepsy panels probably as green (# of individuals, degree of ID relevant, EEG-confirmed epilepsy) or amber (if further functional evidence would be required).

[Please consider eligibility for inclusion in other possibly relevant panels eg. autism, etc].
Sources: Literature; to: Dyment et al. (2019 - https://doi.org/10.1038/s41431-019-0462-x) report on 7 unrelated individuals with a recurrent de novo TRPM3 missense variant [NM_020952.4:c.2509G>A - NP_066003.3:p.(Val837Met)] as well as an additional individual with a further de novo missense variant [c.2810C>A or p.(Pro937Gln) - same ref. sequences].

Overlapping features included hypotonia (7/8 - in one case mixed tone abnormality), DD/ID (8/8 - all individuals at appropriate age - degree relevant), EEG-confirmed epilepsy (7/8). Autism-like features were observed in 4 (out of 6 for whom this information was reported). Other features were noted in a minority (or were private to certain) of these individuals.

Different clinical types of seizures were reported incl. absence, generalized-toni-clonic, infantile spasms as well as subclinical ones. Onset was in infancy or early childhood.

In all individuals the variant was found following trio exome sequencing.

The first variant fulfilled ACMG criteria to be classified as pathogenic due to it's de novo occurrence, prevalence in affected individuals (>=6 affected individuals and in the same time) absence from population databases, in silico predictions in favour of pathogenicity (PS2, PS4_Moderate, PM2, PP3).

The Pro937Gln variant is however also present once in gnomAD (1/251370 alleles or AF:3.98e-6) and is classified as VUS according to the ACMG criteria. The subject harboring this variant had an additional de novo variant in another gene (DDB1) not associated with any phenotype, to date.

Several other genetic causes had previously been ruled out for most individuals by other investigations : aCGH was normal in all, FMR1 testing in 6 subjects, genes (PHF6, MECP2, MCT8) or smaller panels for ID (the latter in 3 subjects), mtDNA or testing of nuclear genes for mitochondrial disorders, etc.

TRPM3 encodes transient receptor potential (TRP) cation channel, subfamily M, member 3. TRP channels are a superfamily of gated cation channels sensitive to various physical or chemical stimuli (Clapham 2003 - PMID: 14654832 cited) eg. temperature or pain.

The gene is highly expressed in the brain in humans and other vertebrates (Grimm et al. 2003 - PMID : 12672799 and GTEx - https://gtexportal.org/home/gene/TRPM3).

Animal models : In rat brain, expression is initially restricted to neurons but later - as myelination progresses - shifts to oligodendrocytes (cited : Hoffmann et al. 2010 - PMID: 20163522). Most subjects had normal brain MRI appart from one individual with nonspecific white matter hyperintensities and another with possible mild cerebral volume loss. Trpm3 -/- mice show attenuated nocifensive behavior after heat or dermal injection of pregnenolone sulfate. Heat or pain insensitivity was reported only for 2 individuals.

Functional studies were not carried out, although some hypotheses are proposed following in silico modeling of the TRPM3 variants using an available structure for TRPM7.

As discussed by Dyment et al., happloinsufficiency appears to be unlikely given the presence of LoF variants in ExAC/gnomAD (pLI of 0), some intragenic copy number variants in DGV. In addition, pathogenicity of deletions spanning only TRPM3 or additional proximal genes was not evident in 2 cases:
- In the first case a exon 1-9 deletion was found in 2 brothers with Becker muscular dystrophy due to DMD intragenic duplication and autism/cognitive impairment though the TRPM3 deletion was found also in unaffected family members. The deletion was also found in unaffected relatives. A multiple hit hypothesis was hypothesized for this family. [Pagnamenta et al. 2011 - PMID: 21484199]
- Kuniba et al. [2009 - PMID: 19343044] reported a 1.27-Mb deletion spanning TRPM3, KLF9, SMC5 and MAMDC2 in a patient with Kabuki syndrome working diagnosis. Segregation studies were however not possible. At the time, the molecular etiology of Kabuki syndrome (KMT2D/KDM6A) was not known.
-----
TRPM3 is not associated with any phenotype in OMIM or G2P.
This gene is included in panels for ID offered by some diagnostic laboratories (eg. GeneDx participating in the above study).
-----
As a result, TRPM3 seems to fulfill criteria for inclusion in the ID/epilepsy panels probably as green (# of individuals, degree of ID relevant, EEG-confirmed epilepsy) or amber (if further functional evidence would be required).

[Please consider eligibility for inclusion in other possibly relevant panels eg. autism, etc].
Sources: Literature
Intellectual disability - microarray and sequencing v2.938 TRPM3 Konstantinos Varvagiannis gene: TRPM3 was added
gene: TRPM3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TRPM3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TRPM3 were set to doi.org/10.1038/s41431-019-0462-x
Phenotypes for gene: TRPM3 were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Autistic behavior
Penetrance for gene: TRPM3 were set to unknown
Mode of pathogenicity for gene: TRPM3 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: TRPM3 was set to GREEN
gene: TRPM3 was marked as current diagnostic
Added comment: Dyment et al. (2019 - https://doi.org/10.1038/s41431-019-0462-x) report on 7 unrelated individuals with a recurrent de novo TRPM3 missense variant [NM_020952.4:c.2509G>A - NP_066003.3:p.(Val837Met)] as well as an additional individual with a further de novo missense variant [c.2810C>A or p.(Pro937Gln) - same ref. sequences].

Overlapping features included hypotonia (7/8 - in one case mixed tone abnormality), DD/ID (8/8 - all individuals at appropriate age - degree relevant), EEG-confirmed epilepsy (7/8). Autism-like features were observed in 4 (out of 6 for whom this information was reported). Other features were noted in a minority (or were private to certain) of these individuals.

Different clinical types of seizures were reported incl. absence, generalized-toni-clonic, infantile spasms as well as subclinical ones. Onset was in infancy or early childhood.

In all individuals the variant was found following trio exome sequencing.

The first variant fulfilled ACMG criteria to be classified as pathogenic due to it's de novo occurrence, prevalence in affected individuals (>=6 affected individuals and in the same time) absence from population databases, in silico predictions in favour of pathogenicity (PS2, PS4_Moderate, PM2, PP3).

The Pro937Gln variant is however classified as a VUS. The subject harboring this variant had an additional de novo variant in another gene (DDB1) not associated with any phenotype, to date.

Several other genetic causes had previously been ruled out for most individuals by other investigations : aCGH was normal in all, FMR1 testing in 6 subjects, genes (PHF6, MECP2, MCT8) or smaller panels for ID (the latter in 3 subjects), mtDNA or testing of nuclear genes for mitochondrial disorders, etc.

TRPM3 encodes transient receptor potential (TRP) cation channel, subfamily M, member 3. TRP channels are a superfamily of gated cation channels sensitive to various physical or chemical stimuli (Clapham 2003 - PMID: 14654832 cited) eg. temperature or pain.

The gene is highly expressed in the brain in humans and other vertebrates (Grimm et al. 2003 - PMID : 12672799 and GTEx - https://gtexportal.org/home/gene/TRPM3).

Animal models : In rat brain, expression is initially restricted to neurons but later - as myelination progresses - shifts to oligodendrocytes (cited : Hoffmann et al. 2010 - PMID: 20163522). Most subjects had normal brain MRI appart from one individual with nonspecific white matter hyperintensities and another with possible mild cerebral volume loss. Trpm3 -/- mice show attenuated nocifensive behavior after heat or dermal injection of pregnenolone sulfate. Heat or pain insensitivity was reported only for 2 individuals.

Functional studies were not carried out, although some hypotheses are proposed following in silico modeling of the TRPM3 variants using an available structure for TRPM7.

As discussed by Dyment et al., happloinsufficiency appears to be unlikely given the presence of LoF variants in ExAC/gnomAD (pLI of 0), some intragenic copy number variants in DGV. In addition, pathogenicity of deletions spanning only TRPM3 or additional proximal genes was not evident in 2 cases:
- In the first case a exon 1-9 deletion was found in 2 brothers with Becker muscular dystrophy due to DMD intragenic duplication and autism/cognitive impairment though the TRPM3 deletion was found also in unaffected family members. The deletion was also found in unaffected relatives. A multiple hit hypothesis was hypothesized for this family. [Pagnamenta et al. 2011 - PMID: 21484199]
- Kuniba et al. [2009 - PMID: 19343044] reported a 1.27-Mb deletion spanning TRPM3, KLF9, SMC5 and MAMDC2 in a patient with Kabuki syndrome working diagnosis. Segregation studies were however not possible. At the time, the molecular etiology of Kabuki syndrome (KMT2D/KDM6A) was not known.
-----
TRPM3 is not associated with any phenotype in OMIM or G2P.
This gene is included in panels for ID offered by some diagnostic laboratories (eg. GeneDx participating in the above study).
-----
As a result, TRPM3 seems to fulfill criteria for inclusion in the ID/epilepsy panels probably as green (# of individuals, degree of ID relevant, EEG-confirmed epilepsy) or amber (if further functional evidence would be required).

[Please consider eligibility for inclusion in other possibly relevant panels eg. autism, etc].
Sources: Literature
Intellectual disability - microarray and sequencing v2.923 TRAPPC12 Louise Daugherty Phenotypes for gene: TRAPPC12 were changed from Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, 617669 to Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, 617669; Developmental delay
Intellectual disability - microarray and sequencing v2.922 TRAPPC12 Louise Daugherty Phenotypes for gene: TRAPPC12 were changed from to Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, 617669
Intellectual disability - microarray and sequencing v2.920 TRAPPC12 Louise Daugherty reviewed gene: TRAPPC12: Rating: GREEN; Mode of pathogenicity: None; Publications: 28777934; Phenotypes: Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, 617669; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v2.878 SETD1B Ivone Leong reviewed gene: SETD1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 31110234; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v2.868 PUF60 Leanne Baxter reviewed gene: PUF60: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Syndromic intellectual disability, prenatal onset growth failure, bifid uvula, retinal atrophy, congenital microcephaly, short stature, long fingers, deviation of toes, short thorax; Mode of inheritance: None
Intellectual disability - microarray and sequencing v2.853 ALKBH8 Konstantinos Varvagiannis gene: ALKBH8 was added
gene: ALKBH8 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ALKBH8 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ALKBH8 were set to Global developmental delay; Intellectual disability; Seizures
Penetrance for gene: ALKBH8 were set to Complete
Review for gene: ALKBH8 was set to AMBER
Added comment: Monies et al. (2019 - PMID: 31079898) report on 7 individuals from 2 different consanguineous Saoudi families, harboring homozygous truncating ALKBH8 pathogenic variants. The same individuals are included in another concurrent publication from the same group (Monies et al. 2019 - PMID: 31130284).

All presented with DD and ID (Fam1 : moderate in the proband, degree not commented on for his 3 sibs / Fam2 : mild in the proband, severe in all his 3 sibs). Epilepsy was reported for 6/7 individuals although the type has not been commented on (onset 9-12 months to 2 years). Variable other features were noted in few.

Affected subjects from the first family were homozygous for a stopgain variant (NM_001301010.1:c.1660C>T or p.Arg554Ter) while individuals from the second family were homozygous for a frameshift one (c.1794delC or p.Trp599Glyfs*19). The variants affected in both cases the last exon of ALKBH8 and RT-PCR confirmed that they escape NMD.

Alternative causes were ruled out, at least for the proband from the second family (chromosomal analysis, SNP-array, metabolic investigations).

Linkage analysis of both families confirmed linkage to the same autozygous interval of chr11q22.3 with a LOD score of 6.

Segregation analyses in both families, confirmed homozygosity for the truncating variants in affected members and heterozygosity in their parents (or several unaffected sibs, none of those studied was homozygous for the ref. allele).

In mouse or human cells, ALKBH8 has previously been shown to be involved in tRNA modifications of the wobble uridines of specific tRNAs (PMIDs cited: 20308323, 20583019, 21653555).

LC-MS/MS analyses of tRNA extracted from LCLs derived from affected individuals, unaffected relatives (UR) and independent controls (IC) revealed that wobble nucleotide modifications were completely absent (or dramatically decreased in the case of mcm5U) in affected individuals but readily detected in UR/IC. As specific modifications were absent, substantial amounts of precursors (eg. cm5U - the precursor of mcm5U) were detected in affected individuals but not in unaffected ones.

Absence of wobble modifications (eg. mchm5U) has equally been observed in Alkbh8 knockout mice. Alkbh8-deficient mice show similar increases in precursors. Alkbh8 KO mice are however phenotypically normal (the authors comment that eventual cognitive defects were not formally evaluated and might have been missed - PMIDs cited: 20123966, 21285950).

As a result, the studies carried out confirmed the loss-of-function effect and were in line with previous functional studies in animal models, although the pathogenesis of ID remains unclear.

The expression profile of ALKBH8 is also unclear (wide profile of expression suggested developmentally, the authors studied LCLs, other studies suggest that embryonic expression is broad but becomes progressively more restricted to specific neuronal cells).

Mutations in other genes involved in tRNA modification (eg. ADAT3, PUS3, PUS7) have been shown underlie disorders affecting the CNS, with ID as a feature.

ALKBH8 is not currently associated with any phenotype in OMIM / G2P.

As a result, this gene can be considered for inclusion in the ID/epilepsy panels as amber pending further evidence.
Sources: Literature
Intellectual disability - microarray and sequencing v2.853 AP2M1 Konstantinos Varvagiannis gene: AP2M1 was added
gene: AP2M1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: AP2M1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: AP2M1 were set to 31104773
Phenotypes for gene: AP2M1 were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Ataxia; Autistic behavior
Penetrance for gene: AP2M1 were set to Complete
Review for gene: AP2M1 was set to GREEN
Added comment: Helbig et al. (2019 - PMID: 31104773) report on 4 individuals with developmental and epileptic encephalopathy due to a recurrent de novo AP2M1 missense variant (NM_004068.3:c.508C>T or p.Arg170Trp). Seizure types included atonic, myoclonic-atonic, absence seizures (with or without eyelid myoclonia), tonic-clonic etc. Hypotonia, developmental delay (prior to the onset of seizures at 1y 3m to 4y) and intellectual disability were observed in all four. Other features included ataxia (3/4) or autism spectrum disorder (2/4).

AP2M1 encodes the μ-subunit of the adaptor protein complex 2 (AP-2). AP2M1 is highly expressed in the CNS. The AP-2 complex is involved in clathrin-mediated endocytosis at the plasma mebrane of neurons and non-neuronal cells. This mechanism is important for recycling synaptic vesicle components at mammalian central synapses. Previous evidence suggests regulation of GABA and/or glutamate receptors at the neuronal surface by AP-2 (several references provided by Helbig et al.).

The authors provide evidence for impaired (reduced) clathrin-mediated endocytosis of transferrin in AP-2μ-depleted human HeLa cells upon plasmid-based re-expression of the Arg170Trp variant compaired to re-expression of WT. A similar defect was demonstrated upon comparison of the same process when WT and Arg170Trp re-expression was studied in primary astrocytes from conditional AP-2μ knockout mice.

Expression levels, protein stability, membrane recruitment and localization of the AP-2 complex in clathrin-coated pits were similar for the Arg170Trp variant and WT. As a result, the effect of the specific variant is suggested to be mediated by alteration of the AP-2 complex function (/impaired recognition of cargo membrane proteins) rather than haploinsufficiency.

AP2M1 is highly intolerant to missense / LoF variants with z-score and pLI in ExAC of 5.82 and 0.99 respectively.

As the authors discuss, heterozygous Ap2m1 mutant mice do not have an apparent phenotype. Homozygous mutant mice die before day 3.5 postcoitus, suggesting a critical role in early embryonic development (PMID 16227583 cited)

AP2M1 is currently not associated with any phenotype in OMIM / G2P.

As a result, this gene can be considered for inclusion in the epilepsy and ID panels probably as green (4 individuals with highly similar phenotype of DEE, relevance of phenotype and/or degree of ID, functional studies, etc) rather than amber (single recurrent variant - although this is also the case for other genes rated green).
Sources: Literature
Intellectual disability - microarray and sequencing v2.847 DYNC1I2 Konstantinos Varvagiannis gene: DYNC1I2 was added
gene: DYNC1I2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DYNC1I2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DYNC1I2 were set to 31079899
Phenotypes for gene: DYNC1I2 were set to Microcephaly; Intellectual disability; Abnormality of nervous system morphology; Abnormality of head or neck
Penetrance for gene: DYNC1I2 were set to Complete
Review for gene: DYNC1I2 was set to AMBER
Added comment: Ansar et al. (2019 - PMID: 31079899) report on five individuals from 3 families, with biallelic likely pathogenic DYNC1I2 variants.

The phenotype consisted of microcephaly, intellectual disability, cerebral malformations and suggestive facial features. 2/5 individuals, from different families presented seizures.

Affected individuals from a consanguineous Pakistani family were homozygous for a splicing variant (c.607+1G>A - RNA was unavailable for further studies). One individual from a futher family was compound heterozygous for a missense variant (c.740A>G or p.Tyr247Cys) and a 374 kb deletion encompassing DYNC1I2 as well as 3 other genes (DCAF17, CYBRD1, SLC25A12). Another individual was found to harbor c.740A>G (p.Tyr247Cys) in trans with c.868C>T (p.Gln290*). [NM_001378.2 used as reference].

DYNC1I2 encodes Dynein Cytoplasmic 1 intermediate chain 2, a component of the cytoplasmic dynein 1 complex. This complex is involved in retrograde cargo transport within the cytoplasmic microtubule network. Emerging evidence suggests a critical role of this complex in neurodevelopment and homeostasis (PMIDs cited by the authors: 25374356, 28395088). Mutations in other genes encoding components of the complex (principally DYNC1H1) give rise to neurological disorders, some of which with ID as a principal feature (eg. Mental retardation, autosomal dominant 13 - MIM 614563).

In zebrafish, DYNC1I2 has 2 orthologs - dync1i2a and dync1i2b. The former is suggested to be the functionally relevant DYNC1I2 ortholog as CRISPR-Cas9 dync1i2a disruption and/or suppression with morpholinos resulted in altered craniofacial patterning and reduction in head size (similar to the microcephaly phenotype reported in affected individuals).

In vivo complementation studies suggested a loss of function effect for the p.Tyr247Cys variant, similar to the p.Gln290* one.

Evidence is provided for a role of increased apoptosis, probably secondary to altered cell cycle progression (prolonged mitosis due to abnormal spindle morphology), to explain the reduced head size/microcephaly phenotype.

There is no associated phenotype in OMIM/G2P.

As a result, DYNC1I2 could be considered for inclusion in the ID panel probably as amber (ID reported for 5 individuals from 3 families, severity of ID not specified for all, eg. fam. 2 for whom the deletion was also spanning other genes which might contribute to the phenotype).
Sources: Literature
Intellectual disability - microarray and sequencing v2.845 ACTL6B Rebecca Foulger commented on gene: ACTL6B: Bell et al., 2019 (PMID:31031012) identified 11 individuals (from 10 families) with biallelic variants in ACTL6B and global developmental delay, epileptic encephalopathy, and spasticity. They also identified 10 unrelated individuals with de novo heterozygous variants with ID, developmental delay, hypotonia, Rett-like stereotypies (e.g. handwringing), and minor facial dysmorphisms: 9/10 of these individuals had the identical de novo c.1027G>A (p.Gly343Arg) mutation. Engineered knock-out of ACTL6B in wild-type human neurons resulted in profound deficits in dendrite development.
Intellectual disability - microarray and sequencing v2.843 ACTL6B Rebecca Foulger Added comment: Comment on mode of pathogenicity: Bell et al., 2019 (PMID:31031012) suggest that biallelic variants are loss-of-function, and heterozygous variants are gain-of-function.
Intellectual disability - microarray and sequencing v2.843 ACTL6B Rebecca Foulger Mode of pathogenicity for gene: ACTL6B was changed from to None
Intellectual disability - microarray and sequencing v2.841 UFC1 Rebecca Foulger Phenotypes for gene: UFC1 were changed from Neurodevelopmental disorder with spasticity and poor growth, 618076 to Neurodevelopmental disorder with spasticity and poor growth, 618076; global developmental delay with progressive microcephaly
Intellectual disability - microarray and sequencing v2.803 PHACTR1 Eleanor Williams Added comment: Comment on mode of pathogenicity: Proposed dominant negative or incomplete penetrance mode of action (PMIDs: 23033978, 28135719)
Intellectual disability - microarray and sequencing v2.803 PHACTR1 Eleanor Williams Mode of pathogenicity for gene: PHACTR1 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability - microarray and sequencing v2.800 ZNF142 Konstantinos Varvagiannis gene: ZNF142 was added
gene: ZNF142 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ZNF142 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF142 were set to 31036918
Phenotypes for gene: ZNF142 were set to Global developmental delay; Intellectual disability; Seizures; Tremor; Dystonia
Penetrance for gene: ZNF142 were set to unknown
Review for gene: ZNF142 was set to GREEN
Added comment: Khan et al. (2019 - PMID: 31036918) describe the phenotype of 7 females from 4 families, harboring biallelic likely pathogenic ZNF142 variants.

