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Severe microcephaly v4.67 BRD4 Arina Puzriakova Phenotypes for gene: BRD4 were changed from Cornelia de Lange-like syndrome, MONDO:0016033 to Cornelia de Lange syndrome 6, OMIM:620568
Severe microcephaly v4.66 STAMBP Arina Puzriakova Phenotypes for gene: STAMBP were changed from Microcephaly-capillary malformation syndrome 614261 to Microcephaly-capillary malformation syndrome, OMIM:614261
Severe microcephaly v4.65 NHEJ1 Arina Puzriakova Phenotypes for gene: NHEJ1 were changed from Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation 611291 to Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation, OMIM:611291
Severe microcephaly v4.64 AKT3 Sarah Leigh reviewed gene: AKT3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe microcephaly v4.64 AKT3 Sarah Leigh Classified gene: AKT3 as Amber List (moderate evidence)
Severe microcephaly v4.64 AKT3 Sarah Leigh Gene: akt3 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v4.63 CAMSAP1 Achchuthan Shanmugasundram changed review comment from: Seven children from five unrelated families were identified with either homozygous or compound heterozygous CAMSAP1 variants and were reported with a severe neurodevelopmental disorder apparent from infancy. Clinical features of the syndrome include a characteristic craniofacial appearance, primary microcephaly, lissencephaly, agenesis or severe hypogenesis of the corpus callosum, severe or profound global developmental delay, cortical visual impairment, and seizures.

This gene has been associated with relevant phenotypes in both OMIM (MIM #620316) and in Gene2Phenotype (with 'moderate' rating in the DD panel).
Sources: Literature; to: Seven children from five unrelated families were identified with either homozygous or compound heterozygous CAMSAP1 variants and were reported with a severe neurodevelopmental disorder apparent from infancy. Clinical features of the syndrome include a characteristic craniofacial appearance, primary microcephaly, lissencephaly, agenesis or severe hypogenesis of the corpus callosum, severe or profound global developmental delay, cortical visual impairment, and seizures. Microcephaly was severe in five children from four families.

This gene has been associated with relevant phenotypes in both OMIM (MIM #620316) and in Gene2Phenotype (with 'moderate' rating in the DD panel).
Sources: Literature
Severe microcephaly v4.63 CAMSAP1 Achchuthan Shanmugasundram Classified gene: CAMSAP1 as Amber List (moderate evidence)
Severe microcephaly v4.63 CAMSAP1 Achchuthan Shanmugasundram Gene: camsap1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v4.62 CAMSAP1 Achchuthan Shanmugasundram Classified gene: CAMSAP1 as Red List (low evidence)
Severe microcephaly v4.62 CAMSAP1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Severe microcephaly v4.62 CAMSAP1 Achchuthan Shanmugasundram Gene: camsap1 has been classified as Red List (Low Evidence).
Severe microcephaly v4.61 CAMSAP1 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: CAMSAP1.
Severe microcephaly v4.61 CAMSAP1 Achchuthan Shanmugasundram gene: CAMSAP1 was added
gene: CAMSAP1 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: CAMSAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAMSAP1 were set to 36283405
Phenotypes for gene: CAMSAP1 were set to Cortical dysplasia, complex, with other brain malformations 12, OMIM:620316
Review for gene: CAMSAP1 was set to GREEN
Added comment: Seven children from five unrelated families were identified with either homozygous or compound heterozygous CAMSAP1 variants and were reported with a severe neurodevelopmental disorder apparent from infancy. Clinical features of the syndrome include a characteristic craniofacial appearance, primary microcephaly, lissencephaly, agenesis or severe hypogenesis of the corpus callosum, severe or profound global developmental delay, cortical visual impairment, and seizures.

This gene has been associated with relevant phenotypes in both OMIM (MIM #620316) and in Gene2Phenotype (with 'moderate' rating in the DD panel).
Sources: Literature
Severe microcephaly v4.60 ZNF335 Achchuthan Shanmugasundram Tag Q1_24_MOI tag was added to gene: ZNF335.
Tag Q1_24_expert_review tag was added to gene: ZNF335.
Severe microcephaly v4.60 ZNF335 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: Other than the one case that was reported by Chicago lab with ZNF335 heterozygous variant (c.2515_2518dupGCCA/ p.Thr840Serfs) and with microcephaly, encephalopathy and developmental delay, all other cases reported in the literature and ClinVar had biallelic variants in ZNF335. Hence, the MOI should be updated to "BIALLELIC, autosomal or pseudoautosomal" in the next GMS review.
Severe microcephaly v4.60 ZNF335 Achchuthan Shanmugasundram Mode of inheritance for gene: ZNF335 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Severe microcephaly v4.59 ZNF335 Achchuthan Shanmugasundram edited their review of gene: ZNF335: Changed rating: GREEN
Severe microcephaly v4.59 ZNF335 Achchuthan Shanmugasundram reviewed gene: ZNF335: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v4.59 ASPM Arina Puzriakova Publications for gene: ASPM were set to
Severe microcephaly v4.58 ASPM Arina Puzriakova Phenotypes for gene: ASPM were changed from Microcephaly 5, primary, autosomal recessive; MCPH; primary microcephaly; Primary Microcephaly, Recessive; Autosomal recessive primary microcephaly (MCPH) ; Microcephaly 5, primary, autosomal recessive, 608716; Microcephaly 5, Primary, Autosomal Recessive to Microcephaly 5, primary, autosomal recessive, OMIM:608716
Severe microcephaly v4.57 WDR62 Arina Puzriakova Publications for gene: WDR62 were set to
Severe microcephaly v4.56 WDR62 Arina Puzriakova Phenotypes for gene: WDR62 were changed from MCPH; primary microcephaly; Primary Microcephaly 2 With or Without Cortical Malformations; Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, 604317; microcephaly cortical malformations and mental retardation (MCMMR), 604317; Microcephaly 2, Primary, Autosomal Recessive, With Or Without Cortical Malformations to Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, OMIM:604317
Severe microcephaly v4.55 MCPH1 Arina Puzriakova Publications for gene: MCPH1 were set to
Severe microcephaly v4.54 MCPH1 Arina Puzriakova Phenotypes for gene: MCPH1 were changed from MCPH; primary microcephaly; Primary Microcephaly, Recessive; Microcephaly 1, primary, autosomal recessive, 251200; Microcephaly 1, Primary, Autosomal Recessive to Microcephaly 1, primary, autosomal recessive, OMIM:251200
Severe microcephaly v4.53 ZNF335 Dmitrijs Rots reviewed gene: ZNF335: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe microcephaly v4.53 ACBD6 Arina Puzriakova Entity copied from Intellectual disability - microarray and sequencing v5.405
Severe microcephaly v4.53 ACBD6 Arina Puzriakova gene: ACBD6 was added
gene: ACBD6 was added to Severe microcephaly. Sources: Expert Review Amber
Q1_24_promote_green tags were added to gene: ACBD6.
Mode of inheritance for gene: ACBD6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACBD6 were set to 21937992; 32108178; 36457943; 37951597
Phenotypes for gene: ACBD6 were set to Neurodevelopmental disorder, MONDO:0700092
Penetrance for gene: ACBD6 were set to Complete
Severe microcephaly v4.52 MECP2 Achchuthan Shanmugasundram Classified gene: MECP2 as Amber List (moderate evidence)
Severe microcephaly v4.52 MECP2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is sufficient evidence available for the association of MECP2 with severe microcephaly, this gene can be promoted to green rating in the next GMS review.
Severe microcephaly v4.52 MECP2 Achchuthan Shanmugasundram Gene: mecp2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v4.51 MECP2 Achchuthan Shanmugasundram Phenotypes for gene: MECP2 were changed from Rett syndrome, MIM# 312750; Encephalopathy, neonatal severe 300673 to Rett syndrome, OMIM:312750; Encephalopathy, neonatal severe, OMIM:300673; Intellectual developmental disorder, X-linked syndromic 13, OMIM:300055; Intellectual developmental disorder, X-linked syndromic, Lubs type, OMIM:300260
Severe microcephaly v4.50 MECP2 Achchuthan Shanmugasundram Publications for gene: MECP2 were set to
Severe microcephaly v4.49 MECP2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: MECP2.
Severe microcephaly v4.49 MECP2 Achchuthan Shanmugasundram reviewed gene: MECP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32393352, 34351885; Phenotypes: Rett syndrome, OMIM:312750, Encephalopathy, neonatal severe, OMIM:300673, Intellectual developmental disorder, X-linked syndromic 13, OMIM:300055, Intellectual developmental disorder, X-linked syndromic, Lubs type, OMIM:300260; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Severe microcephaly v4.49 COG3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated families reported with biallelic COG3 variants and hence this gene should be rated amber with current evidence.; to: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated families reported with biallelic COG3 variants. Microcephaly was severe (-4 to -6 SD) in all three patients measured and hence this gene should be rated amber with current evidence.
Severe microcephaly v4.49 COG3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated cases reported with biallelic COG3 variants and hence this gene should be rated amber with current evidence.; to: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated families reported with biallelic COG3 variants and hence this gene should be rated amber with current evidence.
Severe microcephaly v4.49 COG3 Achchuthan Shanmugasundram Entity copied from Congenital disorders of glycosylation v4.16
Severe microcephaly v4.49 COG3 Achchuthan Shanmugasundram gene: COG3 was added
gene: COG3 was added to Severe microcephaly. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: COG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COG3 were set to 37711075
Phenotypes for gene: COG3 were set to Congenital disorder of glycosylation, type IIbb, OMIM:620546
Severe microcephaly v4.48 DPP6 Achchuthan Shanmugasundram Tag Q4_21_expert_review was removed from gene: DPP6.
Tag Q4_21_rating was removed from gene: DPP6.
Severe microcephaly v4.48 PSMC3 Achchuthan Shanmugasundram Classified gene: PSMC3 as Amber List (moderate evidence)
Severe microcephaly v4.48 PSMC3 Achchuthan Shanmugasundram Gene: psmc3 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v4.47 PSMC3 Achchuthan Shanmugasundram changed review comment from: 23 individuals with neurodevelopmental disorder were identified with 15 different de novo missense variants. Microcephaly was reported in in 6/17 (35%) cases, of which severe macrocephaly was in 2/16 (13%) cases.
Sources: Literature; to: 23 individuals with neurodevelopmental disorder were identified with 15 different de novo missense variants. Microcephaly was reported in in 6/17 (35%) cases, of which severe macrocephaly was in 2/16 (13%) cases.
Sources: Literature
Severe microcephaly v4.47 PSMC3 Achchuthan Shanmugasundram gene: PSMC3 was added
gene: PSMC3 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: PSMC3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PSMC3 were set to 37256937
Phenotypes for gene: PSMC3 were set to neurodevelopmental disorder, MONDO:0700092; microcephaly, MONDO:0001149
Review for gene: PSMC3 was set to AMBER
Added comment: 23 individuals with neurodevelopmental disorder were identified with 15 different de novo missense variants. Microcephaly was reported in in 6/17 (35%) cases, of which severe macrocephaly was in 2/16 (13%) cases.
Sources: Literature
Severe microcephaly v4.46 KMT2B Arina Puzriakova Tag Q3_23_promote_green was removed from gene: KMT2B.
Tag Q4_23_promote_green tag was added to gene: KMT2B.
Severe microcephaly v4.46 KMT2B Arina Puzriakova changed review comment from: At least 80 patients have been reported with either KMT2B intragenic variants or chromosomal microdeletions. Clinical presentation most commonly comprises early-onset dystonia, but there were also reports of atypical patterns of dystonia evolution and a subgroup of patients with a neurodevelopmental disorder in the absence of dystonia.

Microcephaly of relevant severity to this panel has been reported in a sufficient number of cases to warrant inclusion on this panel with a Green rating.
Sources: Literature; to: At least 80 patients have been reported with either KMT2B intragenic variants or chromosomal microdeletions. Clinical presentation most commonly comprises early-onset dystonia, but there were also reports of atypical patterns of dystonia evolution and a subgroup of patients with a neurodevelopmental disorder in the absence of dystonia.

Microcephaly of relevant severity to this panel has been reported in a sufficient number of cases to warrant inclusion on this panel with a Green rating at the next GMS panel update.
Sources: Literature
Severe microcephaly v4.46 KMT2B Arina Puzriakova Classified gene: KMT2B as Amber List (moderate evidence)
Severe microcephaly v4.46 KMT2B Arina Puzriakova Gene: kmt2b has been classified as Amber List (Moderate Evidence).
Severe microcephaly v4.45 KMT2B Arina Puzriakova gene: KMT2B was added
gene: KMT2B was added to Severe microcephaly. Sources: Literature
Q3_23_promote_green tags were added to gene: KMT2B.
Mode of inheritance for gene: KMT2B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KMT2B were set to 27839873; 27839873; 33150406
Phenotypes for gene: KMT2B were set to Dystonia 28, childhood-onset, OMIM:617284; Intellectual developmental disorder, autosomal dominant 68, OMIM:619934
Review for gene: KMT2B was set to GREEN
Added comment: At least 80 patients have been reported with either KMT2B intragenic variants or chromosomal microdeletions. Clinical presentation most commonly comprises early-onset dystonia, but there were also reports of atypical patterns of dystonia evolution and a subgroup of patients with a neurodevelopmental disorder in the absence of dystonia.

Microcephaly of relevant severity to this panel has been reported in a sufficient number of cases to warrant inclusion on this panel with a Green rating.
Sources: Literature
Severe microcephaly v4.44 NSD2 Sarah Leigh changed review comment from: Microcephaly is well recognized as a feature associated with pathogenic NSD2 variants. Of the published reports of microcephaly 50% (7/14) can be regarded as being severe, with a occipitofrontal circumference (OFC) below -3.0 standard deviations below the mean for age (PMID: 33941880 (including a review of previously published reports S4 table, PMID: 33276791).; to: Microcephaly is well recognized as a feature associated with pathogenic NSD2 variants. PMID: 33941880 reports three NSD2 variants in three unrelated cases of Rauch-Steindl syndrome (OMIM:619695), who have severe microcephaly (Occipitofrontal circumference (OFC) below >3.0 SD). Similarly, PMID: 33276791 reports a case with
OFC of 44 cm (<−3SD). Further cases are examined in the supplementary table 4 in PMID: 33941880
Severe microcephaly v4.44 NSD2 Sarah Leigh Classified gene: NSD2 as Amber List (moderate evidence)
Severe microcephaly v4.44 NSD2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be green on this panel.
Severe microcephaly v4.44 NSD2 Sarah Leigh Gene: nsd2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v4.43 NSD2 Sarah Leigh Tag Q4_23_promote_green tag was added to gene: NSD2.
Severe microcephaly v4.43 NSD2 Sarah Leigh reviewed gene: NSD2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe microcephaly v4.43 NSD2 Sarah Leigh Phenotypes for gene: NSD2 were changed from microcephaly, MONDO:0001149 to Rauch-Steindl syndrome, OMIM:619695; Rauch-Steindl syndrome, MONDO:0859219
Severe microcephaly v4.42 NSD2 Sarah Leigh Publications for gene: NSD2 were set to 30345613; 31171569; 29760529; 29892088
Severe microcephaly v4.41 ARF3 Achchuthan Shanmugasundram Classified gene: ARF3 as Amber List (moderate evidence)
Severe microcephaly v4.41 ARF3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated cases reported with severe microcephaly. Hence, this gene can be promoted to green rating in this panel in the next GMS review.
Severe microcephaly v4.41 ARF3 Achchuthan Shanmugasundram Gene: arf3 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v4.40 ARF3 Achchuthan Shanmugasundram Publications for gene: ARF3 were set to 34346499
Severe microcephaly v4.39 ARF3 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: ARF3.
Severe microcephaly v4.39 ARF3 Achchuthan Shanmugasundram reviewed gene: ARF3: Rating: GREEN; Mode of pathogenicity: None; Publications: 36369169; Phenotypes: neurodevelopmental disorder, MONDO:0700092, microcephaly, MONDO:0001149; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Severe microcephaly v4.37 BUB1 Eleanor Williams commented on gene: BUB1
Severe microcephaly v4.37 BUB1 Eleanor Williams Tag Q4_22_promote_green was removed from gene: BUB1.
Tag Q4_23_promote_green tag was added to gene: BUB1.
Severe microcephaly v4.37 SPATA5L1 Achchuthan Shanmugasundram commented on gene: SPATA5L1
Severe microcephaly v4.37 PPFIBP1 Arina Puzriakova Tag Q2_23_promote_green was removed from gene: PPFIBP1.
Tag Q4_23_promote_green tag was added to gene: PPFIBP1.
Severe microcephaly v4.37 PPFIBP1 Arina Puzriakova Entity copied from Early onset or syndromic epilepsy v4.107
Severe microcephaly v4.37 PPFIBP1 Arina Puzriakova gene: PPFIBP1 was added
gene: PPFIBP1 was added to Severe microcephaly. Sources: Literature,Expert Review Amber
Q2_23_promote_green tags were added to gene: PPFIBP1.
Mode of inheritance for gene: PPFIBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPFIBP1 were set to 35830857; 30214071
Phenotypes for gene: PPFIBP1 were set to Neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities, OMIM:620024
Penetrance for gene: PPFIBP1 were set to Complete
Severe microcephaly v4.36 MED11 Arina Puzriakova Phenotypes for gene: MED11 were changed from MED11-associated neurodevelopmental disorder to Neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities, OMIM:620327
Severe microcephaly v4.35 INTS11 Arina Puzriakova Phenotypes for gene: INTS11 were changed from Complex neurodevelopmental disorder, MONDO:0100038 to Neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities, OMIM:620428
Severe microcephaly v4.34 DOHH Arina Puzriakova Phenotypes for gene: DOHH were changed from DOHH associated neurodevelopmental disorder to Neurodevelopmental disorder with microcephaly, cerebral atrophy, and visual impairment, OMIM:620066
Severe microcephaly v4.33 WLS Sarah Leigh Tag Q2_23_promote_green was removed from gene: WLS.
Severe microcephaly v4.33 TRAPPC10 Sarah Leigh Tag Q2_23_promote_green was removed from gene: TRAPPC10.
Severe microcephaly v4.33 SARS Sarah Leigh Tag Q1_23_promote_green was removed from gene: SARS.
Severe microcephaly v4.33 NUP214 Sarah Leigh Tag Q1_23_promote_green was removed from gene: NUP214.
Severe microcephaly v4.33 INTS11 Sarah Leigh Tag Q2_23_promote_green was removed from gene: INTS11.
Severe microcephaly v4.33 GRM7 Sarah Leigh Tag Q2_23_promote_green was removed from gene: GRM7.
Severe microcephaly v4.33 DOHH Sarah Leigh Tag Q4_22_MOI was removed from gene: DOHH.
Tag Q4_22_promote_green was removed from gene: DOHH.
Severe microcephaly v4.33 ARPC4 Sarah Leigh Tag Q2_23_promote_green was removed from gene: ARPC4.
Severe microcephaly v4.33 WLS Sarah Leigh reviewed gene: WLS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v4.33 TRAPPC10 Sarah Leigh reviewed gene: TRAPPC10: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v4.33 SARS Sarah Leigh reviewed gene: SARS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v4.33 NUP214 Sarah Leigh edited their review of gene: NUP214: Added comment: The rating of this gene has been updated to Green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v4.33 INTS11 Sarah Leigh reviewed gene: INTS11: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v4.33 GRM7 Sarah Leigh reviewed gene: GRM7: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v4.33 DOHH Sarah Leigh commented on gene: DOHH: The rating of this gene has been updated to Green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Severe microcephaly v4.33 ARPC4 Sarah Leigh reviewed gene: ARPC4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe microcephaly v4.32 WLS Sarah Leigh Source Expert Review Green was added to WLS.
Source NHS GMS was added to WLS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v4.32 TRAPPC10 Sarah Leigh Source Expert Review Green was added to TRAPPC10.
Source NHS GMS was added to TRAPPC10.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v4.32 SARS Sarah Leigh Source Expert Review Green was added to SARS.
Source NHS GMS was added to SARS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v4.32 NUP214 Sarah Leigh Source Expert Review Green was added to NUP214.
Source NHS GMS was added to NUP214.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v4.32 INTS11 Sarah Leigh Source Expert Review Green was added to INTS11.
Source NHS GMS was added to INTS11.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v4.32 GRM7 Sarah Leigh Source Expert Review Green was added to GRM7.
Source NHS GMS was added to GRM7.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v4.32 DOHH Sarah Leigh Source Expert Review Green was added to DOHH.
Source NHS GMS was added to DOHH.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v4.32 ARPC4 Sarah Leigh Source Expert Review Green was added to ARPC4.
Source NHS GMS was added to ARPC4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v4.31 SPATA5L1 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: SPATA5L1.
Severe microcephaly v4.31 ATP6V0C Achchuthan Shanmugasundram Tag watchlist was removed from gene: ATP6V0C.
Tag Q3_23_promote_green tag was added to gene: ATP6V0C.
Tag Q3_23_NHS_review tag was added to gene: ATP6V0C.
Severe microcephaly v4.31 ATP6V0C Achchuthan Shanmugasundram Classified gene: ATP6V0C as Amber List (moderate evidence)
Severe microcephaly v4.31 ATP6V0C Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for promoting this gene to green rating in the next GMS review.
Severe microcephaly v4.31 ATP6V0C Achchuthan Shanmugasundram Gene: atp6v0c has been classified as Amber List (Moderate Evidence).
Severe microcephaly v4.30 ATP6V0C Achchuthan Shanmugasundram Phenotypes for gene: ATP6V0C were changed from Epilepsy; Intellectual Disability; microcephaly to Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465
Severe microcephaly v4.29 ATP6V0C Achchuthan Shanmugasundram Publications for gene: ATP6V0C were set to 33190975; 33090716
Severe microcephaly v4.28 ATP6V0C Achchuthan Shanmugasundram reviewed gene: ATP6V0C: Rating: GREEN; Mode of pathogenicity: None; Publications: 36074901; Phenotypes: Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe microcephaly v4.28 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
Severe microcephaly v4.28 BUB1 Arina Puzriakova Entity copied from Intellectual disability - microarray and sequencing v5.205
Severe microcephaly v4.28 BUB1 Arina Puzriakova gene: BUB1 was added
gene: BUB1 was added to Severe microcephaly. Sources: Expert Review Amber,Literature
Q4_22_promote_green tags were added to gene: BUB1.
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 Microcephaly 30, primary, autosomal recessive, OMIM:620183
Penetrance for gene: BUB1 were set to Complete
Severe microcephaly v4.27 TTI1 Sarah Leigh Classified gene: TTI1 as Amber List (moderate evidence)
Severe microcephaly v4.27 TTI1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Severe microcephaly v4.27 TTI1 Sarah Leigh Gene: tti1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v4.26 TTI1 Sarah Leigh Tag Q3_23_promote_green tag was added to gene: TTI1.
Severe microcephaly v4.26 TTI1 Sarah Leigh gene: TTI1 was added
gene: TTI1 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: TTI1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTI1 were set to 36724785
Phenotypes for gene: TTI1 were set to neurodevelopmental disorder with microcephaly
Review for gene: TTI1 was set to GREEN
Added comment: TTI1 has not previously been associated with a phenotype in OMIM, Gen2Phen or MONDO. At least 2 variants have been reported. PMID: 36724785 reported 15 TTI1 variants as either homozygotes (2 families) or compound heterozygotes (7 families) in cases with a neurodevelopmental disorder with microcephaly. In all cases the parents were heterozygous carriers of the TTI1 variant identified in the affected child. Development delay was observed in all of the families (9/9), moderate to severe intellectual disability was evident in all families where it could be assessed (8/8) and severe microcephaly was present in members of 5/9 families. Supportive functional results were also presented.
Sources: Literature
Severe microcephaly v4.25 GRM7 Achchuthan Shanmugasundram Tag Q2_23_promote_green tag was added to gene: GRM7.
Severe microcephaly v4.25 GRM7 Achchuthan Shanmugasundram Classified gene: GRM7 as Amber List (moderate evidence)
Severe microcephaly v4.25 GRM7 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (three unrelated cases with severe microcephaly) for this gene to be promoted to GREEN rating at the next GMS review.
Severe microcephaly v4.25 GRM7 Achchuthan Shanmugasundram Gene: grm7 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v4.24 GRM7 Achchuthan Shanmugasundram Publications for gene: GRM7 were set to 2248644; 32286009
Severe microcephaly v4.23 GRM7 Achchuthan Shanmugasundram edited their review of gene: GRM7: Changed publications to: 32286009
Severe microcephaly v4.23 GRM7 Achchuthan Shanmugasundram changed review comment from: PMID:32286009 reported eleven individuals from six unrelated families identified with three different biallelic variants and presenting with a neurodevelopmental disorder comprising severe to profound global developmental delays, intellectual disability, seizures, hypotonia, microcephaly and brain abnormalities. This is also supported by functional evidence from knockout mouse models, where absence of metabotropic glutamate receptor 7 alters the phenotypes within the domains of social behavior, associative learning, motor function, epilepsy and sleep (PMID:32248644).

This gene has also been associated with relevant phenotypes in both OMIM (MIM #618922) and in Gene2Phenotype (with 'strong' rating in the DD panel).
Sources: Literature; to: PMID:32286009 reported eleven individuals from six unrelated families identified with three different biallelic variants and presenting with a neurodevelopmental disorder comprising severe to profound global developmental delays, intellectual disability, seizures, hypotonia, microcephaly and brain abnormalities. Head circumference measurements at time of last visit were available in eight individuals (from six families) and were consistent with microcephaly (−3.8 to −2.7 SD from mean for age). Of these four individuals from three families had severe microcephaly (head circumference beyond 3 SD from mean for age).

This gene has also been associated with relevant phenotypes in both OMIM (MIM #618922) and in Gene2Phenotype (with 'strong' rating in the DD panel).
Sources: Literature
Severe microcephaly v4.23 GRM7 Achchuthan Shanmugasundram edited their review of gene: GRM7: Changed publications to: 32248644, 32286009
Severe microcephaly v4.23 GRM7 Achchuthan Shanmugasundram gene: GRM7 was added
gene: GRM7 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: GRM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GRM7 were set to 2248644; 32286009
Phenotypes for gene: GRM7 were set to Neurodevelopmental disorder with seizures, hypotonia, and brain abnormalities, OMIM:618922
Review for gene: GRM7 was set to GREEN
Added comment: PMID:32286009 reported eleven individuals from six unrelated families identified with three different biallelic variants and presenting with a neurodevelopmental disorder comprising severe to profound global developmental delays, intellectual disability, seizures, hypotonia, microcephaly and brain abnormalities. This is also supported by functional evidence from knockout mouse models, where absence of metabotropic glutamate receptor 7 alters the phenotypes within the domains of social behavior, associative learning, motor function, epilepsy and sleep (PMID:32248644).

This gene has also been associated with relevant phenotypes in both OMIM (MIM #618922) and in Gene2Phenotype (with 'strong' rating in the DD panel).
Sources: Literature
Severe microcephaly v4.22 FILIP1 Achchuthan Shanmugasundram Tag watchlist tag was added to gene: FILIP1.
Severe microcephaly v4.22 FILIP1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are two unrelated cases reported with severe microcephaly and three additional cases with microcephaly. Hence, this gene should be rated amber in this panel with the current evidence. 'watchlist' tag has been added to review the rating in the future new evidence.; to: Comment on list classification: There are two unrelated cases reported with severe microcephaly and three additional cases with microcephaly. Hence, this gene should be rated amber in this panel with the current evidence. The 'watchlist' tag has been added to review the rating in the future with any new evidence.
Severe microcephaly v4.22 FILIP1 Achchuthan Shanmugasundram Classified gene: FILIP1 as Amber List (moderate evidence)
Severe microcephaly v4.22 FILIP1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated cases reported with severe microcephaly and three additional cases with microcephaly. Hence, this gene should be rated amber in this panel with the current evidence. 'watchlist' tag has been added to review the rating in the future new evidence.
Severe microcephaly v4.22 FILIP1 Achchuthan Shanmugasundram Gene: filip1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v4.21 FILIP1 Achchuthan Shanmugasundram gene: FILIP1 was added
gene: FILIP1 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: FILIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FILIP1 were set to 36943452; 37163662
Phenotypes for gene: FILIP1 were set to microcephaly, MONDO:0001149
Review for gene: FILIP1 was set to AMBER
Added comment: PMID:36943452 reported five individuals from three unrelated families with three different biallelic variants in FILIP1 gene (including the variant reported in the patient from PMID:36344539) and presenting with an overlapping phenotype with congenital contractures affecting shoulder, elbow, hand, hip, knee and foot as well as scoliosis, reduced palmar and plantar skin folds, microcephaly and facial dysmorphism. Of these five patients, two unrelated patients had severe microcephaly (head circumference beyond 3 SD below the mean for age) and one patient from the family with three patients also had microcephaly (head circumference beyond 2 SD below the mean for age).

PMID:37163662 reported five individuals from four unrelated families with four different biallelic variants in FILIP1 gene. The main symptoms in childhood included delayed motor milestones (all four families), delayed speech development (three families), intellectual disability (three families), contractures (2 families), clubfeet (2 families) and microcephaly (2 families). One of these cases only had borderline microcephaly (3rd percentile) and the other had OFC below 3rd percentile.
Sources: Literature
Severe microcephaly v4.20 TRA2B Achchuthan Shanmugasundram Classified gene: TRA2B as Amber List (moderate evidence)
Severe microcephaly v4.20 TRA2B Achchuthan Shanmugasundram Added comment: Comment on list classification: There are only two unrelated cases with severe microcephaly. Hence, this gene should be rated AMBER.
Severe microcephaly v4.20 TRA2B Achchuthan Shanmugasundram Gene: tra2b has been classified as Amber List (Moderate Evidence).
Severe microcephaly v4.19 TRA2B Achchuthan Shanmugasundram Phenotypes for gene: TRA2B were changed from neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027 to neurodevelopmental disorder, MONDO:0700092; microcephaly, MONDO:0001149
Severe microcephaly v4.18 TRA2B Achchuthan Shanmugasundram changed review comment from: This gene has already been associated with phenotypes in Gene2Phenotype (with 'moderate' rating in the DD panel), but not in OMIM.
Sources: Literature; to: PMID:36549593 reported 12 individuals from 11 unrelated families identified with 11 different heterozygous variants in TRA2B gene. The variants arose de novo in 10 families, while the variant was inherited from father to son in one family. 6 variants were expected to disrupt the translation start site in exon 1 (start-loss variants), 3 were expected to disrupt the splicing process at the exon 2/3 boundary (splice-affecting variants), and the remaining 2 were expected to produce a premature stop codon (truncating variants).

These patients presented with a neurodevelopmental disorder comprising developmental delay/ intellectual disability (in all patients), axial or global hypotonia (10 patients), delayed motor milestones (all patients), behavioural issues (8 patients), speech impairment (9 patients), epilepsy (7 patients, initial presentation as infantile spasms in 6 and unclassified epileptic encephalopathy in 1), brain abnormalities (10 patients) and microcephaly (5 patients). Of 5 unrelated cases with microcephaly, only two cases had severe microcephaly (head circumference beyond 3 standard deviations below the mean for the age).

In addition, functional studies in mice showed that heterozygous knockout mice developed normal, while complete knockout mice cannot develop embryonically.

This gene has already been associated with phenotypes in Gene2Phenotype (with 'moderate' rating in the DD panel), but not in OMIM.
Sources: Literature
Severe microcephaly v4.18 TRA2B Achchuthan Shanmugasundram edited their review of gene: TRA2B: Changed rating: AMBER; Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092, microcephaly, MONDO:0001149
Severe microcephaly v4.18 TRA2B Achchuthan Shanmugasundram gene: TRA2B was added
gene: TRA2B was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: TRA2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRA2B were set to 36549593
Phenotypes for gene: TRA2B were set to neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027
Review for gene: TRA2B was set to GREEN
Added comment: This gene has already been associated with phenotypes in Gene2Phenotype (with 'moderate' rating in the DD panel), but not in OMIM.
Sources: Literature
Severe microcephaly v4.17 ARPC4 Achchuthan Shanmugasundram Tag Q2_23_promote_green tag was added to gene: ARPC4.
Severe microcephaly v4.17 ARPC4 Achchuthan Shanmugasundram Classified gene: ARPC4 as Amber List (moderate evidence)
Severe microcephaly v4.17 ARPC4 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence for this gene to be rated GREEN at the next GMS review.
Severe microcephaly v4.17 ARPC4 Achchuthan Shanmugasundram Gene: arpc4 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v4.16 ARPC4 Achchuthan Shanmugasundram Phenotypes for gene: ARPC4 were changed from Microcephaly; mild motor delays; significant speech impairment to Developmental delay, language impairment, and ocular abnormalities, OMIM:620141; microcephaly, MONDO:0001149
Severe microcephaly v4.15 ARPC4 Achchuthan Shanmugasundram Publications for gene: ARPC4 were set to DOI:https://doi.org/10.1016/j.xhgg.2021.100072
Severe microcephaly v4.14 ARPC4 Achchuthan Shanmugasundram commented on gene: ARPC4: As reviewed by Zornitza Stark, PMID:35047857 reported seven cases from six unrelated families with the same missense variant (p.Arg158Cys) and presenting with developmental and speech delays, of which six individuals from five families presented with microcephaly. Three individuals from two of these families had severe microcephaly with occipitofrontal circumference (OFC) beyond 3 standard deviations below the mean for age. In addition, functional studies showed that the variant is associated with a decreased amount of F-actin in cells from two affected individuals.

This gene has been associated with relevant phenotypes in both OMIM (MIM #620141) and Gene2Phenotype (ARPC4-related microcephaly and developmental delay with 'strong' rating in the DD panel).
Severe microcephaly v4.14 ARPC4 Achchuthan Shanmugasundram reviewed gene: ARPC4: Rating: GREEN; Mode of pathogenicity: None; Publications: 35047857; Phenotypes: Developmental delay, language impairment, and ocular abnormalities, OMIM:620141, microcephaly, MONDO:0001149; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe microcephaly v4.14 COASY Sarah Leigh Publications for gene: COASY were set to 30089828; 24360804; 27892483
Severe microcephaly v4.13 INTS11 Arina Puzriakova Entity copied from Intellectual disability - microarray and sequencing v5.151
Severe microcephaly v4.13 INTS11 Arina Puzriakova gene: INTS11 was added
gene: INTS11 was added to Severe microcephaly. Sources: Expert Review Amber,Literature
Q2_23_promote_green tags were added to gene: INTS11.
Mode of inheritance for gene: INTS11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INTS11 were set to 37054711
Phenotypes for gene: INTS11 were set to Complex neurodevelopmental disorder, MONDO:0100038
Severe microcephaly v4.12 BLM Arina Puzriakova Phenotypes for gene: BLM were changed from MPD; microcephalic primordial dwarfism; Bloom syndrome, 210900; microcephaly to Bloom syndrome, OMIM:210900
Severe microcephaly v4.11 LHX2 Sarah Leigh Tag Q2_23_promote_green was removed from gene: LHX2.
Severe microcephaly v4.11 LHX2 Sarah Leigh changed review comment from: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 37057675 reports 17 predominanly de novo LHX2 variants in a panel of patients with a variable neurodevelopmental disorder. Haploinsufficiency and functional studies are supportive of a loss-of-function pathogenic action of the reported LHX2 variants.
Sources: Literature; to: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 37057675 reports 17 predominantly de novo LHX2 variants in a panel of patients with a variable neurodevelopmental disorder. Haploinsufficiency and functional studies are supportive of a loss-of-function pathogenic action of the reported LHX2 variants.
Seven out of the ten cases reported in table 1 (PMID: 37057675) are listed as having microcephaly, however, due to lack of clinical information, these cases cannot be classified as severe (personal communication with the author, Christiane Zweier).
Sources: Literature
Severe microcephaly v4.11 LHX2 Sarah Leigh Deleted their comment
Severe microcephaly v4.11 LHX2 Sarah Leigh edited their review of gene: LHX2: Changed rating: AMBER
Severe microcephaly v4.11 LHX2 Sarah Leigh Entity copied from Intellectual disability - microarray and sequencing v5.124
Severe microcephaly v4.11 LHX2 Sarah Leigh gene: LHX2 was added
gene: LHX2 was added to Severe microcephaly. Sources: Literature,Expert Review Amber
Q2_23_promote_green tags were added to gene: LHX2.
Mode of inheritance for gene: LHX2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LHX2 were set to 37057675
Phenotypes for gene: LHX2 were set to neurodevelopmental disorder
Severe microcephaly v4.10 COASY Sarah Leigh Phenotypes for gene: COASY were changed from Pontocerebellar hypoplasia, type 12 OMIM:618266 to Pontocerebellar hypoplasia, type 12, OMIM:618266; pontocerebellar hypoplasia, type 12, MONDO:0032643
Severe microcephaly v4.9 WLS Arina Puzriakova changed review comment from: Comment on list classification: There are sufficient unrelated cases with different homozygous variants in this gene and a consistent phenotype to support a gene-disease association. Some features such as microcephaly and digit malformations may plausibly be detected prenatally and therefore suggesting this gene is rated Green at the next GMS panel update.; to: Comment on list classification: There are sufficient unrelated cases with different homozygous variants in this gene and a consistent phenotype to support a gene-disease association. Progressive microcephaly (head circumference, 2 to 5.9 SD below the mean) was seen in all affected patients for whom data were available. Therefore suggesting this gene is rated Green at the next GMS panel update.
Severe microcephaly v4.9 WLS Arina Puzriakova Entity copied from Fetal anomalies v3.77
Severe microcephaly v4.9 WLS Arina Puzriakova gene: WLS was added
gene: WLS was added to Severe microcephaly. Sources: Literature,Expert Review Amber
Q2_23_promote_green tags were added to gene: WLS.
Mode of inheritance for gene: WLS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WLS were set to 34587386
Phenotypes for gene: WLS were set to Zaki syndrome, OMIM:619648
Severe microcephaly v4.8 NAPB Arina Puzriakova Phenotypes for gene: NAPB were changed from Early infantile epileptic encephalopathy to Developmental and epileptic encephalopathy 107, OMIM:620033
Severe microcephaly v4.7 TRAPPC10 Achchuthan Shanmugasundram Tag Q2_23_promote_green tag was added to gene: TRAPPC10.
Severe microcephaly v4.7 TRAPPC10 Achchuthan Shanmugasundram Classified gene: TRAPPC10 as Amber List (moderate evidence)
Severe microcephaly v4.7 TRAPPC10 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for associating this gene with severe microcephaly (two unrelated cases and supporting functional evidence) and hence can be promoted to GREEN at the next major review.
Severe microcephaly v4.7 TRAPPC10 Achchuthan Shanmugasundram Gene: trappc10 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v4.6 TRAPPC10 Achchuthan Shanmugasundram changed review comment from: Biallelic variants in TRAPPC10 have been identified in two unrelated consanguineous Pakistani families that have been reported with severe microcephalic neurodevelopmental disorder. In addition, neuroanatomical brain defects and microcephaly, paralleling findings seen in the human patients were seen in Trappc9-/- mouse model.

This gene has been associated with relevant phenotypes in both OMIM (MIM #620027) and Gene2Phenotype (with 'limited' rating).; to: Biallelic variants in TRAPPC10 have been identified in two unrelated consanguineous Pakistani families that have been reported with severe microcephalic neurodevelopmental disorder. In addition, neuroanatomical brain defects and microcephaly (paralleling findings seen in the human patients) were seen in Trappc9-/- mouse model.

This gene has been associated with relevant phenotypes in both OMIM (MIM #620027) and Gene2Phenotype (with 'limited' rating).
Severe microcephaly v4.6 TRAPPC10 Achchuthan Shanmugasundram Phenotypes for gene: TRAPPC10 were changed from microcephaly (disease), MONDO:0001149; Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027 to Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027
Severe microcephaly v4.5 TRAPPC10 Achchuthan Shanmugasundram Phenotypes for gene: TRAPPC10 were changed from microcephaly (disease), MONDO:0001149 to microcephaly (disease), MONDO:0001149; Neurodevelopmental disorder with microcephaly, short stature, and speech delay, OMIM:620027
Severe microcephaly v4.4 TRAPPC10 Achchuthan Shanmugasundram Publications for gene: TRAPPC10 were set to 30167849
Severe microcephaly v4.3 TRAPPC10 Achchuthan Shanmugasundram reviewed gene: TRAPPC10: Rating: GREEN; 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
Severe microcephaly v4.3 MED11 Sarah Leigh edited their review of gene: MED11: Changed rating: AMBER
Severe microcephaly v4.3 MED11 Sarah Leigh Tag Q2_23_promote_green was removed from gene: MED11.
Severe microcephaly v4.3 MED11 Sarah Leigh Classified gene: MED11 as Amber List (moderate evidence)
Severe microcephaly v4.3 MED11 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be amber on the Severe microcephaly panel.
Severe microcephaly v4.3 MED11 Sarah Leigh Gene: med11 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v4.2 MED11 Sarah Leigh gene: MED11 was added
gene: MED11 was added to Severe microcephaly. Sources: Literature
Q2_23_promote_green tags were added to gene: MED11.
Mode of inheritance for gene: MED11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED11 were set to 36001086
Phenotypes for gene: MED11 were set to MED11-associated neurodevelopmental disorder
Review for gene: MED11 was set to GREEN
Added comment: Not associated with a phenotype in OMIM, but is associated with MED11-associated neurodevelopmental disorder in Gen2Phen. PMID: 36001086 reports a single MED11 variant (NM_001001683.4: c.325C>T, p.Arg109*), that segregates with the condition in five unrelated families, however, there is homozygosity between two of these families, idicating that they may be related. Global delay was observed in three individuals from three unrelated familes and seizures were evident in four individuals from four unrelated families. Severe microcephaly was apparent in the two unrelated familes where this parameter was recorded. Overall, the MED11-associated neurodevelopmental disorder appeared to result in profound effects and proved fatal at birth and 10 days in two of the cases reported.
Sources: Literature
Severe microcephaly v4.1 TRAPPC10 Aleš Maver edited their review of gene: TRAPPC10: Added comment: The study on biallelic TRAPPC10 variants in microcephaly has now been published in PMID: 35298461, reporting 8 individuals with a homozygous loss-of function variant in one family and two affected individuals from the second, unrelated family.; Changed publications to: PMID: 30167849, PMID: 35298461; Changed phenotypes to: Microcephaly, short stature, developmental delay
Severe microcephaly v4.1 Catherine Snow Panel version 4.0 has been signed off on 2023-03-22
Severe microcephaly v4.0 Catherine Snow promoted panel to version 4.0
Severe microcephaly v3.12 ATP9A Eleanor Williams Phenotypes for gene: ATP9A were changed from Neurodevelopmental delay; Postnatal microcephaly; Failure to thrive; Gastrointestinal symptoms to Neurodevelopmental delay; Postnatal microcephaly; Failure to thrive; Gastrointestinal symptoms; Neurodevelopmental disorder with poor growth and behavioral abnormalities, OMIM:620242
Severe microcephaly v3.11 SARS Arina Puzriakova Phenotypes for gene: SARS were changed from ?Neurodevelopmental disorder with microcephaly, ataxia, and seizures, OMIM:617709 to Neurodevelopmental disorder with microcephaly, ataxia, and seizures, OMIM:617709
Severe microcephaly v3.10 SARS Arina Puzriakova Publications for gene: SARS were set to 28236339; 34570399
Severe microcephaly v3.9 SARS Arina Puzriakova Classified gene: SARS as Amber List (moderate evidence)
Severe microcephaly v3.9 SARS Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. At least three unrelated cases with biallelic variants in this gene - microcephaly detected in all families. Although severity only reaches threshold for this panel in two families, given the extent in these cases and the consistent presentation this feature, this gene should be included on R88.
Severe microcephaly v3.9 SARS Arina Puzriakova Gene: sars has been classified as Amber List (Moderate Evidence).
Severe microcephaly v3.8 SARS Arina Puzriakova Tag watchlist was removed from gene: SARS.
Tag Q1_23_promote_green tag was added to gene: SARS.
Severe microcephaly v3.8 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
Severe microcephaly v3.8 NUP214 Sarah Leigh Entity copied from Genetic epilepsy syndromes v3.67
Severe microcephaly v3.8 NUP214 Sarah Leigh gene: NUP214 was added
gene: NUP214 was added to Severe microcephaly. Sources: Expert list,Expert Review Amber
Q1_23_promote_green tags were added to gene: NUP214.
Mode of inheritance for gene: NUP214 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP214 were set to 31178128; 30758658
Phenotypes for gene: NUP214 were set to Encephalopathy, acute, infection-induced, susceptibility to, 9, OMIM:618426; encephalopathy, acute, infection-induced, susceptibility to, 9, MONDO:0032742
Severe microcephaly v3.7 SPATA5L1 Eleanor Williams Tag gene-checked tag was added to gene: SPATA5L1.
Severe microcephaly v3.7 HMGB1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: HMGB1.
Severe microcephaly v3.7 GINS3 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: GINS3.
Severe microcephaly v3.7 DROSHA Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: DROSHA.
Severe microcephaly v3.7 ISCA-37408-Loss Arina Puzriakova commented on Region: ISCA-37408-Loss
Severe microcephaly v3.7 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
Severe microcephaly v3.6 ISCA-46742-Loss Arina Puzriakova reviewed Region: ISCA-46742-Loss: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe microcephaly v3.6 ISCA-46742-Loss Arina Puzriakova Region: ISCA-46742-Loss was added
Region: ISCA-46742-Loss was added to Severe microcephaly. Sources: Expert Review Green,ClinGen
Mode of inheritance for Region: ISCA-46742-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-46742-Loss were set to 27633570; 32562408; 29274487; 29220674
Severe microcephaly v3.5 HHAT Arina Puzriakova Tag Q4_21_rating was removed from gene: HHAT.
Severe microcephaly v3.5 SPATA5L1 Arina Puzriakova Tag Q1_22_rating was removed from gene: SPATA5L1.
Severe microcephaly v3.5 PRIM1 Arina Puzriakova Tag Q2_21_rating was removed from gene: PRIM1.
Severe microcephaly v3.5 NCAPD3 Arina Puzriakova Tag Q2_22_rating was removed from gene: NCAPD3.
Tag Q2_22_NHS_review was removed from gene: NCAPD3.
Severe microcephaly v3.5 NAPB Arina Puzriakova Tag Q2_22_rating was removed from gene: NAPB.
Tag Q2_22_NHS_review was removed from gene: NAPB.
Severe microcephaly v3.5 HHAT Arina Puzriakova edited their review of gene: HHAT: Changed rating: GREEN
Severe microcephaly v3.5 HHAT Arina Puzriakova changed review comment from: The rating of this gene has been updated to Green and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.; to: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.
Severe microcephaly v3.5 DROSHA Arina Puzriakova Tag Q2_22_rating was removed from gene: DROSHA.
Severe microcephaly v3.5 CCND2 Arina Puzriakova Tag Q1_22_rating was removed from gene: CCND2.
Severe microcephaly v3.5 CCND2 Arina Puzriakova edited their review of gene: CCND2: Changed rating: GREEN
Severe microcephaly v3.5 CCND2 Arina Puzriakova changed review comment from: The rating of this gene has been updated to Green and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.; to: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.
Severe microcephaly v3.5 TUBG1 Arina Puzriakova Tag Q3_22_rating was removed from gene: TUBG1.
Tag Q3_22_NHS_review was removed from gene: TUBG1.
Severe microcephaly v3.5 SLC38A3 Arina Puzriakova Tag Q3_22_rating was removed from gene: SLC38A3.
Severe microcephaly v3.5 NSRP1 Arina Puzriakova Tag Q3_22_rating was removed from gene: NSRP1.
Severe microcephaly v3.5 HMGB1 Arina Puzriakova Tag Q3_22_rating was removed from gene: HMGB1.
Severe microcephaly v3.5 GINS3 Arina Puzriakova Tag Q3_22_rating was removed from gene: GINS3.
Severe microcephaly v3.5 CHKA Arina Puzriakova Tag Q3_22_rating was removed from gene: CHKA.
Tag Q3_22_MOI was removed from gene: CHKA.
Severe microcephaly v3.5 ATP6V0A1 Arina Puzriakova Tag Q3_22_rating was removed from gene: ATP6V0A1.
Severe microcephaly v3.5 SPATA5L1 Arina Puzriakova reviewed gene: SPATA5L1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v3.5 PRIM1 Arina Puzriakova commented on gene: PRIM1: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.
Severe microcephaly v3.5 NCAPD3 Arina Puzriakova commented on gene: NCAPD3: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.
Severe microcephaly v3.5 NAPB Arina Puzriakova edited their review of gene: NAPB: Added comment: The rating of this gene has been updated to Green and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Severe microcephaly v3.5 HHAT Arina Puzriakova commented on gene: HHAT
Severe microcephaly v3.5 DROSHA Arina Puzriakova reviewed gene: DROSHA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v3.5 CCND2 Arina Puzriakova commented on gene: CCND2
Severe microcephaly v3.5 TUBG1 Arina Puzriakova edited their review of gene: TUBG1: Added comment: The rating of this gene has been updated to Green and the mode of inheritance set to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Severe microcephaly v3.5 SLC38A3 Arina Puzriakova reviewed gene: SLC38A3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v3.5 NSRP1 Arina Puzriakova edited their review of gene: NSRP1: Added comment: The rating of this gene has been updated to Green and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Severe microcephaly v3.5 HMGB1 Arina Puzriakova edited their review of gene: HMGB1: Added comment: The rating of this gene has been updated to Green and the mode of inheritance set to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Severe microcephaly v3.5 GINS3 Arina Puzriakova reviewed gene: GINS3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v3.5 CHKA Arina Puzriakova reviewed gene: CHKA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v3.5 ATP6V0A1 Arina Puzriakova reviewed gene: ATP6V0A1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v3.4 TUBG1 Arina Puzriakova Source Expert Review Green was added to TUBG1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v3.4 SPATA5L1 Arina Puzriakova Source Expert Review Green was added to SPATA5L1.
Source NHS GMS was added to SPATA5L1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v3.4 SLC38A3 Arina Puzriakova Source Expert Review Green was added to SLC38A3.
Source NHS GMS was added to SLC38A3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v3.4 PRIM1 Arina Puzriakova Source Expert Review Green was added to PRIM1.
Source NHS GMS was added to PRIM1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v3.4 NSRP1 Arina Puzriakova Source Expert Review Green was added to NSRP1.
Source NHS GMS was added to NSRP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v3.4 NCAPD3 Arina Puzriakova Source Expert Review Green was added to NCAPD3.
Source NHS GMS was added to NCAPD3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v3.4 NAPB Arina Puzriakova Source Expert Review Green was added to NAPB.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v3.4 HMGB1 Arina Puzriakova Source Expert Review Green was added to HMGB1.
Source NHS GMS was added to HMGB1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v3.4 HHAT Arina Puzriakova Source Expert Review Green was added to HHAT.
Source NHS GMS was added to HHAT.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v3.4 GINS3 Arina Puzriakova Source Expert Review Green was added to GINS3.
Source NHS GMS was added to GINS3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v3.4 DROSHA Arina Puzriakova Source Expert Review Green was added to DROSHA.
Source NHS GMS was added to DROSHA.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v3.4 CHKA Arina Puzriakova Source Expert Review Green was added to CHKA.
Source NHS GMS was added to CHKA.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v3.4 CCND2 Arina Puzriakova Source Expert Review Green was added to CCND2.
Source NHS GMS was added to CCND2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v3.4 ATP6V0A1 Arina Puzriakova Source Expert Review Green was added to ATP6V0A1.
Source NHS GMS was added to ATP6V0A1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v3.3 CASK Arina Puzriakova Publications for gene: CASK were set to
Severe microcephaly v3.2 TPR Achchuthan Shanmugasundram gene: TPR was added
gene: TPR was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: TPR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TPR were set to 34494102
Phenotypes for gene: TPR were set to Microcephaly, MONDO:0001149
Review for gene: TPR was set to RED
Added comment: Comment on classification of this gene: This gene should be added with a RED rating as the association of TPR to microcephaly is based on biallelic variants identified from a report of two siblings.

Two siblings harbouring variants c.6625C>T/ p.Arg2209Ter (identified in heterozygous state in both siblings and father) and c.2610 + 5G > A (identified in heterozygous state in both siblings and mother) were reported with ataxia, microcephaly and severe intellectual disability. The occipitofrontal circumference (OFC) was at 3rd centile for individual 1 and at 10th centile for individual 2 and dropped to below 1st centile at eight months and five months respectively.

Functional analyses in patient fibroblasts provide evidence that the variants affect TPR splicing, reduce steady-state TPR levels, abnormal nuclear pore composition and density, and altered global RNA distribution.