Overlapping features included cognitive impairment (ID in 6/7 from 3 families, borderline intellectual functioning was reported one occasion), speech impairement and motor impairment (7/7), and variably penetrant seizures (5/7), tremor (4/7) and dystonia (3/7). Most individuals (5/7) had experienced at least one episode of seizures (tonic-clonic) though seizures were recurrent in 3 sibs.

Other disorders with ID (eg. Angelman syndrome, Rett syndrome, chromosomal disorders) or movement disorders as a feature were previously ruled out for many subjects.

6 individuals were homozygous or compound heterozygous for LoF (stopgain or frameshift) variants. One individual harbored 2 missense SNVs in the compound heterozygous state. Variants reported include (NM_001105537.2): c. 817_818delAA (p.Lys273Glufs*32), c.1292delG (p.Cys431Leufs*11), c.3175C>T (p.Arg1059*), c.4183delC (p.Leu1395*), c.3698G>T (p.Cys1233Phe), c.4498C>T (p.Arg1500Trp) with the LoF variants predicted to result in NMD. Expression or functional studies were not carried out.

ZNF142 encodes a C2H2 domain-containing transcription factor. Mutations in other zinc finger proteins (ZNF/zfp) have been reported in several neurodevelopmental disorders impacting the CNS (eg. ZBTB20 and ZBTB11 heterozygous and biallelic mutations, respectively) and/or presenting with movement disorders among their manifestations (eg. YY1).

As the authors comment, homozygous ablation of the orthologous (Zfp142) locus in mice results in behavioral and neurological phenotypes [MGI ref.ID: J:211773 cited - http://www.informatics.jax.org/marker/reference/J:211773 (though Zfp142 or its locus do not seem to appear in the list)].

ZNF142 is not - at least commonly - included in gene panels for ID offered by diagnostic laboratories. It is not associated with any phenotype in OMIM, nor in G2P.

As a result, this gene can be considered for inclusion in the current panel as probably as green (individuals from 3 families, appropriate degree of ID for the current panel) or amber (if further evidence would be required).
Sources: Literature
Intellectual disability - microarray and sequencing v2.800 ACTL6B Konstantinos Varvagiannis reviewed gene: ACTL6B: Rating: GREEN; Mode of pathogenicity: None; Publications: 31031012, 30656450, 26539891, 27171548, 30237576; Phenotypes: Global developmental delay, Intellectual disability, Seizures, Spasticity, Global developmental delay, Intellectual disability, Stereotypic behavior, Abnormality of the face; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.800 POLA1 Konstantinos Varvagiannis reviewed gene: POLA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31006512; Phenotypes: Global developmental delay, Intellectual disability, Microcephaly, Growth abnormality, Hypogonadism; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.800 SNAP25 Konstantinos Varvagiannis gene: SNAP25 was added
gene: SNAP25 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: SNAP25 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SNAP25 were set to 29491473; 28135719; 29100083; 25381298; 25003006
Phenotypes for gene: SNAP25 were set to ?Myasthenic syndrome, congenital 18, 616330
Penetrance for gene: SNAP25 were set to Complete
Review for gene: SNAP25 was set to GREEN
gene: SNAP25 was marked as current diagnostic
Added comment: Probably 9 individuals with heterozygous SNAP25 pathogenic variants have been reported to date, most summarized in the first reference (NM_130811.2 used as reference for all variants below):
- Fukuda et al. (2018 - PMID: 29491473) 2 sibs (~11 and 2.5 y.o) with seizures and cerebellar ataxia but not ID. harboring c.176G>C (p.Arg59Pro) variant which was inherited from a mosaic unaffected parent.
- DDD study (2017 - PMID: 28135719) [also in Heyne et al. 2018 - PMID: 29942082] 3 inividuals (11 m - 7 y of age) with DD and seizures due to c.118A>G (p.Lys40Glu), c.127G>C (p.Gly43Arg) and c.520C>T (p.Gln174*) de novo variants.
- Hamdan et al. (2017 - PMID: 29100083) a 23 y.o. male with epilepsy and ID and c.496G>T (p.Asp166Tyr) de novo variant
- Shen et al. (2014 - PMID: 25381298) a 11 y.o. female with epilepsy and ID and c.200T>A (p.Ile67Asn) de novo variant
- Rohena et al. (2013 - PMID: 25003006) a 15 y.o. female with epilepsy and ID and c.142G>T (p.Val48Phe) de novo variant
- Decipher patient 292139, a male with c.212T>C (p.Met71Thr) with hypotonia, DD, poor coordination and additional features (epilepsy not reported).

Seizures of variable type [absence seizures, generalized tonic-clonic (most), focal clonic, myoclonic, etc] have been reported for most (8/9) of these individuals. DD was a feature in several subjects and intellectual outcome has been specifically commented on for 5 (2 without and 3 with ID - moderate/severe/not further specified).

SNAP25 encodes a (t-)SNARE protein essential for synaptic vesicle exocytosis. Mutations in genes for other components of the SNARE complex (eg. STXBP1) have been associated with epilepsy and/or ID.

SNAP25a and SNAP25b are the 2 major protein isoforms [corresponding transcripts: ENST00000304886 (NM_003081) and ENST00000254976 (NM_130811) respectively]. These isoforms are produced by utilization of alternative exons 5 (5a or 5b) though the amino-acid sequence encoded by these exons appears to be identical except for 9 residues. Most variants reported to date affect both transcripts (and protein isoforms) although 2 were specific for ENST00000254976 (or SNAP25b isoform - Fukuda et al. and Shen et al.).

Mouse Snap25 has also 2 isoforms. Both are predominantly localized in embryonic and adult mouse brains. Snap25a is produced before Snap25b though the latter becomes the major isoform early postnatally (by the second week) [PMIDs cited: 7878010, 21526988].

Based on the phenotype of some individuals with chromosome 20 deletions in Decipher (note: only 3 deletions spanning SNAP25 however appear currently, the phenotype is not specified and 2 of them are >4.5Mb) or the pLI of 0.96 in gnomAD, haploinsufficiency has been proposed as a likely mechanism. A dominant-negative effect was however suggested for the Ile67Asn studied by Shen et al. Functional studies have not been performed for other variants.

Animal models discussed:
- Snap25 null drosophila show complete loss of synaptic transmission upon electroretinogram recordings (PMID cited: 12242238).
- In mice, elimination of Snap25b expression resulted in developmental defects, seizures and impaired short-term synaptic plasticity (PMID cited: 19043548).
- Mice with a 4.6 Mb deletion encompassing 12 genes (incl. Snap25) display seizure predisposition (PMID cited: 23064108).
- Heterozygosity for Ile67Thr in (blind-drunk mutant) mice results in impaired vesicle trafficking, impaired sensorimotor gating and ataxia (PMID cited:17283335).

In OMIM, heterozygous SNAP25 mutations are associated with ?Myasthenic syndrome, congenital, 18 (with intellectual disability and ataxia). SNAP25 is part of the DD panel, associated with "Epilepsy and intellectual disability" (disease confidence: probable).

This gene is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc). SNAP25 is among the genes discussed by Erger et al. (PMID: 30914295) as associated with ID in OMIM/HPO/G2P/SysID but not included in the current panel.

As a result SNAP25 can be considered for inclusion in the ID panel probably as green (3 individuals with ID, role of SNARES in "synaptopathies", supportive animal models) or amber (if functional studies for individual variants would be required).
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability - microarray and sequencing v2.800 CYP27A1 Philip Dawson reviewed gene: CYP27A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24442603, 29484516; Phenotypes: Cerebrotendinous Xanthomatosis (CTX), 213700, intellectaul disability including childhood & adult onset; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v2.800 CACNA1B Konstantinos Varvagiannis gene: CACNA1B was added
gene: CACNA1B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CACNA1B was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CACNA1B were set to Global developmental delay; Developmental regression; Seizures; Intellectual disability; Abnormality of movement
Penetrance for gene: CACNA1B were set to Complete
Review for gene: CACNA1B was set to GREEN
Added comment: Gorman et al. (2019 - doi.org/10.1016/j.ajhg.2019.03.005) report on 6 individuals from 3 unrelated families, with biallelic LoF CACNA1B variants. The phenotype corresponds to a developmental epilepic encephalopathy with hyperkinetic movement disorder (ID was a universal feature, DD and/or regression occurred prior to the onset of seizures in several individuals) .

CACNA1B encodes calcium channel, voltage-dependent N type, α-1B subunit (Ca v2.2). As commented by the authors, Ca v2.1 and v2.2 are important for SNARE-mediated release of neurotransmitters through modulation of Ca+2 levels. In addition, Ca v2.2 has been postulated to have a role in synaptic plasticity, synaptogenesis, migration of immature neurons, etc. It is thought to have a crucial role in neurotransmission in the early postnatal period (Ca v2.2 channels are subsequently replaced by Ca v2.1 in mature synapses within the thalamus, cerebellum and auditory brainstem). Knockout mice display neurodevelopmental abnormalities including impaired locomotor activity and memory impairment (all ref. cited within the article).

3 sibs, born to 1st cousin parents, harbored p.Leu1222Argfs*29 (NM_000718.4:c.3665del) in the homozygous state. One additional individual was homozygous for p.Arg383*. Compound heterozygosity for a frameshift and a splicing variant (p,Gly1192Cysfs* and c.4857+1G>C) was identified in 2 sibs from a 3rd family.

Expression/functional studies have not been performed for any of the variants reported.

In OMIM, monoallelic CACNA1B pathogenic variants are associated with ?Dystonia 23 (MIM 614860) based on the identification of a heterozygous missense (R1389H) mutation in members of a Dutch with myoclonus-dystonia syndrome (Groen et al. 2015 - PMID: 25296916).

As a result, this gene can be considered for inclusion in the epilepsy and ID panels as green (or amber).
Sources: Literature
Intellectual disability - microarray and sequencing v2.800 DOCK3 Konstantinos Varvagiannis reviewed gene: DOCK3: Rating: AMBER; Mode of pathogenicity: None; Publications: 30976111, 28195318, 29130632; Phenotypes: Neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia, 618292; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.800 BCORL1 Konstantinos Varvagiannis reviewed gene: BCORL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 24123876, 30941876; Phenotypes: Global developmental delay, Intellectual disability, Autism, Behavioral abnormality; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.789 KDM3B Konstantinos Varvagiannis reviewed gene: KDM3B: Rating: AMBER; Mode of pathogenicity: None; Publications: doi.org/10.1016/j.ajhg.2019.02.023; Phenotypes: Global developmental delay, Intellectual disability, Short stature, Behavioral abnormality, Seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v2.789 KDM3B Konstantinos Varvagiannis reviewed gene: KDM3B: Rating: AMBER; Mode of pathogenicity: None; Publications: doi.org/10.1016/j.ajhg.2019.02.023; Phenotypes: Global developmental delay, Intellectual disability, Short stature, Behavioral abnormality, Seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v2.787 CDK8 Konstantinos Varvagiannis reviewed gene: CDK8: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 30905399; Phenotypes: Generalized hypotonia, Feeding difficulties, Global developmental delay, Intellectual disability, Behavioral abnormality, Abnormality of cardiovascular system morphology, Hearing impairment, Abnormality of vision, Anorectal anomaly, Seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v2.787 ARHGEF6 Richard Scott reviewed gene: ARHGEF6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: 300436; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v2.784 KMT2E Konstantinos Varvagiannis reviewed gene: KMT2E: Rating: GREEN; Mode of pathogenicity: None; Publications: https://doi.org/10.1101/56609; Phenotypes: Global developmental delay, Intellectual disability, Autism, Seizures, Abnormality of skull size; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.784 BRSK2 Konstantinos Varvagiannis gene: BRSK2 was added
gene: BRSK2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: BRSK2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: BRSK2 were set to https://doi.org/10.1016/j.ajhg.2019.02.002
Phenotypes for gene: BRSK2 were set to Global developmental delay; Intellectual disability; Autism; Behavioral abnormality
Penetrance for gene: BRSK2 were set to unknown
Review for gene: BRSK2 was set to GREEN
gene: BRSK2 was marked as current diagnostic
Added comment: Hiatt et al. (2019 - https://doi.org/10.1016/j.ajhg.2019.02.002) report on 9 individuals, each with private heterozygous BRSK2 variant.

Features included among others speech or motor delay, ID (8/9), ASD and variable behavioral anomalies.

6 variants predicted LoF (stopgain, frameshift or affecting splice-site) while 3 additional ones were missense (2 in the protein kinase domain and 1 in the kinase-associated 1 domain). In 6 individuals the variant had occurred as a de novo event while for 3 others parental samples were unavailable. Given the unknown inheritance, a single variant did not meet sufficient ACMG criteria to be classified as P/LP.

All variants had in silico predictions supporting a deleterious effect and were absent from bravo database and gnomAD, where the gene appears to be relatively intolerant to protein-altering variation.

As the authors note BRSK2 encodes a serine/threonine protein kinase involved in axonogenesis and polarization of cortical neurons. Although Brsk2- (or Brsk1-) knockout mice appear to be healthy and fertile, double knockouts for these genes resulted in pups with decreased spontaneous movement, poor response to tactile stimulation that died shortly after birth. In mice Brsk2 (and Brsk1) expression is restricted to the nervous system (PMID cited by the authors: 15705853) while in humans this gene is most highly expressed in brain (PMID cited: 23715323 - GTEx project).

BRSK2 has been shown to interact with other neurodevelopmental genes eg. TSC2, PTEN, WDR45.

Within the cohort of individuals studied, there was statistically significant enrichment for de novo BRSK2 variants when compared to the estimated backround mutation rate.

Two further BRSK2 de novo protein-altering variants were previously reported in individuals with neurodevelopmental disorders (Iossifov et al. - PMID: 25363768 and DDD study - PMID: 28135719) although the missense variant in the latter study is also present in gnomAD database.

BRSK2 is not associated with any phenotype in OMIM, nor in G2P.
The gene is included in gene panels for ID offered by some diagnostic laboratories (eg. among those participating in the study).

As a result, this gene can be considered for inclusion in the ID panel as green (or amber).
Sources: Literature
Intellectual disability - microarray and sequencing v2.784 SMARCD1 Konstantinos Varvagiannis reviewed gene: SMARCD1: Rating: GREEN; Mode of pathogenicity: None; Publications: https://doi.org/10.1016/j.ajhg.2019.02.001; Phenotypes: Generalized hypotonia, Feeding difficulties, Global developmental delay, Intellectual disability, Abnormality of the hand, Abnormality of the foot; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v2.784 ATN1 Konstantinos Varvagiannis reviewed gene: ATN1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 30827498; Phenotypes: Generalized hypotonia, Global developmental delay, Intellectual disability, Seizures, Feeding difficulties, Abnormality of the cardiovascular system, Cleft palate, Abnormality of the kidney; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.783 TRRAP Konstantinos Varvagiannis gene: TRRAP was added
gene: TRRAP was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TRRAP was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TRRAP were set to 30827496
Phenotypes for gene: TRRAP were set to Global developmental delay; Intellectual disability; Autism; Microcephaly; Abnormal heart morphology; Abnormality of the urinary system; Seizures
Penetrance for gene: TRRAP were set to unknown
Mode of pathogenicity for gene: TRRAP was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: TRRAP was set to GREEN
gene: TRRAP was marked as current diagnostic
Added comment: Cogné et al. (DDD study among the co-authors - PMID: 30827496) report on 24 individuals with pathogenic TRRAP variants.

17 different variants were reported. All variants were missense SNVs and on most occasions had occurred as de novo or apparently de novo events (paternity and maternity not checked). On one occasion, a parent was not unavailable although the respective grand-parents were not found to harbor the variant. Parental germline mosaicism explained the occurence of a variant in 2 sibs.

The authors suggest a strong genotype-phenotype correlation. Individuals whose variant localized within the residues 1031-1159 (NM_001244580.1) presented with a syndromic form of ID with additional malformations. ID was a universal feature in this group (for those subjects evaluated). For variants outside this cluster of residues the phenotype was rather that of ASD without ID or isolated ID with or without ASD, albeit with some exceptions (eg. F860L also associated with a syndromic presentation). ID was a feature in the majority of individuals belonging to the latter group (67% - all with DD) or overall irrespective of the variant localization (85% for those evaluated - all with DD).

Epilepsy was a feature in 4 individuals (4/24) belonging to either group.

All 17 variants were absent from gnomAD with CADD scores supporting a deleterious effect (SIFT/PolyPhen2 (both) predicted a tolerated/benign effect for some eg. Ala1043Thr). A few variants were recurrent, namely Ala1043Thr (5 individuals), Glu1106Lys (2), Gly1883Arg (2), Pro1932Leu (in 2 sibs).

6 further subjects (individuals 25-30, reported separately in the supplement) harbored 6 additional variants with lesser evidence for pathogenicity.

TRRAP is among the 5 most intolerant genes to missense mutations (z-score of 10.1 in ExAC) while it is also intolerant to LoF variants (pLI of 1). No deletions have been reported in DECIPHER and no LoF were identified in the study. Given type of variants and their clustering rather a gain-of-function effect or dominant-negative effect is suggested. As the authors note a LoF effect of non-clustering variants, associated with a milder phenotype cannot excluded. [Mode of pathogenicity to change if thought to be useful].

TRRAP encodes a protein involved in the recruitment to chromatin of histone acetyltransferases. The latter control the process of acetylation of lysine residues in histones and other DNA-binding proteins thus playing a major role in regulation of gene expression. In line with this, RNA sequencing analysis in skin fibroblasts from affected subjects demonstrated dysregulation of expression for several genes implicated in neuronal function and ion transport.

As summarized by the authors: In mice, Trapp knockout is embryonically lethal. Brain-specific knockout leads to premature differentiation of neural progenitors and abnormal brain development. Brain atrophy and microcephaly are observed (microcephaly was a feature in some affected individuals as well, primarily those with variants affecting residues 1031-1159). [PMIDs cited: 11544477, 24792116].

De novo TRRAP variants have been reported also in individuals with neuropsychiatric disorders (PMIDs: 21822266, 23042115, 28392909, 30424743) while TRRAP has been classified among the prenatally-biased genes relevant to its brain expression (PMID:23042115).

A de novo missense variant (c.11270G>A or p.R3757Q) was also previously reported in a study of 264 individuals with epileptic encephalopathy (Epi4K Consortium - PMID: 23934111 - indiv. ND29352).
-----------
TRRAP is not associated with any phenotype in OMIM, nor in G2P.
The gene is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx participating in the current study).
-----------
As a result, this gene can be considered for inclusion in the ID panel as green (or amber).
Sources: Literature
Intellectual disability - microarray and sequencing v2.782 CARS Konstantinos Varvagiannis gene: CARS was added
gene: CARS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CARS was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CARS were set to Microcephaly; Neurodevelopmental delay; Brittle hair; Fragile nails
Penetrance for gene: CARS were set to Complete
Review for gene: CARS was set to GREEN
Added comment: Kuo et al. (2019 - doi.org/10.1016/j.ajhg.2019.01.006) report on 4 individuals from 3 families with biallelic pathogenic CARS variants.

Common features included microcephaly, DD, brittle hair and nails. All 4 were adults and presented with motor, language and cognitive disabilities.

Reported genotypes (and variants) included [NM_001751.5 and NP_001742.1]:
- c.1138C>T (p.Gln380*) and c.1022G>A (p.Arg341His) (1 individual)
- c.1076C>T (p.Ser359Leu) and c.1199T>A (p.Leu400Gln) (2 sibs)
- c.2061dup (p.Ser688Glnfs ∗2) in homozygous state (1 individual - no reported consanguinity)

Segregation studies confirmed the in trans occurrence of the variants in affected individuals and carrier state in unaffected parents or other family members.

CARS encodes Cysteinyl-tRNA synthetase an aminoacyl-tRNA synthetase (ARS). ARSs are a group of enzymes responsible for ligating amino acids to cognate tRNA molecules. CARS responsible for charging cysteine to tRNA molecules in the cytoplasm (CARS2 is responsible for charging cysteine to tRNA molecules in mitochondria).

Mutations in several ARSs have been linked to disorders with features overlapping to CARS-related phenotype.