This gene has not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Severe microcephaly v3.1 Arina Puzriakova Panel version 3.0 has been signed off on 2022-11-30
Severe microcephaly v3.0 Arina Puzriakova promoted panel to version 3.0
Severe microcephaly v2.322 PRIM1 Eleanor Williams commented on gene: PRIM1
Severe microcephaly v2.322 PRIM1 Eleanor Williams Phenotypes for gene: PRIM1 were changed from Microcephalic primordial dwarfism, MONDO:0017950 to Microcephalic primordial dwarfism, MONDO:0017950; Primordial dwarfism-immunodeficiency-lipodystrophy syndrome, OMIM:620005
Severe microcephaly v2.321 PRIM1 Eleanor Williams Tag gene-checked was removed from gene: PRIM1.
Severe microcephaly v2.321 CTNNB1 Arina Puzriakova Publications for gene: CTNNB1 were set to 25326669; 26968164
Severe microcephaly v2.320 CTNNB1 Arina Puzriakova Phenotypes for gene: CTNNB1 were changed from primary microcephaly; Mental retardation, autosomal dominant 19, 615075 to Neurodevelopmental disorder with spastic diplegia and visual defects, OMIM:615075
Severe microcephaly v2.319 DOHH Eleanor Williams Tag Q4_22_rating was removed from gene: DOHH.
Tag Q4_22_promote_green tag was added to gene: DOHH.
Severe microcephaly v2.319 DPP6 Eleanor Williams commented on gene: DPP6
Severe microcephaly v2.319 DPP6 Eleanor Williams Tag Q4_21_rating tag was added to gene: DPP6.
Severe microcephaly v2.319 DOHH Sarah Leigh Classified gene: DOHH as Amber List (moderate evidence)
Severe microcephaly v2.319 DOHH Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Severe microcephaly v2.319 DOHH Sarah Leigh Gene: dohh has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.318 DOHH Sarah Leigh Entity copied from Intellectual disability v3.1731
Severe microcephaly v2.318 DOHH Sarah Leigh gene: DOHH was added
gene: DOHH was added to Severe microcephaly. Sources: Literature
Q4_22_rating, Q4_22_MOI tags were added to gene: DOHH.
Mode of inheritance for gene: DOHH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DOHH were set to 35858628
Phenotypes for gene: DOHH were set to DOHH associated neurodevelopmental disorder
Severe microcephaly v2.317 CPSF3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as moderate Gen2Phen gene for CPSF3-associated neurodevelopmental disorder with seizures and microcephaly. PMID: 35121750 reports two CPSF3 variants in cases, c.1403G>A, p.Gly468Glu (NM_016207.3) in two Icelandic families and c.1061T>C, p.Ile354Thr (NM_016207.3) in a large consanguineous Mexican family. Intellectual disabililty was evident in all 8/8 cases and seizures and microcephaly was apparent 7/8 cases (PMID: 35121750).; to: Associated with relevant phenotype in OMIM and as moderate Gen2Phen gene for CPSF3-associated neurodevelopmental disorder with seizures and microcephaly. PMID: 35121750 reports two CPSF3 variants in cases, c.1403G>A, p.Gly468Glu (NM_016207.3) in two Icelandic families and c.1061T>C, p.Ile354Thr (NM_016207.3) in a large consanguineous Mexican family. Intellectual disabililty was evident in all 8/8 cases and seizures and microcephaly was apparent 7/8 cases (PMID: 35121750).
The rating of this gene could be changed to green, if further disease associated variants are identified or supportive functional studies are reported.
Severe microcephaly v2.317 CPSF3 Sarah Leigh Entity copied from Genetic epilepsy syndromes v2.575
Severe microcephaly v2.317 CPSF3 Sarah Leigh gene: CPSF3 was added
gene: CPSF3 was added to Severe microcephaly. Sources: Literature,Expert Review Amber
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 Neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures, OMIM:619876
Penetrance for gene: CPSF3 were set to Complete
Severe microcephaly v2.316 CHKA Sarah Leigh Tag Q3_22_rating tag was added to gene: CHKA.
Tag Q3_22_MOI tag was added to gene: CHKA.
Severe microcephaly v2.316 CHKA Sarah Leigh Entity copied from Genetic epilepsy syndromes v2.573
Severe microcephaly v2.316 CHKA Sarah Leigh gene: CHKA was added
gene: CHKA was added to Severe microcephaly. Sources: Expert Review Amber,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
Severe microcephaly v2.315 SLC38A3 Catherine Snow changed review comment from: New gene added by Konstantinos Varvagiannis. There is sufficient evidence to promote to Green at the next GMS panel update.
Gene phenotype relationship captured by OMIM, G2P and PanelApp Australia.
Marafi et al PMID: 34605855 describes 7 families accounting for 10 individuals all with ID or global DD; to: New gene added by Konstantinos Varvagiannis. There is sufficient evidence to promote to Green at the next GMS panel update.
Gene phenotype relationship captured by OMIM, G2P and PanelApp Australia.
Marafi et al PMID: 34605855 describes 7 families accounting for 10 individuals. 8/10 reported to have Microcephaly and and was more commonly postnatal and/or progressive.
Severe microcephaly v2.315 SLC38A3 Catherine Snow Entity copied from Intellectual disability v3.1650
Severe microcephaly v2.315 SLC38A3 Catherine Snow gene: SLC38A3 was added
gene: SLC38A3 was added to Severe microcephaly. Sources: Literature,Other,Expert Review Amber
Q3_22_rating tags were added to gene: SLC38A3.
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 Developmental and epileptic encephalopathy 102, 619881
Penetrance for gene: SLC38A3 were set to Complete
Severe microcephaly v2.314 NSRP1 Arina Puzriakova Entity copied from Intellectual disability v3.1641
Severe microcephaly v2.314 NSRP1 Arina Puzriakova gene: NSRP1 was added
gene: NSRP1 was added to Severe microcephaly. Sources: Literature,Expert Review Amber
Q3_22_rating tags were added to gene: NSRP1.
Mode of inheritance for gene: NSRP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NSRP1 were set to 34385670
Phenotypes for gene: NSRP1 were set to NSRP1-associated developmental delay, epilepsy and microcephaly
Severe microcephaly v2.313 HMGB1 Arina Puzriakova Entity copied from Intellectual disability v3.1639
Severe microcephaly v2.313 HMGB1 Arina Puzriakova gene: HMGB1 was added
gene: HMGB1 was added to Severe microcephaly. Sources: Expert Review Amber,Literature
Q3_22_rating tags were added to gene: HMGB1.
Mode of inheritance for gene: HMGB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HMGB1 were set to 34164801
Phenotypes for gene: HMGB1 were set to Developmental delay and microcephaly
Severe microcephaly v2.312 GINS3 Ivone Leong Tag Q3_22_rating tag was added to gene: GINS3.
Severe microcephaly v2.312 GINS3 Ivone Leong Classified gene: GINS3 as Amber List (moderate evidence)
Severe microcephaly v2.312 GINS3 Ivone Leong Gene: gins3 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.311 GINS3 Ivone Leong Entity copied from Growth failure in early childhood v1.109
Severe microcephaly v2.311 GINS3 Ivone Leong gene: GINS3 was added
gene: GINS3 was added to Severe microcephaly. Sources: Literature,Expert Review Red
Mode of inheritance for gene: GINS3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GINS3 were set to 35603789
Phenotypes for gene: GINS3 were set to Meier-Gorlin syndrome like; Meier-Gorlin syndrome, MONDO:0016817
Penetrance for gene: GINS3 were set to unknown
Mode of pathogenicity for gene: GINS3 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Severe microcephaly v2.310 GINS2 Ivone Leong commented on gene: GINS2: This gene has been copied from the Growth failure panel (panel ID:473), as the Severe microcephaly panel appears to be a better fit for the phenotype. As there is only 1 reported case this gene has been given a Red rating.
Severe microcephaly v2.310 GINS2 Ivone Leong changed review comment from: Comment on list classification: New gene added by Dmitrijs Rots (RadboudUMC). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is currently not enough evidence to support a gene-disease association and other genes associated with Meier-Gorlin syndrome has been given a Red rating in this panel due to the phenotype being not fitting the scope of this panel. Therefore, this gene has been given a Red rating.; to: Comment on list classification: New gene added by Dmitrijs Rots (RadboudUMC). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is currently not enough evidence to support a gene-disease association and other genes associated with Meier-Gorlin syndrome has been given a Red rating in this panel due to the phenotype being not fitting the scope of this panel. Therefore, this gene has been given a Red rating.
Severe microcephaly v2.310 GINS2 Ivone Leong Entity copied from Growth failure in early childhood v1.107
Severe microcephaly v2.310 GINS2 Ivone Leong gene: GINS2 was added
gene: GINS2 was added to Severe microcephaly. Sources: Literature,Expert Review Red
Mode of inheritance for gene: GINS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GINS2 were set to 34353863
Phenotypes for gene: GINS2 were set to Meier-Gorlin syndrome like; Meier-Gorlin syndrome, MONDO:0016817
Penetrance for gene: GINS2 were set to unknown
Mode of pathogenicity for gene: GINS2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Severe microcephaly v2.309 TUBG1 Arina Puzriakova Publications for gene: TUBG1 were set to 23603762; 31151415
Severe microcephaly v2.308 TUBG1 Arina Puzriakova Classified gene: TUBG1 as Amber List (moderate evidence)
Severe microcephaly v2.308 TUBG1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. At least 11 patients with heterozygous variants in this gene have been reported in literature to date (PMIDs: 23603762; 24860126; 29706637; 31151415). Microcephaly is a predominant feature of the phenotype in majority of cases and severity is within the scope of this panel.
Severe microcephaly v2.308 TUBG1 Arina Puzriakova Gene: tubg1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.307 TUBG1 Arina Puzriakova Phenotypes for gene: TUBG1 were changed from to Cortical dysplasia, complex, with other brain malformations 4, OMIM:615412
Severe microcephaly v2.306 TUBG1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: TUBG1.
Tag Q3_22_NHS_review tag was added to gene: TUBG1.
Severe microcephaly v2.306 PCDHGC4 Sarah Leigh Phenotypes for gene: PCDHGC4 were changed from Neurodevelopmental abnormality HP:0012759 to Neurodevelopmental disorder with poor growth and skeletal anomalies, OMIM:619880
Severe microcephaly v2.305 PCDHGC4 Sarah Leigh Tag gene-checked was removed from gene: PCDHGC4.
Severe microcephaly v2.305 ZNF526 Sarah Leigh Tag gene-checked was removed from gene: ZNF526.
Severe microcephaly v2.305 ATP6V0A1 Sarah Leigh edited their review of gene: ATP6V0A1: Added comment: None of the biallelic cases reported by PMID: 34909687, exhibited microcephaly as a result of this, biallelic mode of inheritance has not been included for ATP6V0A1 on the Severe microcephaly panel.; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe microcephaly v2.305 ATP6V0A1 Sarah Leigh Tag Q3_22_MOI was removed from gene: ATP6V0A1.
Tag Q3_22_NHS_review was removed from gene: ATP6V0A1.
Severe microcephaly v2.305 ATP6V0A1 Sarah Leigh Entity copied from Genetic epilepsy syndromes v2.539
Severe microcephaly v2.305 ATP6V0A1 Sarah Leigh gene: ATP6V0A1 was added
gene: ATP6V0A1 was added to Severe microcephaly. Sources: Literature,Expert Review Amber
Q3_22_rating, Q3_22_MOI, Q3_22_NHS_review tags were added to gene: ATP6V0A1.
Mode of inheritance for gene: ATP6V0A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP6V0A1 were set to 30842224; 33057194; 34909687; 33833240
Phenotypes for gene: ATP6V0A1 were set to ATP6V0A1-related developmental disorder (monoallelic)
Severe microcephaly v2.304 TUBG1 Gavin Ryan gene: TUBG1 was added
gene: TUBG1 was added to Severe microcephaly. Sources: NHS GMS
Mode of inheritance for gene: TUBG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TUBG1 were set to 23603762; 31151415
Penetrance for gene: TUBG1 were set to unknown
Mode of pathogenicity for gene: TUBG1 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: TUBG1 was set to GREEN
Added comment: Variant has been reported in number of individuals presenting with microcephaly by Poirier et al 2013, and Yuen et al 2019. All reported variants are missense. Identified individuals through GMS presenting with microcephaly prenatally who have pathogenic variants in this gene identified postnatally. Gene now present on fetal anomalies panel.
Sources: NHS GMS
Severe microcephaly v2.304 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
Severe microcephaly v2.303 HIST1H4C Arina Puzriakova Publications for gene: HIST1H4C were set to 28920961
Severe microcephaly v2.302 HIST1H4C Arina Puzriakova Phenotypes for gene: HIST1H4C were changed from Growth delay, microcephaly and intellectual disability to Tessadori-van Haaften neurodevelopmental syndrome 1, OMIM:61975
Severe microcephaly v2.301 DROSHA Sarah Leigh Entity copied from Genetic epilepsy syndromes v2.526
Severe microcephaly v2.301 DROSHA Sarah Leigh gene: DROSHA was added
gene: DROSHA was added to Severe microcephaly. Sources: Expert Review Amber,Literature
locus-type-rna-micro, Q2_22_rating tags were added to gene: DROSHA.
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
Severe microcephaly v2.300 TUBGCP2 Arina Puzriakova Tag gene-checked tag was added to gene: TUBGCP2.
Severe microcephaly v2.300 TTC5 Arina Puzriakova Tag gene-checked tag was added to gene: TTC5.
Severe microcephaly v2.300 PRIM1 Arina Puzriakova Tag gene-checked tag was added to gene: PRIM1.
Severe microcephaly v2.300 PCDHGC4 Arina Puzriakova Tag gene-checked tag was added to gene: PCDHGC4.
Severe microcephaly v2.300 SMARCA5 Eleanor Williams Tag gene-checked tag was added to gene: SMARCA5.
Severe microcephaly v2.300 SVBP Eleanor Williams Tag gene-checked tag was added to gene: SVBP.
Severe microcephaly v2.300 METTL5 Eleanor Williams Tag gene-checked tag was added to gene: METTL5.
Severe microcephaly v2.300 WDR37 Eleanor Williams Tag gene-checked tag was added to gene: WDR37.
Severe microcephaly v2.300 ZNF526 Eleanor Williams Tag gene-checked tag was added to gene: ZNF526.
Severe microcephaly v2.300 HPDL Eleanor Williams Tag gene-checked tag was added to gene: HPDL.
Severe microcephaly v2.300 FBRSL1 Eleanor Williams Tag gene-checked tag was added to gene: FBRSL1.
Severe microcephaly v2.300 IGF1R Arina Puzriakova Phenotypes for gene: IGF1R were changed from Insulin-like growth factor I, resistance to 270450 to Insulin-like growth factor I, resistance to, OMIM:270450
Severe microcephaly v2.299 NCAPD3 Arina Puzriakova edited their review of gene: NCAPD3: Changed rating: GREEN
Severe microcephaly v2.299 NCAPD3 Arina Puzriakova Classified gene: NCAPD3 as Amber List (moderate evidence)
Severe microcephaly v2.299 NCAPD3 Arina Puzriakova Added comment: Comment on list classification: Given the discovery of a third patient in the NHS presenting a phenotype consistent with previous reports and functional studies providing a plausible disease mechanism, this gene should now be promoted to Green at the next GMS panel update to ensure detection of cases.
Severe microcephaly v2.299 NCAPD3 Arina Puzriakova Gene: ncapd3 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.298 NCAPD3 Arina Puzriakova Tag Q2_22_rating tag was added to gene: NCAPD3.
Tag Q2_22_NHS_review tag was added to gene: NCAPD3.
Severe microcephaly v2.298 NCAPD3 Arina Puzriakova Phenotypes for gene: NCAPD3 were changed from Microcephaly 22, primary, autosomal recessive, 617984 to Microcephaly 22, primary, autosomal recessive, OMIM:617984
Severe microcephaly v2.297 NAPB Arina Puzriakova Entity copied from Genetic epilepsy syndromes v2.506
Severe microcephaly v2.297 NAPB Arina Puzriakova gene: NAPB was added
gene: NAPB was added to Severe microcephaly. Sources: Expert Review Amber,NHS GMS
Q2_22_rating, Q2_22_NHS_review tags were added to gene: NAPB.
Mode of inheritance for gene: NAPB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAPB were set to 28097321; 33189936; 26235277; 21040848
Phenotypes for gene: NAPB were set to Early infantile epileptic encephalopathy
Penetrance for gene: NAPB were set to unknown
Severe microcephaly v2.296 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from Fanconi anemia, complementation group J, 609054 to Fanconi anemia, complementation group J, OMIM:609054
Severe microcephaly v2.295 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Fanconi anemia, complementation group D1, 605724 (Microcephaly) to Fanconi anemia, complementation group D1, OMIM:605724
Severe microcephaly v2.294 ISCA-37501-Loss Arina Puzriakova commented on Region: ISCA-37501-Loss
Severe microcephaly v2.294 ISCA-37425-Gain Arina Puzriakova commented on Region: ISCA-37425-Gain
Severe microcephaly v2.294 ISCA-37408-Loss Ivone Leong commented on Region: ISCA-37408-Loss
Severe microcephaly v2.294 ISCA-37406-Loss Ivone Leong commented on Region: ISCA-37406-Loss
Severe microcephaly v2.294 ISCA-37390-Loss Ivone Leong commented on Region: ISCA-37390-Loss
Severe microcephaly v2.294 ISCA-37425-Gain Arina Puzriakova GRCh38 position for ISCA-37425-Gain was changed from 176301975-177586960 to 176301976-177620792.
Haploinsufficiency Score for ISCA-37425-Gain was changed from None to .
Required Overlap Percentage for ISCA-37425-Gain was changed from 80 to 60.
Severe microcephaly v2.294 ISCA-37390-Loss Arina Puzriakova Triplosensitivity Score for ISCA-37390-Loss was changed from None to .
Required Overlap Percentage for ISCA-37390-Loss was changed from 80 to 60.
Severe microcephaly v2.294 ISCA-37408-Loss Arina Puzriakova Triplosensitivity Score for ISCA-37408-Loss was changed from None to .
Required Overlap Percentage for ISCA-37408-Loss was changed from 80 to 60.
Severe microcephaly v2.294 ISCA-37501-Loss Arina Puzriakova Triplosensitivity Score for ISCA-37501-Loss was changed from None to .
Required Overlap Percentage for ISCA-37501-Loss was changed from 80 to 60.
Severe microcephaly v2.294 ISCA-37406-Loss Arina Puzriakova Triplosensitivity Score for ISCA-37406-Loss was changed from None to .
Required Overlap Percentage for ISCA-37406-Loss was changed from 80 to 60.
Severe microcephaly v2.293 DPP6 Eleanor Williams Tag to_be_confirmed_NHSE tag was added to gene: DPP6.
Severe microcephaly v2.293 CEP63 Eleanor Williams Tag Q2_21_expert_review was removed from gene: CEP63.
Severe microcephaly v2.293 YIPF5 Eleanor Williams Tag Q2_21_rating was removed from gene: YIPF5.
Severe microcephaly v2.293 WDR4 Eleanor Williams Tag Q2_21_rating was removed from gene: WDR4.
Severe microcephaly v2.293 WDR37 Eleanor Williams Tag Q2_21_rating was removed from gene: WDR37.
Severe microcephaly v2.293 WDR11 Eleanor Williams Tag Q4_21_rating was removed from gene: WDR11.
Severe microcephaly v2.293 VRK1 Eleanor Williams Tag Q3_21_rating was removed from gene: VRK1.
Severe microcephaly v2.293 UNC80 Eleanor Williams Tag Q2_21_rating was removed from gene: UNC80.
Severe microcephaly v2.293 UGP2 Eleanor Williams Tag Q2_21_rating was removed from gene: UGP2.
Severe microcephaly v2.293 TSEN54 Eleanor Williams Tag Q2_21_rating was removed from gene: TSEN54.
Severe microcephaly v2.293 TSEN15 Eleanor Williams Tag Q2_21_rating was removed from gene: TSEN15.
Severe microcephaly v2.293 TRIO Eleanor Williams Tag Q2_21_rating was removed from gene: TRIO.
Severe microcephaly v2.293 TRAPPC9 Eleanor Williams Tag Q2_21_rating was removed from gene: TRAPPC9.
Severe microcephaly v2.293 TRAPPC6B Eleanor Williams Tag Q2_21_rating was removed from gene: TRAPPC6B.
Severe microcephaly v2.293 TP53RK Eleanor Williams Tag Q2_21_rating was removed from gene: TP53RK.
Severe microcephaly v2.293 TNPO2 Eleanor Williams Tag Q3_21_rating was removed from gene: TNPO2.
Severe microcephaly v2.293 SMARCA5 Eleanor Williams Tag Q2_21_rating was removed from gene: SMARCA5.
Severe microcephaly v2.293 SLC1A4 Eleanor Williams Tag Q2_21_rating was removed from gene: SLC1A4.
Severe microcephaly v2.293 RAD51 Eleanor Williams Tag Q4_21_rating was removed from gene: RAD51.
Severe microcephaly v2.293 RAD50 Eleanor Williams Tag Q2_21_rating was removed from gene: RAD50.
Severe microcephaly v2.293 PUS7 Eleanor Williams Tag Q2_21_rating was removed from gene: PUS7.
Severe microcephaly v2.293 PUF60 Eleanor Williams Tag Q2_21_rating was removed from gene: PUF60.
Severe microcephaly v2.293 PTPN23 Eleanor Williams Tag Q2_21_rating was removed from gene: PTPN23.
Severe microcephaly v2.293 POGZ Eleanor Williams Tag Q2_21_rating was removed from gene: POGZ.
Severe microcephaly v2.293 PCDH12 Eleanor Williams Tag Q3_21_rating was removed from gene: PCDH12.
Severe microcephaly v2.293 OSGEP Eleanor Williams Tag Q3_21_rating was removed from gene: OSGEP.
Severe microcephaly v2.293 NUP107 Eleanor Williams Tag Q3_21_rating was removed from gene: NUP107.
Severe microcephaly v2.293 MINPP1 Eleanor Williams Tag Q2_21_rating was removed from gene: MINPP1.
Severe microcephaly v2.293 LAGE3 Eleanor Williams Tag Q3_21_rating was removed from gene: LAGE3.
Severe microcephaly v2.293 HPDL Eleanor Williams Tag Q2_21_rating was removed from gene: HPDL.
Severe microcephaly v2.293 HIST1H4C Eleanor Williams Tag Q3_21_rating was removed from gene: HIST1H4C.
Severe microcephaly v2.293 GTF2E2 Eleanor Williams Tag Q3_21_rating was removed from gene: GTF2E2.
Severe microcephaly v2.293 GPT2 Eleanor Williams Tag Q4_21_rating was removed from gene: GPT2.
Severe microcephaly v2.293 FOXG1 Eleanor Williams Tag Q2_21_rating was removed from gene: FOXG1.
Severe microcephaly v2.293 EIF5A Eleanor Williams Tag Q2_21_rating was removed from gene: EIF5A.
Severe microcephaly v2.293 EIF2S3 Eleanor Williams Tag Q3_21_rating was removed from gene: EIF2S3.
Severe microcephaly v2.293 DYNC1I2 Eleanor Williams Tag Q4_21_rating was removed from gene: DYNC1I2.
Severe microcephaly v2.293 DPM1 Eleanor Williams Tag Q2_21_rating was removed from gene: DPM1.
Severe microcephaly v2.293 DNA2 Eleanor Williams Tag Q2_21_rating was removed from gene: DNA2.
Severe microcephaly v2.293 CTU2 Eleanor Williams Tag Q2_21_rating was removed from gene: CTU2.
Severe microcephaly v2.293 CTCF Eleanor Williams Tag Q2_21_rating was removed from gene: CTCF.
Severe microcephaly v2.293 CSNK2A1 Eleanor Williams Tag Q2_21_rating was removed from gene: CSNK2A1.
Severe microcephaly v2.293 CHAMP1 Eleanor Williams Tag Q2_21_rating was removed from gene: CHAMP1.
Severe microcephaly v2.293 CEP63 Eleanor Williams Phenotypes for gene: CEP63 were changed from MCPH; primary microcephaly; ?Seckel syndrome 6, 614728; Microcephaly to MCPH; primary microcephaly; ?Seckel syndrome 6, OMIM:614728; Microcephaly
Severe microcephaly v2.292 CEP57 Eleanor Williams Tag Q2_21_rating was removed from gene: CEP57.
Severe microcephaly v2.292 CAMK2B Eleanor Williams Tag Q2_21_rating was removed from gene: CAMK2B.
Severe microcephaly v2.292 BUB1B Eleanor Williams Tag Q2_21_rating was removed from gene: BUB1B.
Severe microcephaly v2.292 BPTF Eleanor Williams Tag Q2_21_rating was removed from gene: BPTF.
Severe microcephaly v2.292 AARS Eleanor Williams Tag Q2_21_rating was removed from gene: AARS.
Severe microcephaly v2.292 YIPF5 Sarah Leigh commented on gene: YIPF5
Severe microcephaly v2.292 WDR4 Sarah Leigh commented on gene: WDR4
Severe microcephaly v2.292 WDR37 Sarah Leigh commented on gene: WDR37
Severe microcephaly v2.292 WDR11 Sarah Leigh commented on gene: WDR11
Severe microcephaly v2.292 VRK1 Sarah Leigh commented on gene: VRK1
Severe microcephaly v2.292 UNC80 Sarah Leigh commented on gene: UNC80
Severe microcephaly v2.292 UGP2 Sarah Leigh commented on gene: UGP2
Severe microcephaly v2.292 TSEN54 Sarah Leigh commented on gene: TSEN54
Severe microcephaly v2.292 TSEN15 Sarah Leigh commented on gene: TSEN15
Severe microcephaly v2.292 TRIO Sarah Leigh commented on gene: TRIO
Severe microcephaly v2.292 TRAPPC9 Sarah Leigh commented on gene: TRAPPC9
Severe microcephaly v2.292 TRAPPC6B Sarah Leigh commented on gene: TRAPPC6B
Severe microcephaly v2.292 TP53RK Sarah Leigh commented on gene: TP53RK
Severe microcephaly v2.292 TNPO2 Sarah Leigh commented on gene: TNPO2
Severe microcephaly v2.292 SMARCA5 Sarah Leigh commented on gene: SMARCA5
Severe microcephaly v2.292 SLC1A4 Sarah Leigh commented on gene: SLC1A4
Severe microcephaly v2.292 RAD51 Sarah Leigh commented on gene: RAD51
Severe microcephaly v2.292 RAD50 Sarah Leigh commented on gene: RAD50
Severe microcephaly v2.292 PUS7 Sarah Leigh commented on gene: PUS7
Severe microcephaly v2.292 PUF60 Sarah Leigh commented on gene: PUF60
Severe microcephaly v2.292 PTPN23 Sarah Leigh commented on gene: PTPN23
Severe microcephaly v2.292 POGZ Sarah Leigh commented on gene: POGZ
Severe microcephaly v2.292 PCDH12 Sarah Leigh commented on gene: PCDH12
Severe microcephaly v2.292 OSGEP Sarah Leigh commented on gene: OSGEP
Severe microcephaly v2.292 NUP107 Sarah Leigh commented on gene: NUP107
Severe microcephaly v2.292 MINPP1 Sarah Leigh commented on gene: MINPP1
Severe microcephaly v2.292 LAGE3 Sarah Leigh commented on gene: LAGE3
Severe microcephaly v2.292 HPDL Sarah Leigh commented on gene: HPDL
Severe microcephaly v2.292 HIST1H4C Sarah Leigh commented on gene: HIST1H4C
Severe microcephaly v2.292 GTF2E2 Sarah Leigh commented on gene: GTF2E2
Severe microcephaly v2.292 GPT2 Sarah Leigh commented on gene: GPT2
Severe microcephaly v2.292 FOXG1 Sarah Leigh commented on gene: FOXG1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Severe microcephaly v2.292 EIF5A Sarah Leigh commented on gene: EIF5A
Severe microcephaly v2.292 EIF2S3 Sarah Leigh commented on gene: EIF2S3
Severe microcephaly v2.292 DYNC1I2 Sarah Leigh commented on gene: DYNC1I2
Severe microcephaly v2.292 DPM1 Sarah Leigh commented on gene: DPM1
Severe microcephaly v2.292 DNA2 Sarah Leigh commented on gene: DNA2
Severe microcephaly v2.292 CTU2 Sarah Leigh commented on gene: CTU2
Severe microcephaly v2.292 CTCF Sarah Leigh commented on gene: CTCF
Severe microcephaly v2.292 CSNK2A1 Sarah Leigh commented on gene: CSNK2A1
Severe microcephaly v2.292 CHAMP1 Sarah Leigh commented on gene: CHAMP1
Severe microcephaly v2.292 CEP63 Sarah Leigh commented on gene: CEP63
Severe microcephaly v2.292 CEP57 Sarah Leigh commented on gene: CEP57
Severe microcephaly v2.292 CAMK2B Sarah Leigh commented on gene: CAMK2B
Severe microcephaly v2.292 BUB1B Sarah Leigh commented on gene: BUB1B
Severe microcephaly v2.292 BPTF Sarah Leigh commented on gene: BPTF
Severe microcephaly v2.292 AARS Sarah Leigh commented on gene: AARS
Severe microcephaly v2.291 YIPF5 Eleanor Williams Source Expert Review Green was added to YIPF5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 WDR4 Eleanor Williams Source Expert Review Green was added to WDR4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 WDR37 Eleanor Williams Source Expert Review Green was added to WDR37.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 WDR11 Eleanor Williams Source Expert Review Green was added to WDR11.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 VRK1 Eleanor Williams Source Expert Review Green was added to VRK1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 UNC80 Eleanor Williams Source Expert Review Green was added to UNC80.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 UGP2 Eleanor Williams Source Expert Review Green was added to UGP2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 TSEN54 Eleanor Williams Source Expert Review Green was added to TSEN54.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 TSEN15 Eleanor Williams Source Expert Review Green was added to TSEN15.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 TRIO Eleanor Williams Source Expert Review Green was added to TRIO.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 TRAPPC9 Eleanor Williams Source Expert Review Green was added to TRAPPC9.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 TRAPPC6B Eleanor Williams Source Expert Review Green was added to TRAPPC6B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 TP53RK Eleanor Williams Source Expert Review Green was added to TP53RK.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 TNPO2 Eleanor Williams Source Expert Review Green was added to TNPO2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 SMARCA5 Eleanor Williams Source Expert Review Green was added to SMARCA5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 SLC1A4 Eleanor Williams Source Expert Review Green was added to SLC1A4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 RAD51 Eleanor Williams Source Expert Review Green was added to RAD51.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 RAD50 Eleanor Williams Source Expert Review Green was added to RAD50.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 PUS7 Eleanor Williams Source Expert Review Green was added to PUS7.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 PUF60 Eleanor Williams Source Expert Review Green was added to PUF60.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 PTPN23 Eleanor Williams Source Expert Review Green was added to PTPN23.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 POGZ Eleanor Williams Source Expert Review Green was added to POGZ.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 PCDH12 Eleanor Williams Source Expert Review Green was added to PCDH12.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 OSGEP Eleanor Williams Source Expert Review Green was added to OSGEP.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 NUP107 Eleanor Williams Source Expert Review Green was added to NUP107.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 MINPP1 Eleanor Williams Source Expert Review Green was added to MINPP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 LAGE3 Eleanor Williams Source Expert Review Green was added to LAGE3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 HPDL Eleanor Williams Source Expert Review Green was added to HPDL.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 HIST1H4C Eleanor Williams Source Expert Review Green was added to HIST1H4C.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 GTF2E2 Eleanor Williams Source Expert Review Green was added to GTF2E2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 GPT2 Eleanor Williams Source Expert Review Green was added to GPT2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 FOXG1 Eleanor Williams Source Expert Review Green was added to FOXG1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 EIF5A Eleanor Williams Source Expert Review Green was added to EIF5A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 EIF2S3 Eleanor Williams Source Expert Review Green was added to EIF2S3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 DYNC1I2 Eleanor Williams Source Expert Review Green was added to DYNC1I2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 DPM1 Eleanor Williams Source Expert Review Green was added to DPM1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 DNA2 Eleanor Williams Source Expert Review Green was added to DNA2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 CTU2 Eleanor Williams Source Expert Review Green was added to CTU2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 CTCF Eleanor Williams Source Expert Review Green was added to CTCF.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 CSNK2A1 Eleanor Williams Source Expert Review Green was added to CSNK2A1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 CHAMP1 Eleanor Williams Source Expert Review Green was added to CHAMP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 CEP63 Eleanor Williams Source Expert Review Red was added to CEP63.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Severe microcephaly v2.291 CEP57 Eleanor Williams Source Expert Review Green was added to CEP57.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 CAMK2B Eleanor Williams Source Expert Review Green was added to CAMK2B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 BUB1B Eleanor Williams Source Expert Review Green was added to BUB1B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 BPTF Eleanor Williams Source Expert Review Green was added to BPTF.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 AARS Eleanor Williams Source Expert Review Green was added to AARS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.290 METTL5 Eleanor Williams Phenotypes for gene: METTL5 were changed from Intellectual developmental disorder, autosomal recessive 72, 618665 to Intellectual developmental disorder, autosomal recessive 72, OMIM:618665
Severe microcephaly v2.289 METTL5 Eleanor Williams Tag for-review was removed from gene: METTL5.
Severe microcephaly v2.289 AP4S1 Eleanor Williams Publications for gene: AP4S1 were set to 21620353; 25552650; 27444738
Severe microcephaly v2.288 AP4S1 Eleanor Williams Tag for-review was removed from gene: AP4S1.
Severe microcephaly v2.288 AP4M1 Eleanor Williams Tag for-review was removed from gene: AP4M1.
Tag missense tag was added to gene: AP4M1.
Severe microcephaly v2.288 AP4B1 Eleanor Williams Tag for-review was removed from gene: AP4B1.
Severe microcephaly v2.288 UBE3A Eleanor Williams Phenotypes for gene: UBE3A were changed from Angelman syndrome 105830 to Angelman syndrome, OMIM:105830
Severe microcephaly v2.287 UBE3A Eleanor Williams Tag for-review was removed from gene: UBE3A.
Severe microcephaly v2.287 ZNF526 Eleanor Williams Tag for-review was removed from gene: ZNF526.
Severe microcephaly v2.287 SMG8 Eleanor Williams Tag for-review was removed from gene: SMG8.
Severe microcephaly v2.287 NARS Eleanor Williams Tag for-review was removed from gene: NARS.
Severe microcephaly v2.287 MORC2 Eleanor Williams Tag for-review was removed from gene: MORC2.
Severe microcephaly v2.287 LMNB2 Eleanor Williams Tag for-review was removed from gene: LMNB2.
Severe microcephaly v2.287 LMNB1 Eleanor Williams Tag for-review was removed from gene: LMNB1.
Severe microcephaly v2.287 DNMT3A Eleanor Williams Tag for-review was removed from gene: DNMT3A.
Severe microcephaly v2.287 ZNF335 Eleanor Williams Phenotypes for gene: ZNF335 were changed from Microcephaly 10, primary, autosomal recessive, 615095 to Microcephaly 10, primary, autosomal recessive, OMIM:615095
Severe microcephaly v2.286 ZNF335 Eleanor Williams Tag for-review was removed from gene: ZNF335.
Severe microcephaly v2.286 ATP1A2 Eleanor Williams Tag for-review was removed from gene: ATP1A2.
Severe microcephaly v2.286 KIF14 Eleanor Williams Tag for-review was removed from gene: KIF14.
Severe microcephaly v2.286 AP4E1 Eleanor Williams Tag for-review was removed from gene: AP4E1.
Severe microcephaly v2.286 SVBP Eleanor Williams Tag for-review was removed from gene: SVBP.
Severe microcephaly v2.286 CEP55 Eleanor Williams Tag for-review was removed from gene: CEP55.
Severe microcephaly v2.286 TMX2 Eleanor Williams Tag for-review was removed from gene: TMX2.
Severe microcephaly v2.286 TUBGCP2 Eleanor Williams Phenotypes for gene: TUBGCP2 were changed from Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures, 618737 to Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures, OMIM:618737
Severe microcephaly v2.285 TUBGCP2 Eleanor Williams Tag for-review was removed from gene: TUBGCP2.
Severe microcephaly v2.285 TTC5 Eleanor Williams Tag for-review was removed from gene: TTC5.
Severe microcephaly v2.285 NUP188 Eleanor Williams Phenotypes for gene: NUP188 were changed from Sandestig-Stefanova syndrome, 618804 to Sandestig-Stefanova syndrome, OMIM:618804
Severe microcephaly v2.284 NUP188 Eleanor Williams Tag for-review was removed from gene: NUP188.
Severe microcephaly v2.284 NCAPD2 Eleanor Williams Phenotypes for gene: NCAPD2 were changed from Microcephaly 21, primary, autosomal recessive, 617983 to Microcephaly 21, primary, autosomal recessive, OMIM:617983
Severe microcephaly v2.283 NCAPD2 Eleanor Williams Tag for-review was removed from gene: NCAPD2.
Severe microcephaly v2.283 ADARB1 Eleanor Williams Phenotypes for gene: ADARB1 were changed from Neurodevelopmental disorder with hypotonia, microcephaly, and seizures, 618862 to Neurodevelopmental disorder with hypotonia, microcephaly, and seizures, OMIM:618862
Severe microcephaly v2.282 ADARB1 Eleanor Williams Tag for-review was removed from gene: ADARB1.
Severe microcephaly v2.282 PPIL1 Eleanor Williams Tag for-review was removed from gene: PPIL1.
Severe microcephaly v2.282 FBRSL1 Eleanor Williams Tag for-review was removed from gene: FBRSL1.
Severe microcephaly v2.282 ANKLE2 Eleanor Williams Tag for-review was removed from gene: ANKLE2.
Severe microcephaly v2.282 COASY Eleanor Williams Tag watchlist was removed from gene: COASY.
Tag for-review was removed from gene: COASY.
Severe microcephaly v2.282 TRAPPC12 Eleanor Williams Tag for-review was removed from gene: TRAPPC12.
Severe microcephaly v2.282 METTL5 Sarah Leigh commented on gene: METTL5
Severe microcephaly v2.282 AP4S1 Sarah Leigh commented on gene: AP4S1: Comment from NHS Genomic Medicine Service: primary presentation is ID/DD/spasticity/hypotonia: green on ID and HSP and hypotonic infant panels - not clear if severe microephaly exists in absence of these.
Severe microcephaly v2.282 AP4S1 Sarah Leigh commented on gene: AP4S1
Severe microcephaly v2.282 AP4M1 Sarah Leigh commented on gene: AP4M1: Comment from NHS Genomic Medicine Service: primary presentation is ID/DD/spasticity/hypotonia: green on ID and HSP and hypotonic infant panels - not clear if severe microephaly exists in absence of these.
Severe microcephaly v2.282 AP4M1 Sarah Leigh commented on gene: AP4M1
Severe microcephaly v2.282 AP4B1 Sarah Leigh commented on gene: AP4B1: Comment from NHS Genomic Medicine Service: primary presentation is ID/DD/spasticity/hypotonia: green on ID and HSP and hypotonic infant panels - not clear if severe microephaly exists in absence of these
Severe microcephaly v2.282 AP4B1 Sarah Leigh commented on gene: AP4B1
Severe microcephaly v2.282 UBE3A Sarah Leigh commented on gene: UBE3A: Comment from NHS Genomic Medicine Service: Primary presentation is ID/DD: green on ID & other panels - not clear if severe microephaly exists in absence of these other features? Microcephaly isn't listed as a key feature in Genereviews for females, ands is only present in some males (with severe epilepsy).
Severe microcephaly v2.282 UBE3A Sarah Leigh commented on gene: UBE3A: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed.
Severe microcephaly v2.282 ZNF526 Sarah Leigh commented on gene: ZNF526
Severe microcephaly v2.282 SMG8 Sarah Leigh commented on gene: SMG8
Severe microcephaly v2.282 NARS Sarah Leigh commented on gene: NARS
Severe microcephaly v2.282 MORC2 Sarah Leigh commented on gene: MORC2
Severe microcephaly v2.282 LMNB2 Sarah Leigh commented on gene: LMNB2: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Severe microcephaly v2.282 LMNB1 Sarah Leigh commented on gene: LMNB1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Severe microcephaly v2.282 DNMT3A Sarah Leigh commented on gene: DNMT3A: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Severe microcephaly v2.282 ZNF335 Sarah Leigh commented on gene: ZNF335
Severe microcephaly v2.282 ATP1A2 Sarah Leigh commented on gene: ATP1A2
Severe microcephaly v2.282 KIF14 Sarah Leigh commented on gene: KIF14
Severe microcephaly v2.282 AP4E1 Sarah Leigh commented on gene: AP4E1
Severe microcephaly v2.282 SVBP Sarah Leigh commented on gene: SVBP
Severe microcephaly v2.282 CEP55 Sarah Leigh commented on gene: CEP55
Severe microcephaly v2.282 TMX2 Sarah Leigh commented on gene: TMX2: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Severe microcephaly v2.282 TUBGCP2 Sarah Leigh commented on gene: TUBGCP2
Severe microcephaly v2.282 TTC5 Sarah Leigh commented on gene: TTC5: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Severe microcephaly v2.282 NUP188 Sarah Leigh commented on gene: NUP188
Severe microcephaly v2.282 NCAPD2 Sarah Leigh commented on gene: NCAPD2
Severe microcephaly v2.282 ADARB1 Sarah Leigh commented on gene: ADARB1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Severe microcephaly v2.282 PPIL1 Sarah Leigh commented on gene: PPIL1
Severe microcephaly v2.282 FBRSL1 Sarah Leigh commented on gene: FBRSL1
Severe microcephaly v2.282 ANKLE2 Sarah Leigh commented on gene: ANKLE2
Severe microcephaly v2.282 COASY Sarah Leigh commented on gene: COASY: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Severe microcephaly v2.282 TRAPPC12 Sarah Leigh commented on gene: TRAPPC12
Severe microcephaly v2.281 METTL5 Eleanor Williams Source Expert Review Green was added to METTL5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 ZNF526 Eleanor Williams Source Expert Review Green was added to ZNF526.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 SMG8 Eleanor Williams Source Expert Review Green was added to SMG8.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 NARS Eleanor Williams Source Expert Review Green was added to NARS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 MORC2 Eleanor Williams Source Expert Review Green was added to MORC2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 LMNB2 Eleanor Williams Source Expert Review Green was added to LMNB2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 LMNB1 Eleanor Williams Source Expert Review Green was added to LMNB1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 DNMT3A Eleanor Williams Source Expert Review Green was added to DNMT3A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 ZNF335 Eleanor Williams Source Expert Review Green was added to ZNF335.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 ATP1A2 Eleanor Williams Source Expert Review Green was added to ATP1A2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 KIF14 Eleanor Williams Source Expert Review Green was added to KIF14.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 AP4E1 Eleanor Williams Source Expert Review Green was added to AP4E1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 SVBP Eleanor Williams Source Expert Review Green was added to SVBP.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 CEP55 Eleanor Williams Source Expert Review Green was added to CEP55.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 TMX2 Eleanor Williams Source Expert Review Green was added to TMX2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 TUBGCP2 Eleanor Williams Source Expert Review Green was added to TUBGCP2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 TTC5 Eleanor Williams Source Expert Review Green was added to TTC5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 NUP188 Eleanor Williams Source Expert Review Green was added to NUP188.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 NCAPD2 Eleanor Williams Source Expert Review Green was added to NCAPD2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 ADARB1 Eleanor Williams Source Expert Review Green was added to ADARB1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 PPIL1 Eleanor Williams Source Expert Review Green was added to PPIL1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 FBRSL1 Eleanor Williams Source Expert Review Green was added to FBRSL1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 ANKLE2 Eleanor Williams Source Expert Review Green was added to ANKLE2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 COASY Eleanor Williams Source Expert Review Green was added to COASY.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 TRAPPC12 Eleanor Williams Source Expert Review Green was added to TRAPPC12.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.280 CCND2 Sarah Leigh Publications for gene: CCND2 were set to 34087052
Severe microcephaly v2.279 CCND2 Sarah Leigh edited their review of gene: CCND2: Added comment: Not associated with a phenotype in OMIM, Gen2Phen. At least three terminating variants have been reported in three unrelated cases with severe microcephaly. These variants are located within the proximal region of the gene, in contrast to the previously reported megalencephaly-associated CCND2 variants, which are localized to
the terminal exon, resulting in gain of function (PMID:34087052;24705253).; Changed rating: GREEN
Severe microcephaly v2.279 CCND2 Sarah Leigh Phenotypes for gene: CCND2 were changed from Microcephaly, MONDO# 0001149 to Microcephaly, MONDO:0001149
Severe microcephaly v2.278 CCND2 Sarah Leigh Classified gene: CCND2 as Amber List (moderate evidence)
Severe microcephaly v2.278 CCND2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Severe microcephaly v2.278 CCND2 Sarah Leigh Gene: ccnd2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.277 CCND2 Sarah Leigh Tag Q1_22_rating tag was added to gene: CCND2.
Severe microcephaly v2.277 CCND2 Zornitza Stark gene: CCND2 was added
gene: CCND2 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: CCND2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CCND2 were set to 34087052
Phenotypes for gene: CCND2 were set to Microcephaly, MONDO# 0001149
Review for gene: CCND2 was set to GREEN
Added comment: Novel phenotype of microcephaly and mild developmental delay described in three unrelated families. Variants associated with this phenotype located in the proximal region of the gene.

Variants in distal region of gene associated with a reciprocal phenotype of macrocephaly/megalencephaly with severe cortical malformation.
Sources: Literature
Severe microcephaly v2.277 NCAPD3 Ronnie Wright reviewed gene: NCAPD3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.277 SPATA5L1 Ivone Leong Entity copied from Intellectual disability v3.1491
Severe microcephaly v2.277 SPATA5L1 Ivone Leong gene: SPATA5L1 was added
gene: SPATA5L1 was added to Severe microcephaly. Sources: Expert Review Amber,Literature
Q1_22_rating tags were added to gene: SPATA5L1.
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, OMIM:619616
Severe microcephaly v2.276 HHAT Eleanor Williams Tag Q4_21_rating tag was added to gene: HHAT.
Severe microcephaly v2.276 HHAT Eleanor Williams Classified gene: HHAT as Amber List (moderate evidence)
Severe microcephaly v2.276 HHAT Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber, with a recommendation for green rating following GMS review. 3 cases with microcephaly progressing to severe microcephaly reported.
Severe microcephaly v2.276 HHAT Eleanor Williams Gene: hhat has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.275 HHAT Eleanor Williams Entity copied from Skeletal dysplasia v2.161
Severe microcephaly v2.275 HHAT Eleanor Williams gene: HHAT was added
gene: HHAT was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: HHAT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HHAT were set to 24784881; 30912300; 33749989
Phenotypes for gene: HHAT were set to Nivelon-Nivelon-Mabille syndrome, OMIM:600092
Severe microcephaly v2.274 TP53RK Eleanor Williams edited their review of gene: TP53RK: Changed rating: GREEN
Severe microcephaly v2.274 ARPC4 Zornitza Stark gene: ARPC4 was added
gene: ARPC4 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: ARPC4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARPC4 were set to DOI:https://doi.org/10.1016/j.xhgg.2021.100072
Phenotypes for gene: ARPC4 were set to Microcephaly; mild motor delays; significant speech impairment
Review for gene: ARPC4 was set to GREEN
Added comment: 7 affected individuals from 6 families (gonadal mosaicism was confirmed in the mother of the 2 affected siblings) with a recurrent missense variant (NM_005718.4:c.472C>T; p.R158C). 6/7 affected individuals had microcephaly. The variant was associated with a decreased amount of F-actin in cells from two affected individuals.
Sources: Literature
Severe microcephaly v2.274 GPT2 Arina Puzriakova Classified gene: GPT2 as Amber List (moderate evidence)
Severe microcephaly v2.274 GPT2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at then next GMS panel update.
Severe microcephaly v2.274 GPT2 Arina Puzriakova Gene: gpt2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.273 GPT2 Arina Puzriakova gene: GPT2 was added
gene: GPT2 was added to Severe microcephaly. Sources: Literature
Q4_21_rating tags were added to gene: GPT2.
Mode of inheritance for gene: GPT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GPT2 were set to 25758935; 27601654; 29226631; 29882329; 31471722
Phenotypes for gene: GPT2 were set to Neurodevelopmental disorder with microcephaly and spastic paraplegia, OMIM:616281
Review for gene: GPT2 was set to GREEN
Added comment: Microcephaly is a prominent features of the neurodevelopmental disorder associated with biallelic variants in the GPT2 gene. Mostly all patients are to some degree microcephalic but at least 6 unrelated families (out of 11 total) have been reported with microcephaly of relevant severity to this panel (≥ -3SD). This gene is associated with a relevant phenotype in OMIM (OMIM:616281) but is not yet listed in G2P.
Sources: Literature
Severe microcephaly v2.272 ATP9A Sarah Leigh Publications for gene: ATP9A were set to 34379057; 34764295
Severe microcephaly v2.271 ATP9A Sarah Leigh reviewed gene: ATP9A: Rating: AMBER; Mode of pathogenicity: None; Publications: 27626380; Phenotypes: ; Mode of inheritance: None
Severe microcephaly v2.271 ATP9A Sarah Leigh Publications for gene: ATP9A were set to 34379057
Severe microcephaly v2.270 LMNB2 Arina Puzriakova Phenotypes for gene: LMNB2 were changed from Congenital microcephaly; Global developmental delay; Intellectual disability to Microcephaly 27, primary, autosomal dominant, OMIM:619180
Severe microcephaly v2.269 LMNB1 Arina Puzriakova Phenotypes for gene: LMNB1 were changed from Congenital microcephaly; Global developmental delay; Intellectual disability; LMNB1-associated developmental disorder to Microcephaly 26, primary, autosomal dominant, OMIM:619179
Severe microcephaly v2.268 EIF5A Arina Puzriakova Phenotypes for gene: EIF5A were changed from Intellectual disability; microcephaly; dysmorphism to Faundes-Banka syndrome, OMIM:619376
Severe microcephaly v2.267 DPP6 Ivone Leong Tag Q4_21_expert_review tag was added to gene: DPP6.
Severe microcephaly v2.267 DYNC1I2 Ivone Leong Classified gene: DYNC1I2 as Amber List (moderate evidence)
Severe microcephaly v2.267 DYNC1I2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype (probable). There is sufficient evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.267 DYNC1I2 Ivone Leong Gene: dync1i2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.266 DYNC1I2 Ivone Leong Tag Q4_21_rating tag was added to gene: DYNC1I2.
Severe microcephaly v2.266 ARCN1 Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype (probable). Patients 1, 3 and 4 (patients 3 and 4 are from the same family) from PMID:27476655 have a head circumference <-3 SD. Patient 2 has head circumference of -1.53 SD, which is not severe enough for this panel.

The patients in the 2 additional papers (PMID: 31075182 and 33154040) do have microcephaly; however, it is not clear as to what the severity is of the patients currently (only their birth head circumferences was given, which were not severe enough for this panel, and no measurements were given at later time points).

Therefore, there is currently not enough evidence for a gene-disease association. This gene has been given an Amber rating.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype (probable). Patients 1, 3 and 4 (patients 3 and 4 are from the same family) from PMID:27476655 have a head circumference <-3 SD. Patient 2 has head circumference of -1.53 SD, which is not severe enough for this panel.

The patients in the 2 additional papers (PMID: 31075182 and 33154040) do have microcephaly; however, it is not clear as to what the severity is of the patients currently (only their birth head circumferences were given, which were not severe enough for this panel, and no measurements were given at later time points).

Therefore, there is currently not enough evidence for a gene-disease association. This gene has been given an Amber rating.
Severe microcephaly v2.266 BRD4 Ivone Leong Phenotypes for gene: BRD4 were changed from Cornelia de Lange-like syndrome to Cornelia de Lange-like syndrome, MONDO:0016033
Severe microcephaly v2.265 BRD4 Ivone Leong Classified gene: BRD4 as Amber List (moderate evidence)
Severe microcephaly v2.265 BRD4 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 (probable) but not OMIM. Based on the available evidence this gene has been given an Amber rating.
Severe microcephaly v2.265 BRD4 Ivone Leong Gene: brd4 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.264 BRD4 Ivone Leong Tag watchlist tag was added to gene: BRD4.
Severe microcephaly v2.264 RAD51 Arina Puzriakova Classified gene: RAD51 as Amber List (moderate evidence)
Severe microcephaly v2.264 RAD51 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 3 unrelated cases with relevant phenotype and different de novo variants. Phenotype-gene relationship listed in OMIM (MIM# 617244).
Severe microcephaly v2.264 RAD51 Arina Puzriakova Gene: rad51 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.263 RAD51 Arina Puzriakova gene: RAD51 was added
gene: RAD51 was added to Severe microcephaly. Sources: Literature
Q4_21_rating tags were added to gene: RAD51.
Mode of inheritance for gene: RAD51 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RAD51 were set to 26681308; 26253028; 30907510
Phenotypes for gene: RAD51 were set to Fanconi anemia, complementation group R, OMIM:617244
Review for gene: RAD51 was set to GREEN
Added comment: Three unrelated patients have been identified to date (PMIDs: 26681308; 26253028; 30907510) with an atypical FA phonotype involving chromosomal instability without bone marrow failure or malignancies along with private heterozygous variants (c.877G>A; c.391A>C; c.725A>G) in the RAD51 gene. Variants occurred de novo with a dominant negative effect. All three individuals presented with thumb and radial abnormalities, microcephaly, and DD/ID (third patient showed early DD but above average IQ by age 13); and two individuals also had growth retardation (probable in third case but not reported on) and hearing impairment.
Sources: Literature
Severe microcephaly v2.262 SARS Ivone Leong Entity copied from Intellectual disability v3.1356
Severe microcephaly v2.262 SARS Ivone Leong gene: SARS was added
gene: SARS was added to Severe microcephaly. Sources: Expert Review Amber,Literature
watchlist, new-gene-name tags were added to gene: SARS.
Mode of inheritance for gene: SARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SARS were set to 28236339; 34570399
Phenotypes for gene: SARS were set to ?Neurodevelopmental disorder with microcephaly, ataxia, and seizures, OMIM:617709
Severe microcephaly v2.261 ATP6V0C Ivone Leong Entity copied from Intellectual disability v3.1354
Severe microcephaly v2.261 ATP6V0C Ivone Leong gene: ATP6V0C was added
gene: ATP6V0C was added to Severe microcephaly. Sources: Literature,Expert Review Amber
watchlist tags were added to gene: ATP6V0C.
Mode of inheritance for gene: ATP6V0C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP6V0C were set to 33190975; 33090716
Phenotypes for gene: ATP6V0C were set to Epilepsy; Intellectual Disability; microcephaly
Severe microcephaly v2.260 ATP11A Ivone Leong Classified gene: ATP11A as Red List (low evidence)
Severe microcephaly v2.260 ATP11A Ivone Leong Gene: atp11a has been classified as Red List (Low Evidence).
Severe microcephaly v2.259 ATP11A Ivone Leong changed review comment from: 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.; to: 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 the mouse model did not show signs of microcephaly, there is currently not enough evidence to support a gene-disease association, this gene has been given an Red rating.
Severe microcephaly v2.259 ATP11A Ivone Leong Entity copied from Intellectual disability v3.1353
Severe microcephaly v2.259 ATP11A Ivone Leong gene: ATP11A was added
gene: ATP11A was added to Severe microcephaly. Sources: Expert Review Amber,Literature
watchlist tags were added to gene: ATP11A.
Mode of inheritance for gene: ATP11A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP11A were set to 34403372
Phenotypes for gene: ATP11A were set to Neurodevelopmental disorder
Severe microcephaly v2.258 WDR11 Ivone Leong changed review comment from: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in Gene2Phenotype (probable) but not in OMIM. There is enough evidence to support a gene-disease association; however, the severity of ID in the patients described in PMID:34413497 does not fit the criteria for this panel (panel is for moderate to severe ID, patients have mild ID). Therefore, this gene has been given an Amber rating.

The OFC of patients in PMID: 34413497 ranged from -3.09 SD to -4.93 SD); to: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in Gene2Phenotype (probable) but not in OMIM. The OFC of patients in PMID: 34413497 ranged from -3.09 SD to -4.93 SD). There is enough evidence to support a gene-disease association, this gene should be rated Green at the next review.
Severe microcephaly v2.258 WDR11 Ivone Leong Tag watchlist was removed from gene: WDR11.
Tag Q4_21_rating tag was added to gene: WDR11.
Severe microcephaly v2.258 WDR11 Ivone Leong Entity copied from Intellectual disability v3.1348
Severe microcephaly v2.258 WDR11 Ivone Leong gene: WDR11 was added
gene: WDR11 was added to Severe microcephaly. Sources: Expert Review Amber
watchlist tags were added to gene: WDR11.
Mode of inheritance for gene: WDR11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR11 were set to 26350204; 34413497
Phenotypes for gene: WDR11 were set to Intellectual disability, MONDO:0001071; Microcephaly, MONDO:0001149; Short stature,HP:0004322
Penetrance for gene: WDR11 were set to Complete
Severe microcephaly v2.257 ZNF668 Ivone Leong Entity copied from Intellectual disability v3.1332
Severe microcephaly v2.257 ZNF668 Ivone Leong gene: ZNF668 was added
gene: ZNF668 was added to Severe microcephaly. Sources: Expert Review Amber,Literature
watchlist tags were added to gene: ZNF668.
Mode of inheritance for gene: ZNF668 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF668 were set to 34313816; 26633546
Phenotypes for gene: ZNF668 were set to DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism
Severe microcephaly v2.256 VPS50 Ivone Leong changed review comment from: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 34037727. Both patients have severe microcephaly (-7.65 to -10.35 z-score), height at 2 years (-2.65 to -3.84 z-score), seizures, hypoplastic coprus callosum, neonatal cholestasis and feeding difficulties.

Based on the available evidence there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.; to: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 34037727. Both patients have severe microcephaly (-7.65 to -10.35 z-score), height at 2 years (-2.65 to -3.84 z-score), seizures, hypoplastic corpus callosum, neonatal cholestasis and feeding difficulties.

Based on the available evidence there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Severe microcephaly v2.256 VPS50 Ivone Leong Entity copied from Intellectual disability v3.1322
Severe microcephaly v2.256 VPS50 Ivone Leong gene: VPS50 was added
gene: VPS50 was added to Severe microcephaly. Sources: Expert Review Amber,Literature
watchlist tags were added to gene: VPS50.
Mode of inheritance for gene: VPS50 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS50 were set to 34037727
Phenotypes for gene: VPS50 were set to Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum
Penetrance for gene: VPS50 were set to Complete
Severe microcephaly v2.255 ARF3 Ivone Leong Tag watchlist was removed from gene: ARF3.
Severe microcephaly v2.255 ARF3 Ivone Leong Classified gene: ARF3 as Red List (low evidence)
Severe microcephaly v2.255 ARF3 Ivone Leong Added comment: Comment on list classification: Demoted from Amber to Red as per my review.
Severe microcephaly v2.255 ARF3 Ivone Leong Gene: arf3 has been classified as Red List (Low Evidence).
Severe microcephaly v2.254 ARF3 Ivone Leong changed review comment from: 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.; to: 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.

As only 1 patient has severe microcephaly. This gene has been given a Red rating.
Severe microcephaly v2.254 ARF3 Ivone Leong Entity copied from Intellectual disability v3.1321
Severe microcephaly v2.254 ARF3 Ivone Leong gene: ARF3 was added
gene: ARF3 was added to Severe microcephaly. Sources: Expert Review Amber,Literature
watchlist tags were added to gene: ARF3.
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, MONDO:0001071; Seizures; Morphological abnormality of the central nervous system; microcephaly, MONDO:0001149
Penetrance for gene: ARF3 were set to unknown
Severe microcephaly v2.253 GTF2E2 Arina Puzriakova Classified gene: GTF2E2 as Amber List (moderate evidence)
Severe microcephaly v2.253 GTF2E2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - two distinct homozygous variants identified in 5 individuals from 4 families who all had microcephaly among other features. Supportive in vitro studies that demonstrate functional impairment.
Severe microcephaly v2.253 GTF2E2 Arina Puzriakova Gene: gtf2e2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.252 GTF2E2 Arina Puzriakova gene: GTF2E2 was added
gene: GTF2E2 was added to Severe microcephaly. Sources: Literature
Q3_21_rating tags were added to gene: GTF2E2.
Mode of inheritance for gene: GTF2E2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GTF2E2 were set to 26996949; 28973399
Phenotypes for gene: GTF2E2 were set to Trichothiodystrophy 6, nonphotosensitive, OMIM:616943
Review for gene: GTF2E2 was set to GREEN
Added comment: Four individuals from 3 different Moroccan families with the same homozygous variant (c.C559T) in the GTF2E2 gene have been identified, as well as an additional patient from Asian origin with a distinct homozygous variant (c.448G>C). Predominant phenotype was that of trichothiodystrophy; however, all 5 individuals also had ID/DD, microcephaly and ichthyosis - and therefore adding GTF2E2 to these relevant panel.
Sources: Literature
Severe microcephaly v2.251 PCDHGC4 Sarah Leigh Tag Q3_21_rating was removed from gene: PCDHGC4.
Severe microcephaly v2.251 PCDHGC4 Sarah Leigh reviewed gene: PCDHGC4: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe microcephaly v2.251 PCDHGC4 Sarah Leigh Deleted their review
Severe microcephaly v2.251 PCDHGC4 Sarah Leigh Deleted their comment
Severe microcephaly v2.251 PCDHGC4 Sarah Leigh Entity copied from Intellectual disability v3.1307
Severe microcephaly v2.251 PCDHGC4 Sarah Leigh gene: PCDHGC4 was added
gene: PCDHGC4 was added to Severe microcephaly. Sources: Literature,Expert Review Amber
Q3_21_rating tags were added to gene: PCDHGC4.
Mode of inheritance for gene: PCDHGC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCDHGC4 were set to 34244665
Phenotypes for gene: PCDHGC4 were set to Neurodevelopmental abnormality HP:0012759
Severe microcephaly v2.250 TNPO2 Arina Puzriakova Classified gene: TNPO2 as Amber List (moderate evidence)
Severe microcephaly v2.250 TNPO2 Arina Puzriakova Added comment: Comment on list classification: There are sufficient unrelated cases presenting were a relevant phenotype associated with variants in this gene to rate as Green at the next GMS panel update.
Severe microcephaly v2.250 TNPO2 Arina Puzriakova Gene: tnpo2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.249 TNPO2 Arina Puzriakova gene: TNPO2 was added
gene: TNPO2 was added to Severe microcephaly. Sources: Literature
Q3_21_rating tags were added to gene: TNPO2.
Mode of inheritance for gene: TNPO2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TNPO2 were set to 34314705
Phenotypes for gene: TNPO2 were set to Intellectual disability; Dysmorphic features; Microcephaly; Seizures; Hypotonia
Review for gene: TNPO2 was set to GREEN
Added comment: Goodman et al., 2021 (PMID: 34314705) reported on 15 unrelated individuals with different variants in this gene (14 de novo, 1 mosaic in mother; 12 SNVs, 3 in-frame deletions, 1 deletion-insertion). All had GDD and all those who were assessed also had ID (9/9), ranging from mild to severe. ID also suspected but not investigated in another 3 cases. 6 had seizures starting between 1 and 2.5 years of age. 5 individuals had microcephaly (HC ranging -2.77 to -4.53 SD). Other less common features were also observed such as variable brain, gastrointestinal and ophthalmologic abnormalities.