Studies included:
- Western blot (pat. fibroblasts) confirmed expression of stable truncated p.Ser688Glnfs ∗2 but absence of the predicted truncating p.Gln380*. Expression in fibroblasts from the individual with compound heteroz. for the missense variants was similar to controls.
- Subcellular localization did not appear to be affected.
- Aminocacylation was significantly reduced (~40-80%) using protein lysates from affected individual fibroblasts (all families) supporting a LoF effect.
- A yeast complementation assay suggested LoF/hypomorphic effect with no or reduced yeast cell growth depending on the variant tested (hypomorphic variants: Arg341His and Ser359Leu). Aminoacylation assays (in yeast) showed reduced activity (by 50% and 84% respectively) for the 2 hypomorphic variants (compatible with the observations in patient fibroblasts).
- Conservation and the presumed effect of individual variants (in catalytic domain, truncation upstream of anticodon-binding domain or in a region affecting binding specificity of CARS and tRNA-cys) also supported pathogenicity.

All individuals demonstrated strikingly similar hair-shaft anomalies upon polarized light microscopy (eg. trichorrhexis/tiger-tail patterns/abnormal shaft diameter) in line with macroscopical observations of fine brittle hair suggesting a common underlying genetic cause (presumably explained by high cysteine content of keratins).
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CARS is not associatated with any phenotype in OMIM, nor in G2P.
The gene is not - at least commonly - included in gene panels for ID offered by diagnostic laboratories.
-------
As a result, this gene can be considered for inclusion in the current panel as green (or amber).
Sources: Literature
Intellectual disability - microarray and sequencing v2.742 HK1 Konstantinos Varvagiannis reviewed gene: HK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30778173, 28135719; Phenotypes: Abnormal muscle tone, Global developmental delay, Intellectual disability, Visual impairment, Neurological speech impairment, Ataxia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.706 ASNS Louise Daugherty Added comment: Comment on list classification: New gene added by external expert and reviewed by curation team, enough evidence to support gene-disease association and relevance to this panel to rate this gene Green. From PMID: 29375865 (2018) A. Abhyankar et al. summarised Ruzzo et al. (PMID:24139043) studied nine children from four families presenting with similar phenotypes and reported two missense mutations‐c.1084T>G (p.F362V; NM_183356) and c.1648C>T (p.R550C; NM_183356) in the asparagine synthetase domain that dramatically reduce ASNS protein abundance. The authors concluded that accumulation of aspartate/glutamate secondary to ASNS depletion in the brain resulted in the neurologic impairment. One of the two mutations reported in that study, c.1084T>G (p.F362V; NM_183356), is four residues upstream of NP_001664.3:p.Gly366Glu seen in our patient. HEK293 cells expressing c.1084T>G (p.F362V; NM_183356) mutant allele showed dramatic reduction in protein abundance. Additionally, Ruzzo et al. reported a hypomorphic ASNS mouse knockout with structural brain abnormalities and deficits in learning/memory. Subsequently, eight more cases of ASNSD have been reported in the literature PMID: 2566342,27422383, 27469131, 27743885.
Intellectual disability - microarray and sequencing v2.654 CUX1 Konstantinos Varvagiannis gene: CUX1 was added
gene: CUX1 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: CUX1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CUX1 were set to 30014507; 20510857; 25059644
Phenotypes for gene: CUX1 were set to Global developmental delay with or without impaired intellectual development, 618330
Penetrance for gene: CUX1 were set to unknown
Review for gene: CUX1 was set to GREEN
gene: CUX1 was marked as current diagnostic
Added comment: Heterozygous pathogenic variants in CUX1 cause Global developmental delay with or without impaired intellectual development (MIM 618330).

Platzer et al. (2018 - PMID: 30014507) report on 9 individuals from 7 families with heterozygous null-allele variants in CUX1.

All individuals displayed DD (speech delay 9/9 - motor delay 7/9 - hypotonia 3/7 for whom this information was available). Mild/moderate ID was a feature in 5/8. Catch up was observed in 3/8 individuals who - despite a history of previous significant DD - displayed a normal age-related intelligence. For 1/9 individual (Decipher 338131) information on eventual ID was unavailable. Overall the phenotype was compatible with non-syndromic DD with possible ID.

CUX1 encodes Cut homebox-1 transcription factor.

5 LoF variants (Gln21*, Gln800Argfs*19, Gln873*, Ala1067Cysfs*3, Leu1262Argfs*10) and 2 intragenic deletions (deletion of exons 9-24 in one subject and 3-24 in another) are reported.

In 6/9 individuals the variant (SNV/CNV) had occurred as a de novo event. Mosaic de novo intragenic deletion was reported for the subject from Decipher. In one family 2 sibs with mild ID had inherited a LoF variant from their affected mother with moderate ID (origin of the variant unknown in her case).

Leu1262Argfs*10 lies in the penultimate exon (NM_001202543.1 used as ref.) and is presumed to escape NMD.

Expression studies (or functional studies) are not performed for any of the variants.

As Gln800Argfs*19, found in one subject with mild ID in the present study, has been reported once in gnomAD, and given the presence of 12 individuals overall with LoF variants in the specific database, plausible explanations are discussed (among others : mild phenotype, incomplete penetrance, somatic mosaicism, exclusion of individuals with severe early-onset disorders in gnomAD, etc).

Given the reported variants, the probability of LoF intolerance (pLI:1.00), and the haploinsufficiency score (% HI) of 7.19, haploinsufficiency is thought to be the underlying mechanism. CUX1 however appears to be intolerant also to missense SNVs (z-score : 5.05).

Mouse models suggest a role for Cux1 in brain development and signaling. As the authors note, Cux1 (similar to its paralog, Cux2) is selectively expressed in layer II to IV cortical neurons. In Cux1-deficient mice, dendrites display a simpler morphology with decrease in dendritic length and number of branches (PMIDs cited: 20510857, 25059644). (MGI db for Cux1 - http://www.informatics.jax.org/marker/MGI:88568 : "Homozygotes for a targeted null mutation exhibit delayed lung development and neonatal mortality. Survivors show growth retardation and hair defects. Homozygotes for a partially deleted protein have curly hair, and females tend to lose their litters").

Finally, heterozygous mutations in CUX2, encoding cut-like homeobox-2 transcription factor, cause Epileptic encephalopathy, early infantile, 67 (MIM 618141 - in all cases reported to date due to a recurrent missense variant. Gene rated green in the current panel).
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CUX1 is not associated with any phenotype in G2P.
This gene is included in panels for ID offered by diagnostic laboratories (incl. Radboudumc).
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As a result, CUX1 can be considered for inclusion in the ID panel as green (or amber).
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability - microarray and sequencing v2.632 PHF21A Alistair Pagnamenta reviewed gene: PHF21A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30487643, 22770980, 27124303, 28127865, 26333423; Phenotypes: intellectual disability, craniofacial anomalies, epilepsy, ASD, overgrowth; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v2.620 RNF135 Konstantinos Varvagiannis reviewed gene: RNF135: Rating: RED; Mode of pathogenicity: None; Publications: 30665703, 17632510, 26368817; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v2.617 FRMPD4 Konstantinos Varvagiannis reviewed gene: FRMPD4: Rating: GREEN; Mode of pathogenicity: None; Publications: 29267967, 25644381; Phenotypes: Mental retardation, X-linked 104, 300983; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.614 INTS1 Konstantinos Varvagiannis reviewed gene: INTS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28542170, 30622326, 17544522; Phenotypes: Hypotonia, Global developmental delay, Cataract, Abnormality of the skeletal system; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.611 USP7 Konstantinos Varvagiannis reviewed gene: USP7: Rating: GREEN; Mode of pathogenicity: None; Publications: 26365382, 19946331; Phenotypes: Global developmental delay, Delayed speech and language development, Intellectual disability, Behavioral abnormality, Seizures, Abnormality of brain morphology, Hypogonadism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.611 CYFIP2 Konstantinos Varvagiannis gene: CYFIP2 was added
gene: CYFIP2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CYFIP2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CYFIP2 were set to 29534297; 29667327; 30664714; 25432536; 27524794; 12818175; 20537992
Phenotypes for gene: CYFIP2 were set to Epileptic encephalopathy, early infantile 65, 618008
Penetrance for gene: CYFIP2 were set to unknown
Review for gene: CYFIP2 was set to GREEN
gene: CYFIP2 was marked as current diagnostic
Added comment: Heterozygous pathogenic variants in CYFIP2 cause Epileptic encephalopathy, early infantile, 65 (MIM 618008)
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[Apologies for any eventual mistakes esp.as for the functional evidence]:

Nakashima et al. (2018 - PMID: 29534297) report on 4 unrelated individuals with early-onset epileptic encephalopathy due to de novo missense CYFIP2 variants.

The phenotype consisted of early-onset intractable seizures (diagnosis of West syndrome in 2, Ohtahara syndrome in further individuals) with hypotonia (3/4), DD/ID (4/4) and microcephaly (3/4).

All variants affected Arg87 residue (NM_001037333.2:c.259C>T or p.Arg87Cys in 2 individuals, the 2 other subjects harbored Arg87Leu and Arg87Pro respectively).

CYFIP2 encodes the cytoplasmic FMRP interacting protein 2. CYFIP2 (similar to CYFIP1) is a component of the WAVE regulatory complex (WRC) which has been shown to play a role in actin remodeling, axon elongation, dendritic morphogenesis and synaptic plasticity (several PMIDs cited).

In the inactive state of the WRC complex, CYFIP2 binds to the VCA domain of WAVE. GTP-bound Rac1 (GTPase) leads to release of the VCA domain from CYFIP2 which allows binding of this domain to the Arp2/3 complex (active WRC state) and in turn stimulates actin polymerization and lamellipodia formation.

Using lymphoblastoid cell lines from affected individuals and healthy controls and CYFIP2 expression was evaluated by Western Blot and was found to be similar between the 2 groups.

Additional studies suggested weaker binding of the WAVE1 VCA domain to mutant CYFIP2 compared to WT CYFIP2 (upon transfection of HEK293T cells). This could possibly favor activation of WRC (/the WAVE signalling pathway).

As a result a gain-of-function effect on the WAVE signalling pathway is suggested as a possible mechanism.

Using B16F1 mouse melanoma cells lamellipodia formation (process in which CYFIP2 has previously been implicated) was not shown to be impaired in the case of mutant CYFIP2. However aberrant accumulation of F-actin (and co-localization with mutant CYFIP2) was observed in the present study.

Only large 5q deletions spanning CYFIP2 (and several other genes) have been described to date.

Cyfip2 heterozygous knockout in mice results in abnormal behavior and memory loss. WAVE activity was enhanced (despite reduced WAVE protein production). Homozygous Cyfip2 loss is lethal (PMIDs cited by the authors: 25432536, 27524794). Impaired axonal growth, guidance and branching is noted in Drosophila mutants (CYFIP1/2 ortholog) (PMID cited: 12818175). The authors comment that Cyfip2 (nev) mutant zebrafish show a similar phenotype to mutant flies (PMID cited: 20537992).
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Peng et al. (2018 - PMID: 29667327) in a study of 56 Chinese families with West Syndrome (epileptic/infantile spasms, hypsarrhytmia and ID) identified 1 individual with the Arg87Cys CYFIP2 variant as a de novo occurrence.
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Zweier et al. (2019 - DDD study among the co-authors - PMID: 30664714) report on 12 unrelated subjects with heterozygous pathogenic de novo CYFIP2 variants.

The common phenotype consisted of tone abnormalities (12/12), DD/ID (12/12) and seizures (12/12 though a single individual had experienced a single episode of febrile seizure). Absolute or relative microcephaly and/or additional features were also noted in several individuals.

7 missense variants (4 occurrences of the Arg87Cys variant) as well as splice variant (shown to lead to exon skipping) are reported, as de novo events in these individuals. The splice variant was expected to escape NMD producing a truncating protein.

Although the variants are distantly located in the primary structure, spatial clustering (in the tertiary structure) is suggested by in silico modelling (all in proximity at the CYFIP2-WAVE1 interface).

CYFIP2 appears to be intolerant to both missense and LoF variants (Z-score of 6.15 and pLI of 1 respectively in ExAC).

The authors comment that haploinsufficiency as a mechanism is rather unlikely given the absence of small CNVs or variants predicted to lead to NMD. Again, a gain-of-function effect of these variants on WAVE activation (partial-loss-of function in terms of WRC stabilization and/or conformation of the VCA region in the inactive state) is proposed.
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CYFIP2 is not associated with any phenotype in G2P.
The gene is included in gene panels for intellectual disability offered by some diagnostic laboratories (eg. participants in these studies).
--------------
As a result this gene could be considered for inclusion in this panel as green.
Sources: Literature
Intellectual disability - microarray and sequencing v2.597 PLEKHG2 Konstantinos Varvagiannis gene: PLEKHG2 was added
gene: PLEKHG2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PLEKHG2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PLEKHG2 were set to 26539891; 26573021; 24001768
Phenotypes for gene: PLEKHG2 were set to Leukodystrophy and acquired microcephaly with or without dystonia, 616763
Penetrance for gene: PLEKHG2 were set to unknown
Review for gene: PLEKHG2 was set to AMBER
gene: PLEKHG2 was marked as current diagnostic
Added comment: Karaca et al. (2015 - PMID: 26539891) in a study of 128 - mostly consanguineous - families with neurogenetic disorders and brain malformations, identified an individual homozygous for a PLEKHG2 missense variant (NM_022835.2:c.1708G>A or p.Gly570Arg). This individual (BAB4830) had a similarly affected sib. Features included hypotonia, intellectual disability, microcephaly, cerebellar atrophy and nystagmus (description provided in supplement - Table S1). This variant has been submitted in ClinVar as likely pathogenic by the corresponding laboratory (SCV000537940.1).
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Edvardson et al. (2016 - PMID: 26573021) reported on 5 individuals from 2 unrelated consanguineous Palestinian families, harboring a missense variant in the homozygous state (NM_022835.2:c.610C>T or p.Arg204Trp - 1/5 was unavailable for testing).
Unaffected relatives here either heterozygous for this variant or homozygous for the reference allele.

Common features included hypotonia (5/5), DD/ID (5/5), postnatal microcephaly (5/5), dystonia (3/5), nystagmus (2/5) or seizures (1/5) [many of these similar to those reported by Karaca et al]. Brain MRI images were consistent with leukodystrophy and prolonged relaxation of dorsal tegmental tracts (similar findings were not commented by Karaca et al).

PLEKHG2 encodes a Rho guanine exchange factor (RhoGEF). RhoGEFs activate RhoGTPases through release of GDP and binding of GTP. Mutations in other RhoGEFs have been associated with neurodevelopmental disorders.

PLEKHG2 activity was shown to be significantly decreased in HEK293A cells transfected with R204W-PLEKHG2 when compared to tranfection with wt. Western blotting suggested that this was not the result of defective expression.

Using lymphoblastoid cell lines from peripheral B lymphocytes from individuals homozygous for R204W and controls, similar levels of expression were shown between the 2 groups.

As the authors note, PLEKHG2 is required for Rac- and Cdc42-stimulated actin polymerization in leukocytes (PMID cited: 24001768).

SDF1a-stimulated actin polymerization was studied in patient cells and was shown to be significantly impaired. In line with this actin polymerization was also impaired upon siRNA-mediated downregulation of PLEKHG2 expression in control cells.
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A subsequent submission of the Gly570Arg variant in ClinVar (2017 - SCV000609979.1 - same variant as the one reported by Karaca et al) reports this as a VUS.
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PLEKHG2 is associated with Leukodystrophy and acquired microcephaly with or without dystonia (616763) in OMIM.
This gene is not associated with any phenotype in G2P.
PLEKHG2 is included in gene panels for ID offered by some diagnostic laboratories.
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As a result, this gene could be considered for inclusion in this panel probably as amber (or green if the current evidence is considered to be sufficient).
Sources: Literature
Intellectual disability - microarray and sequencing v2.597 DHPS Konstantinos Varvagiannis gene: DHPS was added
gene: DHPS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DHPS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DHPS were set to 21389784; 21850436
Phenotypes for gene: DHPS were set to Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; EEG abnormality; Behavioral abnormality; Abnormality of head or neck
Penetrance for gene: DHPS were set to Complete
Review for gene: DHPS was set to GREEN
Added comment: Ganapathi et al. (doi.org/10.1016/j.ajhg.2018.12.017 - PMID : NA) report on 5 individuals from 4 unrelated families with biallelic pathogenic variants in DHPS.

The phenotype consisted of DD/ID (5/5), tone abnormalities (hypotonia/hypertonia/spasticity - 5/5), seizures (5/5 - in one case though unclear staring spells) with EEG abnormalities (5/5). Additionally most individuals displayed behavioral issues, or some common facial features.

Several other disorders had been ruled prior to the diagnosis, in all cases by exome sequencing.

All individuals harbored a specific missense variant (c.518A>G or p.Asn173Ser) in trans with various other variants incl. a splice site mutation (c.1014+1G>A), an in-frame deletion of 2 amino acids (c.912_917delTTACAT or p.Tyr305_Ile306del) or a variant abolishing the translation initiation codon (c.1A>G or p.Met1?) [All variants using NM_001930.3 as a reference].

Deoxyhypusine synthase (encoded by DHPS) is an enzyme participating in the first step of hypusine synthesis, an amino-acid which is specific to eukaryotic initiation factor 5A (eIF5A) and its homolog (eIF5A2).

eIF5A, its hypusinated form and DHPS have all been previously implicated in cellular proliferation/differentiation. eIF5A has also been proposed to be a mRNA translation elongation factor. A role of eIF5A in neuronal growth and survival has been proposed previously (all ref. in present article).

Neither eIF5A, nor DHPS or DOHH (an enzyme required for the second step of hypusination) have been associated to any disorders previously. Mutations in genes encoding other eukaryotic elongator factors (eg. EEF1A2, EEF2) have been associated with neurodevelopmental disorders.

Concerning the DHPS variants reported:

cDNA studies suggested that the c.1014+1G>A variant is translated but results in aberrant splicing and truncation of the protein before its active site.

The in-frame deletion as well as the missense variant were shown to have absent or partial (20%) enzyme activity in vitro respectively compared to wild-type (following expression in E.coli BL21(DE3) cells).

In line with this, reduced hypusination of eIF5A was observed for these 2 variants when compared to wild-type DHPS, upon co-transfection of constructs overexpressing DHPS (wt or mut.) and eIF5A in HEK293T cells.

Absence of homozygous DHPS LoF variants in population databases might suggest that complete deficiency is incompatible with normal embryonic development. Mice heterozygous for Dhps deletion do not demonstrate severe phenotypes, though homozygosity is embryonically lethal (PMIDs: 21389784, 21850436).
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DHPS is not associated with any phenotype in G2P, nor in OMIM.
This gene is not - at least commonly - included in gene panels for ID offered by diagnostic laboratories.
---------
As a result, DHPS can be considered for inclusion in this panel as green (or amber).
Sources: Literature
Intellectual disability - microarray and sequencing v2.595 NUS1 Konstantinos Varvagiannis gene: NUS1 was added
gene: NUS1 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: NUS1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: NUS1 were set to 25066056; 29100083; 24824130; 30348779
Phenotypes for gene: NUS1 were set to #617082 - ?Congenital disorder of glycosylation, type 1aa; #617831 - Mental retardation, autosomal dominant 55, with seizures; Abnormality of extrapyramidal motor function
Penetrance for gene: NUS1 were set to unknown
Review for gene: NUS1 was set to AMBER
gene: NUS1 was marked as current diagnostic
Added comment: Mutations in NUS1 have been implicated in recessive as well as dominant forms of ID (1 and 3 unrelated individuals respectively). The latter individuals presented with a developmental and epileptic encephalopathy with ID. At least 2 of these individuals had tremor and other movement disorders. A recent study proposes that NUS1 variants contribute to Parkinson's disease (1 individual with de novo variant affecting the canonical splice site, 26 additional individuals with missense variants - for which segregation studies where not however performed). ID is not commented on for these individuals.

NUS1 is included in the DD panel of G2P, associated with "Epilepsy and intellectual disability". (Monoallelic LoF variants / Disease confidence : probable). This gene is included in gene panels for ID offered by diagnostic laboratories (incl. Radboudumc). Associated phenotypes in OMIM and others discussed in the literature are summarized below (to my understanding).

As a result, NUS1 can be considered for inclusion in the ID panel probably as amber.
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Recessive - [MIM #617082 - ?Congenital disorder of glycosylation, type 1aa] :

Park et al. (2014 - PMID: 25066056) report on an individual homozygous for a NUS1 missense variant (R290H) and suggest that biallelic variants cause a congenital disorder of glycosylation.

The authors based in studies in yeast, mice and man provide evidence that NUS1 encodes the Nogo-B receptor (NgBR), a subunit of cis-prenyltransferase (cis-PTase), important for its activation. cis-PTase catalyzes one of the reactions for dolichol biosynthesis. Dolichol, in turn, is a carrier of glycans for N-linked glycosylation, O-mannosylation and GPI anchor biosynthesis.

Genetic defects in the dolichol biosynthetic pathway have been linked to other forms of CDG and/or other recessive or dominant neurodevelopmental disorders (eg. SRD5A3- and DHDDS-related disorders).

Similarities are provided at the cellular level between different organisms. Heterozygous knockout mice appear normal. Homozygosity is associated with embryonic lethality before E6.5. Conditional knockout in mouse embryonic fibroblasts led to accumulation of free cholesterol, decreased cis-PTase activity, and mannose incorporation in protein (the first & third rescued by transduction with lentiviral human NgBR).

In patient fibroblasts protein levels appeared similar to controls. Interaction with Nogo-B (and hCIT - the product of DHDDS) was not affected. As in mice, accumulation of free cholesterol was observed in cells, with decreased cis-PTase activity and mannose incorporation. LAMP-1 and ICAM-1 were hypoglycosylated in patient fibroblasts. Altered dolichol profiles in serum and urine were observed in carriers of the NUS1 variant, similarly to what described in individuals with DHDDS LoF variants.
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Dominant - [MIM #617831 - Mental retardation, autosomal dominant 55, with seizures].

Hamdan et al. (2017 - PMID: 29100083) report on 3 unrelated individuals with developmental and epileptic encephalopathy (onset: 10m - 2.5y) and ID. Two individuals harbored de novo LoF variants while a third subject had a deletion of exon 2. Movement disorders were noted in all 3 and included tremor (2 subjects) or ataxia (1 additional subject).

The authors cite a previous study on 6q22.1 deletions the critical region of which encompassed only NUS1 and the promoter of SLC35F1 (Szafranski et al. - PMID: 24824130). Haploinsufficiency is discussed as a possible mechanism (pLI of 0.87). A more severe phenotype due to dramatic reduction of NUS1 activity is proposed for the previously reported patient with CDG.
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Other:
Guo et al. (2018 - PMID: 30348779) suggest that NUS1 pathogenic variants contribute to Parkinson's disease. By performing WES in 39 individuals with early onset Parkinson's disease and their unaffected patients (and sibs) the authors identified 1 individual with de novo insertion affecting a NUS1 canonical splice site. RT-PCR demonstrated increased mRNA levels compared with controls. Skipping of 91 bp of exon 3 was demonstrated.

Study in 2 large sporadic PD-patient (N=1852+3237)/control cohorts (N=1565+2858) suggested association between NUS1 non-synonymous variants and PD (P=1.01e-5, OR:11.3). Other genetic causes of PD were excluded in 26 additional individuals with NUS1 missense variants.

Phenotypes of all 27 individuals are provided in Dataset_S04.

NUS1 has been found to be differentially expressed in PD mouse models.

RNAi-mediated knockdown of Tango14 (the Drosophila NUS1) resulted in impaired climbing activity, reduction in brain dopamine levels and abnormal apoptotic signals in brain.
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability - microarray and sequencing v2.595 STAG2 Konstantinos Varvagiannis gene: STAG2 was added
gene: STAG2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: STAG2 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: STAG2 were set to 29263825; 28296084; 30158690; 30447054; 19449417; 26443594; 25677961; 23637084; 25450604
Phenotypes for gene: STAG2 were set to Global developmental delay; Intellectual disability; Abnormality of head or neck; Microcephaly; Growth delay; Hearing impairment; Abnormal heart morphology
Penetrance for gene: STAG2 were set to unknown
Review for gene: STAG2 was set to GREEN
gene: STAG2 was marked as current diagnostic
Added comment: Several affected individuals (from at least 8 unrelated) families have been reported in the literature. The phenotype consists - among others - of DD/ID. STAG2 is located on long arm of chromosome X (Xq25). Based on these reports, both males and females can be affected.

Soardi et al. (2017 - PMID: 29263825) report an affected male belonging to a large pedigree with 4 other similarly affected males. The disorder in this pedigree followed a typical X-linked inheritance pattern. All affected males were hemizygous for a missense variant (NM_001042749.1:c.980G>A or p.Ser327Asn). Common phenotype consisted of moderate ID, short stature, sensory hearing loss and some similar facial features. Unaffected males did not harbor the variant. Heterozygous females were not affected. Co-segragation of the variant with the affected status under an X-linked model, appeared unlikely to have occurred by chance (probability of 1/131,072 - logarithm of odds score of 5.12).

Mullegama et al. (2017 - PMID: 28296084) report on an 8-year-old girl harboring a de novo nonsense variant in STAG2 (NM_001042749.1:c.205C>T or p.Arg69Ter). This individual presented - among others with - DD, microcephaly, growth delay, digit anomalies, particular facial features, and anomalies of other systems (eg. hearing loss, cardiac defect, etc). The authors summarize the features of 2 subjects from the DDD study as available in DECIPHER, without additional details. [Variants of these individuals NM_001042749.1:c.1913_1922del10 or p.(A638Vfs*10) / NM_001042749.1:c.1811G>A p.(R604Q)].

Yuan et al. (2018 - PMID: 30158690) report on 4 females with de novo LoF STAG2 variants as well as 1 male subject with a de novo missense one. DD (5/5) and ID (4/4) were features in all individuals for whom this information was available. One additional female had an intragenic STAG2 deletion, although this subject was not reported to have DD or ID (table S6 : microcephaly, seizures and facial phenotype). It is not known whether the deletion was inherited or had occurred as a de novo event. All variants from this study have been submitted in ClinVar (phenotype : STAG2-related disorder).

Mullegama et al. (2018 - PMID: 30447054) report on a 4-year-old male with DD, microcephaly, growth delay, digit anomalies due to a de novo missense STAG2 variant (c.3027A>T or p.Lys1009Asn). As discussed by the authors at the time of the study 33 males with Xq25 duplications and ID had been reported (PMIDs cited: 19449417, 26443594, 25677961, 23637084, 25450604).

Discussed in these articles :

STAG2 (or STAG1) is one of the 4 core proteins of the cohesin complex, the other 3 being SMC1A, SMC3 and RAD21. Mutations in genes encoding these proteins or their interactors (eg. NIBPL, HDAC8, ESCO2, etc) have been associated cohesinopathies, a group of multisystem developmental disorders (eg. Cornelia de Lange syndrome, Roberts/SC phocomelia, etc).

It has been commented that the phenotype of STAG2-related disorder presents overlap with other cohesinopathies (eg. DD, microcephaly and growth retardation, craniofacial features, anomalies of the digits, etc).

Decreased proportion of nuclei with premature sister chromatid separation compared to controls was found on one occasion (suggestive of tighter sister chromatid cohesion) [Mullegama-A]. Sister chromatid cohesion was not affected in another report [Soardi et al.].

Western blot demonstrated significant reduction of STAG2 levels for a nonsense variant [Mullegama-A]. Levels were not perturbed for a missense variant [Soardi et al.].

Upon immunofluorescence STAG2 presented normal (nuclear) localization for a missense variant for which this was studied [Soardi et al.].

Perturbation of the cell cycle profile (higher percentage of G2/M cells) was demonstrated for patient fibroblasts compared to controls on one occasion where this was studied. [Soardi et al.].

Microarray expression studies in patient fibroblasts demonstrated altered transcription (upregulation) of genes implicated in cell division, mitosis and DNA replication upon comparison with normal fibroblasts [Soardi et al.].

The effect of a missense variant on STAG2 binding to other cohesin subunits (SCC1, SMC1 and SMC3) and regulators was studied. Binding was found to be reduced in vivo (in HeLa cells) for SCC1 (its direct binding partner) as well as SMC1, SMC3 (possibly indirectly). Reduced STAG2 binding to cohesin regulators was also shown in vivo. However, in vitro studies were not suggestive of impaired binding of STAG2 to SCC1 (a finding difficult to explain) [Soardi et al.].

STAG2 appears to be intolerant to LoF variants (pLI of 1 in ExAC). Z-Score for missense variants is 5.11.

Mullegama et al. (B) comment that Xq25 duplications in males may be associated with milder phenotypes compared to intragenic variants. They further hypothesize that males are able to survive less damaging variants while females are able to survive more deleterious (eg. LoF) ones though with more severe phenotypes (similarity to the MECP2 model is discussed).
----------
STAG2 is not associated with any phenotype in OMIM.
In G2P this gene is associated with STAG2-related developmental delay with microcephaly and congenital anomalies (disease confidence : confirmed / Both DD and ID among the phenotypes assigned to this entry).
----------
STAG2 is included in gene panels for ID offered by some diagnostic laboratories.
----------
As a result, this gene can be considered for inclusion in the ID panel as green (or amber).
Sources: Literature
Intellectual disability - microarray and sequencing v2.595 ZMIZ1 Konstantinos Varvagiannis gene: ZMIZ1 was added
gene: ZMIZ1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ZMIZ1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZMIZ1 were set to 29754769; 18053775; 17967885; 26163108; 27479843
Phenotypes for gene: ZMIZ1 were set to Global developmental delay; Intellectual disability; Feeding difficulties; Growth abnormality; Microcephaly; Abnormality of the skeletal system; Abnormality of the urinary system; Abnormality of the cardiovascular system; Abnormality of head or neck
Penetrance for gene: ZMIZ1 were set to unknown
Review for gene: ZMIZ1 was set to GREEN
gene: ZMIZ1 was marked as current diagnostic
Added comment: Carapito et al. (doi.org/10.1016/j.ajhg.2018.12.007 - PMID to add) report on 19 individuals with variants affecting ZMIZ1 (alternative symbols RAI17/KIAA1224/ZIMP10).

Features included DD/ID (19/19), feeding difficulties, growth failure, microcephaly and variable congenital malformations. Seizures were noted in 3 unrelated individuals (with different variants).

Variants included 6 missense SNVs, 5 frameshift variants, 1 splice site variant, 1 synonymous variant with probable impact on splicing (not studied) and 2 translocations.

In all individuals for whom parental studies were possible (n=16), the variants had occurred as de novo events while for 3 sibs harboring a frameshift variant parental samples were unavailable. These subjects however harbored the same variant as a DDD study participant included in the current report.

One translocation disrupted only ZMIZ1 while a second [t(X;10)] did not disrupt the coding sequence of any gene but only a distal enhancer 276 kb upstream of ZMIZ1. A previous study had found recurrent SNVs of the same region in ASD subjects and suggested possible interaction with the ZMIZ1 promoter (Liu et al. - PMID: 29754769).

The deleterious effect of both translocations was confirmed by quantitative RT-PCR. For 4 missense SNVs as well as a splice variant mRNA levels were similar to controls. The splice site (-2) variant was shown to produce 2 new splicing isoforms from utilization of alternative splice site acceptors.

ZMIZ1 belongs to the PIAS-like family of transcriptional coregulators.

Five missense variants were located in an alanine rich domain (aa 280-305). Seven other variants were predicted to shorten or remove the C-terminal transactivation domain.

This gene enhances - among others - the transcriptional activity of androgen receptor (AR). In vitro studies using HEK293T cell lines supported impaired coactivation of the AR for 3 variants studied. In utero electroporation of pathogenic variants in mouse embryos (E14.5) led to impaired neuronal positioning of the electroporated neurons and disruption of the morphology/polarization.

As the authors note previous studies have shown expression of Zimp10 in the developing mouse brain, craniofacial tissue as well as the interdigital region of limbs (PMIDs cited : 18053775 and 17967885) in line with ID, facial phenotype and syndactyly observed in some patients.

Finally the authors cite a previous report on an individual with ID due to a translocation [t(10;19)] disrupting both ZMIZ1 and PRR12 (Córdova-Fletes al. - PMID: 26163108). Although disruption of ZMIZ1 is discussed as a cause, PRR12 has recently been proposed as (also) an ID gene (Leduc et al. - PMID: 29556724). [For details see PRR12 in the current panel].
------------
One of the variants found in 2 unrelated individuals in the aforementioned study [NM_020338.3:c.899C>T or p.(T300M)] has been reported in a further individual investigated for ID in the context of a bigger cohort (Lelieveld et al. - PMID: 27479843).
[ Details in the denovo-db : http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=ZMIZ1 ]
------------
ZMIZ1 is not associated with any phenotype in OMIM, nor in G2P.
This gene has been included in gene panels for intellectual disability offered by some diagnostic laboratories.
------------
As a result, ZMIZ1 can be considered for inclusion in the ID panel as green.
Sources: Literature
Intellectual disability - microarray and sequencing v2.588 LINS1 Konstantinos Varvagiannis reviewed gene: LINS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21937992, 23773660, 28181389, 30090841; Phenotypes: Mental retardation, autosomal recessive 27 (MIM 614340); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.588 MAPK8IP3 Konstantinos Varvagiannis reviewed gene: MAPK8IP3: Rating: GREEN; Mode of pathogenicity: None; Publications: 25363768, 28213671, 28135719; Phenotypes: Abnormal muscle tone, Global developmental delay, Intellectual disability, Abnormality of nervous system morphology; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v2.588 MAPK8IP3 Konstantinos Varvagiannis gene: MAPK8IP3 was added
gene: MAPK8IP3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MAPK8IP3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: MAPK8IP3 were set to 25363768; 28213671; 28135719
Penetrance for gene: MAPK8IP3 were set to unknown
Review for gene: MAPK8IP3 was set to GREEN
Added comment: Platzer et al. (doi.org/10.1016/j.ajhg.2018.12.008) report on 13 unrelated individuals with de novo pathogenic variants in MAPK8IP3.

The phenotype consisted - among others - of DD with ID (13/13) as well as variable brain anomalies (incl. cerebral or cerebellar atrophy, corpus callosum anomalies, perisylvian polymicrogyria, etc). Microcephaly, seizures, ataxia, ASD were features seen in fewer individuals.

The variants reported included 2 nonsense, 1 frameshift as well as 6 missense mutations (3 missense variants were found - each - in 2 or more individuals).

All three LoF variants were located in the first exon. (mRNA levels were not studied for these variants although NMD is presumed). The brain anomalies were more consistent for missense variants.

MAPK8IP3 appears intolerant to LoF variants (pLI of 1) with constraint also for missense variants (Z-score of 4.06).

In silico structural modeling was possible for 4 missense variants based on available crystal structures and different mechanisms were presumed (disruption of contacts between Leu444 of adjacent subunits, altered interaction between proximal residues at positions 461 and 466, or disruption of protein protein interactions).

The C.elegans MAPK8IP3 ortholog is encoded by the unc-16 gene. Impaired clearance and accumulation of organelles (incl. lysosomes) in axons is observed in unc-16 mutants (recessive phenotype).

For 6 variants, also conserved in C.elegans, mutants were engineered using CRISPR genome editing. The observed mutant phenotypes (increased axonal lysosomal density compared to controls for 2 variants, sluggish locomotion with lower swimming cycle rate for 1 nonsense and 4 missense variants) were rescued upon CRISPR reverse engineering of each mutant allele back to its wild-type sequence.

The authors cite 3 previous studies, in which individuals investigated for neurodevelopmental disorders where found to harbor de novo MAPK8IP3 variants, namely:
- PMID 25363768 (Iossifov et al.) : p.Tyr94Cys [ASD without ID]
- PMID 28213671 (Berger et al.) : p.Glu461Gly [Smith-Magenis-like phenotype)
- PMID 28135719 (DDD study) p.Arg1146Cys [This variant was found in 3 individuals in the study by Platzer et al.]
------------
A few additional individuals with neurodevelopmental disorders appear in the denovo-db after filtering for coding variants:
http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=MAPK8IP3
------------
NM_015133.4:c.111C>G (p.Tyr37Ter) has been submitted in ClinVar by the Undiagnosed Diseases Network (NIH) as likely pathogenic, associated with MAPK8IP3-related disorder (hypotonia, DD, EEG anomalies among the phenotypes). It is not clear whether this subject corresponds to individual #3 reported by the previous study (possibly not the case).
------------
MAPK8IP3 is not associated with any phenotype in OMIM, nor in G2P.
This gene is not commonly included in gene panels for ID.
------------
As a result, MAPK8IP3 can be considered for inclusion in this panel as green (rather than amber).
Sources: Literature
Intellectual disability - microarray and sequencing v2.588 ZNF462 Konstantinos Varvagiannis gene: ZNF462 was added
gene: ZNF462 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: ZNF462 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZNF462 were set to 28513610; 29427787; 14564155; 12825074
Phenotypes for gene: ZNF462 were set to Ptosis; Prominent metopic ridge; Craniosynostosis; Global developmental delay; Intellectual disability; Autistic behavior
Penetrance for gene: ZNF462 were set to unknown
Review for gene: ZNF462 was set to AMBER
gene: ZNF462 was marked as current diagnostic
Added comment: Weiss et al. (PMID: 28513610) report on 8 individuals (from 6 unrelated families) with heterozygous pathogenic variants affecting ZNF462.

Frequent features included ptosis metopic ridging, craniosynostosis, dysgenesis of corpus callosum. DD (with or without ASD) was a feature in 4 (4/8), one of whom was reported to present mild ID.

4 LoF mutations as well as 2 9q31.2 deletions spanning also other genes are reported [NM_021224.4]:
Fam. 1 - c.3787C>T p.(Arg1263*) (familial) - Normal development in all 3 family members
Fam. 2 - c.2979_2980delinsA p.(Val994Trpfs*147) (de novo) - DD
Fam. 3 - c.4263delA p.(Glu1422Serfs*6) (de novo) - DD
Fam. 4 - Chr9:g.(108940763-110561397)del (hg19) (de novo) - Normal development
Fam. 5- Chr9:g(108464368-110362345)del (hg19) (de novo) - DD with mild ID
Fam. 6 - c.5145delC p.(Tyr1716Thrfs*28) (de novo) - DD

There were no expression/functional studies performed although haploinsufficiency can be presumed based on these variants (ZNF462 has a pLI of 1 in ExAC).
-----------
Cosemans et al. (PMID: 29427787) report on an individual investigated - among others - for mild ID and ASD. This individual harbored a de novo (complex) translocation disrupting ZNF462 and KLF12.

As this subject presented similar features to those reported by Weiss et al. (eg. craniofacial anomalies, abn. development, ASD) and given that KLF12 is not associated with any disorder, the phenotype of this individual was thought to be secondary to disruption of ZNF462.

Details on this patient - before delineation of the translocation breakpoints - were provided previously by Fryns and Hendrickx ( PMID:9297446).
-----------
Cited by the previous article, a further case of ZNF462 disruption due to translocation was previously published in the literature (same individual - Talisetti et al. PMID: 14564155 / Ramocki et al. PMID: 12825074). Profound ID was among the features of this individual although the translocation disrupted also a further ID gene (ASXL2).
-----------
In ClinVar 8 variants have been submitted as pathogenic/likely pathogenic although a phenotype is provided only for 3 variants published by Weiss et al.(submitting lab participating in PMID: 28513610 / SCV000494060.1 corresp. to Fam.1 / SCV000494061.1 - Fam.2 / SCV000494062.1 - Fam. 3).
-----------
Several individuals with de novo coding variants in ZNF462 have been reported in the context of larger cohorts (some with ID as a principal feature).
http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=ZNF462
-----------
In Decipher apart from the DDD study participants DDD4K.03663 and DDD4K.03792 (appearing in the denovo-db) with LoF and abnormality of the nervous system, several further individuals have been submitted.

2 of these subjects, harbored a de novo LoF (submitted as pathogenic) and had ID as a feature.
----------
ZNF462 is included in the DD panel of G2P, associated with Craniofacial anomalies, corpus callosum dysgenesis, ptosis, and developmental delay [Disease confidence: probable / Global DD (but not ID) among the phenotypes assigned to this entry].