Notably 6 individuals had additional SNVs/CNVs of uncertain significance, some of which include known ID genes (e.g. SETBP1, CUX2, ARMC9, PDE4D), but were discounted due to lack of explanation of the overall patient phenotype.

Some functional studies conducted in Drosophila demonstrated that patient-associated variants caused neurodevelopmental defects that were dosage and location (of variant within protein) dependent.
Sources: Literature
Severe microcephaly v2.248 ARCN1 Ivone Leong Phenotypes for gene: ARCN1 were changed from Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay (MIM#617164) to Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay, OMIM:617164
Severe microcephaly v2.247 ARCN1 Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype (probable). Patients 1, 3 and 4 (patients 3 and 4 are from the same family) from PMID:27476655 have a head circumference <-3 SD. Patient 2 has head circumference of -1.53 SD, which is not severe enough for this panel. Therefore, there is currently not enough evidence for a gene-disease association. This gene has been given an Amber rating.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype (probable). Patients 1, 3 and 4 (patients 3 and 4 are from the same family) from PMID:27476655 have a head circumference <-3 SD. Patient 2 has head circumference of -1.53 SD, which is not severe enough for this panel.

The patients in the 2 additional papers (PMID: 31075182 and 33154040) do have microcephaly; however, it is not clear as to what the severity is of the patients currently (only their birth head circumferences was given, which were not severe enough for this panel, and no measurements were given at later time points).

Therefore, there is currently not enough evidence for a gene-disease association. This gene has been given an Amber rating.
Severe microcephaly v2.247 ARCN1 Ivone Leong changed review comment from: Comment on publications: PMID:27476655. OMIM description of the patients, "exhibited rhizomelic short stature (4/4) as well as microcephaly (3/4), micrognathia (4/4), laxity of the small joints (3/4), and developmental delay (4/4). Other variable features included posterior cataract (1/4), cleft palate (1/4), ventricular septal defect (1/4), cryptorchidism (1/2), seizures (1/4), and autism (1/4)."

Additional publications. PMID: 31075182 describes a 5th case with de novo loss-of-function variant in ARCN1. Head circumference at birth (prematurely after 33 + 3 weeks of pregnancy) was 27.3 cm (<3rd percentile). The publication says the patient presented with microcephaly; however, I cannot find any recent head circumference measurements (child is 23 months old). From the paper "we report a de novo loss-of-function mutation in the delta-COP subunit of COPI, associated with microcephaly, retrognathia, muscular hypotonia, short stature, rhizomelic shortening, and transiently hypoglycosylation during febrile infections."

PMID: 33154040; to: Comment on publications: PMID:27476655. OMIM description of the patients, "exhibited rhizomelic short stature (4/4) as well as microcephaly (3/4), micrognathia (4/4), laxity of the small joints (3/4), and developmental delay (4/4). Other variable features included posterior cataract (1/4), cleft palate (1/4), ventricular septal defect (1/4), cryptorchidism (1/2), seizures (1/4), and autism (1/4)."

Additional publications. PMID: 31075182 describes a 5th case with de novo loss-of-function variant in ARCN1. Head circumference at birth (prematurely after 33 + 3 weeks of pregnancy) was 27.3 cm (<3rd percentile). The publication says the patient presented with microcephaly; however, I cannot find any recent head circumference measurements (child is 23 months old). From the paper "we report a de novo loss-of-function mutation in the delta-COP subunit of COPI, associated with microcephaly, retrognathia, muscular hypotonia, short stature, rhizomelic shortening, and transiently hypoglycosylation during febrile infections."

PMID: 33154040 describes another case. "3.5-yr-old Caucasian/Peruvian/Native American boy with microcephaly, severe global developmental delay, and multiple congenital abnormalities. At birth he was documented to have a small ventricular septal defect (which was closed by 3 wk), a patent foramen ovale, rhizomelic shortening of extremities on clinical examination, pectus carinatum, and underdeveloped genitalia including severe penoscrotal hypospadias and cryptorchidism." OFC at birth was just above 10th centile, at 3.5 yr OFC is below 3rd centile but no actual measurements were given. Microarrays identified a 95-kb loss at 12q23.2 including exons 1–4 of the NUP37 gene and exons 1–9 of the PARPBP gene, which were deemed nondiagnostic (neither parents had this deletion). A heterozygous variant was also found in HSPG2 (c.9893 C > T, p. Pro3298Leu). Biallelic variants in this gene is associated with skeletal disorders that did not fit the patient's phenotype and as the patient is heterozygous for a variant in HSPG2 it was deemed that this variant was not causative. WGS identified a de novo splice variant in ARCN1. mRNA studies showed that the variant caused retention of part of an intron in the transcript. The authors deemed the ARCN1 variant as the causative variant in this patient.
Severe microcephaly v2.247 ARCN1 Ivone Leong Added comment: Comment on publications: PMID:27476655. OMIM description of the patients, "exhibited rhizomelic short stature (4/4) as well as microcephaly (3/4), micrognathia (4/4), laxity of the small joints (3/4), and developmental delay (4/4). Other variable features included posterior cataract (1/4), cleft palate (1/4), ventricular septal defect (1/4), cryptorchidism (1/2), seizures (1/4), and autism (1/4)."

Additional publications. PMID: 31075182 describes a 5th case with de novo loss-of-function variant in ARCN1. Head circumference at birth (prematurely after 33 + 3 weeks of pregnancy) was 27.3 cm (<3rd percentile). The publication says the patient presented with microcephaly; however, I cannot find any recent head circumference measurements (child is 23 months old). From the paper "we report a de novo loss-of-function mutation in the delta-COP subunit of COPI, associated with microcephaly, retrognathia, muscular hypotonia, short stature, rhizomelic shortening, and transiently hypoglycosylation during febrile infections."

PMID: 33154040
Severe microcephaly v2.247 ARCN1 Ivone Leong Publications for gene: ARCN1 were set to 27476655
Severe microcephaly v2.246 ARCN1 Ivone Leong Tag Q3_21_rating was removed from gene: ARCN1.
Tag watchlist tag was added to gene: ARCN1.
Severe microcephaly v2.246 ARCN1 Ivone Leong Classified gene: ARCN1 as Amber List (moderate evidence)
Severe microcephaly v2.246 ARCN1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype (probable). Patients 1, 3 and 4 (patients 3 and 4 are from the same family) from PMID:27476655 have a head circumference <-3 SD. Patient 2 has head circumference of -1.53 SD, which is not severe enough for this panel. Therefore, there is currently not enough evidence for a gene-disease association. This gene has been given an Amber rating.
Severe microcephaly v2.246 ARCN1 Ivone Leong Gene: arcn1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.245 ARCN1 Ivone Leong Tag Q3_21_rating tag was added to gene: ARCN1.
Severe microcephaly v2.245 ATP9A Arina Puzriakova Publications for gene: ATP9A were set to http://dx.doi.org/10.1136/jmedgenet-2021-107843
Severe microcephaly v2.244 EIF2S3 Ivone Leong Tag Q3_21_rating tag was added to gene: EIF2S3.
Severe microcephaly v2.244 EIF2S3 Ivone Leong Classified gene: EIF2S3 as Amber List (moderate evidence)
Severe microcephaly v2.244 EIF2S3 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype (probable). There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.244 EIF2S3 Ivone Leong Gene: eif2s3 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.243 EIF2S3 Ivone Leong Phenotypes for gene: EIF2S3 were changed from MEHMO syndrome, MIM# 300148 to MEHMO syndrome, OMIM:300148
Severe microcephaly v2.242 HIST1H4C Ivone Leong Tag Q3_21_rating tag was added to gene: HIST1H4C.
Severe microcephaly v2.242 HIST1H4C Ivone Leong Classified gene: HIST1H4C as Amber List (moderate evidence)
Severe microcephaly v2.242 HIST1H4C 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 (possible) but not OMIM. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.242 HIST1H4C Ivone Leong Gene: hist1h4c has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.241 HIST1H4C Ivone Leong commented on gene: HIST1H4C
Severe microcephaly v2.241 HIST1H4C Ivone Leong Tag new-gene-name tag was added to gene: HIST1H4C.
Severe microcephaly v2.241 LAGE3 Ivone Leong Tag Q3_21_rating tag was added to gene: LAGE3.
Severe microcephaly v2.241 LAGE3 Ivone Leong Classified gene: LAGE3 as Amber List (moderate evidence)
Severe microcephaly v2.241 LAGE3 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype (possible). There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.241 LAGE3 Ivone Leong Gene: lage3 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.240 LAGE3 Ivone Leong Phenotypes for gene: LAGE3 were changed from Galloway-Mowat syndrome 2, X-linked, MIM# 301006 to Galloway-Mowat syndrome 2, X-linked, OMIM:301006
Severe microcephaly v2.239 MED17 Ivone Leong Classified gene: MED17 as Amber List (moderate evidence)
Severe microcephaly v2.239 MED17 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. This gene as been given an Amber rating as 2 out of 3 cases (PMID:20950787 is caused by founder effect) have severe microcephaly. Until further evidence is available this gene will remain as Amber.
Severe microcephaly v2.239 MED17 Ivone Leong Gene: med17 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.238 MED17 Ivone Leong Tag watchlist tag was added to gene: MED17.
Severe microcephaly v2.238 MED17 Ivone Leong Phenotypes for gene: MED17 were changed from Microcephaly, postnatal progressive, with seizures and brain atrophy, MIM# 613668 to Microcephaly, postnatal progressive, with seizures and brain atrophy, OMIM:613668
Severe microcephaly v2.237 MED17 Ivone Leong Publications for gene: MED17 were set to 20950787; 30345598; 26004231
Severe microcephaly v2.236 NSD2 Ivone Leong Classified gene: NSD2 as Amber List (moderate evidence)
Severe microcephaly v2.236 NSD2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There are >3 unrelated cases associated with this gene; however, the severity of microcephaly in these cases do not satisfy our criteria for severe microcephaly. Therefore, this gene has been given an Amber rating.
Severe microcephaly v2.236 NSD2 Ivone Leong Gene: nsd2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.235 NSD2 Ivone Leong Publications for gene: NSD2 were set to 30345613; 31171569
Severe microcephaly v2.234 NSD2 Ivone Leong Phenotypes for gene: NSD2 were changed from microcephaly; intellectual disability to microcephaly, MONDO:0001149
Severe microcephaly v2.233 NUP107 Ivone Leong Phenotypes for gene: NUP107 were changed from Galloway-Mowat syndrome 7, MIM# 618348 to Galloway-Mowat syndrome 7, OMIM:618348
Severe microcephaly v2.232 NUP107 Ivone Leong Classified gene: NUP107 as Amber List (moderate evidence)
Severe microcephaly v2.232 NUP107 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype (possible). There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.232 NUP107 Ivone Leong Gene: nup107 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.231 NUP107 Ivone Leong Tag Q3_21_rating tag was added to gene: NUP107.
Severe microcephaly v2.231 PCDH12 Ivone Leong Classified gene: PCDH12 as Amber List (moderate evidence)
Severe microcephaly v2.231 PCDH12 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.231 PCDH12 Ivone Leong Gene: pcdh12 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.230 PCDH12 Ivone Leong Tag Q3_21_rating tag was added to gene: PCDH12.
Severe microcephaly v2.230 PCDH12 Ivone Leong Phenotypes for gene: PCDH12 were changed from Diencephalic-mesencephalic junction dysplasia syndrome 1, MIM# 251280 to Diencephalic-mesencephalic junction dysplasia syndrome 1, OMIM:251280
Severe microcephaly v2.229 COPB2 Eleanor Williams gene: COPB2 was added
gene: COPB2 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: COPB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COPB2 were set to 29036432
Phenotypes for gene: COPB2 were set to Microcephaly, HP:0000252
Review for gene: COPB2 was set to RED
Added comment: PMID: 29036432 - DiStasio et al 2017 - report of severe microcephaly (developing to be below -4.0 SD) and severe intellectual disability in the two siblings with a COPB2 homozygous variant.

The siblings were later investigated for low bone mass in PMID: 34450031 - Marom et al 2021 (in which heterozygous variants in COPB2 in 4 other families with probands with osteoporosis and developmental delay were identified, but no microcephaly reported).
Sources: Literature
Severe microcephaly v2.228 OSGEP Ivone Leong Tag Q3_21_rating tag was added to gene: OSGEP.
Severe microcephaly v2.228 OSGEP Ivone Leong Classified gene: OSGEP as Amber List (moderate evidence)
Severe microcephaly v2.228 OSGEP Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.228 OSGEP Ivone Leong Gene: osgep has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.227 OSGEP Ivone Leong Phenotypes for gene: OSGEP were changed from Galloway-Mowat syndrome 3, MIM# 617729 to Galloway-Mowat syndrome 3, OMIM:617729
Severe microcephaly v2.226 VRK1 Ivone Leong Tag Q3_21_rating tag was added to gene: VRK1.
Severe microcephaly v2.226 VRK1 Ivone Leong Classified gene: VRK1 as Amber List (moderate evidence)
Severe microcephaly v2.226 VRK1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.226 VRK1 Ivone Leong Gene: vrk1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.225 VRK1 Ivone Leong Phenotypes for gene: VRK1 were changed from Pontocerebellar hypoplasia type 1A MIM#607596 to Pontocerebellar hypoplasia type 1A, OMIM:607596
Severe microcephaly v2.224 NUF2 Ivone Leong Classified gene: NUF2 as Red List (low evidence)
Severe microcephaly v2.224 NUF2 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. As there is only 1 case there is currently not enough evidence to support a gene-disease association. This gene has been given a Red rating.
Severe microcephaly v2.224 NUF2 Ivone Leong Gene: nuf2 has been classified as Red List (Low Evidence).
Severe microcephaly v2.223 TRAPPC10 Ivone Leong Classified gene: TRAPPC10 as Red List (low evidence)
Severe microcephaly v2.223 TRAPPC10 Ivone Leong Added comment: Comment on list classification: New gene added by Aleš Maver (Clinical Institute of Medical Genetics). This gene is not associated with a phenotype in OMIM, but is possibly associated with a disease in Gene2Phenotype. The affected individuals in PMID:30167849 (2 individuals from the same family) had severe ID. As I do not have access to the ESHG2021 talk, this gene has been given a Red rating until further evidence is available.
Severe microcephaly v2.223 TRAPPC10 Ivone Leong Gene: trappc10 has been classified as Red List (Low Evidence).
Severe microcephaly v2.222 TRAPPC10 Ivone Leong Phenotypes for gene: TRAPPC10 were changed from to microcephaly (disease), MONDO:0001149
Severe microcephaly v2.221 TRAPPC10 Ivone Leong Publications for gene: TRAPPC10 were set to PMID: 30167849
Severe microcephaly v2.220 TRAPPC10 Aleš Maver gene: TRAPPC10 was added
gene: TRAPPC10 was added to Severe microcephaly. Sources: Other
Mode of inheritance for gene: TRAPPC10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC10 were set to PMID: 30167849
Penetrance for gene: TRAPPC10 were set to Complete
Review for gene: TRAPPC10 was set to RED
Added comment: This gene was originally reported in association with microcephalic NDD in PMID:30167849 (biallelic missense variant) and was replicated in a large family consanguineous family with a biallelic frameshift variant - reported at the ESHG2021 conference, talk C16.4 by Rawlins).
Sources: Other
Severe microcephaly v2.220 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
Severe microcephaly v2.220 NAA20 Sarah Leigh Classified gene: NAA20 as Amber List (moderate evidence)
Severe microcephaly v2.220 NAA20 Sarah Leigh Gene: naa20 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.219 NAA20 Sarah Leigh changed review comment from: Comment on phenotypes: Currently there is not phenotype associated with this gene in OMIM, Gen2Phen or MONDO (13/07/2021).; to: Comment on phenotypes: Currently there is no phenotype associated with this gene in OMIM, Gen2Phen or MONDO (13/07/2021).
Severe microcephaly v2.219 NAA20 Sarah Leigh Added comment: Comment on phenotypes: Currently there is not phenotype associated with this gene in OMIM, Gen2Phen or MONDO (13/07/2021).
Severe microcephaly v2.219 NAA20 Sarah Leigh Phenotypes for gene: NAA20 were changed from autosomal recessive developmental delay, intellectual disability, and microcephaly to autosomal recessive developmental delay, intellectual disability, and microcephaly
Severe microcephaly v2.218 NAA20 Sarah Leigh gene: NAA20 was added
gene: NAA20 was added to Severe microcephaly. 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
Severe microcephaly v2.217 NUF2 Zornitza Stark gene: NUF2 was added
gene: NUF2 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: NUF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NUF2 were set to 33721060
Phenotypes for gene: NUF2 were set to microcephaly; short stature; bilateral vocal cord paralysis; micrognathia; atrial septal defect
Review for gene: NUF2 was set to RED
Added comment: PMID: 33721060 - de novo missense variant identified in one male patient with microcephaly and short stature, with additional features, such as bilateral vocal cord paralysis, micrognathia and atrial septal defect.
Sources: Literature
Severe microcephaly v2.217 RING1 Eleanor Williams changed review comment from: Not associated with any phenotype in OMIM.

PMID: 29386386 - Pierce et al 2018 - report a 13 yo female with a de novo RING1 p.R95Q variant and syndromic neurodevelopmental disabilities. Head circumference at birth was -4.9 SD, and -4.2 SD at age 13. C. elegans with either the missense mutation or complete knockout of spat-3 (the suggested RING1 ortholog) were defective in monoubiquitylation of histone H2A and had defects in neuronal migration and axon guidance.
Sources: Literature; to: Not associated with any phenotype in OMIM.

PMID: 29386386 - Pierce et al 2018 - report a 13 yo female with a de novo RING1 p.R95Q variant and syndromic neurodevelopmental disabilities. Head circumference at birth was -4.9 SD, and -4.2 SD at age 13 which falls into the severe microcephaly category. C. elegans with either the missense mutation or complete knockout of spat-3 (the suggested RING1 ortholog) were defective in monoubiquitylation of histone H2A and had defects in neuronal migration and axon guidance.
Sources: Literature
Severe microcephaly v2.217 RING1 Eleanor Williams gene: RING1 was added
gene: RING1 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: RING1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RING1 were set to 29386386
Phenotypes for gene: RING1 were set to microcephaly; intellectual disability
Review for gene: RING1 was set to RED
Added comment: Not associated with any phenotype in OMIM.

PMID: 29386386 - Pierce et al 2018 - report a 13 yo female with a de novo RING1 p.R95Q variant and syndromic neurodevelopmental disabilities. Head circumference at birth was -4.9 SD, and -4.2 SD at age 13. C. elegans with either the missense mutation or complete knockout of spat-3 (the suggested RING1 ortholog) were defective in monoubiquitylation of histone H2A and had defects in neuronal migration and axon guidance.
Sources: Literature
Severe microcephaly v2.216 ATP9A Arina Puzriakova changed review comment from: Vogt et al. 2021 report on 3 individuals from 2 unrelated consanguineous families with different homozygous truncating variants in ATP9A, presenting with DD/ID of variable degree, postnatal microcephaly (OFC range: −2.33 SD to −3.58 SD), failure to thrive, and gastrointestinal symptoms. Patient-derived fibroblasts showed reduced expression of ATP9A, and consistent with previous findings also overexpression of interacting partners, ARPC3 and SNX3.
Sources: Literature; to: Vogt et al. 2021 report on 3 individuals from 2 unrelated consanguineous families with different homozygous truncating variants in ATP9A, presenting with DD/ID of variable degree (2 mild, 1 severe), postnatal microcephaly (OFC range: −2.33 SD to −3.58 SD), failure to thrive, and gastrointestinal symptoms. Patient-derived fibroblasts showed reduced expression of ATP9A, and consistent with previous findings also overexpression of interacting partners, ARPC3 and SNX3.
Sources: Literature
Severe microcephaly v2.216 ATP9A Arina Puzriakova Classified gene: ATP9A as Amber List (moderate evidence)
Severe microcephaly v2.216 ATP9A Arina Puzriakova Added comment: Comment on list classification: Rating Amber, awaiting further cases/clinical evidence.
Severe microcephaly v2.216 ATP9A Arina Puzriakova Gene: atp9a has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.215 ATP9A Arina Puzriakova gene: ATP9A was added
gene: ATP9A was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: ATP9A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATP9A were set to http://dx.doi.org/10.1136/jmedgenet-2021-107843
Phenotypes for gene: ATP9A were set to Neurodevelopmental delay; Postnatal microcephaly; Failure to thrive; Gastrointestinal symptoms
Review for gene: ATP9A was set to AMBER
Added comment: Vogt et al. 2021 report on 3 individuals from 2 unrelated consanguineous families with different homozygous truncating variants in ATP9A, presenting with DD/ID of variable degree, postnatal microcephaly (OFC range: −2.33 SD to −3.58 SD), failure to thrive, and gastrointestinal symptoms. Patient-derived fibroblasts showed reduced expression of ATP9A, and consistent with previous findings also overexpression of interacting partners, ARPC3 and SNX3.
Sources: Literature
Severe microcephaly v2.214 DPM1 Arina Puzriakova changed review comment from: At least 12 individuals from 10 unrelated families described in literature. 12/13 had a variable degree of microcephaly - a sufficient number of cases (>3) had microcephaly of relevant severity to this panel. Acquired postnatally, and progressive in some cases.; to: At least 12 individuals from 10 unrelated families described in literature. 11/12 had a variable degree of microcephaly - a sufficient number of cases (>3) had microcephaly of relevant severity to this panel. Acquired postnatally, and progressive in some cases.
Severe microcephaly v2.214 DPM1 Arina Puzriakova changed review comment from: At least 13 individuals from 11 unrelated families described in literature. 12/13 had a variable degree of microcephaly - a sufficient number of cases (>3) had microcephaly of relevant severity to this panel. Acquired postnatally, and progressive in some cases.; to: At least 12 individuals from 10 unrelated families described in literature. 12/13 had a variable degree of microcephaly - a sufficient number of cases (>3) had microcephaly of relevant severity to this panel. Acquired postnatally, and progressive in some cases.
Severe microcephaly v2.214 DPM1 Arina Puzriakova Tag Q2_21_rating tag was added to gene: DPM1.
Severe microcephaly v2.214 DPM1 Arina Puzriakova Phenotypes for gene: DPM1 were changed from Congenital disorder of glycosylation, type Ie 608799 to Congenital disorder of glycosylation, type Ie, OMIM:608799
Severe microcephaly v2.213 DPM1 Arina Puzriakova Publications for gene: DPM1 were set to 16641202; 10642602; 10642597
Severe microcephaly v2.212 DPM1 Arina Puzriakova Classified gene: DPM1 as Amber List (moderate evidence)
Severe microcephaly v2.212 DPM1 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.
Severe microcephaly v2.212 DPM1 Arina Puzriakova Gene: dpm1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.211 DPM1 Arina Puzriakova reviewed gene: DPM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10642597, 10642602, 15669674, 16641202, 23856421, 27481510, 28139241, 30653653; Phenotypes: Congenital disorder of glycosylation, type Ie, OMIM:608799; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.211 TP53RK Eleanor Williams Classified gene: TP53RK as Amber List (moderate evidence)
Severe microcephaly v2.211 TP53RK Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber, but with a recommendation for green rating following GMS review. Following consultation with the Genomics England clinical team it was decided that a green recommendation would be appropriate as primary microcephaly might be the presenting feature before renal issues appear.
Severe microcephaly v2.211 TP53RK Eleanor Williams Gene: tp53rk has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.210 TP53RK Eleanor Williams Tag Q2_21_rating tag was added to gene: TP53RK.
Severe microcephaly v2.210 TCF4 Eleanor Williams Classified gene: TCF4 as Red List (low evidence)
Severe microcephaly v2.210 TCF4 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to red. After consultation with the Genomics England Clinical Team it was decided that patients with Pitt-Hopkins syndrome are more likely to be following a route for explanation of global developmental delay/intellectual disability than severe microcephaly.
Severe microcephaly v2.210 TCF4 Eleanor Williams Gene: tcf4 has been classified as Red List (Low Evidence).
Severe microcephaly v2.209 PTPN23 Eleanor Williams Classified gene: PTPN23 as Amber List (moderate evidence)
Severe microcephaly v2.209 PTPN23 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber, but with a recommendation for a green rating following GMS review. 1 confirmed case with severe microcephaly plus several further cases of microcephaly, not all of which have the degree of severity stated. Genomics England clinician confirms proposal for green rating.
Severe microcephaly v2.209 PTPN23 Eleanor Williams Gene: ptpn23 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.208 PTPN23 Eleanor Williams Tag Q2_21_rating tag was added to gene: PTPN23.
Severe microcephaly v2.208 ZPR1 Ivone Leong Entity copied from Growth failure in early childhood v1.70
Severe microcephaly v2.208 ZPR1 Ivone Leong gene: ZPR1 was added
gene: ZPR1 was added to Severe microcephaly. Sources: Expert Review Red,Literature
founder-effect tags were added to gene: ZPR1.
Mode of inheritance for gene: ZPR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZPR1 were set to 29851065
Phenotypes for gene: ZPR1 were set to ?Growth restriction, hypoplastic kidneys, alopecia, and distinctive facies, OMIM:619321
Severe microcephaly v2.207 SMARCA5 Arina Puzriakova Tag Q2_21_NHS_review was removed from gene: SMARCA5.
Severe microcephaly v2.207 SMARCA5 Arina Puzriakova changed review comment from: Comment on list classification: New gene added and reviewed Green by Julia Baptista (RD&E NHS FT). SMARCA5 should be promoted to Green at the next GMS panel update.

Variants have been associated with a variable neurodevelopmental phenotype including predominantly mild DD, short stature, and microcephaly (PMID:33980485). Regarding cognition, four probands had mild ID and one had severe ID. Although relatively mild in most patients, the number of unrelated families presenting ID is sufficient for a Green rating and inclusion on this panel should increase the likelihood of detecting cases.; to: Comment on list classification: New gene added and reviewed Green by Julia Baptista (RD&E NHS FT). SMARCA5 should be promoted to Green at the next GMS panel update.

Variants have been associated with a variable neurodevelopmental phenotype including predominantly mild DD, short stature, and microcephaly (PMID:33980485). Postnatal microcephaly [HC ranging between -2.33 and -6.21 SD] was evident in 10/12 individuals, and three had a birth HC less than −2.5 SD. Overall sufficient number of unrelated families presenting microcephaly of relevant severity to warrant a Green rating on this panel.
Severe microcephaly v2.207 SMARCA5 Arina Puzriakova Entity copied from Intellectual disability v3.1117
Severe microcephaly v2.207 SMARCA5 Arina Puzriakova gene: SMARCA5 was added
gene: SMARCA5 was added to Severe microcephaly. Sources: Literature,Expert Review Amber
Q2_21_rating, Q2_21_NHS_review tags were added to gene: SMARCA5.
Mode of inheritance for gene: SMARCA5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMARCA5 were set to 33980485
Phenotypes for gene: SMARCA5 were set to intellectual disability; postnatal microcephaly; hypotonia; failure to thrive
Penetrance for gene: SMARCA5 were set to unknown
Severe microcephaly v2.206 SLC1A4 Eleanor Williams Classified gene: SLC1A4 as Amber List (moderate evidence)
Severe microcephaly v2.206 SLC1A4 Eleanor Williams Added comment: Comment on list classification: Following confirmation from the Genomics England clinical team that progressive microcephaly (to the severe range) is within scope of this panel, recommending a green rating for this gene at the next review.
Severe microcephaly v2.206 SLC1A4 Eleanor Williams Gene: slc1a4 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.205 MPLKIP Ivone Leong Phenotypes for gene: MPLKIP were changed from Trichothiodystrophy 4, nonphotosensitive, OMIM:234050; microcephaly (disease), MONDO:0001149 to microcephaly (disease), MONDO:0001149
Severe microcephaly v2.204 MPLKIP Ivone Leong Classified gene: MPLKIP as Amber List (moderate evidence)
Severe microcephaly v2.204 MPLKIP Ivone Leong Gene: mplkip has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.203 MPLKIP Ivone Leong gene: MPLKIP was added
gene: MPLKIP was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: MPLKIP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MPLKIP were set to 25655951; 25290684; 26518168; 25606444; 26880286; 29421601; 30580289; 30598092; 16977596; 33043633; 33729667
Phenotypes for gene: MPLKIP were set to Trichothiodystrophy 4, nonphotosensitive, OMIM:234050; microcephaly (disease), MONDO:0001149
Review for gene: MPLKIP was set to AMBER
Added comment: This gene is associated with a phenotype in OMIM and Gene2Phenotype. Microcephaly has been reported for 6/20 cases (2 cases <-3SD), growth retardation 15/20 and 7/20 had gonadal dysfunction. There is not enough evidence to support a gene-disease association, this gene has been given an Amber rating.
Sources: Literature
Severe microcephaly v2.202 PDCD6IP Arina Puzriakova Tag watchlist tag was added to gene: PDCD6IP.
Severe microcephaly v2.202 PDCD6IP Arina Puzriakova Classified gene: PDCD6IP as Amber List (moderate evidence)
Severe microcephaly v2.202 PDCD6IP Arina Puzriakova Added comment: 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.
Severe microcephaly v2.202 PDCD6IP Arina Puzriakova Gene: pdcd6ip has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.201 POGZ Arina Puzriakova Publications for gene: POGZ were set to 26942287
Severe microcephaly v2.200 POGZ Arina Puzriakova Tag Q2_21_rating tag was added to gene: POGZ.
Severe microcephaly v2.200 POGZ Arina Puzriakova Classified gene: POGZ as Amber List (moderate evidence)
Severe microcephaly v2.200 POGZ Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Microcephaly is a variable feature (reported in at least 14/31 individuals) but severity is not stated in most cases. However, this can be a presenting feature of the disorder and there are sufficient cases from unrelated families to warrant a Green rating on this panel.
Severe microcephaly v2.200 POGZ Arina Puzriakova Gene: pogz has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.199 POGZ Arina Puzriakova Phenotypes for gene: POGZ were changed from White-Sutton syndrome, MIM# 616364 to White-Sutton syndrome, OMIM:616364
Severe microcephaly v2.198 FOXG1 Sarah Leigh edited their review of gene: FOXG1: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. PMID 27029630 reports 85% (23/27) of patients with FOXG1 variants have microcephaly, defined as greater than 2 SDs below the mean for age, acquired postnatally in most cases.; Changed rating: GREEN
Severe microcephaly v2.198 FOXG1 Sarah Leigh Phenotypes for gene: FOXG1 were changed from Rett syndrome, congenital variant, MIM# 613454 to Rett Syndrome, congenital variant OMIM:613454; Rett syndrome, congenital variant MONDO:0013270
Severe microcephaly v2.197 FOXG1 Sarah Leigh Publications for gene: FOXG1 were set to 21441262; 19564653; 19578037
Severe microcephaly v2.196 FOXG1 Sarah Leigh Classified gene: FOXG1 as Amber List (moderate evidence)
Severe microcephaly v2.196 FOXG1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Severe microcephaly v2.196 FOXG1 Sarah Leigh Gene: foxg1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.195 FOXG1 Sarah Leigh Tag Q2_21_rating tag was added to gene: FOXG1.
Severe microcephaly v2.195 MCM7 Arina Puzriakova Classified gene: MCM7 as Amber List (moderate evidence)
Severe microcephaly v2.195 MCM7 Arina Puzriakova Added comment: Comment on list classification: Currently there are 3 unrelated pedigrees in literature with different biallelic MCM7 variants associated with disease (PMIDs: 33654309; 34059554). Although there is some functional data in support of variant-level deleteriousness or gene-level pathogenicity, the clinical gestalt is very different between the 3 families.

As no clear phenotype correlations can be made at this time, rating as Amber in anticipation of further cases (2/3 presented severe microcephaly).
Severe microcephaly v2.195 MCM7 Arina Puzriakova Gene: mcm7 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.194 MCM7 Arina Puzriakova gene: MCM7 was added
gene: MCM7 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: MCM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MCM7 were set to 33654309; 34059554
Phenotypes for gene: MCM7 were set to Meier-Gorlin syndrome; Microcephaly; Intellectual disability
Review for gene: MCM7 was set to AMBER
Added comment: MCM7 is a component of the MCM complex, a DNA helicase which is essential for DNA replication. Other components have been linked to disease with phenotypes including microcephaly and ID. Currently, MCM7 is not associated with any phenotype in OMIM or G2P.

- PMID: 33654309 (2021) - Two unrelated individuals with different compound het variants in MCM7 but disparate clinical features. One patient had typical Meier-Gorlin syndrome (including growth retardation, microcephaly, congenital lung emphysema, absent breast development, microtia, facial dysmorphism) whereas the second case had a multi-system disorder with neonatal progeroid appearance, lipodystrophy and adrenal insufficiency. While small at birth, the second patient did not demonstrate reduced stature or microcephaly at age 14.5 years. Both individuals had normal neurodevelopment.
Functional studies using patient-derived fibroblasts demonstrate that the identified MCM7 variants were deleterious at either transcript or protein levels and through interfering with MCM complex formation, impact efficiency of S phase progression.

- PMID: 34059554 (2021) - Homozygous missense variant identified in three affected individuals from a consanguineous family with severe primary microcephaly, severe ID and behavioural abnormalities. Knockdown of Mcm7 in mouse neuroblastoma cells lead to reduced cell viability and proliferation with increased apoptosis, which were rescued by overexpression of wild-type but not mutant MCM7.
Sources: Literature
Severe microcephaly v2.193 TPRKB Eleanor Williams Phenotypes for gene: TPRKB were changed from Galloway-Mowat syndrome 5, MIM# 617731 to Galloway-Mowat syndrome 5, OMIM:617731
Severe microcephaly v2.192 TPRKB Eleanor Williams Publications for gene: TPRKB were set to 28805828; 30053862
Severe microcephaly v2.191 TPRKB Eleanor Williams Classified gene: TPRKB as Red List (low evidence)
Severe microcephaly v2.191 TPRKB Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to red. 2 unrelated cases reported but the degree of microcephaly is not reported, so can't confirm it is in the severe range.
Severe microcephaly v2.191 TPRKB Eleanor Williams Gene: tprkb has been classified as Red List (Low Evidence).
Severe microcephaly v2.190 TPRKB Eleanor Williams reviewed gene: TPRKB: Rating: RED; Mode of pathogenicity: None; Publications: 28805828; Phenotypes: Galloway-Mowat syndrome 5, OMIM:617731; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.190 SLC1A4 Eleanor Williams Phenotypes for gene: SLC1A4 were changed from Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, MIM# 616657 to Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, OMIM:616657
Severe microcephaly v2.189 PTPN23 Eleanor Williams Phenotypes for gene: PTPN23 were changed from Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity, MIM# 618890 to Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity, OMIM:618890
Severe microcephaly v2.188 TP53RK Eleanor Williams Phenotypes for gene: TP53RK were changed from Galloway-Mowat syndrome 4, MIM# 617730 to Galloway-Mowat syndrome 4, OMIM:617730
Severe microcephaly v2.187 TP53RK Eleanor Williams reviewed gene: TP53RK: Rating: RED; Mode of pathogenicity: None; Publications: 28805828, 30053862; Phenotypes: Galloway-Mowat syndrome 4, OMIM:17730; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.187 TCF4 Eleanor Williams Phenotypes for gene: TCF4 were changed from Pitt-Hopkins syndrome, MIM# 610954 to Pitt-Hopkins syndrome, OMIM:610954
Severe microcephaly v2.186 TCF4 Eleanor Williams Publications for gene: TCF4 were set to 18728071; 22934316
Severe microcephaly v2.185 TCF4 Eleanor Williams reviewed gene: TCF4: Rating: AMBER; Mode of pathogenicity: None; Publications: 18728071, 21671391, 29318938; Phenotypes: Pitt-Hopkins syndrome OMIM:610954; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Severe microcephaly v2.185 SLC1A4 Eleanor Williams Classified gene: SLC1A4 as Amber List (moderate evidence)
Severe microcephaly v2.185 SLC1A4 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber but with a recommendation for Green review, following confirmation that progressive microcephaly is within the scope of this panel. 4 different variants reported.
Severe microcephaly v2.185 SLC1A4 Eleanor Williams Gene: slc1a4 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.184 SLC1A4 Eleanor Williams Tag founder-effect tag was added to gene: SLC1A4.
Tag Q2_21_rating tag was added to gene: SLC1A4.
Severe microcephaly v2.184 SLC1A4 Eleanor Williams reviewed gene: SLC1A4: Rating: GREEN; Mode of pathogenicity: None; Publications: 25930971, 26138499, 26041762, 27193218, 29989513; Phenotypes: Spastic tetraplegia, thin corpus callosum, and progressive microcephaly OMIM:616657; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.184 HIKESHI Ivone Leong Classified gene: HIKESHI as Red List (low evidence)
Severe microcephaly v2.184 HIKESHI Ivone Leong Added comment: Comment on list classification: Downgraded from Amber to Red as microcephaly is not severe enough in the patients and also only seen in Ashkenazi Jewish families.
Severe microcephaly v2.184 HIKESHI Ivone Leong Gene: hikeshi has been classified as Red List (Low Evidence).
Severe microcephaly v2.183 HIKESHI Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.119
Severe microcephaly v2.183 HIKESHI Ivone Leong gene: HIKESHI was added
gene: HIKESHI was added to Severe microcephaly. Sources: Expert list,Expert Review Amber
Mode of inheritance for gene: HIKESHI was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HIKESHI were set to 26545878; 28000699
Phenotypes for gene: HIKESHI were set to Leukodystrophy, hypomyelinating, 13, OMIM:616881
Severe microcephaly v2.182 SASS6 Eleanor Williams Classified gene: SASS6 as Amber List (moderate evidence)
Severe microcephaly v2.182 SASS6 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber as now two cases reported with severe microcephaly. Pubmed search did not find further cases at this time.
Severe microcephaly v2.182 SASS6 Eleanor Williams Gene: sass6 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.181 SASS6 Eleanor Williams Phenotypes for gene: SASS6 were changed from autosomal recessive primary microcephaly (MCPH); ?Microcephaly 14, primary, autosomal recessive, 616402 to ?Microcephaly 14, primary, autosomal recessive, OMIM:616402
Severe microcephaly v2.180 SASS6 Eleanor Williams edited their review of gene: SASS6: Changed phenotypes to: ?Microcephaly 14, primary, autosomal recessive, OMIM:616402
Severe microcephaly v2.180 SASS6 Eleanor Williams changed review comment from: Provisionally associated with ?Microcephaly 11, primary, autosomal recessive #615414 (AR) in OMIM.

PMID: 24951542 - Khan et al 2014 - large consanguineous Pakistani family with 4 patients diagnosed with autosomal recessive primary microcephaly (MCPH). Sequencing of genes following homozygosity mapping identified a homozygous missense variant in HsSAS-6 (c.185T>C, p.Ile62Thr ). Analysed unaffected individuals were either heterozygous for this variant, or had two wild type alleles. All 4 affected individuals had severe microcephaly (occipitofrontal circumference ranged from -6.63 to -19.6 SD).

PMID: 30639237 - Zhang et al 2019 - report a non-consanguineous Chinese family in which two foetuses were identified with microcephaly. In the later pregnancy the foetus had a head circumference -4 SD at 24 weeks of gestation. Compound heterozygous splice variants in SASS6 were identified by WES ( c.127-13A>G and c.1867+2T>A), one inherited from each of the parents. RT-PCR confirmed the effect on splicing.; to: Provisionally associated with ?Microcephaly 14, primary, autosomal recessive #616402 (AR) in OMIM.

PMID: 24951542 - Khan et al 2014 - large consanguineous Pakistani family with 4 patients diagnosed with autosomal recessive primary microcephaly (MCPH). Sequencing of genes following homozygosity mapping identified a homozygous missense variant in HsSAS-6 (c.185T>C, p.Ile62Thr ). Analysed unaffected individuals were either heterozygous for this variant, or had two wild type alleles. All 4 affected individuals had severe microcephaly (occipitofrontal circumference ranged from -6.63 to -19.6 SD).

PMID: 30639237 - Zhang et al 2019 - report a non-consanguineous Chinese family in which two foetuses were identified with microcephaly. In the later pregnancy the foetus had a head circumference -4 SD at 24 weeks of gestation. Compound heterozygous splice variants in SASS6 were identified by WES ( c.127-13A>G and c.1867+2T>A), one inherited from each of the parents. RT-PCR confirmed the effect on splicing.
Severe microcephaly v2.180 SASS6 Eleanor Williams Publications for gene: SASS6 were set to 24951542
Severe microcephaly v2.179 SASS6 Eleanor Williams reviewed gene: SASS6: Rating: AMBER; Mode of pathogenicity: None; Publications: 24951542, 30639237; Phenotypes: ?Microcephaly 11, primary, autosomal recessive, OMIM:615414; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.179 RUSC2 Eleanor Williams Classified gene: RUSC2 as Red List (low evidence)
Severe microcephaly v2.179 RUSC2 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to red. 2 families reported with homozgyous nonsense variants in RUSC2 but the microcephaly phenotype is relatively mild although progressive.
Severe microcephaly v2.179 RUSC2 Eleanor Williams Gene: rusc2 has been classified as Red List (Low Evidence).
Severe microcephaly v2.178 RUSC2 Eleanor Williams reviewed gene: RUSC2: Rating: RED; Mode of pathogenicity: None; Publications: 27612186; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.178 PUS7 Eleanor Williams Tag Q2_21_rating tag was added to gene: PUS7.
Severe microcephaly v2.178 PUS7 Eleanor Williams Classified gene: PUS7 as Amber List (moderate evidence)
Severe microcephaly v2.178 PUS7 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber but with a recommendation for a green rating following GMS review. 4 families reported with a severe microcephaly phenotype.
Severe microcephaly v2.178 PUS7 Eleanor Williams Gene: pus7 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.177 PUS7 Eleanor Williams Phenotypes for gene: PUS7 were changed from Intellectual developmental disorder with abnormal behavior, microcephaly, and short stature, OMIM #618342 to Intellectual developmental disorder with abnormal behavior, microcephaly, and short stature, OMIM:618342
Severe microcephaly v2.176 PUS7 Eleanor Williams reviewed gene: PUS7: Rating: GREEN; Mode of pathogenicity: None; Publications: 30526862, 30778726, 31583274; Phenotypes: Intellectual developmental disorder with abnormal behavior, microcephaly, and short stature, OMIM:618342; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.176 PUF60 Eleanor Williams Classified gene: PUF60 as Amber List (moderate evidence)
Severe microcephaly v2.176 PUF60 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber but with a recommendation for green rating at the next GMS review. 3 cases reported with heterozygous variants in PUF60 and a severe microcephaly phenotype.
Severe microcephaly v2.176 PUF60 Eleanor Williams Gene: puf60 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.175 PUF60 Eleanor Williams Phenotypes for gene: PUF60 were changed from Verheij syndrome, MIM# 615583 to Verheij syndrome, OMIM:615583
Severe microcephaly v2.174 PUF60 Eleanor Williams Publications for gene: PUF60 were set to 28327570
Severe microcephaly v2.173 PUF60 Eleanor Williams Tag Q2_21_rating tag was added to gene: PUF60.
Severe microcephaly v2.173 PUF60 Eleanor Williams reviewed gene: PUF60: Rating: GREEN; Mode of pathogenicity: None; Publications: 24140112, 27804958, 28327570, 28074499, 28471317, 32851780; Phenotypes: Verheij syndrome, OMIM:615583; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Severe microcephaly v2.173 CAMK2B Arina Puzriakova Tag Q2_21_rating tag was added to gene: CAMK2B.
Severe microcephaly v2.173 CAMK2B Arina Puzriakova Publications for gene: CAMK2B were set to 32875707
Severe microcephaly v2.172 CAMK2B Arina Puzriakova Classified gene: CAMK2B as Amber List (moderate evidence)
Severe microcephaly v2.172 CAMK2B Arina Puzriakova Added comment: Comment on list classification: Gene added to this panel and rated Green by Zornitza Stark. Variable degree of microcephaly has been reported in 9/13 individuals with CAMK2B variants (PMIDs: 29100089; 29560374; 30842224; 32875707). Severe microcephaly (HC ≤ -3 SD) is reported in at least 4 unrelated individuals.

Overall sufficient cases to rate as Green on this panel. Inclusion may be particularly beneficial for cases with milder degree of DD/ID for which this gene is also Green.
Severe microcephaly v2.172 CAMK2B Arina Puzriakova Gene: camk2b has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.171 CAMK2B Arina Puzriakova Phenotypes for gene: CAMK2B were changed from microcephaly; intellectual disability; behavioural problems to Mental retardation, autosomal dominant 54, OMIM:617799
Severe microcephaly v2.170 YIPF5 Arina Puzriakova Tag Q2_21_rating tag was added to gene: YIPF5.
Severe microcephaly v2.170 YIPF5 Arina Puzriakova Classified gene: YIPF5 as Amber List (moderate evidence)
Severe microcephaly v2.170 YIPF5 Arina Puzriakova Added comment: Comment on list classification: New gene added and rated Green by Zornitza Stark. Sufficient evidence and appropriate phenotype (all affected individuals present progressive severe microcephaly, generalised tonic clonic seizures with onset at 1 - 7 months, diabetes diagnosed at 4 weeks - 15 months, and 5/6 also had severe DD) for inclusion on this panel: 6 patients from 5 families with different YIPF5 variants identified in PMID: 33164986. Functional analysis demonstrated that YIPF5 deficiency enhances ER stress and sensitises beta-cells to ER stress-induced apoptosis.

YIPF5 is also associated with a relevant phenotype in OMIM (MIM# 619278) but is not yet listed in G2P.

There is enough evidence to rate this gene as Green at the next GMS panel update.
Severe microcephaly v2.170 YIPF5 Arina Puzriakova Gene: yipf5 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.169 YIPF5 Arina Puzriakova Phenotypes for gene: YIPF5 were changed from Neonatal diabetes; microcephaly; seizures to Microcephaly, epilepsy, and diabetes syndrome 2, OMIM:619278
Severe microcephaly v2.168 RRP7A Arina Puzriakova Classified gene: RRP7A as Amber List (moderate evidence)
Severe microcephaly v2.168 RRP7A Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. PMID:33199730 report a homozygous missense variant (c.465G>C; p.Trp155Cys) in RRP7A that segregated with primary microcephaly in a consanguineous family with 10 affected individuals. Supported by animal model data. Rating Amber, awaiting further cases.
Severe microcephaly v2.168 RRP7A Arina Puzriakova Gene: rrp7a has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.167 UNC80 Arina Puzriakova Tag Q2_21_rating tag was added to gene: UNC80.
Severe microcephaly v2.167 UNC80 Arina Puzriakova Classified gene: UNC80 as Amber List (moderate evidence)
Severe microcephaly v2.167 UNC80 Arina Puzriakova Added comment: Comment on list classification: Gene added to panel and rated Green by Zornitza Stark. Variable degrees reported but there are enough unrelated cases (>3) with sufficiently severe microcephaly and distinct UNC80 variants to rate as Green on this panel.
Severe microcephaly v2.167 UNC80 Arina Puzriakova Gene: unc80 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.166 UNC80 Arina Puzriakova Phenotypes for gene: UNC80 were changed from Hypotonia, infantile, with psychomotor retardation and characteristic facies 2 MIM#616801 to Hypotonia, infantile, with psychomotor retardation and characteristic facies 2, OMIM:616801
Severe microcephaly v2.165 UGP2 Arina Puzriakova Tag Q2_21_rating tag was added to gene: UGP2.
Severe microcephaly v2.165 UGP2 Arina Puzriakova Classified gene: UGP2 as Amber List (moderate evidence)
Severe microcephaly v2.165 UGP2 Arina Puzriakova Added comment: Comment on list classification: Gene added to panel and rated Green by Zornitza Stark. Sufficient evidence and appropriate phenotype (progressive microcephaly seen in all patients with available data) for inclusion on panel: 22 patients from 15 families all with the same variant identified in PMID:31820119. Therefore there is sufficient evidence to rate this gene as Green at the next GMS panel update.
Severe microcephaly v2.165 UGP2 Arina Puzriakova Gene: ugp2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.164 UGP2 Arina Puzriakova Phenotypes for gene: UGP2 were changed from Epileptic encephalopathy; intellectual disability; microcephaly to Developmental and epileptic encephalopathy 83, OMIM:618744
Severe microcephaly v2.163 TSEN54 Arina Puzriakova Tag Q2_21_rating tag was added to gene: TSEN54.
Severe microcephaly v2.163 TSEN54 Arina Puzriakova Classified gene: TSEN54 as Amber List (moderate evidence)
Severe microcephaly v2.163 TSEN54 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Progressive microcephaly is a feature associated with PCH types 2 and 4. Sufficient number of unrelated cases (>3) to rate this gene as Green at the next GMS panel review.
Severe microcephaly v2.163 TSEN54 Arina Puzriakova Gene: tsen54 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.162 TSEN54 Arina Puzriakova Publications for gene: TSEN54 were set to 20952379; 20301773
Severe microcephaly v2.161 TSEN54 Arina Puzriakova Phenotypes for gene: TSEN54 were changed from Pontocerebellar hypoplasia type 2A (MIM#277470) and type 4 (MIM#225753) to Pontocerebellar hypoplasia type 2A, OMIM:277470; Pontocerebellar hypoplasia type 4, OMIM:225753
Severe microcephaly v2.160 TSEN15 Arina Puzriakova Tag Q2_21_rating tag was added to gene: TSEN15.
Severe microcephaly v2.160 TSEN15 Arina Puzriakova Classified gene: TSEN15 as Amber List (moderate evidence)
Severe microcephaly v2.160 TSEN15 Arina Puzriakova Added comment: Comment on list classification: TSEN15 was added and rated Green by Zornitza Stark based on PMID:27392077 (Breuss et al, 2016) who report three homozygous TSEN15 variants in four individuals from three families. All affected individuals developed progressive microcephaly of relevant severity, which represented an early and main feature of the disease presentation.

There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Severe microcephaly v2.160 TSEN15 Arina Puzriakova Gene: tsen15 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.159 TSEN15 Arina Puzriakova Phenotypes for gene: TSEN15 were changed from Pontocerebellar hypoplasia, type 2F MIM#617026 to Pontocerebellar hypoplasia, type 2F, OMIM:617026
Severe microcephaly v2.158 TRIO Arina Puzriakova Classified gene: TRIO as Amber List (moderate evidence)
Severe microcephaly v2.158 TRIO Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is sufficient evidence to promote this gene to Green status at the next GMS panel update - microcephaly of relevant severity to this panel is observed in at least 12 unrelated families with TRIO variants. Pathogenicity is supported by functional data and animal model.
Severe microcephaly v2.158 TRIO Arina Puzriakova Gene: trio has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.157 TRIO Arina Puzriakova Publications for gene: TRIO were set to 26721934; 32109419
Severe microcephaly v2.156 TRIO Arina Puzriakova Tag Q2_21_rating tag was added to gene: TRIO.
Severe microcephaly v2.156 TRIO Arina Puzriakova Phenotypes for gene: TRIO were changed from Mental retardation, autosomal dominant 44, MIM# 617061 to Intellectual developmental disorder, autosomal dominant 44, with microcephaly, OMIM:617061
Severe microcephaly v2.155 TRAPPC9 Arina Puzriakova Publications for gene: TRAPPC9 were set to 22549410; 20004765; 20004763; 30853973
Severe microcephaly v2.154 TRAPPC9 Arina Puzriakova Tag Q2_21_rating tag was added to gene: TRAPPC9.
Severe microcephaly v2.154 TRAPPC9 Arina Puzriakova Classified gene: TRAPPC9 as Amber List (moderate evidence)
Severe microcephaly v2.154 TRAPPC9 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 32 affected individuals from 9 families have been reported worldwide. Variable degrees of microcephaly are reported in almost all subjects and there are enough unrelated cases with sufficiently severe microcephaly to include as diagnostic-grade on this panel.
Severe microcephaly v2.154 TRAPPC9 Arina Puzriakova Gene: trappc9 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.153 TRAPPC9 Arina Puzriakova Phenotypes for gene: TRAPPC9 were changed from Mental retardation, autosomal recessive 13, MIM# 613192 to Mental retardation, autosomal recessive 13, OMIM:613192
Severe microcephaly v2.152 TRAPPC6B Arina Puzriakova Tag Q2_21_rating tag was added to gene: TRAPPC6B.
Severe microcephaly v2.152 TRAPPC6B Arina Puzriakova Phenotypes for gene: TRAPPC6B were changed from Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, MIM# 617862 to Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, OMIM:617862
Severe microcephaly v2.151 TRAPPC6B Arina Puzriakova Classified gene: TRAPPC6B as Amber List (moderate evidence)
Severe microcephaly v2.151 TRAPPC6B Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 9 individuals from 5 families have been reported, all harbouring loss-of-function variants in homozygous state. Progressive microcephaly of relevant severity to this panel (HC ≤ -3 SD) was reported in 7/7 cases (clinical details limited for one family).

TRAPPC6B is associated with a relevant phenotype in OMIM (MIM# 617862)
Severe microcephaly v2.151 TRAPPC6B Arina Puzriakova Gene: trappc6b has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.150 PTPN23 Eleanor Williams changed review comment from: Associated with Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity #618890 in OMIM,

Severe microcephaly confirmed in 2 cases, a further 3 cases with microcephaly reported.

PMID:31395947 - Bend et al 2020 - 7 patients with biallelic variants in PTPN23. 2 have microcephaly noted (1 with occipito-frontal head circumference (OFC) −3SD along with severe growth restriction, in the other the degree is not noted). In a 3rd case borderline microcephaly is reported (10th percentile).

PMID:29899372 - Smigiel et al 2018 - 1 patient with severe developmental delay, epilepsy, cortical blindness, hypomyelination and brain atrophy and compound heterozygous PTPN23 variants (c.1902C>G;p.(Asn634Lys), c.2974delC;p.(Leu992Tyrfs*168) identified by WES. OFC at birth was 30 cm (2 cm below 3 percentile), weight 2320 g (300 g below 3 percentile), length 52 cm (50–90 percentile),

PMID: 29090338 - Sowada et al 2017- 1 patient with developmental and epileptic encephalopathy with compound heterozygous PTPN23 variants (c.3586C>T (p.Arg1196*) and c.1595C>T (p.Pro532Leu)). OFC at birth was 31 cm (− 2.6 SD) but weight was 50th and length 26th percentile.

PMID: 27848944 - Trujillano et al 2017 - 1 patient with homozygous c.904A>G p.(M302V) variant in PTPN23 and microcephaly reported as part of the clinical phenotype. No details as to severity of the microcephaly. They classify the variant as a VUS.

PMID: 25558065 - Alazami et al 2015 - 1 patient with a variant (NM_015466:c.3995G >
T:p.R1332L) in PTPN23 and Global developmental delay, epilepsy and brain atrophy. Microcephaly not mentioned in publication, however in Bend et al 2020 Table 1 says this patient has progressive microcephaly.; to: Associated with Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity #618890 in OMIM,

Severe microcephaly (OFC > 3 SD below mean) confirmed in 1 case, a further 4 cases with microcephaly reported.

PMID:31395947 - Bend et al 2020 - 7 patients with biallelic variants in PTPN23. 2 have microcephaly noted (1 with occipito-frontal head circumference (OFC) −3SD along with severe growth restriction, in the other the degree is not noted). In a 3rd case borderline microcephaly is reported (10th percentile).