This gene is not associated with any phenotype in OMIM.
----------
ZNF462 is included in gene panels for ID offered by diagnostic laboratories (incl. Radboudumc).
----------
As a result this gene can be considered for inclusion in the ID panel probably as amber (or green if the current evidence is thought to be sufficient).
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability - microarray and sequencing v2.588 CWF19L1 Konstantinos Varvagiannis reviewed gene: CWF19L1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25361784, 15981765, 26197978, 27016154; Phenotypes: Spinocerebellar ataxia, autosomal recessive 17 (MIM 616127); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.588 RNF13 Konstantinos Varvagiannis gene: RNF13 was added
gene: RNF13 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RNF13 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: RNF13 were set to Congenital microcephaly; Feeding difficulties; Failure to thrive; Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; Cortical visual impairment; Sensorineural hearing impairment
Penetrance for gene: RNF13 were set to unknown
Mode of pathogenicity for gene: RNF13 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: RNF13 was set to GREEN
Added comment: Edvardson et al. (doi.org/10.1016/j.ajhg.2018.11.018) report on 3 unrelated individuals with heterozygous de novo missense RNF13 variants.

Features included (rather borderline) congenital microcephaly, feeding difficulties, tone abnormalities, DD/ID (3/3), seizures (3/3), hearing loss and cortical visual impairment.

One individual harbored the p.Leu311Ser variant while 2 others the p.Leu312Pro.

RNF13 encodes a protein known to interact and activate IRE1a, an endoplasmatic reticulum (ER) stress sensor.

The 2 variants are predicted in silico not to affect the tertiary structure of the protein. Further to this, RNF13 is tolerant to LoF variants (pLI of 0 in ExAC). Therefore a gain-of-function mechanism was hypothesized for the 2 missense variants and demonstrated for the Leu311Ser:
- Protein levels were similar to controls upon Western blotting in patient fibroblasts.
- Enhanced IRE1a activation was demonstrated in patient cells when compared to controls, confirming gain-of-function.
- Increased activation (/ER stress), in turn, resulted in abnormally increased apoptosis similarly to what is observed in other neurological disorders.

Fibroblast/lymphoblast cells were not available from individuals with the Leu312Pro variant although a similar mechanism is presumed.

Although neurodegeneration is suggested by the above pathophysiologic mechanism, this is manifested by failure to achieve milestones (rather than eg. regression after a normal period of postnatal development / loss of milestones).
---------
RNF13 is not associated with any phenotype in OMIM, nor in G2P.
This gene is not commonly included in gene panels for ID offered by diagnostic laboratories.
---------
As a result, RNF13 can be considered for inclusion in this panel possibly as green (or amber).
Sources: Literature
Intellectual disability - microarray and sequencing v2.588 RAB11A Konstantinos Varvagiannis gene: RAB11A was added
gene: RAB11A was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RAB11A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RAB11A were set to 29100083
Phenotypes for gene: RAB11A were set to Global developmental delay; Intellectual disability
Penetrance for gene: RAB11A were set to unknown
Review for gene: RAB11A was set to AMBER
gene: RAB11A was marked as current diagnostic
Added comment: PMID: 29100083 (by Hamdan et al.) is a study on de novo mutations in individuals with developmental and epileptic encephalopathies (DEE).

One subject from this study was found to harbor a de novo missense RAB11A variant [NM_004663.4:c.244C>T or p.(Arg82Cys)]. This individual presented with epilepsy, developmental regression and severe ID.

In their cohort the authors also identified an additional individual with a de novo missense variant [(c.71A>G or p.(Lys24Arg)] who had moderate ID and abnormal EEG albeit without seizures.

De novo variants in RAB11A had previously been identified in 3 DDD study participants with ID.

The authors obtained clinical details on the 2 individuals with the p.(Ser154Leu) variant [NM_004663.4:c.461C>T]. One of them had moderate ID without seizures while the other had moderate global DD at the age of 4 years, also without seizures.

A third DDD study participant harbored another missense variant p.(Lys13Asn) [NM_004663.4:c.39A>C] as a de novo occurence. The authors did not manage to obtain clinical details although this patient was reported to have abnormalities of the nervous system in Decipher.

The features of all 4 individuals for whom clinical details were available are summarized in table 7.

Previous studies suggest that RAB11A has a role in NTRK2 and AMPA receptor recycling at the post-synaptic membrane of neurons and - as a result - in regulation of synaptic plasticity.
-----------
RAB11A is not associated with any phenotype in OMIM.

This gene is included in the DD panel of G2P, associated with epilepsy and intellectual disability (disease confidence: probable).

It is also included in gene panels for ID offered by some diagnostic laboratories.
-----------
As a result, it can be considered for inclusion in this panel as amber or possibly green (3 unrelated individuals with ID, 1 further with DD at a young age).
Sources: Literature
Intellectual disability - microarray and sequencing v2.588 SLC35A1 Konstantinos Varvagiannis reviewed gene: SLC35A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30115659, 23873973, 28856833; Phenotypes: Congenital disorder of glycosylation, type IIf (MIM 603585); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.588 KARS Zornitza Stark reviewed gene: KARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 28887846, 25330800, 29615062, 30252186, 28496994; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.588 FAH Konstantinos Varvagiannis reviewed gene: FAH: Rating: AMBER; Mode of pathogenicity: None; Publications: 28377889; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v2.588 HEPACAM Konstantinos Varvagiannis reviewed gene: HEPACAM: Rating: GREEN; Mode of pathogenicity: None; Publications: 21419380; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.588 ABAT Konstantinos Varvagiannis reviewed gene: ABAT: Rating: GREEN; Mode of pathogenicity: None; Publications: 28411234; Phenotypes: GABA-transaminase deficiency (MIM 613163); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.588 ABAT Konstantinos Varvagiannis reviewed gene: ABAT: Rating: AMBER; Mode of pathogenicity: None; Publications: 28411234; Phenotypes: GABA-transaminase deficiency (MIM 613163); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.588 SMARCC2 Konstantinos Varvagiannis reviewed gene: SMARCC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27392482; Phenotypes: Hypotonia, Feeding difficulties, Global developmental delay, Intellectual disability, Behavioral abnormality, Abnormality of head or neck; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.587 CDK10 Konstantinos Varvagiannis reviewed gene: CDK10: Rating: GREEN; Mode of pathogenicity: None; Publications: 28886341; Phenotypes: Al Kaissi syndrome (MIM 617694); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.587 COLEC10 Konstantinos Varvagiannis reviewed gene: COLEC10: Rating: RED; Mode of pathogenicity: None; Publications: 28301481; Phenotypes: 3MC syndrome 3 (MIM 248340); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v2.587 SETD1B Konstantinos Varvagiannis reviewed gene: SETD1B: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.587 EPB41L1 Konstantinos Varvagiannis reviewed gene: EPB41L1: Rating: AMBER; Mode of pathogenicity: None; Publications: 21376300, 19503082, 11050113, 26539891, 25961944; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.587 GTF3C3 Konstantinos Varvagiannis reviewed gene: GTF3C3: Rating: AMBER; Mode of pathogenicity: None; Publications: 30552426, 28940097, 28097321; Phenotypes: Global developmental delay, Intellectual disability, Seizures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v2.587 KCNQ3 Konstantinos Varvagiannis reviewed gene: KCNQ3: Rating: GREEN; Mode of pathogenicity: None; Publications: 24851285, 24375629, 25524373, 23934111, 28135719; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.587 STAT1 Konstantinos Varvagiannis reviewed gene: STAT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 27114460; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v2.587 TCF20 Konstantinos Varvagiannis reviewed gene: TCF20: Rating: GREEN; Mode of pathogenicity: None; Publications: 27436265, 25228304, 28135719, 27479843, 28333917, 28554332; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.587 MED23 Konstantinos Varvagiannis reviewed gene: MED23: Rating: GREEN; Mode of pathogenicity: None; Publications: 21868677, 25845469, 27311965; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.587 MED23 Konstantinos Varvagiannis reviewed gene: MED23: Rating: GREEN; Mode of pathogenicity: None; Publications: 21868677, 25845469, 27311965; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v2.584 ATP8B1 Konstantinos Varvagiannis reviewed gene: ATP8B1: Rating: RED; Mode of pathogenicity: None; Publications: 20301474, 30266155, 20422494, 26382629; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.584 ACAN Konstantinos Varvagiannis reviewed gene: ACAN: Rating: RED; Mode of pathogenicity: None; Publications: 27353333, 29464738, 27870580, 19110214, 11389160; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v2.584 ZBTB11 Konstantinos Varvagiannis gene: ZBTB11 was added
gene: ZBTB11 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ZBTB11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZBTB11 were set to 29893856; 28382966
Phenotypes for gene: ZBTB11 were set to Intellectual disability
Penetrance for gene: ZBTB11 were set to Complete
Review for gene: ZBTB11 was set to AMBER
Added comment: Fattahi et al. (PMID: 29893856) report on 9 individuals from 2 broader consanguineous pedigrees with biallelic ZBTB11 mutations.

Features in the first family (from Iran) consisted of moderate ID, microcephaly, ataxic gait, and spasticity with MRI findings of cerebellar atrophy and ventriculomegaly.

Individuals from the second family (from Pakistan) presented with moderate ID and variable features.

Homozygosity for missense ZBTB11 variants, private to each family was shown (NM_014415.3:c.2185C>T / p.H729Y and c.2640T>G / p.H880Q for the first and second family respectively).

As the authors note, ZBTB11 is predicted to be a zinc finger transcriptional regulator and one of the hypotheses emitted suggests possible disruption of DNA binding.

Functional studies performed demonstrated that the mutant proteins were excluded from the nucleolus where the (wt) protein localizes.

Previous zebrafish models (PMID: 28382966) suggested CNS degeneration among other phenotypes in Zbtb11 mutants.

Knockdown of the drosophila ZBTB11-ortholog (CkIIα-i1) resulted in recognizable shrinking of the mushroom body with significant reduction in the number of neurons compared to controls.

Other Zinc Finger and BTB Domain-Containing proteins cause disorders with ID as a prominent feature (eg. ZBTB16, ZBTB20, etc.).

ZBTB11 is not associated with any phenotype in OMIM nor in G2P.

As a result, this gene can be considered for inclusion in this panel probably as amber (2 pedigrees only) or green (given the supportive functional studies).
Sources: Literature
Intellectual disability - microarray and sequencing v2.584 ELN Konstantinos Varvagiannis reviewed gene: ELN: Rating: RED; Mode of pathogenicity: None; Publications: 20301427, 14556246, 11701637; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.584 ELN Konstantinos Varvagiannis reviewed gene: ELN: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: 20301427, 14556246, 11701637; Mode of inheritance: None; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.584 TRPS1 Konstantinos Varvagiannis reviewed gene: TRPS1: Rating: AMBER; Mode of pathogenicity: None; Publications: 28426188, 25792522, 28256045, 11112658, 17689056, 22127049, 14560312, 17854380; Phenotypes: Trichorhinophalangeal syndrome, type I (MIM 190350), Trichorhinophalangeal syndrome, type III (MIM 190351); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.584 GUCY2C Konstantinos Varvagiannis reviewed gene: GUCY2C: Rating: RED; Mode of pathogenicity: None; Publications: 22436048; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v2.584 RASA1 Konstantinos Varvagiannis reviewed gene: RASA1: Rating: RED; Mode of pathogenicity: None; Publications: 29891884, 21348050, 21626678; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v2.584 VPS11 Konstantinos Varvagiannis gene: VPS11 was added
gene: VPS11 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: VPS11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS11 were set to 27120463; 26307567; 27473128
Phenotypes for gene: VPS11 were set to Leukodystrophy, hypomyelinating, 12 (MIM 616683)
Penetrance for gene: VPS11 were set to Complete
Review for gene: VPS11 was set to GREEN
gene: VPS11 was marked as current diagnostic
Added comment: Biallelic mutations in VPS11 cause Leukodystrophy, hypomyelinating, 12 (MIM 616683).

PMIDs: 27120463, 26307567, 27473128 all report on this disorder.

The phenotype consists of global DD, ID, (variable) acquired microcephaly with hypomyelination upon brain MRI. Seizures appear to be a feature in several individuals.

Almost all individuals appear to be of Ashkenazi Jewish descent, homozygous for a founder mutation (NM_021729.5:c.2536T>G or p.Cys846Gly). PMIDs: 27120463 and 26307567 report on 13 individuals from 7 Ashkenazi families.

A second variant (p.Leu387_Gly395del) was however found in the homozygous state in 2 sibs born to consanguineous parents.

Pathogenicity is supported by extensive functional studies in all relevant articles.

VPS11 is not associated with any phenotype in G2P.

The gene is included in gene panels for ID offered by diagnostic laboratories (incl. Radboudumc).

As a result, this gene can be considered for inclusion in this panel as green.

[Please consider inclusion in the lysosomal disorders panel as well as in the undiagnosed metabolic disorders panel].
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability - microarray and sequencing v2.584 PITRM1 Konstantinos Varvagiannis gene: PITRM1 was added
gene: PITRM1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PITRM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PITRM1 were set to 26697887; 29764912; 29383861
Phenotypes for gene: PITRM1 were set to Intellectual disability; Ataxia
Penetrance for gene: PITRM1 were set to Complete
Review for gene: PITRM1 was set to GREEN
gene: PITRM1 was marked as current diagnostic
Added comment: Biallelic pathogenic variants in PITRM1 seem to be associated with a phenotype of DD/ID and spinocerebellar ataxia.

6 individuals from 3 unrelated families have been reported.

PMID: 26697887 reports on 2 individuals from a consanguineous Norwegian family homozygous for a missense variant (NM_014889.2:c.548G> or p.Arg183Gln).

PMID: 29764912 reports on 2 consanguineous Palestinian families each with 2 affected boys. All affected individuals for both families were homozygous for a further missense variant (p.Thr931Met).

The boys from one Palestinian family appeared to be more severely affected - compared to the sibs from the other family with the same variant - due to a concurrent X-chromosome rearrangement.

Pathogenicity is supported by extensive functional studies performed in both articles as well as an additional one (PMID: 29383861) on Arg183Gln.

PITRM1 is included in gene panels for ID offered by (few) diagnostic laboratories.

The gene is not associated with any phenotype in OMIM nor in G2P.

As a result, PITRM1 can be considered for inclusion in the ID panel as green (or amber).
Sources: Literature
Intellectual disability - microarray and sequencing v2.584 SLC1A2 Konstantinos Varvagiannis reviewed gene: SLC1A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27476654, 28777935; Phenotypes: Epileptic encephalopathy, early infantile, 41 (MIM 617105); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.584 ABCC6 Konstantinos Varvagiannis reviewed gene: ABCC6: Rating: AMBER; Mode of pathogenicity: None; Publications: 20301292, 25392903, 22209248; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v2.584 ABCB11 Konstantinos Varvagiannis reviewed gene: ABCB11: Rating: RED; Mode of pathogenicity: None; Publications: 30236549, 20232290; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v2.584 PAK1 Konstantinos Varvagiannis gene: PAK1 was added
gene: PAK1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PAK1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PAK1 were set to 30290153
Phenotypes for gene: PAK1 were set to Intellectual developmental disorder with macrocephaly, seizures, and speech delay (MIM 618158)
Penetrance for gene: PAK1 were set to unknown
Mode of pathogenicity for gene: PAK1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: PAK1 was set to AMBER
Added comment: Heterozygous pathogenic PAK1 variants cause Intellectual developmental disorder with macrocephaly, seizures, and speech delay (MIM 618158).

Harms et al. (PMID: 30290153) report on two unrelated individuals with de novo missense mutations in PAK1. Common features included developmental delay with associated intellectual disability, seizures, ataxic gait. Postnatal-onset microcephaly as well as some facial features were also common to both subjects.

Each patient was found to harbour a (private) de novo missense variant [NM_001128620.1:c.392A>G or p.(Tyr131Cys) - c.1286A>G or p.(Tyr429Cys)]. Expression studies demonstrated similar levels for the mutant and wt transcript and Western blot confirmed similar amounts of protein in patient fibroblasts when compared to controls. Functional studies suggest that gain-of-function is the underlying mechanism for both variants.

PAK1 is not associated with any phenotype in G2P.

As a result, this gene can be considered for inclusion in this panel as amber.
Sources: Literature
Intellectual disability - microarray and sequencing v2.584 PTRHD1 Konstantinos Varvagiannis gene: PTRHD1 was added
gene: PTRHD1 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: PTRHD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTRHD1 were set to 30398675; 27134041; 29143421; 27753167
Phenotypes for gene: PTRHD1 were set to Parkinsonism; Intellectual disability
Penetrance for gene: PTRHD1 were set to Complete
Review for gene: PTRHD1 was set to AMBER
gene: PTRHD1 was marked as current diagnostic
Added comment: 7 individuals with biallelic PTRHD1 mutations from 3 pedigrees have been reported. The phenotype in all consisted of early-onset Parkinsonism with intellectual disability (overview in Table 1 - PMID: 30398675).

Jaberi et al. (PMID: 27134041) first reported on 2 sibs born to consanguineous Iranian parents. Both presented with parkinsonism with ID. After homozygosity mapping and exome sequencing, one variant in PTRHD1 (NM_001013663.1:c.155G>A or p.Cys52Tyr) as well as another variant in ADORA1 were the only candidates for the patients phenotype. At the time, the authors favored ADORA1 as the causative gene for their patients' phenotype but could not exclude pathogenicity of PTRHD1.

Khodadadi et al. (PMID: 27753167) published on 2 additional sibs from Iran with a similar phenotype. These individuals - born to consanguineous parents - were homozygous for a further PTRHD1 missense variant (p.His53Tyr) which is proximal to the variant reported by Jaberi et al.

This led the authors of the first publication to acknowledge that PTRHD1 was probably responsible for their patients' phenotype (PMID: 29143421). [A recent study of exome sequencing data of a Parkinson disease 1214-patient cohort failed to find any case explained by biallelic ADORA1 mutations - PMID: 27987235].

The variants reported in these 2 publications are classified as VUS in OMIM (last update : 02/23/2017).

Kuipers et al. (PMID: 30398675) report on 3 additional individuals of African origin with identical phenotype. These individuals, whose parents originated from an isolated african community, were homozygous for a frameshift PTRHD1 deletion (c.169_196del or p.Ala57Argfs*26). This variant is rare in gnomAD (MAF of 0.018% overall or 0.15% in the African subpopulation). Alternative causes of PD / parkinsonism were previously excluded.

The phenotype of all reported individuals is summarized in Table 1 of this article.

PTRHD1 is not assocated with any phenotype in OMIM nor in G2P.

This gene is included in the gene panel for ID, offered by Radboudumc.

Therefore, this gene can be considered for inclusion in this panel as amber or green.

[Please consider inclusion of this gene in the Parkinson Disease and Complex Parkinsonism gene panel].
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability - microarray and sequencing v2.579 TMEM94 Konstantinos Varvagiannis gene: TMEM94 was added
gene: TMEM94 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TMEM94 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TMEM94 were set to Global developmental delay; Intellectual disability; Abnormal heart morphology; Abnormality of head or neck
Penetrance for gene: TMEM94 were set to Complete
Review for gene: TMEM94 was set to AMBER
Added comment: Stephen et al. (https://doi.org/10.1016/j.ajhg.2018.11.001) report on 10 individuals from 6 unrelated families with bi-allelic truncating TMEM94 variants. The common phenotype consisted of global DD/ID, similar facial features as well as the presence of congenital heart defects (in all but one).

Speech as well as motor delay and learning difficulties were universal features. ID is mentioned in the abstract, explicitly specified for one individual and implied for some of the rest.

Overall 6 different LoF variants are reported. Reduced expression was demonstrated while gene expression microarray and RNA sequencing expression studies demonstrated dysregulation of several essential genes. Using a CRISPR/Cas9 mouse model loss of Tmem94 was shown to be embryonically lethal with craniofacial, cardiac anomalies as well as abnormal neuronal migration pattern observed in homozygous mutant mice embryos.

TMEM94 is not associated with any phenotype in G2P nor in OMIM.

As a result this gene can be considered for inclusion in this panel probably as amber (or green).
Sources: Literature
Intellectual disability - microarray and sequencing v2.579 PUS3 Konstantinos Varvagiannis reviewed gene: PUS3: Rating: AMBER; Mode of pathogenicity: None; Publications: 27055666, 30308082; Phenotypes: ?Mental retardation, autosomal recessive 55 (MIM 617051); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.579 PUS3 Konstantinos Varvagiannis gene: PUS3 was added
gene: PUS3 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: PUS3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PUS3 were set to 27055666; 30308082
Phenotypes for gene: PUS3 were set to Global developmental delay; Intellectual disability; Microcephaly
Penetrance for gene: PUS3 were set to Complete
Review for gene: PUS3 was set to AMBER
gene: PUS3 was marked as current diagnostic
Added comment: PUS3 (Pseudouridylate synthase 3) is proposed as a gene related to ID in a recent publication on PUS7.

Biallelic mutations in this gene are associated in OMIM with ?Mental retardation, autosomal recessive 55 (MIM 617051).

PMID: 27055666 reports on 3 sisters from a consanguineous Saudi Arabian family with failure to thrive, DD/ID, microcephaly and some common (coarse) facial features. These individuals were homozygous for a stopgain mutation in the last exon of the gene. Pseudouridylation appeared to be defective (as has also been the case with other genes related to ID, eg. PUS7).

PMID: 30308082 describes 1 individual born to consanguineous Palestinian parents, homozygous for a further LoF variant. Despite the localisation of this variant (again in the last exon of the gene) qPCR analyses were suggestive of degradation of the abnormal transcript possibly by NMD. The phenotype consisted of DD/ID and microcephaly.

In a further publication (http://dx.doi.org/10.7124/bc.0008D6) Gulkovskyi et al. report on 2 siblings with ID, born to non-consanguineous Ukranian parents. Pathogenicity of the variant is disputed. [NM_031307.4:c.212A>G or p.(Tyr71Cys) is found in an apparent homozygous state in the sibs but was only found in their father. De novo occurence in the maternal allele is proposed although the possibility of microdeletion missed by aCGH or other plausible mechanisms are not considered. This variant has maximum pathogenicity scores in silico (not discussed) and has an allele frequency of 0.00006717 in gnomAD. The authors did not perform studies of pseudouridylation but examined for the presence of hypoproteinemia, observed in some disorders affecting this process).

PUS3 is not associated with any phenotype in G2P but is associated with disease in OMIM.

The gene is included in gene panels for ID offered by various diagnostic laboratories (including Radboudumc). PUS1 is included in the current panel as green and PUS7 has been suggested for inclusion.

As a result, these gene can be considered for inclusion as amber (2 families) or green (given the supportive functional studies and/or the proposed role for the gene).
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability - microarray and sequencing v2.579 PBX1 Konstantinos Varvagiannis reviewed gene: PBX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28270404, 28566479, 29036646; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.579 PBX1 Konstantinos Varvagiannis reviewed gene: PBX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28270404, 28566479, 29036646; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.579 PPP1R21 Zornitza Stark reviewed gene: PPP1R21: Rating: GREEN; Mode of pathogenicity: None; Publications: 30520571, 29808498, 2894097; Phenotypes: severe intellectual disability, hypotonia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.579 PUS7 Konstantinos Varvagiannis reviewed gene: PUS7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual disability, Microcephaly, Short stature, Behavioral abnormality; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.576 PPP1R21 Konstantinos Varvagiannis gene: PPP1R21 was added
gene: PPP1R21 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PPP1R21 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPP1R21 were set to 29808498; 28940097
Phenotypes for gene: PPP1R21 were set to Generalized hypotonia; Feeding difficulties; Profound global developmental delay; Abnormality of the face; Abnormality of vision; Abnormal heart morphology; Abnormality of the respiratory system; Hepatosplenomegaly
Penetrance for gene: PPP1R21 were set to Complete
Review for gene: PPP1R21 was set to GREEN
Added comment: Biallelic pathogenic variants in PPP1R21 have been reported so far in 9 individuals from 7 unrelated families. All (7 different) variants reported to date are truncating.

PMID: 29808498 is the first detailed clinical description on the related phenotype. 3 individuals from 3 families are reported. One of these individuals was previously included in a larger patient cohort (in PMID: 28940097).

In a subsequent further publication, Rehman et al. (https://doi.org/10.1002/humu.23694) describe 6 additional patients from 4 unrelated consanguineous families. Again, these individuals were homozygous for truncating mutations. The authors summarize the findings in their patients as well as the previously reported ones.

Common features included feeding difficulties, hypotonia with severe global DD and mildly coarsened facial features (all were observed in 9/9), visual anomalies (8/9), respiratory problems (7/9), cardiac anomalies (4/9) and hepato-/splenomegaly (3/7). Brain MRI anomalies were observed in the majority. DD was severe in all and ID (which is not explicitly mentioned) was evident from the clinical description of several individuals (eg. in PMID: 29808498).

In total 7 loss-of-function variants have been reported. The authors in the first article, underscore the possibility of less severe phenotypes associated to biallelic missense variants (although none has been reported so far).

Functional studies have shown great reduction (but not complete absence) of PPP1R21 mRNA levels in patient fibroblasts compared to controls. A role of PPP1R21 in the endosomal-lysosomal function is demonstrated in line with the presence of myelin figures in patient fibroblasts as well as some phenotypic similarities to neurometabolic/lysosomal storage disorders.

Most variants reported in the most recent publication except one (NM_001135629.2:c.1607dupT) seem to affect all 3 PPP1R21 isoforms (which also seems to be the case for previously published variants). c.1607dupT appears to be the single truncating variant affecting 2 (of 3) isoforms. This variant was however shown to have severely reduced expression in fibroblasts upon qPCR, absent protein staining, and increase in myelin figures.

The protein is expressed in embryonic mouse cortex.

Overall, this gene can be considered for inclusion in this panel as green (or amber).
Sources: Literature
Intellectual disability - microarray and sequencing v2.576 GRIN2D Konstantinos Varvagiannis gene: GRIN2D was added
gene: GRIN2D was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: GRIN2D was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: GRIN2D were set to 27616483; 30280376
Phenotypes for gene: GRIN2D were set to Epileptic encephalopathy, early infantile, 46 (MIM 617162)
Penetrance for gene: GRIN2D were set to unknown
Review for gene: GRIN2D was set to GREEN
gene: GRIN2D was marked as current diagnostic
Added comment: Heterozygous pathogenic variants in GRIN2D cause Epileptic encephalopathy, early infantile, 46 (MIM 617162).

As commented in the previous review, PMID: 27616483 is the first report on 2 unrelated individuals with severe epileptic encephalopathy (onset of seizures at the age of 2 and 4 months). Severe DD with ID was noted in both.

Each of these individuals were heterozygous for the same missense variant (NM_000836.2:c.1999G>A p.Val667Ile) as a de novo event. Functional studies demonstrated a gain-of-function effect.

GRIN2D encodes for an NMDA receptor subunit, and the gain-of-function effect shown for this variant suggests that NMDAR antagonists might be useful as adjuvant therapy (some improvement noted in both individuals).

[The mode of pathogenicity selected here may be modified as more evidence on further variants becomes available. GRIN2D appears to be intolerant also to LoF mutations with a pLI of 1. Both LoF and GoF mutations have been described for genes encoding other NMDAR subunits].

PMID: 30280376 reports on 3 additional unrelated patients with developmental and epileptic encephalopathy and pathogenic or likely pathogenic missense variants in GRIN2D.

Three additional missense variants are reported (Met681Ile, Ser694Arg, Asp449Asn). Parental studies were possible only for the patient with Met681Ile (de novo) as well as for the individual with Ser694Arg (only one parent available though).

Significant developmental delay was evident in all prior to the onset of seizures (1m/2y/3y respectively) and subsequent developmental stagnation/regression with ID.

The phenotype of these 3 individuals as well as of the 2 previously described is summarized in table 1 of the latter article.

GRIN2D is a probable DD gene in G2P and is included in gene panels for ID offered by diagnostic laboratories.

Several other genes for NMDA receptor subunits (eg. GRIN2A, GRIN2B, GRIN1) and relevant/similar phenotypes are included in this panel as green.

As a result, this gene can be considered for inclusion in the ID panel as green (or amber).
Sources: Literature
Intellectual disability - microarray and sequencing v2.574 SET Konstantinos Varvagiannis reviewed gene: SET: Rating: GREEN; Mode of pathogenicity: None; Publications: 29688601, 25356899, 28135719; Phenotypes: Mental retardation, autosomal dominant 58 (MIM 618106); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.564 TRMT1 Konstantinos Varvagiannis reviewed gene: TRMT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30289604, 21937992, 26308914, 28784718; Phenotypes: Global developmental delay, Intellectual disability, Seizures, Microcephaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.564 PRR12 Konstantinos Varvagiannis reviewed gene: PRR12: Rating: GREEN; Mode of pathogenicity: None; Publications: 29556724, 26163108, 28135719; Phenotypes: Global developmental delay, Intellectual disability, Abnormality of the iris, Abnormality of vision, Behavioral abnormality; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.564 PRR12 Konstantinos Varvagiannis gene: PRR12 was added
gene: PRR12 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PRR12 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRR12 were set to 29556724; 26163108
Phenotypes for gene: PRR12 were set to Global developmental delay; Intellectual disability; Abnormality of the iris; Abnormality of vision; Behavioral abnormality
Penetrance for gene: PRR12 were set to unknown
Review for gene: PRR12 was set to GREEN
gene: PRR12 was marked as current diagnostic
Added comment: PMID: 29556724 (Leduc et al. 2018) reports on 3 unrelated individuals with de novo pathogenic variants in PRR12. The common phenotype consisted of DD/ID (3/3), iris anomalies (colobomas in 2/3 with stellate iris patern in all) as well as additional vision problems and behavioral anomalies.

3 different loss-of-function variants are reported. These variants affected the longer transcript (Ensembl ENST00000418929.6 or NM_020719 - short : ENST00000615927.1) with a single one affecting both.

PRR12 appears to be intolerant to loss-of-function muatations (pLI of 1). Some LoF variants exist in ExAC/gnomAD although the majority appear to be low-quality variants.

As commented by the authors 2 individuals with de novo variants exist in Decipher (1 in-frame deletion and a missense SNV - both variants appear in fig.2 of the article) [a few more DDD study participants in the denovo-db all from PMID: 28135719 : http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=PRR12].

Alternative explanations for the phenotype (eg. CHARGE syndrome, etc) were ruled out in many individuals in the article.

Functional studies have not been performed. //

PMID: 26163108 (Córdova-Fletes al. 2015) is a previous report cited by Leduc et al. One individual with balanced translocation [t(10;19)] with disruption of PRR12 is described. This individual presented with ID and behavioral anomalies (without details on eventual coloboma or other iris anomalies).

The translocation was balanced and led to fusion of PRR12 with LMIZ1. The breakpoint was located within intron 11 (PRR12 is a 14-exon gene) with fusion of PRR12 exon 11 with ZMIZ1 exon 8 upon RT-PCR. Both PRR12/ZMIZ1 products were predicted to be truncated due to frameshift and introduction of premature stop codon.

[Surprisingly qPCR and Western blot in patient LCLs were suggestive of increased PRR12 expression compared to controls suggesting either a compensation mechanism or longer half-life/accumulation of the aberrant PRR12].

Expression of wt PRR12 was highest during embryonic development in mouse/rat brain cells suggesting a role in early CNS development. The transcript studied (corresponding to the longest human transcript) was exclusively located in the nucleus compared to a shorter one located primary in the nucleus but also outside suggesting that PRR12 might be involved in regulation of transcription.

In line with this several genes linked to neurodevelopmental processes/neuronal communication appeared be dysregulated in lymphoblastoid cell lines (LCLs) from the translocation patient.

A role for ZMIZ1 is similarly discussed. //

PRR12 is included in gene panels for ID offered by diagnostic laboratories. //

As a result, this gene can be considered for inclusion in this panel as green (or amber).
Sources: Literature
Intellectual disability - microarray and sequencing v2.562 CAD Konstantinos Varvagiannis gene: CAD was added
gene: CAD was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CAD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAD were set to 25678555; 28007989
Phenotypes for gene: CAD were set to Epileptic encephalopathy, early infantile, 50 - MIM 616457
Penetrance for gene: CAD were set to Complete
Review for gene: CAD was set to AMBER
gene: CAD was marked as current diagnostic
Added comment: Biallelic pathogenic variants in CAD cause Epileptic encephalopathy, early infantile, 50 - MIM 616457.

Overall 5 individuals from 4 unrelated families have been reported in detail in PMIDs 25678555 and 28007989 (table 1 in this article provides a summary).

The phenotype consisted of developmental delay which preceded the onset of seizures (6 months to 2 years) and hematologic anomalies (anemia and anisopoikilocytosis). The patients presented developmental stagnation/regression, which in most cases occurred several months following the seizure onset.

CAD is a tri-functional protein catalyzing the first 3 steps of the de novo pyrimidine biosynthesis.

In total, 5 variants have been reported (2 missense, 1 nonsense and 2 splice-site SNVs) with functional studies (cDNA, metabolites) supporting pathogenicity and disruption of this pathway.

CAD mutations have previously been studied in other model organisms.

Mutations in enzymes catalyzing downstream steps of the same pathway are associated with other syndromes.

The disorder appears to be amenable to dietary intervention (uridine supplementation).

CAD is included in gene panels for intellectual disability offered by different diagnostic laboratories.

As a result, this gene can be considered for inclusion in the ID panel as amber or green.
Sources: Literature
Intellectual disability - microarray and sequencing v2.562 PHF21A Konstantinos Varvagiannis reviewed gene: PHF21A: Rating: GREEN; Mode of pathogenicity: None; Publications: 22770980, 30487643; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.562 RALA Konstantinos Varvagiannis gene: RALA was added
gene: RALA was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RALA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: RALA were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology
Penetrance for gene: RALA were set to unknown
Mode of pathogenicity for gene: RALA was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: RALA was set to GREEN
Added comment: Hiatt et al. (doi.org/10.1371/journal.pgen.1007671) report on 11 individuals (incl. a pair of monozygotic twins) from 10 unrelated families, most (10/11) with de novo mutations in RALA.

DD/ID was a prominent feature (the authors note that ID was specifically noted in 8 but could not be excluded in 3 further individuals who appear to be very young in the table). Structural brain anomalies (9/11), seizures (6/11) and common facial features were also noted.

RALA belongs to the RAS superfamily of small GTPases.

5 different de novo missense variants and 1 in-frame deletion, all within a GTP/GDP binding region of RALA (although appart in the protein primary structure) were observed. 7 occurrences of missense variants concerned Val25 and Lys128 (V25M, V25L, K128R), one Asp130 (D130G) and a further one Ser157 (S157A). The in-frame deletion concerned Ala158.

Missense variants in corresponding positions of RAS proteins (HRAS/KRAS/NRAS) have been reported in RASopathies, while the authors observed some phenotypic overlap with the latter group of disorders (DD/ID, growth delay, macrocephaly, high forehead and position of ears).

Functional studies demonstrated reduction in GTPase activity (for all variants) and altered RALA effector binding (for most reduction - in the case of S157A, increase).

Several lines of evidence are provided to show that alteration of the GTP/GTP-binding rather than a dosage effect is considered the likely mechanism. RALA is depleted in missense mutations in its GTP/GDP binding domain.

For these reasons and others (segregation studies not possible, variant observed 2x in Bravo database, phenotypic differences compared to the rest of the cohort, ROH suggesting parental consanguinity in the specific individual) the single nonsense variant (R176X) reported in the study is considered a VUS.

As a result, this gene can be considered for inclusion in this panel as green.
Sources: Literature
Intellectual disability - microarray and sequencing v2.558 DOCK6 Konstantinos Varvagiannis reviewed gene: DOCK6: Rating: GREEN; Mode of pathogenicity: None; Publications: 25824905, 27077170; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.558 KMT2B Konstantinos Varvagiannis reviewed gene: KMT2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 29697234; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.556 DPH1 Konstantinos Varvagiannis gene: DPH1 was added
gene: DPH1 was added to Intellectual disability. Sources: Literature,Expert Review
Mode of inheritance for gene: DPH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DPH1 were set to 25558065; 26220823; 29362492; 29410513
Phenotypes for gene: DPH1 were set to Developmental delay with short stature, dysmorphic features, and sparse hair, 616901
Penetrance for gene: DPH1 were set to Complete
Review for gene: DPH1 was set to GREEN
gene: DPH1 was marked as current diagnostic
Added comment: Biallelic mutations in DPH1 cause Developmental delay with short stature, dysmorphic features, and sparse hair, MIM 616901.

Overall 11 patients from 6 different families have probably been reported in detail. DD/ID is a universal feature.

In PMID 25558065, Alazami et al. identified 1 patient from the same consanguineous Saudi Arabian family (of 8 total similarly affected individuals) homozygous for the Leu234Pro (NM_001383.3:c.701T>C) variant. This individual was part of a large cohort of patients with neurogenetic disorders from consanguineous families. The phenotype is not described in detail.

In PMID 26220823 Louks et al. report on 4 patients from 3 families belonging to the same genetic isolate from North America and provide details on 4 of the individuals identified by Alazami et al.

The individuals identified in this study were homozygous for Met6Lys which was however predicted to be benign and tolerated (by PolyPhen2 and SIFT respectively) in silico.

DD/ID, unusual skull shape, ectodermal anomalies were universal (8/8) with additional features including short stature (7/8), renal (4/6) or cardiac anomalies (3/8). Some facial features appeared to be common, too.

Functional studies were not performed. However Dph1 pathogenic variants in mice result in restricted growth, craniofacial and developmental defects similar to the human phenotypes (PMIDs 14744934 and 24895408 are cited).

PMIDs 29362492 and 29410513 report on 3 further patients with similar (as well as some additional) features including DD/ID. The individual in the first article was compound heterozygous for a missense (Leu164Pro) and a frameshift variant (c.289delG) while 2 sibs born to consanguineous parents in the second article were homozygous for a frameshift variant (c.1227delG).

The phenotype appears to be consistent among all the published patients.

DPH1 is included in gene panels for intellectual disability offered by different diagnostic laboratories.

As a result, this gene can be considered for inclusion in this panel as green.
Sources: Literature, Expert Review
Intellectual disability - microarray and sequencing v2.555 TELO2 Konstantinos Varvagiannis gene: TELO2 was added
gene: TELO2 was added to Intellectual disability. Sources: Literature,Expert Review
Mode of inheritance for gene: TELO2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TELO2 were set to 27132593; 28944240
Phenotypes for gene: TELO2 were set to You-Hoover-Fong syndrome, MIM 616954
Penetrance for gene: TELO2 were set to Complete
Review for gene: TELO2 was set to GREEN
gene: TELO2 was marked as current diagnostic
Added comment: Biallelic mutations in TELO2 cause You-Hoover-Fong syndrome (MIM 616954). //

PMID: 27132593 reports on 6 patients (from 4 non-consanguineous families) with biallelic TELO2 variants and a similar phenotype.

Intellectual disability and microcephaly were universal features (6/6). Abnormal hearing (3/6), cortical visual impairment (3/6), abnormality of the cardiovascular system (3/6), behavioral problems (laughter outbursts in 3/6) and abnormal balance and movement disorder (6/6) were part of the phenotype. One individual had seizures.

5 missense variants and a complex allele with a stopgain variant localized in cis with a splice-site variant (NM_016111.3:c.514C>T or p.Gln172* in cis with c.2034+1G>A) are reported.

As a result heterozygosity for the complex variant may be confounded with compound heterozygous state until segregation studies are performed.

Functional studies support pathogenicity of the missense variants (reduced protein steady-state levels of TELO2 as well as TTI1 and TTI2 - the 2 other members of the TTT complex) suggesting loss of function.

PMID: 28944240 reports on 2 sisters born to non-consanguineous parents. Both were compound heterozygous for 2 novel variants, a missense and a frameshift one. Severe microcephaly (-8.5 SD and -10.7 SD) and seizures were noted in both. The first sister passed away at the age of 2 months due to a respiratory infection. The other sister demonstrated a compatible, though much more severe phenotype (of ID, dwarfism, retinitis pigmentosa, etc) compared to previously reported patients. //

Biallelic mutations in TTI2 (of the same complex) lead to similar phenotypes (gene rated green in the ID panel). //

TELO2 is included in gene panels for intellectual disability offered by different diagnostic laboratories. //

As a result this gene can be considered for inclusion in this panel as green.
Sources: Literature, Expert Review
Intellectual disability - microarray and sequencing v2.555 TTI2 Konstantinos Varvagiannis reviewed gene: TTI2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23956177; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v2.555 ATP8A2 Konstantinos Varvagiannis reviewed gene: ATP8A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22892528, 27679995, 30012219, 29531481; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.555 MACF1 Konstantinos Varvagiannis gene: MACF1 was added
gene: MACF1 was added to Intellectual disability. Sources: Literature,Expert Review
Mode of inheritance for gene: MACF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: MACF1 were set to Intellectual disability; Seizures; Lissencephaly; Brainstem dysplasia
Penetrance for gene: MACF1 were set to unknown
Mode of pathogenicity for gene: MACF1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: MACF1 was set to GREEN
Added comment: Dobyns et al. (doi.org/10.1016/j.ajhg.2018.10.019) report on 9 individuals (all unrelated appart from a pair of monozygotic twins) with de novo variants in MACF1.

All patients presented lissencephaly and brainstem hypoplasia with associated intellectual disability (9/9) and seizures (9/9).