PMID:29899372 - Smigiel et al 2018 - 1 patient with severe developmental delay, epilepsy, cortical blindness, hypomyelination and brain atrophy and compound heterozygous PTPN23 variants (c.1902C>G;p.(Asn634Lys), c.2974delC;p.(Leu992Tyrfs*168) identified by WES. OFC at birth was 30 cm (2 cm below 3 percentile), weight 2320 g (300 g below 3 percentile), length 52 cm (50–90 percentile),

PMID: 29090338 - Sowada et al 2017- 1 patient with developmental and epileptic encephalopathy with compound heterozygous PTPN23 variants (c.3586C>T (p.Arg1196*) and c.1595C>T (p.Pro532Leu)). OFC at birth was 31 cm (− 2.6 SD) but weight was 50th and length 26th percentile.

PMID: 27848944 - Trujillano et al 2017 - 1 patient with homozygous c.904A>G p.(M302V) variant in PTPN23 and microcephaly reported as part of the clinical phenotype. No details as to severity of the microcephaly. They classify the variant as a VUS.

PMID: 25558065 - Alazami et al 2015 - 1 patient with a variant (NM_015466:c.3995G >
T:p.R1332L) in PTPN23 and Global developmental delay, epilepsy and brain atrophy. Microcephaly not mentioned in publication, however in Bend et al 2020 Table 1 says this patient has progressive microcephaly.
Severe microcephaly v2.150 PTPN23 Eleanor Williams reviewed gene: PTPN23: Rating: AMBER; Mode of pathogenicity: None; Publications: 31395947, 29899372, 29090338, 27848944, 25558065; Phenotypes: Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity, OMIM:618890; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.150 PPP1R15B Eleanor Williams changed review comment from: Comment on list classification: Promoting from red to amber. 3 unrelated cases with microcephaly, but two have the same variant reported.; to: Comment on list classification: Promoting from red to amber. 3 unrelated cases with microcephaly (2 severe), but two have the same variant reported.
Severe microcephaly v2.150 MINPP1 Arina Puzriakova Entity copied from Ataxia and cerebellar anomalies - narrow panel v2.174
Severe microcephaly v2.150 MINPP1 Arina Puzriakova gene: MINPP1 was added
gene: MINPP1 was added to Severe microcephaly. Sources: Literature,Expert Review Amber
Q2_21_rating tags were added to gene: MINPP1.
Mode of inheritance for gene: MINPP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MINPP1 were set to 33257696; 33168985
Phenotypes for gene: MINPP1 were set to Pontocerebellar hypoplasia
Severe microcephaly v2.149 PPP1R15B Eleanor Williams Added comment: Comment on publications: Previous publication entry:
26307080: In a Canadian sister and brother, born of second-cousin parents, with severe microcephaly, short stature, hypoplastic brainstem and cord, delayed myelination, and intellectual disability, Kernohan et al. (2015) identified homozygosity for a c.1972C-T mutation in PPP1R15B (R658C);26159176: In a brother and sister from a consanguineous Algerian family with microcephaly, short stature, intellectual disability, and diabetes (MSSGM2, 616817), Abdulkarim et al. (2015) identified homozygosity for the R658C substitution.
Severe microcephaly v2.149 PPP1R15B Eleanor Williams Publications for gene: PPP1R15B were set to 26307080: In a Canadian sister and brother, born of second-cousin parents, with severe microcephaly, short stature, hypoplastic brainstem and cord, delayed myelination, and intellectual disability, Kernohan et al. (2015) identified homozygosity for a c.1972C-T mutation in PPP1R15B (R658C); 26159176: In a brother and sister from a consanguineous Algerian family with microcephaly, short stature, intellectual disability, and diabetes (MSSGM2, 616817), Abdulkarim et al. (2015) identified homozygosity for the R658C substitution.
Severe microcephaly v2.148 PPP1R15B Eleanor Williams Classified gene: PPP1R15B as Amber List (moderate evidence)
Severe microcephaly v2.148 PPP1R15B Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber. 3 unrelated cases with microcephaly, but two have the same variant reported.
Severe microcephaly v2.148 PPP1R15B Eleanor Williams Gene: ppp1r15b has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.147 PPP1R15B Eleanor Williams changed review comment from: Associated with Microcephaly, short stature, and impaired glucose metabolism 2 #616817 in OMIM.

PubMed: 27640355 - Mohammad et al 2016 - report WES of 2 siblings who presented with cirrhosis and required liver transplantation at age 7 and 22 months. Compound heterozygous mutations in PPP1R15B were identified. Microcephaly was also noted in both siblings. One sibling at age 4 years had head circumference at the third percentile, the other had holoprosencephaly and head circumference was below the 3rd percentile for gestational age at birth. Compound het variants in PPP1R15B; c.63G>A (p.W21*), inherited from the father, and c.674delC (p.P225LfsX10), inherited from the mother.

PubMed: 26159176 - Abdulkarim et al 2015 - report a homozygous c.1972C>T, p.R658C variant in PPP1R15B in two siblings from a consanguineous family of Algerian origin with young-onset diabetes, microcephaly, and short stature. First sibling had adult cranial perimeter: 46 cm, −4.0 SD. The sister had a similar presentation but was not available for detailed evaluation.

PubMed: 26307080 - Kernohan et al 2015 - report a consanguineous family (ethnicity not stated) with severe microcephaly, short stature, hypoplastic brainstem and cord, delayed myelination and intellectual disability in two siblings and a homozygous c.1972G>A; p.R658C variant in PPP1R15B. First sibling had head circumference of 28.5 cm (−5.0 SD) at birth, second sibling had a head circumference of head circumference of 37 cm (−6 to −7 SD) at 15 months.; to: Associated with Microcephaly, short stature, and impaired glucose metabolism 2 #616817 in OMIM.

PubMed: 27640355 - Mohammad et al 2016 - report WES of 2 siblings who presented with cirrhosis and required liver transplantation at age 7 and 22 months. Compound heterozygous mutations in PPP1R15B were identified. Microcephaly was also noted in both siblings. One sibling at age 4 years had head circumference at the third percentile, the other had holoprosencephaly and head circumference was below the 3rd percentile for gestational age at birth. Compound het variants in PPP1R15B; c.63G>A (p.W21*), inherited from the father, and c.674delC (p.P225LfsX10), inherited from the mother.

PubMed: 26159176 - Abdulkarim et al 2015 - report a homozygous c.1972C>T, p.R658C variant in PPP1R15B in two siblings from a consanguineous family of Algerian origin with young-onset diabetes, microcephaly, and short stature. First sibling had adult cranial perimeter: 46 cm, −4.0 SD. The sister had a similar presentation but was not available for detailed evaluation.

PubMed: 26307080 - Kernohan et al 2015 - report a consanguineous family (enrolled in Canada) with severe microcephaly, short stature, hypoplastic brainstem and cord, delayed myelination and intellectual disability in two siblings and a homozygous c.1972G>A; p.R658C variant in PPP1R15B. First sibling had head circumference of 28.5 cm (−5.0 SD) at birth, second sibling had a head circumference of head circumference of 37 cm (−6 to −7 SD) at 15 months.
Severe microcephaly v2.147 PPP1R15B Eleanor Williams Phenotypes for gene: PPP1R15B were changed from Microcephaly, short stature, and impaired glucose metabolism 2, 616817; MSSGM2 to Microcephaly, short stature, and impaired glucose metabolism 2, OMIM:616817
Severe microcephaly v2.146 PPP1R15B Eleanor Williams reviewed gene: PPP1R15B: Rating: AMBER; Mode of pathogenicity: None; Publications: 27640355, 26159176, 26307080; Phenotypes: Microcephaly, short stature, and impaired glucose metabolism 2, OMIM:616817; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.146 CTU2 Ivone Leong Tag Q2_21_rating tag was added to gene: CTU2.
Severe microcephaly v2.146 CTU2 Ivone Leong Classified gene: CTU2 as Amber List (moderate evidence)
Severe microcephaly v2.146 CTU2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype.

PMID:26633546. Affected members of all 3 families have microcephaly, facial dysmorphia and unilateral renal agenesis. 2/3 families have ambiguous genitalia; however, only 1 family had karyotyping done, which showed normal male karyotype (46 XY). 2/3 had congenital heart disease.

PMID: 27480277. Same variant as PMID:26633546. Affected individuals in this extended family have similar phenotype as PMID:26633546. Patient 1: in addition to microcephaly also has renal anomalies (small kidneys) and possible ambiguous genitalia with normal XY karyotype. Patient 2: cousin of patient 1. In addition to microcephaly did not have renal anomalies and nor ambiguous genitalia. Both patients have congenital heart disease.

PMID: 31301155. 5 new cases, all with microcephaly. 4/5 with renal anomalies, 2/5 with ambiguous genitalia, 4/5 congenital heart disease.

There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.146 CTU2 Ivone Leong Gene: ctu2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.145 DYNC1I2 Arina Puzriakova Phenotypes for gene: DYNC1I2 were changed from Neurodevelopmental disorder with microcephaly and structural brain anomalies , MIM#618492 to Neurodevelopmental disorder with microcephaly and structural brain anomalies, OMIM:618492
Severe microcephaly v2.144 DNA2 Arina Puzriakova Publications for gene: DNA2 were set to 24389050; 31045292
Severe microcephaly v2.143 DNA2 Arina Puzriakova Phenotypes for gene: DNA2 were changed from Seckel syndrome 8, OMIM:615807 to Seckel syndrome 8, OMIM:615807; Microcephalic primordial dwarfism, MONDO:0017950
Severe microcephaly v2.142 DNA2 Arina Puzriakova Tag Q2_21_rating tag was added to gene: DNA2.
Severe microcephaly v2.142 DNA2 Arina Puzriakova Classified gene: DNA2 as Amber List (moderate evidence)
Severe microcephaly v2.142 DNA2 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber but there is sufficient evidence to promote this gene to Green at the next GMS panel update - 4 different homozygous variants identified in at least 5 unrelated families with microcephalic primordial dwarfism (PMIDs: 24389050; 31045292)
Severe microcephaly v2.142 DNA2 Arina Puzriakova Gene: dna2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.141 DNA2 Arina Puzriakova Publications for gene: DNA2 were set to 24389050
Severe microcephaly v2.140 DNA2 Arina Puzriakova Phenotypes for gene: DNA2 were changed from ?Seckel syndrome 8, 615807; SCKL8 to Seckel syndrome 8, OMIM:615807
Severe microcephaly v2.139 CTU2 Ivone Leong Publications for gene: CTU2 were set to 26633546
Severe microcephaly v2.138 CTU2 Ivone Leong Phenotypes for gene: CTU2 were changed from Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome (MIM#618142) to Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome, OMIM:618142
Severe microcephaly v2.137 CTCF Ivone Leong Classified gene: CTCF as Amber List (moderate evidence)
Severe microcephaly v2.137 CTCF Ivone Leong Gene: ctcf has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.136 CTCF Ivone Leong gene: CTCF was added
gene: CTCF was added to Severe microcephaly. Sources: Expert list
Q2_21_rating tags were added to gene: CTCF.
Mode of inheritance for gene: CTCF was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CTCF were set to 23746550; 30893510; 28619046
Phenotypes for gene: CTCF were set to Mental retardation, autosomal dominant 21, OMIM:615502
Review for gene: CTCF was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. New gene added by Zornitza Stark (however, it was added under the gene symbol CTSF but should be CTCF) with the following review:

"Recommended gene rating: Green
PMID: 23746550
- 4 probands, 2x PTV, 1x missense, 1x 280kb deletion (all de novo)
- OFCs ranges from -0.8 SD (the proband with the deletion) to -3.51 SD

PMID: 30893510
- 3 probands, de novo 2x PTV and 1x missense
- OFCs ranges from < -2 to < -3 SD

PMID: 28619046
- 1x proband with de novo fs
- head circumference was under 10th centle
Sources: Expert list
Created: 4 Sep 2020, 10:18 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Mental retardation, autosomal dominant 21 (MIM#615502)

Publications

23746550
30893510
28619046

Variants in this GENE are reported as part of current diagnostic practice
Created: 4 Sep 2020, 10:18 a.m."

There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Sources: Expert list
Severe microcephaly v2.135 CTSF Ivone Leong edited their review of gene: CTSF: Added comment: This gene has been tagged with "curated_removed" as it should be CTCF not CTSF gene added to this panel.; Changed rating: RED
Severe microcephaly v2.135 CTSF Ivone Leong Tag curated_removed tag was added to gene: CTSF.
Severe microcephaly v2.135 CTSF Ivone Leong changed review comment from: Comment on phenotypes: CTSF is no longer associated with Mental retardation, autosomal dominant 21, OMIM:615502 on OMIM.; to: Comment on phenotypes: CTSF is not associated with Mental retardation, autosomal dominant 21, OMIM:615502 on OMIM.
Severe microcephaly v2.135 CTSF Ivone Leong Added comment: Comment on phenotypes: CTSF is no longer associated with Mental retardation, autosomal dominant 21, OMIM:615502 on OMIM.
Severe microcephaly v2.135 CTSF Ivone Leong Phenotypes for gene: CTSF were changed from Mental retardation, autosomal dominant 21, OMIM:615502 to Ceroid lipofuscinosis, neuronal, 13, Kufs type, OMIM:615362
Severe microcephaly v2.134 CTSF Ivone Leong Phenotypes for gene: CTSF were changed from Mental retardation, autosomal dominant 21 (MIM#615502) to Mental retardation, autosomal dominant 21, OMIM:615502
Severe microcephaly v2.133 CSNK2A1 Ivone Leong Classified gene: CSNK2A1 as Amber List (moderate evidence)
Severe microcephaly v2.133 CSNK2A1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.133 CSNK2A1 Ivone Leong Gene: csnk2a1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.132 CSNK2A1 Ivone Leong Tag Q2_21_rating tag was added to gene: CSNK2A1.
Severe microcephaly v2.132 CSNK2A1 Ivone Leong Phenotypes for gene: CSNK2A1 were changed from Okur-Chung neurodevelopmental syndrome MIM#617062 to Okur-Chung neurodevelopmental syndrome, OMIM:617062
Severe microcephaly v2.131 CHAMP1 Ivone Leong Classified gene: CHAMP1 as Amber List (moderate evidence)
Severe microcephaly v2.131 CHAMP1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.131 CHAMP1 Ivone Leong Gene: champ1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.130 CHAMP1 Ivone Leong Tag Q2_21_rating tag was added to gene: CHAMP1.
Severe microcephaly v2.130 CHAMP1 Ivone Leong Added comment: Comment on publications: PMID: 26751395 additional paper
Severe microcephaly v2.130 CHAMP1 Ivone Leong Publications for gene: CHAMP1 were set to 27148580; 26340335
Severe microcephaly v2.129 CHAMP1 Ivone Leong Phenotypes for gene: CHAMP1 were changed from Mental retardation, autosomal dominant 40 (MIM#616579) to Mental retardation, autosomal dominant 40, OMIM:616579
Severe microcephaly v2.128 CEP63 Ivone Leong commented on gene: CEP63
Severe microcephaly v2.128 CEP63 Ivone Leong Tag Q2_21_expert_review tag was added to gene: CEP63.
Severe microcephaly v2.128 CEP57 Ivone Leong Classified gene: CEP57 as Amber List (moderate evidence)
Severe microcephaly v2.128 CEP57 Ivone Leong Gene: cep57 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.127 CEP57 Ivone Leong gene: CEP57 was added
gene: CEP57 was added to Severe microcephaly. Sources: Literature
Q2_21_rating tags were added to gene: CEP57.
Mode of inheritance for gene: CEP57 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP57 were set to 24259107; 30010053; 21552266
Phenotypes for gene: CEP57 were set to Mosaic variegated aneuploidy syndrome 2, OMIM:614114
Review for gene: CEP57 was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There are 7 reported cases (9 affected individuals) with homozygous/compound heterzygous variants in this gene (4 variants - c.520_521delGA, c.915_925dup11, c241C>T, c.697delA). Microcephaly is reported in 5/9 individuals (4 families - in 1 family with 2 affected sibs only 1 sib had microcephaly). Those with microcephaly are either compound heterozygous or homozygous for c.915_925dup11 (Mexican, Caucasian, Moroccan origin). There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Sources: Literature
Severe microcephaly v2.126 TRIP13 Ivone Leong Classified gene: TRIP13 as Amber List (moderate evidence)
Severe microcephaly v2.126 TRIP13 Ivone Leong Gene: trip13 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.125 TRIP13 Ivone Leong gene: TRIP13 was added
gene: TRIP13 was added to Severe microcephaly. Sources: Literature
watchlist tags were added to gene: TRIP13.
Mode of inheritance for gene: TRIP13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRIP13 were set to 28553959
Phenotypes for gene: TRIP13 were set to Mosaic variegated aneuploidy syndrome 3, OMIM:617598
Review for gene: TRIP13 was set to AMBER
Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. PMID: 28553959 describes 6 probands with variants in this gene. 3/6 probands had microcephaly (2 of these probands have the same homozygous variant and may be due to a founder effect). Therefore, there is currently not enough evidence to support a gene-disease association. This gene has been rated Amber for now.
Sources: Literature
Severe microcephaly v2.124 BUB1B Ivone Leong Classified gene: BUB1B as Amber List (moderate evidence)
Severe microcephaly v2.124 BUB1B Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is enough evidence to support gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.124 BUB1B Ivone Leong Gene: bub1b has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.123 BUB1B Ivone Leong Tag Q2_21_rating tag was added to gene: BUB1B.
Severe microcephaly v2.123 BUB1B Ivone Leong Phenotypes for gene: BUB1B were changed from Mosaic variegated aneuploidy syndrome 1 (MIM#257300) to Mosaic variegated aneuploidy syndrome 1, OMIM:257300
Severe microcephaly v2.122 BPTF Ivone Leong Classified gene: BPTF as Amber List (moderate evidence)
Severe microcephaly v2.122 BPTF Ivone Leong Added comment: Comment on list classification: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support gene-diseas association. This gene should be rated Green at the next review.
Severe microcephaly v2.122 BPTF Ivone Leong Gene: bptf has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.121 BPTF Ivone Leong Tag Q2_21_rating tag was added to gene: BPTF.
Severe microcephaly v2.121 BPTF Ivone Leong Added comment: Comment on publications: PMID:33522091 additonal paper describing 12/20 unrelated cases with microcephaly
Severe microcephaly v2.121 BPTF Ivone Leong Publications for gene: BPTF were set to 28942966
Severe microcephaly v2.120 BPTF Ivone Leong Phenotypes for gene: BPTF were changed from Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies, MIM# 617755 to Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies, OMIM:617755
Severe microcephaly v2.119 AARS Ivone Leong Tag Q2_21_rating tag was added to gene: AARS.
Severe microcephaly v2.119 AARS Ivone Leong Classified gene: AARS as Amber List (moderate evidence)
Severe microcephaly v2.119 AARS Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant disorder in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.119 AARS Ivone Leong Gene: aars has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.118 AARS Ivone Leong commented on gene: AARS
Severe microcephaly v2.118 AARS Ivone Leong Tag new-gene-name tag was added to gene: AARS.
Severe microcephaly v2.118 WDR4 Ivone Leong reviewed gene: WDR4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe microcephaly v2.118 WDR4 Ivone Leong Tag Q2_21_rating tag was added to gene: WDR4.
Severe microcephaly v2.118 WDR4 Ivone Leong Publications for gene: WDR4 were set to 26416026; 29597095; 30079490; 29597095
Severe microcephaly v2.117 WDR4 Ivone Leong Publications for gene: WDR4 were set to 26416026; 29597095
Severe microcephaly v2.116 WDR4 Ivone Leong Phenotypes for gene: WDR4 were changed from MPD; microcephalic primordial dwarfism to Galloway-Mowat syndrome 6, OMIM:61834; Microcephaly, growth deficiency, seizures, and brain malformations, OMIM:618347
Severe microcephaly v2.115 WDR37 Ivone Leong Classified gene: WDR37 as Amber List (moderate evidence)
Severe microcephaly v2.115 WDR37 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support this gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.115 WDR37 Ivone Leong Gene: wdr37 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.114 WDR37 Ivone Leong Tag Q2_21_rating tag was added to gene: WDR37.
Severe microcephaly v2.114 WDR37 Ivone Leong Phenotypes for gene: WDR37 were changed from Neurooculocardiogenitourinary syndrome MIM#618652 to Neurooculocardiogenitourinary syndrome, OMIM:618652
Severe microcephaly v2.113 COPB1 Arina Puzriakova Classified gene: COPB1 as Amber List (moderate evidence)
Severe microcephaly v2.113 COPB1 Arina Puzriakova Gene: copb1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.112 COPB1 Arina Puzriakova gene: COPB1 was added
gene: COPB1 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: COPB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COPB1 were set to 33632302
Phenotypes for gene: COPB1 were set to Baralle-Macken syndrome, OMIM:619255; Severe intellectual disability; Cataracts; Variable microcephaly
Added comment: COPB1 is associated with a relevant phenotype in OMIM (MIM# 619255) and has a 'possible' disease confidence rating for 'COPB1-related severe intellectual disability syndrome with cataracts and variable microcephaly' in Gene2Phenotype.

- PMID: 33632302 (2021) - six individuals from two unrelated families with different homozygous variants in this gene. Affected patients developed cataracts, severe ID and variable microcephaly - at least 1 individual from each family with microcephaly of relevant severity to this panel (HC ≥ -3SD). Some supportive functional data.

Rating Amber, awaiting further cases.
Sources: Literature
Severe microcephaly v2.111 PRIM1 Arina Puzriakova edited their review of gene: PRIM1: Changed rating: GREEN
Severe microcephaly v2.111 PRIM1 Arina Puzriakova Classified gene: PRIM1 as Amber List (moderate evidence)
Severe microcephaly v2.111 PRIM1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that there is sufficient evidence to rate this gene Green at the next review
Severe microcephaly v2.111 PRIM1 Arina Puzriakova Gene: prim1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.110 PRIM1 Arina Puzriakova Tag watchlist was removed from gene: PRIM1.
Tag Q2_21_rating tag was added to gene: PRIM1.
Severe microcephaly v2.110 EIF5A Arina Puzriakova Classified gene: EIF5A as Amber List (moderate evidence)
Severe microcephaly v2.110 EIF5A Arina Puzriakova Gene: eif5a has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.109 EIF5A Arina Puzriakova gene: EIF5A was added
gene: EIF5A was added to Severe microcephaly. Sources: Literature
Q2_21_rating tags were added to gene: EIF5A.
Mode of inheritance for gene: EIF5A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EIF5A were set to 33547280
Phenotypes for gene: EIF5A were set to Intellectual disability; microcephaly; dysmorphism
Review for gene: EIF5A was set to GREEN
Added comment: EIF5A is currently not associated with any phenotype in OMIM (last edited on 18/07/2019), but is listed in Gene2Phenotype with a 'probable' disease confidence rating for 'EIF5A-related craniofacial-neurodevelopmental disorder'

- PMID: 33547280 (2021) reports 7 unrelated individuals with different de novo heterozygous variants in the EIF5A gene. Microcephaly was evident at birth in 3/5 individuals, and assessments in later life indicated microcephaly in 5/7 cases (HC ranging between -1.94 and -7.47 SD). Other features include DD/ID and craniofacial dysmorphism, including micrognathia. Supportive functional data included.

Overall sufficient (>3) unrelated cases of microcephaly in patients with EIF5A variants, for inclusion on this panel.
Sources: Literature
Severe microcephaly v2.108 RAD50 Arina Puzriakova Phenotypes for gene: RAD50 were changed from Nijmegen breakage syndrome-like disorder, 613078 to Nijmegen breakage syndrome-like disorder, OMIM:613078
Severe microcephaly v2.107 RAD50 Arina Puzriakova Publications for gene: RAD50 were set to 1887849; 19409520; 32212377
Severe microcephaly v2.106 RAD50 Arina Puzriakova Classified gene: RAD50 as Amber List (moderate evidence)
Severe microcephaly v2.106 RAD50 Arina Puzriakova Added comment: Comment on list classification: There are now a total of 3 unrelated cases (PMIDs: 19409520; 32212377; 33378670) with a RAD50‐related syndrome including microcephaly. This therefore reaches the threshold for promotion of this gene to Green status at the next review (removed 'watchlist' tag and added 'Q2_21_rating' tag)
Severe microcephaly v2.106 RAD50 Arina Puzriakova Gene: rad50 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.105 RAD50 Arina Puzriakova Tag watchlist was removed from gene: RAD50.
Tag Q2_21_rating tag was added to gene: RAD50.
Severe microcephaly v2.105 RAD50 Arina Puzriakova edited their review of gene: RAD50: Added comment: - PMID: 33378670 (2020) - single patient described with bone marrow failure, immunodeficiency and developmental defects (including microcephaly), who was compound heterozygous for a frameshift and premature stop codon (c.2165dup; p.Glu723Glyfs∗5 - maternally inherited) and in-frame deletion (c.3109_3111del; p.Glu1035del - de novo) in the RAD50 gene.
Functional characterisation using patient-derived fibroblasts indicated defects in DNA replication, DNA repair, and DNA end resection; however, ATM-dependent DNA damage response remained intact. Studies in yeast modelling the variant corresponding to p.Glu1035del produced defects in both DNA repair and Tel1ATM-dependent signalling following thermal activation.; Changed rating: GREEN; Changed publications: 19409520, 32212377, 33378670; Changed phenotypes: Nijmegen breakage syndrome-like disorder, OMIM:613078; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.105 PRIM1 Arina Puzriakova gene: PRIM1 was added
gene: PRIM1 was added to Severe microcephaly. Sources: Literature
watchlist tags were added to gene: PRIM1.
Mode of inheritance for gene: PRIM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRIM1 were set to 33060134
Phenotypes for gene: PRIM1 were set to Microcephalic primordial dwarfism, MONDO:0017950
Review for gene: PRIM1 was set to AMBER
Added comment: PRIM1 is currently not associated with any phenotype in OMIM (last edited in 2004) or Gene2Phenotype.

- PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant.
Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD).

Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinemia, and lymphopenia accompanied by intermittent anaemia/thrombocytopenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections.

Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype.
Sources: Literature
Severe microcephaly v2.104 PPP1R35 Arina Puzriakova Classified gene: PPP1R35 as Red List (low evidence)
Severe microcephaly v2.104 PPP1R35 Arina Puzriakova Added comment: Comment on list classification: Rating this gene as Red, but with a watchlist tag, until more evidence is available.
Severe microcephaly v2.104 PPP1R35 Arina Puzriakova Gene: ppp1r35 has been classified as Red List (Low Evidence).
Severe microcephaly v2.103 PPP1R35 Arina Puzriakova gene: PPP1R35 was added
gene: PPP1R35 was added to Severe microcephaly. Sources: Other
watchlist tags were added to gene: PPP1R35.
Mode of inheritance for gene: PPP1R35 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PPP1R35 were set to Primary microcephaly
Added comment: Conference poster (Genomics of Rare Disease 2021) - 'Biallelic frameshift indel in PPP1R35 as a cause of primary microcephaly' by Dawood et al, Baylor College of Medicine -

Proband from a Turkish consanguineous family with primary microcephaly (-4.3 SD at birth, -6.1 SD by 42 months) and GDD. Brain imaging showed thinning of corpus collosum, mild cerebellar volume loss, increased extra-axial CSF spaces, pachygyria, dysmorphic ventricular system and delayed myelination of the internal capsule. Exome sequencing revealed a biallelic frameshifting indel in the PPP1R35 gene (c.753_*3delGGAAGCGTAGACCinsCG; p.Trp251Cysfs*22), resulting in deletion of the canonical stop codon in the last exon. Sequencing of unaffected parents and 2 unaffected sibs confirmed segregation with the phenotype. Droplet digital PCR demonstrated expression of mutant mRNA, with comparable gene expression levels observed for mutant and wild-type alleles in fibroblasts.

Authors note a second Iranian consanguineous family in literature with two sibs with microcephaly and the same, p.Trp251Cysfs*22 variant - however, this paper could not be found in PubMed.
Sources: Other
Severe microcephaly v2.102 C7orf43 Arina Puzriakova changed review comment from: Added new-gene-name tag, new approved HGNC gene symbol for C7orf43 is MAP11; to: Added new-gene-name tag, new approved HGNC gene symbol for C7orf43 is TRAPPC14
Severe microcephaly v2.102 HPDL Arina Puzriakova changed review comment from: Comment on list classification: HPDL was added to this panel following with clinical feedback from Helen Brittain (Genomics England Clinical Team). There is enough evidence for this gene to be rated Green at the next major review.; to: Comment on list classification: HPDL was added to this panel following clinical feedback from Helen Brittain (Genomics England Clinical Team). There is enough evidence for this gene to be rated Green at the next major review.
Severe microcephaly v2.102 HPDL Arina Puzriakova Classified gene: HPDL as Amber List (moderate evidence)
Severe microcephaly v2.102 HPDL Arina Puzriakova Added comment: Comment on list classification: HPDL was added to this panel following with clinical feedback from Helen Brittain (Genomics England Clinical Team). There is enough evidence for this gene to be rated Green at the next major review.
Severe microcephaly v2.102 HPDL Arina Puzriakova Gene: hpdl has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.101 HPDL Arina Puzriakova gene: HPDL was added
gene: HPDL was added to Severe microcephaly. Sources: Literature
Q2_21_rating tags were added to gene: HPDL.
Mode of inheritance for gene: HPDL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HPDL were set to 32707086; 33188300
Phenotypes for gene: HPDL were set 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
Review for gene: HPDL was set to GREEN
Added comment: Associated with relevant phenotype in OMIM and has a 'probable' disease confidence for 'HPDL Neurodegenerative Disease' in Gene2Phenotype.