Seven of these individuals had de novo missense variants within the GAR domain and an eighth had a deletion of several exons also spanning this domain and leading to an in-frame deletion. A further ninth patient had a de novo missense variant in the spectrin repeat domain and was found to have similar features although the brainstem dysplasia was rather subtle.

5 missense variants (4 of which in the GAR domain) and an intragenic deletion are reported in total.

The variants in the GAR domain were predicted to have important effect in the zinc-binding pocket. The spectrin repeat (SR4) is thought to have an important role for the function of MACF1 and further to neuronal migration.

Knockdown of Macf1 in mice has been shown to result in developmental defects similar to the human malformation.

The authors note that several high-confidence loss-of-function mutations are listed in ExAC and as a result this type of variants could be non-pathogenic (or lead to neurodevelopmental disorders with reduced penetrance). Still MACF1 has a pLI of 1.0.

As for the missense variants, the authors suggest either a gain-of-function or dominant negative mechanism.

Caution should be taken when interpreting variants as the ENST00000372915.7 (or MACF1-204) transcript is used for the predicted protein changes, although ENST00000361689.6 or MACF1-203 (corresponding to NM_012090.5) has also been used in some tables or figures.

As a result, this gene can be considered for inclusion in this panel probably as green.
Sources: Literature, Expert Review
Intellectual disability - microarray and sequencing v2.554 PHACTR1 Konstantinos Varvagiannis reviewed gene: PHACTR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30256902, 23033978, 28135719; Phenotypes: Global developmental delay, Intellectual disability, Seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v2.550 UFM1 Konstantinos Varvagiannis reviewed gene: UFM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28931644, 29868776; Phenotypes: Leukodystrophy hypomyelinating 14, 617899; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v2.545 UFC1 Konstantinos Varvagiannis gene: UFC1 was added
gene: UFC1 was added to Intellectual disability. Sources: Literature,Expert Review
Mode of inheritance for gene: UFC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UFC1 were set to 29868776
Phenotypes for gene: UFC1 were set to Neurodevelopmental disorder with spasticity and poor growth, 618076
Penetrance for gene: UFC1 were set to Complete
Review for gene: UFC1 was set to GREEN
Added comment: Biallelic UFC1 mutations cause Neurodevelopmental disorder with spasticity and poor growth, MIM 618076.

PMID: 29868776 describes 7 individuals (most) born to consanguineous Saudi families (in one case the parents were not consanguineous but originated from the same tribe) as well as a further individual born to distantly related Swiss parents. One of these patients was previously briefly published by the same authors (PMID: 27431290).

The phenotype consisted of developmental delay (8/8 - usually profound), failure to thrive (8/8), short stature and microcephaly (both observed in 7/8), seizures (4/8) and variable brain MRI anomalies in some of these subjects.

Overall, two UFC1 missense variants are reported [NM_016406.3:c.317C>T or p.(Thr106Ile) and c.68G>A or p.(Arg23Gln) the former in the Saudi individuals]. Functional studies demonstrated the hypomorphic nature of the variants.

UFC1 (as well as UFM1 also discussed in the same article) participate in ufmylation, with mutations in other enzymes of the same process (notably UBA5 - gene rated Green in the ID and epilepsy panels) having already been described in neurodevelopmental disorders.

As a result this gene can be considered for inclusion in the ID panel as green (or amber).
Sources: Literature, Expert Review
Intellectual disability - microarray and sequencing v2.545 CCDC88A Konstantinos Varvagiannis reviewed gene: CCDC88A: Rating: AMBER; Mode of pathogenicity: None; Publications: 26917597, 30392057; Phenotypes: ?PEHO syndrome-like, 617507; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v2.537 GNB5 Konstantinos Varvagiannis gene: GNB5 was added
gene: GNB5 was added to Intellectual disability. Sources: Literature,Expert Review
Mode of inheritance for gene: GNB5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GNB5 were set to 27523599; 27677260; 28697420; 29368331
Phenotypes for gene: GNB5 were set to Intellectual developmental disorder with cardiac arrhythmia, 617173; Language delay and ADHD/cognitive impairment with or without cardiac arrhythmia, 617182
Penetrance for gene: GNB5 were set to Complete
Review for gene: GNB5 was set to GREEN
gene: GNB5 was marked as current diagnostic
Added comment: Biallelic GNB5 pathogenic variants cause Intellectual developmental disorder with cardiac arrhythmia (MIM 617173) or language delay and ADHD/cognitive impairment with or without cardiac arrhythmia (MIM 617182).

PMID: 27523599 is the first report on the associated phenotype. A total of 9 individuals from 6 different families (from various ethnic backgrounds) are described.

The common features included hypotonia (noted in 6 out of 9 patients), intellectual disability (9/9 - in 3 cases mild, in 6 severe), heart rate disturbance (9/9 - in most cases sick sinus syndrome), seizures (4/9), ophthalmological problems (nystagmus in 6 out of 7 for whom this information was available) as well as gastric problems (5/8 with G-E reflux).

The 6 variants (summarized in table S1) included : 2 nonsense mutations, 1 synonymous (demonstrated to affect splicing and leading to retention of 25 intronic bp), 2 further splice variants (positions +1 and +3) and a missense one (S81L).

Nonsense mediated decay was the case for the product of the synonymous/splice variant as well as for a stopgain one.

As noted by the authors, individuals homozygous for the S81L variant had a less severe phenotype - among others - with mild degree of intellectual disability.

Functional studies included knockout of gnb5 in zebrafish, which was able to reproduce the human neurological, cardiac and ophthalmological phenotypes.

Alternative causes for these phenotypes (incl. chromosomal or metabolic disorders) were ruled out.

Affected individuals might benefit interventions for their heart rate disturbance as appears to be the case in the article as well as subsequent studies.

PMID: 27677260 describes an extended consanguineous Saudi family with 5 individuals homozygous for the S81L variant. Common features included severe language delay, ADHD, but normal cognition in those available for evaluation. Seizures were not reported. Pathogenicity of the S81L variant is further supported by functional studies.

PMID: 28697420 describes in detail 2 individuals from a large consanguineous pedigree confirmed to be homozygous for a single nucleotide deletion in GNB5. The phenotype included severe DD/ID, seizures, sinus bradycardia with frequent sinus pauses and ophthalmological problems. Sinus arrhythmia and or seizures were documented in several other relatives deceased and unavailable for testing.

PMID: 28327206 reports on 2 subjects previously included in PMID: 27523599.

PMID: 29368331 describes a child with severe developmental delay, nystagmus and sinus arrhythmia necessitating a pacemaker. EEG was abnormal although no frank seizures were observed. The child was compound heterozygous for a novel missense variant (R246Q) as well a 5 basepair deletion.

GNB5 is included in diagnostic gene panels for intellectual disability offered by different laboratories.

As a result this gene can be considered for inclusion in this panel as green.
Sources: Literature, Expert Review
Intellectual disability - microarray and sequencing v2.535 KDM5B Konstantinos Varvagiannis reviewed gene: KDM5B: Rating: GREEN; Mode of pathogenicity: None; Publications: 29276005, 30409806; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v2.535 EIF3F Konstantinos Varvagiannis gene: EIF3F was added
gene: EIF3F was added to Intellectual disability. Sources: Literature,Expert Review
Mode of inheritance for gene: EIF3F was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EIF3F were set to 30409806
Phenotypes for gene: EIF3F were set to Intellectual disability; Seizures; Behavioral abnormality; Sensorineural hearing impairment
Penetrance for gene: EIF3F were set to Complete
Review for gene: EIF3F was set to GREEN
Added comment: EIF3F was identified in a recent DDD publication (PMID: 30409806) as a cause of autosomal recessive intellectual disability.

All 9 individuals reported were homozygous for a missense variant (Phe232Val - rs141976414) which has a frequency of 0.12% in non-Finnish Europeans.

Features included intellectual disability (9/9), seizures (6/9), behavioral problems (3/9) and sensorineural hearing loss (3/9). Facial features were not specific.

Extensive functional studies were performed and support pathogenicity of the variant in the homozygous state (reduced protein levels, reduced translation rate in line with the role of EIF3F encoding a subunit for eukaryotic translation initiation factor 3, as well as reduced proliferation rates).

As a result this gene can be considered for inclusion in this panel as green.
Sources: Literature, Expert Review
Intellectual disability - microarray and sequencing v2.535 ATP6V1A Konstantinos Varvagiannis gene: ATP6V1A was added
gene: ATP6V1A was added to Intellectual disability. Sources: Literature,Expert Review
Mode of inheritance for gene: ATP6V1A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATP6V1A were set to 29668857; 28065471
Phenotypes for gene: ATP6V1A were set to # 618012 EPILEPTIC ENCEPHALOPATHY, INFANTILE OR EARLY CHILDHOOD, 3; IECEE3
Penetrance for gene: ATP6V1A were set to unknown
Review for gene: ATP6V1A was set to GREEN
Added comment: Heterozygous mutations in ATP6V1A cause Epileptic encephalopathy, infantile or early childhood, type 3 (MIM 618012).

PMID: 29668857 reports 4 individuals from 4 families with de novo pathogenic variants in ATP6V1A. The phenotype was consistent with a developmental encephalopathy with epilepsy.

All patients were found to harbor missense variants. The variants resulted in altered lysosomal homeostasis, abnormal neuritogenesis and synaptic density. However in one of the variants tested (p.Asp100Tyr) pathogenicity was mediated by loss-of-function mechanism while for another (p.Asp349Asn) by gain-of-function mechanism.

Differences in severity were noted, with two variants (incl. Asp100Tyr) being associated with a more severe phenotype and the two other (incl. Asp349Asn) with milder degrees of ID and epilepsy.

Biallelic ATP6V1A mutations cause Cutis laxa type IID (MIM 617403). PMID: 28065471 is the first report on 3 individuals from 3 different families (2 of which were consanguineous). All patients were homozygous for ATP6V1A pathogenic variants. All three presented with hypotonia, one (or possibly two) with developmental delay and two with seizures although the developmental phenotype is not further commented on. (Additional patients described in the article harbored mutations in other genes and were not considered).

As a result, this gene can be considered for inclusion in this panel as green (or amber).
Sources: Literature, Expert Review
Intellectual disability - microarray and sequencing v2.532 TBR1 Konstantinos Varvagiannis reviewed gene: TBR1: Rating: AMBER; Mode of pathogenicity: None; Publications: 30268909, 25356899, 23160955, 22495311, 30250039; Phenotypes: Intellectual disability, Autism, Abnormal cortical gyration; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.530 DCPS Konstantinos Varvagiannis gene: DCPS was added
gene: DCPS was added to Intellectual disability. Sources: Expert Review,Literature
Mode of inheritance for gene: DCPS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DCPS were set to 25712129; 25701870; 30289615
Phenotypes for gene: DCPS were set to Al-Raqad syndrome (OMIM 616459)
Penetrance for gene: DCPS were set to Complete
Review for gene: DCPS was set to GREEN
gene: DCPS was marked as current diagnostic
Added comment: Biallelic pathogenic DCPS variants cause Al-Raqad syndrome (OMIM 616459).

7 patients from 3 families have been reported to date, all summarized in PMID 30289615 (first reports on the disorder - PMIDs : 25712129, 25701870).

Most individuals belong to consanguineous families although a compound heterozygous patient belonging to a broader consanguineous family (in PMID 25701870) and a further individual was born to unrelated parents originating from the same region (in PMID 30289615) have been described.

Overall, 2 splice site and 2 missense variants have been reported. Functional studies were carried out and support pathogenicity of the variants in the first 2 studies.

Developmental delay and intellectual disability are universal features.

DCPS is included in gene panels for intellectual disability offered by different diagnostic labs.

As a result this gene can be considered for inclusion in this panel as green.
Sources: Expert Review, Literature
Intellectual disability - microarray and sequencing v2.530 RHOBTB2 Konstantinos Varvagiannis gene: RHOBTB2 was added
gene: RHOBTB2 was added to Intellectual disability. Sources: Expert Review,Literature
Mode of inheritance for gene: RHOBTB2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RHOBTB2 were set to 29276004; 29768694; 26740508
Phenotypes for gene: RHOBTB2 were set to Global developmental delay; Intellectual disability; Seizures; Postnatal microcephaly
Penetrance for gene: RHOBTB2 were set to unknown
Mode of pathogenicity for gene: RHOBTB2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: RHOBTB2 was set to GREEN
gene: RHOBTB2 was marked as current diagnostic
Added comment: PMID: 29276004 reports on 10 unrelated patients with de novo pathogenic missense variants in RHOBTB2. The phenotype in all individuals was compatible with a developmental and epileptic encephalopathy including early-onset seizures, severe intellectual disability, postnatal onset microcephaly (6/10) and movement disorders (8/10).

The variants occured as de novo events and clustered within the BTB-domain encoding region (within and between the 2 BTB domains). Three missense variants were recurrent and/or concerned the same residue (p.Arg483His in 4 individuals, Arg511Gln was reported in 2, and Arg511Trp was was found in another 2 individuals).

Functional studies in HEK293 cells suggested increased abundance of the mutant protein secondary to decreased proteasome degradation. Using Drosophila as a model organism, altered expression of RhoBTB (the single ortholog of the 3 vertebrate paralogs, closest to RHOBTB2) was shown to result in neurological phenotypes. RhoBTB overexpression in particular was associated with increased bang sensitivity (which was not the case or milder in the case if knockdown of this gene) and impaired performance upon the negative geotaxis assay, similar to the human neurological phenotypes. Altered RhoBTB dosage was shown to be associated with impaired dendrite development.

As commented by the authors, these results as well as the clustering of missense variants and the pLI score of 0.51 reported for RHOBTB2 are consistent with altered protein function (due to the missense variants) rather than haploinsufficiency or loss-of-function.

PMID: 29768694 describes 3 additional individuals, all found to harbor de novo missense variants again within the BTB-domain encoding region. Two of the variants had been reported in the previous study (Arg511Gln and Arg483His) while the third was a private one (Arg507Cys). The phenotype was similar to the previous descriptions. Functional studies were suggestive of impaired degradation of the mutant protein by the CUL3 complex although this was not secondary to decreased binding with CUL3.

PMID: 26740508 (cited by the two aforementioned publications) reports briefly on an individual with de novo missense variant in the same region of RHOBTB2 (Asn510Asp) and Rett-like phenotype.

RHOBTB2 is included in gene panels for intellectual disability offered by different diagnostic laboratories.

As a result the gene can be considered for inclusion in the intellectual disability and epilepsy panels as green.
Sources: Expert Review, Literature
Intellectual disability - microarray and sequencing v2.530 TUBA8 Rebecca Foulger Added comment: Comment on list classification: Demoted from Green to Amber based on re-review of evidence. Demotion agreed by Clinical Fellow Helen Brittain.

TUBA8 was originally rated Green on the panel because TUBA8 is a confirmed DD-G2P gene for 'POLYMICROGYRIA WITH OPTIC NERVE HYPOPLASIA' (the former name for Cortical dysplasia, complex, with other brain malformations 8, 613180) and TUBA8 is on the UKGTN 43 gene panel for brain malformations:
https://ukgtn.nhs.uk/find-a-test/search-by-disorder-gene/brain-malformation-disorders-cortical-43-gene-panel-886/.

However, the reported evidence comes from one 2009 paper (PMID:19896110) with 4 literature cases coming from 2 consaguineous families (1 variant); at least PMID:25008804 questions whether the families are related. A 2017 paper identifies an additional VUS (compound heterozygous) in a chinese EE patient (PMID:29588952).

Anna de Burca confirmed that there are lots of cases with CNVs involving TUBA8 in DECIPHER but there are only two cases with SNVs in the gene. One of them is classified as unknown pathogenicity, the other likely benign.

I contacted Usha Kini at Oxford, and also the Leeds and Cardiff genetic testing groups (as recommended by Usha) since they all offer cortical malformation panels. All three confirmed (pers. comm. via email) that they have no further cases for TUBA8.

The literature evidence and communications from Oxford, Leeds and Cardiff all support demotion of TUBA8 to Amber rating: The phenotype is still appropriate for the panel but insufficient cases for diagnostic rating.

Added 'watchlist' tag to look out for further cases.
Intellectual disability - microarray and sequencing v2.515 PCGF2 Louise Daugherty Mode of pathogenicity for gene: PCGF2 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability - microarray and sequencing v2.510 CACNA1E Konstantinos Varvagiannis gene: CACNA1E was added
gene: CACNA1E was added to Intellectual disability. Sources: Expert Review,Literature
Mode of inheritance for gene: CACNA1E was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CACNA1E were set to 29942082
Phenotypes for gene: CACNA1E were set to Global developmental delay; Intellectual disability; Seizures; Dystonia; Congenital contracture; Macrocephaly
Penetrance for gene: CACNA1E were set to Incomplete
Mode of pathogenicity for gene: CACNA1E was set to Other
Review for gene: CACNA1E was set to GREEN
Added comment: Helbig et al. (https://doi.org/10.1016/j.ajhg.2018.09.006) report on 30 individuals with pathogenic variants in CACNA1E.

The phenotype was consistent with a developmental and epileptic encephalopathy, with hypotonia, early-onset and refractory seizures, severe to profound developmental delay and intellectual disability. Additional relatively common features included hyperkinetic movement disorder (severe dystonia which was observed in 40%, other dyskinesias in another 20%), congenital joint contractures of variable degree and joint involvement (approx. 40% of individuals) and macrocephaly (approx. 40%). There were no common facial dysmorphic features observed.

Of note, epilepsy was not a feature in 4 cases (age 1 to 4 years) so few of these individuals may be investigated for their developmental delay/intellectual disability or other features.

Missense variants:
All the 30 subjects described harbored a missense variant in CACNA1E which in all cases where parental studies were possible (29/30) occurred as a de novo event. There were 4 recurrent variants, explaining the phenotype in 20 patients in total while the rest of the individuals had private mutations. Functional studies were performed and suggested a gain-of-function effect for these variants (increased calcium inward currents).

Loss-of-function (LoF) variants:
Apart from the main cohort of patients, the authors note the presence of 3 individuals with such variants incl.:
- one individual with a nonsense variant present in the mosaic state (6/22 reads) in peripheral blood.
- one individual with a frameshift variant inherited from his unaffected parent.
- one individual with a nonsense variant for whom parental studies were not possible.

The authors comment that these indivdiduals presented with milder phenotype compared to those with missense variants. More information on these subjects is provided in the supplement as the article focuses on missense SNVs.

As the authors also note, several LoF variants exist in gnomAD, although the gene appears to be LoF intolerant (pLI=1).

Penetrance:
Seems to be complete for missense SNVs and possibly incomplete for LoF ones.

---

A previous study by Heyne et al. (PMID: 29942082) implicated de novo variants (DNVs) in CACNA1E with neurodevelopmental disorders for the first time. This study however does not provide clinical details on the phenotype of the affected individuals, while it seems to present overlap as to the individuals reported (eg. includes subjects from the DDD study and others).

---

Details as to a few - possibly further - de novo coding variants reported to date can be found at the denovo-db:
http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=CACNA1E

---

As a result this gene can be considered for inclusion in this panel as green.
Sources: Expert Review, Literature
Intellectual disability - microarray and sequencing v2.510 DLG4 Konstantinos Varvagiannis reviewed gene: DLG4: Rating: GREEN; Mode of pathogenicity: None; Publications: 29460436, 27479843, 28135719, 23020937; Phenotypes: Intellectual disability, Marfanoid habitus; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v2.510 PCGF2 Konstantinos Varvagiannis reviewed gene: PCGF2: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: ; Phenotypes: Global developmental delay, Intellectual disability, Abnormality of the cardiovascular system, Abnormality of the cerebrum, Abnormality of the skeletal system; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v2.510 ZNF81 Eleanor Williams reviewed gene: ZNF81: Rating: RED; Mode of pathogenicity: None; Publications: 12345; Phenotypes: test phenotype; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v2.510 KARS Konstantinos Varvagiannis reviewed gene: KARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 29615062, 30252186, 28496994; Phenotypes: Global developmental delay, Intellectual disability, Seizures, Charcot-Marie-Tooth disease, recessive intermediate, B - 613641, Deafness, autosomal recessive 89 - 613916; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.510 ARL13B Konstantinos Varvagiannis reviewed gene: ARL13B: Rating: GREEN; Mode of pathogenicity: None; Publications: 18674751, 25138100, 29255182, 16541367; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.510 ARL13B Konstantinos Varvagiannis reviewed gene: ARL13B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.510 PIGW Konstantinos Varvagiannis reviewed gene: PIGW: Rating: GREEN; Mode of pathogenicity: None; Publications: 30078644; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.510 NBEA Konstantinos Varvagiannis reviewed gene: NBEA: Rating: GREEN; Mode of pathogenicity: None; Publications: 30269351, 28554332, 12746398, 12826745, 11450821, 3377648, 23277425, 22109531, 23153818; Phenotypes: Global developmental delay, Intellectual disability, Seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.510 MEIS2 Konstantinos Varvagiannis reviewed gene: MEIS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30291340, 30055086; Phenotypes: Oral cleft, Abnormal heart morphology, Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.510 MAP1B Konstantinos Varvagiannis gene: MAP1B was added
gene: MAP1B was added to Intellectual disability. Sources: Literature,Expert Review
Mode of inheritance for gene: MAP1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAP1B were set to 30150678; 29738522
Phenotypes for gene: MAP1B were set to Intellectual disability
Penetrance for gene: MAP1B were set to unknown
Review for gene: MAP1B was set to AMBER
Added comment: In PMID 30150678 the authors report on a family with 5 individuals diagnosed with intellectual disability (ID, IQ <= 70 and associated impairments in adaptive function) and 3 further relatives with IQ below 70, not fulfilling the criteria for a clinical diagnosis of ID. A frameshift variant in MAP1B segregated with the ID/low IQ phenotype. This variant was not found in 31463 Icelanders for whom whole genome sequencing data were available.

The authors confirmed association of MAP1B loss-of-function (LoF) variants by demonstrating the presence of 2 other stopgain mutations in 2 further families. Among the 6 mutation carriers in these families, the average IQ was 81 with 2 of these subjects fulfilling the criteria for intellectual disability. 3 of the 6 mutation carriers had a diagnosis of autism spectrum disorder. Carriers demonstrated 24% less white matter volume (-2.1 SD) and 47% less corpus callosum volume (-2.4 SD) compared to controls.

Mean full-scale IQ, performance IQ and verbal IQ were 68.3 (with a SD of 10.5), 66.4 (SD of 9.3) and 74.5 (SD of 14.8) in MAP1B LoF carriers.

All 3 LoF variants reported result in a truncated but stable MAP1B protein as demonstrated by western blot analysis.

MAP1B undergoes post-translational modification and is cleaved (at position 2206) into a heavy chain and a light chain. The authors note that all LoF variants lead to truncation prior to the cleavage site.

As commented by the authors, LoF variants are found in publicly available databases at a frequency of approx. 1 in 10000.

One individual with de novo frameshift variant in Decipher ( https://decipher.sanger.ac.uk/search?q=gene%3AMAP1B#research-variants/results ).

De novo and inherited MAP1B variants have previously been described in individuals with periventricular nodular heterotopia (PMID: 29738522). This was also a feature in 9 individuals in the previous ID study.

Although PMID 30150678 is entitled "MAP1B mutations cause intellectual disability and extensive white matter deficit", intellectual disability was not a feature in all individuals or was rather mild when present.
Sources: Literature, Expert Review
Intellectual disability - microarray and sequencing v2.510 CAMK2G Konstantinos Varvagiannis reviewed gene: CAMK2G: Rating: AMBER; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 30184290; Phenotypes: Generalized hypotonia, Global developmental delay, Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.510 AGO1 Konstantinos Varvagiannis reviewed gene: AGO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30213762, 22495306, 23020937, 25363768, 25356899, 27620904, 29346770; Phenotypes: Generalized hypotonia, Global developmental delay, Intellectual disability, Autism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Intellectual disability - microarray and sequencing v2.510 AGO1 Konstantinos Varvagiannis reviewed gene: AGO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30213762, 22495306, 23020937, 25363768, 25356899, 27620904, 29346770; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v2.510 KCNK4 Konstantinos Varvagiannis gene: KCNK4 was added
gene: KCNK4 was added to Intellectual disability. Sources: Literature,Expert Review
Mode of inheritance for gene: KCNK4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KCNK4 were set to 30290154
Phenotypes for gene: KCNK4 were set to Neurodevelopmental delay; Intellectual disability; Seizures; Gingival overgrowth; Hypertrichosis
Penetrance for gene: KCNK4 were set to unknown
Mode of pathogenicity for gene: KCNK4 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: KCNK4 was set to AMBER
Added comment: PMID: 30290154 reports on 3 unrelated individuals with de novo missense KCNK4 variants. All three individuals presented with developmental delay and epilepsy. Severe intellectual disability was a feature in two of these individuals while the third displayed low average intellectual functioning (IQ of 85). Other features common in all included facial dysmorphism (bushy eyebrows, long eyelashes, thin everted upper lip, micrognathia), generalized hypertrichosis and gingival overgrowth.

The two missense variants reported [(p.Ala172Glu) and (p.Ala244Pro)] occurred as de novo events in all subjects, while the first SNV was observed in 2 (of the 3) patients with severe intellectual disability.

Functional studies were suggestive of a gain-of-function effect. In line with this mechanism, Kcnk4 knockout mice did not seem to exhibit seizures, deficits in cognition or other neurodevelopmental phenotypes in a study conducted earlier and cited by the authors (PMID: 15175651).

As a result this gene can be considered for inclusion in the panel as amber (or green).
Sources: Literature, Expert Review
Intellectual disability - microarray and sequencing v2.509 RAC3 Konstantinos Varvagiannis gene: RAC3 was added
gene: RAC3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RAC3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RAC3 were set to 30293988; 29276006
Phenotypes for gene: RAC3 were set to Abnormality of brain morphology; Abnormal muscle tone; Neurodevelopmental delay; Intellectual disability
Penetrance for gene: RAC3 were set to unknown
Mode of pathogenicity for gene: RAC3 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: RAC3 was set to GREEN
Added comment: PMID: 30293988 reports on 5 individuals (from 4 different families) with de novo missense variants in RAC3. All individuals demonstrated structural anomalies on brain MRI (notably agenesis/dysgenesis of the corpus callosum, variable degrees of polymicrogyria and ventricular anomalies) as well as shared non-specific neurological features including abnormal muscular tone, global developmental delay and severe to profound intellectual disability. Feeding difficulties were observed in 4/5 patients.

All variants reported are missense and are presumed to result in constitutive protein activation, as suggested by previous observations either in RAC3 [eg. the p.(Gln61Leu) mutation] or the highly homologous RAC1 and RAC2. According to the authors this is further supported by the fact that Rac3 -/- mice do not show a severe phenotype while missense variants are underrepresented in the ExAC database (z=1.97) as opposed to loss-of-function variants (pLI=0.04 / probability of loss-of-function intolerance).

Of the 3 SNVs reported, 2 variants were in adjacent amino-acid positions [p.(Gln61Leu) and p.(Glu62Lys)]. The latter variant was found in 2 half-sibs born to different fathers, due to suspected maternal gonadal mosaicism (variant absent in all sequencing reads in the maternal DNA sample). The specific variant was also found in a further affected individual from an unrelated family.

Finally, as the authors point out a further individual with de novo RAC3 missense variant [p.(Ala59Gly)] was reported previously in an individual with thin corpus callosum and global developmental delay, although the phenotype was felt to be more reminiscent of Robinow syndrome (PMID: 29276006).

As a result, this gene can be considered for inclusion in the ID panel as green (or amber).
Sources: Literature
Intellectual disability - microarray and sequencing v2.509 MSL3 Konstantinos Varvagiannis reviewed gene: MSL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 30224647; Phenotypes: Muscular hypotonia, Feeding difficulties, Neurodevelopmental delay, Intellectual disability; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability - microarray and sequencing v2.439 C12orf4 Louise Daugherty Phenotypes for gene: C12orf4 were changed from Autosomal recessive intellectual disability; Attention deficit hyperactivity disorder; Muscular hypotonia to Autosomal recessive intellectual disability, Attention deficit hyperactivity disorder, Muscular hypotonia
Intellectual disability - microarray and sequencing v2.439 C12orf4 Louise Daugherty Phenotypes for gene: C12orf4 were changed from Autosomal recessive intellectual disability to Autosomal recessive intellectual disability; Attention deficit hyperactivity disorder; Muscular hypotonia
Intellectual disability - microarray and sequencing v2.409 CISD2 Louise Daugherty reviewed gene: CISD2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v2.408 FGFR1 Louise Daugherty reviewed gene: FGFR1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v2.402 ISCA-37433-Gain Louise Daugherty 22q11.2 recurrent (DGS/VCFS) region (proximal region, LCR22-A to -B) Gain was changed to 22q11.2 recurrent (DGS/VCFS) region (proximal, A-B) (includes TBX1) Gain
Added phenotypes 608363; Chromosome 22q11.2 microduplication syndrome; dysmorphic facial features, cognitive deficits, velopharyngeal insufficiency, congenital heart defects and immunologic derangement; delayed psychomotor development, growth retardation, and/or hypotonia for Region: ISCA-37433-Gain
Intellectual disability - microarray and sequencing v2.402 ISCA-37446-Loss Louise Daugherty 22q11.2 recurrent (DGS/VCFS) region (proximal region, LCR22-A to -D) Loss was changed to 22q11.2 recurrent (DGS/VCFS) region (proximal, A-D) (includes TBX1) Loss
Added phenotypes neonatal hypocalcemia, which may present as tetany or seizures, due to hypoplasia of the parathyroid glands, and susceptibility to infection due to a deficit of T cells; micrognathia; clefting; Hearing deficits; Velocardiofacial syndrome; cardiac malformations; DiGeorge syndrome for Region: ISCA-37446-Loss
Intellectual disability - microarray and sequencing v2.398 ISCA-37418-Gain Louise Daugherty Region: ISCA-37418-Gain was added
Region: ISCA-37418-Gain was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37418-Gain was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for Region: ISCA-37418-Gain were set to infantile hypotonia, failure to thrive, mental retardation, autistic features, sleep apnea, and structural cardiovascular anomalies; 610883; characterized by hypotonia, poor feeding, failure to thrive, developmental delay, mild-moderate intellectual deficit, and neuropsychiatric disorders. Structural cardiovascular anomalies (dilated aortic root, bicommissural aortic valve, atrial/ventricular and septal defects) and sleep disturbance (obstructive and central sleep apnea) are also frequently associated
Intellectual disability - microarray and sequencing v2.398 ISCA-37418-Loss Louise Daugherty Region: ISCA-37418-Loss was added
Region: ISCA-37418-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37418-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for Region: ISCA-37418-Loss were set to Potocki-Lupski syndrome; hypotonia, poor feeding, failure to thrive, developmental delay particularly cognitive and language deficity, mild-moderate intellectual deficit, and neuropsychiatric disorders; Smith-Magenis syndrome; Structural cardiovascular anomalies (dilated aortic root, bicommissural aortic valve, atrial/ventricular and septal defects) and sleep disturbance; 182290; moderate intellectual disability, delayed speech and language skills, distinctive facial features, sleep disturbances, and behavioral problems; hypotonia, failure to thrive, mental retardation, pervasive developmental disorders, congenital anomalies; Dental abnormalities
Intellectual disability - microarray and sequencing v2.398 ISCA-37421-Gain Louise Daugherty Region: ISCA-37421-Gain was added
Region: ISCA-37421-Gain was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37421-Gain was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37421-Gain were set to 3298277; 3817079
Phenotypes for Region: ISCA-37421-Gain were set to Chromosome 1q21.1 duplication syndrome; ncomplete penetrance and variable expression characterized by macrocephaly, developmental delay, intellectual disability, psychiatric disturbances (autism spectrum disorder, attention deficit hyperactivity disorder, schizophrenia, mood disorders) and mild facial dysmorphism (high forehead, hypertelorism). Other associated features include congenital heart defects, hypotonia, short stature, scoliosis; 612475; 1q21.1 microduplication syndrome
Intellectual disability - microarray and sequencing v2.398 ISCA-37423-Gain Louise Daugherty Region: ISCA-37423-Gain was added
Region: ISCA-37423-Gain was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37423-Gain was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37423-Gain were set to 21933911; 23345203
Phenotypes for Region: ISCA-37423-Gain were set to Behavioral problems, cleft lip and/or palate, macrocephaly, and seizures were confirmed as additional features among the new patients, and novel features included neonatal respiratory distress, attention deficit hyperactivity disorder (ADHD), ocular anomalies, balance problems, hypotonia, and hydrocele.; mild to moderate developmental delay, intellectual disability, mild facial dysmorphism (incl. prominent forehead, arched eyebrows, broad nasal bridge, upturned nares, cleft lip and/or palate) and congenital cardiac anomalies (e.g., atrioventricular septal defect). Other reported features include macrocephaly, behavioral abnormalities (e.g., attention deficit disorder), seizures, hypotonia and ocular and digital anomalies (poly/syndactyly); congenital heart disease; 8p23.1 duplication syndrome
Intellectual disability - microarray and sequencing v2.398 ISCA-37423-Loss Louise Daugherty Region: ISCA-37423-Loss was added
Region: ISCA-37423-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37423-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37423-Loss were set to 23239632; 20969981
Phenotypes for Region: ISCA-37423-Loss were set to prenatal and postnatal growth retardation, low birth weight, mild to moderate intellectual deficit, psychomotor retardation, poor speech, seizures, behavioral problems such as hyperactivity and impulsiveness. Frequent craniofacial abnormalities include microcephaly, high and narrow forehead, broad nasal bridge, epicanthic folds, high arched palate, short neck and low set unusually shaped ears. Furthermore congenital heart defects (atrioventricular, septal defects, pulmonary stenosis), congenital diaphragmatic hernia and in boys cryptorchidism and hypospadias have been frequently reported.; congenital heart defects, microcephaly, psychomotor delay and behavioural problems; hyperactivity, craniofacial abnormalities; 8p23.1 microdeletion syndrome; moderate intellectual disability
Intellectual disability - microarray and sequencing v2.398 ISCA-37430-Loss Louise Daugherty Region: ISCA-37430-Loss was added
Region: ISCA-37430-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37430-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for Region: ISCA-37430-Loss were set to microcephaly, dysgenesis of the corpus callosum, and cerebellar atrophy, as well as neurobehavioral disorders, including delayed development, mental retardation, and attention deficit-hyperactivity disorder. Patients with duplications of YWHAE tended to have macrosomia, facial dysmorphism, and mild developmental delay; growth restriction, craniofacial dysmorphisms, structural abnormalities of brain and cognitive impairment; Chromosome 17p13.3 duplication syndrome; prominent forehead, bitemporal hollowing, short nose with upturned nares, protuberant upper lip, thin vermilion border, and small jaw; Characteristic facies, pre- and post-natal growth retardation; 247200; classic lissencephaly (pachygyria, incomplete or absent gyration of the cerebrum), microcephaly, wrinkled skin over the glabella and frontal suture, prominent occiput, narrow forehead, downward slanting palpebral fissures, small nose and chin, cardiac malformations, hypoplastic male extrenal genitalia, growth retardation, and mental deficiency with seizures and EEG abnormalities; Miller-Dieker lissencephaly syndrome
Intellectual disability - microarray and sequencing v2.398 ISCA-37433-Gain Louise Daugherty Region: ISCA-37433-Gain was added
Region: ISCA-37433-Gain was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37433-Gain was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37433-Gain were set to 17250668; 20301749; 18414210
Phenotypes for Region: ISCA-37433-Gain were set to delayed psychomotor development, growth retardation, and/or hypotonia; dysmorphic facial features, cognitive deficits, velopharyngeal insufficiency, congenital heart defects and immunologic derangement; Chromosome 22q11.2 microduplication syndrome; 608363
Intellectual disability - microarray and sequencing v2.398 ISCA-37446-Loss Louise Daugherty Region: ISCA-37446-Loss was added
Region: ISCA-37446-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37446-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for Region: ISCA-37446-Loss were set to cardiac malformations; clefting; neonatal hypocalcemia, which may present as tetany or seizures, due to hypoplasia of the parathyroid glands, and susceptibility to infection due to a deficit of T cells; Velocardiofacial syndrome; DiGeorge syndrome; micrognathia; Hearing deficits
Intellectual disability - microarray and sequencing v2.398 ISCA-37500-Loss Louise Daugherty Region: ISCA-37500-Loss was added
Region: ISCA-37500-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37500-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37500-Loss were set to 23166063; 17847001; 24352913
Phenotypes for Region: ISCA-37500-Loss were set to mild to moderate cognitive deficit; Diamond-Blackfan anemia; intellectual disability; 614294; anemia; congenital diaphragmatic hernia; cryptorchidism in males; severe speech and psychomotor delay; mental retardation; postnatal short stature; behavioral problem; mild dysmorphic feature; developmental delay
Intellectual disability - microarray and sequencing v2.398 ISCA-37400-Gain Louise Daugherty Region: ISCA-37400-Gain was added
Region: ISCA-37400-Gain was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37400-Gain was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37400-Gain were set to 21841781; 18184952; 21731881
Phenotypes for Region: ISCA-37400-Gain were set to 614671; intellectual disability; delayed development; autism; specific deficits in speech or language
Intellectual disability - microarray and sequencing v2.398 ISCA-37408-Loss Louise Daugherty Region: ISCA-37408-Loss was added
Region: ISCA-37408-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37408-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37408-Loss were set to 16963482; 22579565; 18245392
Phenotypes for Region: ISCA-37408-Loss were set to PMID: 16963482 idiopathic intellectual disability including moderate to severe intellectual disability, autism/autistic features, microcephaly, structural brain anomalies including cortical dysplasia/pachygyria, renal anomalies (multicystic kidney, hydronephrosis), digital camptodactyly, visual impairment, strabismus, neuromotor deficits, communication and attention impairments, and a distinctive pattern of craniofacial features. Dysmorphic craniofacial features include progressive microcephaly, flat occiput, widened inner canthal distance, small palpebral fissures, ptosis, long and straight eyelashes, broad and high nasal root extending to a widened, prominent nasal tip with elongated, smooth philtrum, rounding of the upper vermillion border and everted lower lips. PMID: 18245392 A 32-year-old, mentally retarded male was referred to our centre for further clinical genetic analysis. He was born to non-consanguineous parents after 42 weeks gestation with a birth weight of 3500 g. He had a healthy older brother. In the neonatal period he was hypotonic and at 8 weeks of age he underwent surgery because of an inguinal hernia with removal of an atrophic right testis. His motor development was severely delayed with sitting at 3.5 years and walking at 5 years of age. Speech was poorly developed, characterised by the usage of only a few words. During infancy an optic nerve hypoplasia was diagnosed, and during childhood he frequently suffered from luxations of the patellae, which required surgery. At the age of 32 years his height is 163 cm (_3 SDS) and head circumference 52.5 cm (_2.5 SDS). He has a narrow receding forehead, widened inner canthal distance of 3.5 cm (90th centile), normal outer canthal distance of 8.5 cm (25th centile), telecanthus, short and down slanting palpebral fissures, epicanthal folds, ptosis, long, straight eyelashes, high nasal bridge, low set large ears, flat philtrum, small mouth with high, narrow palate and retrognathia. The thorax is broad with increased internipple distance and slight gynaecomastia. A recent renal ultrasound revealed multiple cysts in the left, dystrophic kidney and two uncomplicated cysts in the enlarged, right kidney. The patient has a normally sized phallus with absent right testis and small left testis. His hands show a simian crease right and tapering fingers with broad proximal interphalangeal joints. He shows sandal gaps on both flat feet with clinodactyly of the fourth and fifth toes (and more); 612513; PMID: 22579565 severe developmental delay, congenital microcephaly, intractable epilepsy, and renal anomalies, as well as a congenital choledochal cyst which has not been previously reported in other patients with this cytogenetic defect
Intellectual disability - microarray and sequencing v2.398 ISCA-37411-Loss Louise Daugherty Region: ISCA-37411-Loss was added
Region: ISCA-37411-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37411-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37411-Loss were set to 19289393; 19136953; 18278044
Phenotypes for Region: ISCA-37411-Loss were set to PMID: 19289393 incomplete penetrance for developmental delay, mental retardation, or borderline IQ in most and autistic spectrum disorder (6/14), speech delay, aggressiveness, attention deficit hyperactivity disorder, and other behavioural problems; 612001; PMID: 18278044 mental retardation, epilepsy and variable facial and digital dysmorphisms; PMID: 19136953 idiopathic generalized epilepsy without other features previously associated with 15q13.3 microdeletions, such as intellectual disability, autism or schizophrenia
Intellectual disability - microarray and sequencing CIT Richard Scott marked CIT as ready
Intellectual disability - microarray and sequencing CIT Richard Scott classified CIT as green
Intellectual disability - microarray and sequencing CIT Richard Scott added CIT to panel
Intellectual disability - microarray and sequencing CIT Richard Scott reviewed CIT