At least 34 cases from 21 unrelated families with a paediatric-onset spastic movement disorder and biallelic variants in this gene (PMIDs: 32707086 and 33188300). There is broad clinical variability ranging from severe, neonatal-onset neurodevelopmental delay with neuroimaging findings resembling mitochondrial encephalopathy to milder manifestation of adolescent-onset, isolated HSP. Microcephaly of relevant severity (HC ≤ 3 SD) was observed in 13/30 cases.

Supportive functional studies were reported, including localization of HPDL protein to the mitochondria and muscle fibre abnormalities and a KO mouse model displaying features of seizures, early lethality, smaller brain sizes, and cellular apoptosis.
Sources: Literature
Severe microcephaly v2.100 PRUNE1 Eleanor Williams Publications for gene: PRUNE1 were set to Brain 2017 awx014. doi: 10.1093/brain/awx014
Severe microcephaly v2.99 PRUNE1 Eleanor Williams Phenotypes for gene: PRUNE1 were changed from microcephaly, spasticity, developmental delay to microcephaly, spasticity, developmental delay; Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies OMIM:617481; neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies MONDO:0060490
Severe microcephaly v2.98 PRUNE1 Eleanor Williams reviewed gene: PRUNE1: Rating: ; Mode of pathogenicity: None; Publications: 33105479; Phenotypes: ; Mode of inheritance: None
Severe microcephaly v2.98 COASY Sarah Leigh edited their review of gene: COASY: Changed rating: GREEN
Severe microcephaly v2.98 COASY Sarah Leigh Classified gene: COASY as Amber List (moderate evidence)
Severe microcephaly v2.98 COASY Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Severe microcephaly v2.98 COASY Sarah Leigh Gene: coasy has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.97 COASY Sarah Leigh Publications for gene: COASY were set to 30089828; 24360804
Severe microcephaly v2.96 COASY Sarah Leigh Tag for-review tag was added to gene: COASY.
Severe microcephaly v2.96 COASY Sarah Leigh commented on gene: COASY: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen (although it has a confirmed associated with Neurodegeneration with brain iron accumulation 6 OMIM:615643, PMID 24360804). At least two terminating variants have been reported in four cases of Pontocerebellar hypoplasia, type 12 OMIM:618266 in two unrelated families (PMID 30089828). Segregation and supportive functional studies were reported, together with a zebrafish morpholino knockdown, where the lack of COASY expression was rescued by addition of CoA to the water or by injection of CoA in the brain ventricle (PMID 27892483). It was proposed that the human fetuses survived gestation due to exposure to maternal CoA (PMID 30089828).
Severe microcephaly v2.96 COASY Sarah Leigh Added comment: Comment on phenotypes: Variants are also associated with Neurodegeneration with brain iron accumulation 6 OMIM:615643, but this phenotype is not relevant to the Severe microcephaly panel (PMID 24360804).
Severe microcephaly v2.96 COASY Sarah Leigh Phenotypes for gene: COASY were changed from Pontocerebellar hypoplasia, type 12 OMIM:618266 to Pontocerebellar hypoplasia, type 12 OMIM:618266
Severe microcephaly v2.95 COASY Sarah Leigh Phenotypes for gene: COASY were changed from Severe prenatal onset pontocerebellar hypoplasia, microcephaly, arthrogryposis to Pontocerebellar hypoplasia, type 12 OMIM:618266
Severe microcephaly v2.94 MSMO1 Arina Puzriakova Phenotypes for gene: MSMO1 were changed from Microcephaly, congenital cataract, and psoriasiform dermatitis, 616834 to Microcephaly, congenital cataract, and psoriasiform dermatitis, OMIM:616834; Microcephaly-congenital cataract-psoriasiform dermatitis syndrome, MONDO:0014793
Severe microcephaly v2.93 KNL1 Arina Puzriakova Phenotypes for gene: KNL1 were changed from MCPH; primary microcephaly; Primary Microcephaly, Recessive; Microcephaly 4, primary, autosomal recessive, 604321; Microcephaly 4, Primary, Autosomal Recessive to Microcephaly 4, primary, autosomal recessive, OMIM:604321; Microcephaly 4, primary, autosomal recessive, MONDO:0011437
Severe microcephaly v2.92 TMX2 Arina Puzriakova Phenotypes for gene: TMX2 were changed from 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
Severe microcephaly v2.91 ERCC5 Arina Puzriakova Publications for gene: ERCC5 were set to 24700531; 9096355 (Retracted)
Severe microcephaly v2.90 ERCC5 Arina Puzriakova Classified gene: ERCC5 as Amber List (moderate evidence)
Severe microcephaly v2.90 ERCC5 Arina Puzriakova Added comment: Comment on list classification: Gene reassessed in view of recent expert review. Upgraded from Red to Amber as there are at least 9 fetuses from 4 unrelated families with cerebrooculofacioskeletal syndrome due to biallelic variants in this gene (PMIDs: 24700531; 32052936; 32557569). Microcephaly is reported in all affected cases; however, as extent of this presentation is not specified ERCC5 cannot be promoted to Green on this panel at present.

Nonetheless, we would expect this phenotype to be picked up via the Fetal anomalies panel, for which this gene is already Green (v.1.92).
Severe microcephaly v2.90 ERCC5 Arina Puzriakova Gene: ercc5 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.89 AP4S1 Arina Puzriakova Phenotypes for gene: AP4S1 were changed from Spastic paraplegia 52, autosomal recessive (MIM#614067) to Spastic paraplegia 52, autosomal recessive, OMIM:614067; Hereditary spastic paraplegia 52, MONDO:0013552
Severe microcephaly v2.88 AP4S1 Arina Puzriakova changed review comment from: Literature search revealed at least 23 individuals from 17 unrelated families reported in literature with biallelic variants in this gene (PMID: 21620353; 25552650; 27444738; 30283821; 32216065; 32979048). Microcephaly was observed in 15/21 cases but precise details regarding head circumference were mostly omitted or presentation was too mild relative to the scope of this panel. However, at least 2 individuals (2 families) did have microcephaly of relevant severity (OFC ≤ -3 SD) (see PMIDs: 21620353 and 25552650).

This disorder may be better represented by other panels (e.g. HSP, ID) for which this gene is already Green.; to: Literature search revealed at least 23 individuals from 17 unrelated families reported in literature with biallelic variants in this gene (PMID: 21620353; 25552650; 27444738; 30283821; 32216065; 32979048). Microcephaly was observed in 15/21 cases but precise details regarding head circumference were mostly omitted or presentation was too mild relative to the scope of this panel. However, at least 2 individuals (2 families) did have microcephaly of relevant severity (OFC ≤ -3 SD) (see PMIDs: 21620353 and 25552650).

This disorder may be better represented by other panels (e.g. HSP, ID) for which this gene is already Green.

- PMID: 32216065 (2020) - Zebrafish model recapitulates several human phenotypes, including decreased head size.
Severe microcephaly v2.88 AP4S1 Arina Puzriakova Classified gene: AP4S1 as Amber List (moderate evidence)
Severe microcephaly v2.88 AP4S1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Rating Amber with recommendation of review by the GMS team to assess whether there is sufficient evidence to support a Green rating (added 'for-review' tag)
Severe microcephaly v2.88 AP4S1 Arina Puzriakova Gene: ap4s1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.87 AP4S1 Arina Puzriakova Tag for-review tag was added to gene: AP4S1.
Severe microcephaly v2.87 AP4S1 Arina Puzriakova reviewed gene: AP4S1: Rating: ; Mode of pathogenicity: None; Publications: 21620353, 25552650, 27444738, 30283821, 32216065, 32979048; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.87 AP4E1 Arina Puzriakova changed review comment from: Comment on list classification: New gene added by Zornitza Stark. Rating Amber but there is sufficient evidence to rate Green at the next GMS panel update (added 'for-review' tag)

At least 21 individuals from 11 unrelated families reported in literature with variants in this gene (PMID: 32979048). Microcephaly was observed in 14/16 cases but details regarding head circumference were mostly unavailable. At least 5 individuals (2 families) had microcephaly of relevant severity to this panel (OFC ≤ -3 SD) (see PMIDs: 21620353 and 20972249).; to: Comment on list classification: New gene added by Zornitza Stark. Rating Amber with recommendation of review by the GMS team to assess whether there is sufficient evidence to support a Green rating (added 'for-review' tag)

At least 21 individuals from 11 unrelated families reported in literature with variants in this gene (PMID: 32979048). Microcephaly was observed in 14/16 cases but precise details regarding head circumference were mostly omitted (no relevant info was provided for the remaining 5 patients). However, at least 5 individuals (2 families) had microcephaly of relevant severity to this panel (OFC ≤ -3 SD) (see PMIDs: 21620353 and 20972249).
Severe microcephaly v2.87 AP4M1 Arina Puzriakova Phenotypes for gene: AP4M1 were changed from Spastic paraplegia 50, autosomal recessive (MIM#612936) to Spastic paraplegia 50, autosomal recessive, OMIM:612936; Hereditary spastic paraplegia 50, MONDO:0013048
Severe microcephaly v2.86 AP4M1 Arina Puzriakova Classified gene: AP4M1 as Amber List (moderate evidence)
Severe microcephaly v2.86 AP4M1 Arina Puzriakova Added comment: Comment on list classification: Microcephaly is a variable feature of the disease presentation - often too mild relative to the scope of this panel, or absent altogether. However, there are at least 3 unrelated cases with sufficiently severe microcephaly. Although the overall disorder may be better represented by other panels (e.g. HSP, ID) for which this gene is already Green, microcephaly can be an early manifestation that may be evident prior to other AP4M1-related phenotypes. Therefore, there may be value in inclusion on this panel.

Rating Amber, with recommendation of review by the GMS team to assess whether there is sufficient evidence to support a Green rating on this panel (added 'for-review' tag)
Severe microcephaly v2.86 AP4M1 Arina Puzriakova Gene: ap4m1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.85 AP4M1 Arina Puzriakova Tag for-review tag was added to gene: AP4M1.
Severe microcephaly v2.85 AP4M1 Arina Puzriakova reviewed gene: AP4M1: Rating: ; Mode of pathogenicity: None; Publications: 19559397, 21937992, 24700674, 25496299, 28464862, 29473051, 32337850; Phenotypes: Spastic paraplegia 50, autosomal recessive, OMIM:612936; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.85 ANKLE2 Arina Puzriakova Tag for-review tag was added to gene: ANKLE2.
Severe microcephaly v2.85 ANKLE2 Arina Puzriakova Phenotypes for gene: ANKLE2 were changed from ?Microcephaly 16, primary, autosomal recessive, 616681 to Microcephaly 16, primary, autosomal recessive, OMIM:616681; Microcephaly 16, primary, autosomal recessive, MONDO:0014730
Severe microcephaly v2.84 ANKLE2 Arina Puzriakova Publications for gene: ANKLE2 were set to 25259927
Severe microcephaly v2.83 ANKLE2 Arina Puzriakova Classified gene: ANKLE2 as Amber List (moderate evidence)
Severe microcephaly v2.83 ANKLE2 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber, but there is enough evidence to rate Green at the next GMS panel update (added 'for-review' tag).

At least 5 individuals from 4 unrelated families with primary microcephaly (HC -4.33 to -16.30 SD) and biallelic variants in ANKLE2 (PMIDs: 25259927 and 30214071). Several lines of supporting evidence using Drosophila Ankle2 mutants, including reduced brain size which could be rescued by expression of wildtype human ANKLE2.

This gene-disease association is also listed in OMIM (MIM# 616681).
Severe microcephaly v2.83 ANKLE2 Arina Puzriakova Gene: ankle2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.82 AGMO Arina Puzriakova Classified gene: AGMO as Amber List (moderate evidence)
Severe microcephaly v2.82 AGMO Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber. With addition of the publication identified by Zornitza Stark, there are now 2/3 unrelated cases with microcephaly (PMIDs: 31555905 and 27000257). Rating Amber awaiting further cases prior to inclusion as diagnostic-grade.
Severe microcephaly v2.82 AGMO Arina Puzriakova Gene: agmo has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.81 AGMO Arina Puzriakova Publications for gene: AGMO were set to 27000257
Severe microcephaly v2.80 AGMO Arina Puzriakova commented on gene: AGMO
Severe microcephaly v2.80 PPIL1 Arina Puzriakova Classified gene: PPIL1 as Amber List (moderate evidence)
Severe microcephaly v2.80 PPIL1 Arina Puzriakova Added comment: Comment on list classification: Sufficient evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag) - sufficient number of unrelated cases with relevant phenotype, supported by functional data.
Severe microcephaly v2.80 PPIL1 Arina Puzriakova Gene: ppil1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.79 PPIL1 Arina Puzriakova gene: PPIL1 was added
gene: PPIL1 was added to Severe microcephaly. Sources: Literature
for-review tags were added to gene: PPIL1.
Mode of inheritance for gene: PPIL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPIL1 were set to 33220177
Phenotypes for gene: PPIL1 were set to PPIL1-related Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly
Review for gene: PPIL1 was set to GREEN
Added comment: 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.

- PMID: 33220177 (2021) - At least 12 variants identified in 17 individuals from 9 unrelated families. All displayed pontocerebellar hypoplasia and progressive congenital microcephaly (-4 to -8 SD HC). Further common phenotypes included hypotonia, seizures, intellectual disability with delayed language and motor development, and cortical changes on brain MRI, most notably simplified gyri pattern. Pathogenicity is supported by mouse model.
Sources: Literature
Severe microcephaly v2.78 FBRSL1 Arina Puzriakova Phenotypes for gene: FBRSL1 were changed from to Intellectual disability; Microcephaly; Heart defect; Cleft palate; Contractures; Hearing impairment; Skin creases
Severe microcephaly v2.77 FBRSL1 Arina Puzriakova Publications for gene: FBRSL1 were set to
Severe microcephaly v2.76 FBRSL1 Arina Puzriakova edited their review of gene: FBRSL1: Changed publications: 32424618; Changed phenotypes: Intellectual disability, Microcephaly, Heart defect, Cleft palate, Contractures, Hearing impairment, Skin creases
Severe microcephaly v2.76 FBRSL1 Arina Puzriakova Tag for-review tag was added to gene: FBRSL1.
Severe microcephaly v2.76 FBRSL1 Arina Puzriakova Classified gene: FBRSL1 as Amber List (moderate evidence)
Severe microcephaly v2.76 FBRSL1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag) - sufficient number of unrelated cases with distinct variants and relevant phenotype, supported by functional data.
Severe microcephaly v2.76 FBRSL1 Arina Puzriakova Gene: fbrsl1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.75 FBRSL1 Arina Puzriakova gene: FBRSL1 was added
gene: FBRSL1 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: FBRSL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Review for gene: FBRSL1 was set to GREEN
Added comment: Currently not associated with any phenotype in OMIM or Gene2Phenotype.

- PMID: 32424618 (2020): Three different de novo truncating variants identified by WES in three unrelated individuals with a congenital malformation syndrome. Clinical characteristics include respiratory insufficiency, postnatal growth restriction, microcephaly, ID/GDD and other malformations. 2/3 had heart defects, cleft palate and hearing impairment.

Knockdown of Fbrsl1 in Xenopus laevis embryos resulted in disturbance in the outgrowth of cranial nerves and motor neurons, and craniofacial abnormalities which were rescued with the short N-terminal isoform but not with the isoform bearing one of the human variants.
Sources: Literature
Severe microcephaly v2.74 TRAPPC12 Arina Puzriakova Phenotypes for gene: TRAPPC12 were changed from Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, MIM# 617669 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
Severe microcephaly v2.73 TRAPPC12 Arina Puzriakova Classified gene: TRAPPC12 as Amber List (moderate evidence)
Severe microcephaly v2.73 TRAPPC12 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag) - sufficient unrelated published cases, plus an internally diagnosed individual; where measurements were indicated (3/5 cases), microcephaly was of relevant severity to this panel (<−3 SD)
Severe microcephaly v2.73 TRAPPC12 Arina Puzriakova Gene: trappc12 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.72 TRAPPC12 Arina Puzriakova Tag for-review tag was added to gene: TRAPPC12.
Severe microcephaly v2.72 TRAPPC12 Arina Puzriakova reviewed gene: TRAPPC12: Rating: GREEN; Mode of pathogenicity: None; Publications: 28777934, 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: None
Severe microcephaly v2.72 SMO Eleanor Williams Phenotypes for gene: SMO were changed from Microcephaly, congenital heart disease, polydactyly, aganglionosis to Microcephaly HP:0000252; postaxial polydactyly MONDO:0020927; congenital heart disease MONDO:0005453; Hirschsprung disease MONDO:0018309
Severe microcephaly v2.71 SMO Eleanor Williams Classified gene: SMO as Red List (low evidence)
Severe microcephaly v2.71 SMO Eleanor Williams Added comment: Comment on list classification: Comment on list classification: Promoting from grey to red. Although the expert reviewer recommends green, there is only one case in PMID: 32413283 where the patient is reported as having microcephaly.
Severe microcephaly v2.71 SMO Eleanor Williams Gene: smo has been classified as Red List (Low Evidence).
Severe microcephaly v2.70 SMO Eleanor Williams commented on gene: SMO
Severe microcephaly v2.70 ATP1A2 Arina Puzriakova Classified gene: ATP1A2 as Amber List (moderate evidence)
Severe microcephaly v2.70 ATP1A2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. At least 4 unrelated families with multiple congenital abnormalities and different homozygous truncating variants in the ATP1A2 gene. All were affected by microcephaly, and where measurements were specified, the severity was within the scope of this panel.

Rating Amber but there is sufficient evidence to promote to Green at the next GMS panel update (added 'for-review' tag)
Severe microcephaly v2.70 ATP1A2 Arina Puzriakova Gene: atp1a2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.69 ATP1A2 Arina Puzriakova Tag for-review tag was added to gene: ATP1A2.
Severe microcephaly v2.69 KIF14 Arina Puzriakova Tag for-review tag was added to gene: KIF14.
Severe microcephaly v2.69 KIF14 Arina Puzriakova Classified gene: KIF14 as Amber List (moderate evidence)
Severe microcephaly v2.69 KIF14 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Associated with relevant phenotype in OMIM and Gene2Phenotype. At least 8 unrelated families reported (PMIDs: 28892560 and 29343805) with severe primary microcephaly due to different biallelic variants in the KIF14 gene. Kif14 knockout mice also exhibit primary microcephaly.

Rating Amber but should be promoted to Green at the next GMS panel update (added 'for-review' tag)
Severe microcephaly v2.69 KIF14 Arina Puzriakova Gene: kif14 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.68 KIF14 Arina Puzriakova Phenotypes for gene: KIF14 were changed from Microcephaly 20, primary, autosomal recessive, MIM# 617914 to Microcephaly 20, primary, autosomal recessive, OMIM:617914; Microcephaly 20, primary, autosomal recessive, MONDO:0054761
Severe microcephaly v2.67 ZNF526 Arina Puzriakova Classified gene: ZNF526 as Amber List (moderate evidence)
Severe microcephaly v2.67 ZNF526 Arina Puzriakova Added comment: Comment on list classification: Rating Amber but may be promoted to Green at the next GMS panel update (added for-review' tag).

Sufficient number of unrelated cases (3) with microcephaly of relevant severity to this panel (more than -3 SD). Truncating variants appear to be associated with a more severe disease presentation (PMID: 33397746).
Severe microcephaly v2.67 ZNF526 Arina Puzriakova Gene: znf526 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.66 ZNF526 Arina Puzriakova gene: ZNF526 was added
gene: ZNF526 was added to Severe microcephaly. Sources: Literature
for-review tags were added to gene: ZNF526.
Mode of inheritance for gene: ZNF526 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF526 were set to 33397746
Phenotypes for gene: ZNF526 were set to Intellectual disability; Microcephaly; Cataracts; Epilepsy; Hypertonia; Dystonia
Review for gene: ZNF526 was set to GREEN
Added comment: Currently not associated with any phenotype in OMIM (last updated on 09/12/2011), but has a 'possible' disease confidence rating for 'Autosomal Recessive Mental Retardation' in Gene2Phenotype.

- PMID: 33397746 (2021) - Five individuals from four unrelated families with homozygous ZNF526 variants. Four harboured truncating variants, and were all affected by profound DD and severe ID, microcephaly (ranging from -4 SD to -8 SD), bilateral progressive cataracts, hypertonic-dystonic movements, epilepsy and brain MRI anomalies. The fifth patient had a homozygous missense variant and a slightly less severe disorder, with postnatal microcephaly (-2 SD), progressive bilateral cataracts, severe ID, and normal brain MRI. Zebrafish model demonstrated brain and eye malformations resembling findings seen in the human holoprosencephaly spectrum
Sources: Literature
Severe microcephaly v2.65 CAMK2B Zornitza Stark gene: CAMK2B was added
gene: CAMK2B was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: CAMK2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CAMK2B were set to 32875707
Phenotypes for gene: CAMK2B were set to microcephaly; intellectual disability; behavioural problems
Review for gene: CAMK2B was set to GREEN
Added comment: 5 individuals in review of literature with same de novo monoallelic variant reported with microcephaly
Sources: Literature
Severe microcephaly v2.65 AP4E1 Arina Puzriakova Publications for gene: AP4E1 were set to 20972249; 21620353; 21937992
Severe microcephaly v2.64 AP4E1 Arina Puzriakova Tag for-review tag was added to gene: AP4E1.
Severe microcephaly v2.64 AP4E1 Arina Puzriakova Classified gene: AP4E1 as Amber List (moderate evidence)
Severe microcephaly v2.64 AP4E1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Rating Amber but there is sufficient evidence to rate Green at the next GMS panel update (added 'for-review' tag)

At least 21 individuals from 11 unrelated families reported in literature with variants in this gene (PMID: 32979048). Microcephaly was observed in 14/16 cases but details regarding head circumference were mostly unavailable. At least 5 individuals (2 families) had microcephaly of relevant severity to this panel (OFC ≤ -3 SD) (see PMIDs: 21620353 and 20972249).
Severe microcephaly v2.64 AP4E1 Arina Puzriakova Gene: ap4e1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.63 AP4E1 Arina Puzriakova Phenotypes for gene: AP4E1 were changed from Spastic paraplegia 51, autosomal recessive, MIM# 613744 to Spastic paraplegia 51, autosomal recessive, OMIM:613744; Hereditary spastic paraplegia 51, MONDO:0013401
Severe microcephaly v2.62 AP4B1 Arina Puzriakova Phenotypes for gene: AP4B1 were changed from Spastic paraplegia 47, autosomal recessive, MIM# 614066 to Spastic paraplegia 47, autosomal recessive, OMIM:614066; Hereditary spastic paraplegia 47, MONDO:0013551
Severe microcephaly v2.61 AP4B1 Arina Puzriakova Publications for gene: AP4B1 were set to 21620353; 22290197; 24700674; 24781758
Severe microcephaly v2.60 AP4B1 Arina Puzriakova Classified gene: AP4B1 as Amber List (moderate evidence)
Severe microcephaly v2.60 AP4B1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Rating Amber but will be flagged for review at the next GMS panel update to assess whether clinical utility is sufficient for inclusion as Green (added 'for-review' tag).

Literature search revealed at least 24 unrelated published cases with biallelic variants in this gene. Microcephaly is commonly reported but often mild, and particularly in the context of other more prominent/universal features (ID, HSP, etc) this disorder may be better represented by other panels.

Nonetheless, microcephaly of relevant severity to this panel (OFC ≤ -3 SD) has been recorded in at least 8 unrelated families which reaches the threshold for inclusion (PMIDs: 21620353; 29193663; 30337681; 32166732)
Severe microcephaly v2.60 AP4B1 Arina Puzriakova Gene: ap4b1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.59 AP4B1 Arina Puzriakova Tag for-review tag was added to gene: AP4B1.
Severe microcephaly v2.59 C7orf43 Arina Puzriakova Phenotypes for gene: C7orf43 were changed from Microcephaly 25, primary, autosomal recessive, MIM# 618351 to Microcephaly 25, primary, autosomal recessive, OMIM:618351; Microcephaly 25, primary, autosomal recessive, MONDO:0032694
Severe microcephaly v2.58 C7orf43 Arina Puzriakova Tag new-gene-name tag was added to gene: C7orf43.
Severe microcephaly v2.58 C7orf43 Arina Puzriakova commented on gene: C7orf43: Added new-gene-name tag, new approved HGNC gene symbol for C7orf43 is MAP11
Severe microcephaly v2.58 C7orf43 Arina Puzriakova Classified gene: C7orf43 as Amber List (moderate evidence)
Severe microcephaly v2.58 C7orf43 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Associated with relevant phenotype in OMIM (MIM# 618351) but not yet in Gene2Phenotype.

Three individuals from one family with severe ID and primary microcephaly of relevant severity (-5 SD to -6 SD). Zebrafish model recapitulates human microcephaly phenotype.

Rating Amber as additional cases required prior to inclusion on a diagnostic panel.
Severe microcephaly v2.58 C7orf43 Arina Puzriakova Gene: c7orf43 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.57 SMC1A Arina Puzriakova Phenotypes for gene: SMC1A were changed from Cornelia de Lange syndrome 2, 300590 (includes microcephaly) to Cornelia de Lange syndrome 2, OMIM:300590; Cornelia de Lange syndrome 2, MONDO:0010370; Developmental and epileptic encephalopathy 85, with or without midline brain defects, OMIM:301044; Developmental and epileptic encephalopathy, 85, with or without midline brain defects, MONDO:0026771
Severe microcephaly v2.56 SMG8 Arina Puzriakova Classified gene: SMG8 as Amber List (moderate evidence)
Severe microcephaly v2.56 SMG8 Arina Puzriakova Added comment: Comment on list classification: Rating Amber but can be promoted to Green at the next GMS panel update (added 'for-review' tag).

At least 5 unrelated families with microcephaly and different homozygous variants in the SMG8 gene. OFC recorded for only 3 families, but each includes at least one microcephalic individual with severity relevant to this panel (more than -3 SD)
Severe microcephaly v2.56 SMG8 Arina Puzriakova Gene: smg8 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.55 SMG8 Arina Puzriakova gene: SMG8 was added
gene: SMG8 was added to Severe microcephaly. Sources: Literature
for-review tags were added to gene: SMG8.
Mode of inheritance for gene: SMG8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMG8 were set to 31130284; 33242396
Phenotypes for gene: SMG8 were set to Intellectual disability; Microcephaly; Short stature; Facial dysmorphism
Review for gene: SMG8 was set to GREEN
Added comment: Currently not associated with any phenotype in OMIM or G2P.
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- PMID: 31130284 (2019) - Two individuals with distinct homozygous variants in this gene identified as part of a large candidate gene discovery study. Phenotype in one patient included microcephaly, ID, cataract, and neck hyperpigmentation; while the other presented short stature, microcephaly, fine motor delay, ventricular septal defect, failure to thrive, and facial dysmorphism.

- PMID: 33242396 (2020) - 9 affected individuals from 4 consanguineous families with different biallelic variants in the SMG8 gene. Clinical features include GDD/ID (8/8), dysmorphic features (9/9) microcephaly (6/9), short stature (4/9), brain imaging anomalies (4/5), congenital heart disease (3/9) and cataract (3/8). Some supportive functional data also provided. Microcephaly was recorded in 3/4 families, ranging in severity from -2.5 SD to -4.1 SD.
Sources: Literature
Severe microcephaly v2.54 AARS Arina Puzriakova Phenotypes for gene: AARS were changed from Epileptic encephalopathy, early infantile, 29, MIM# 616339 to Developmental and epileptic encephalopathy 29, OMIM:616339; Developmental and epileptic encephalopathy, 29, MONDO:0014593
Severe microcephaly v2.53 NARS Arina Puzriakova commented on gene: NARS: Added new-gene-name tag, new approved HGNC gene symbol for NARS is NARS1
Severe microcephaly v2.53 NARS Arina Puzriakova Classified gene: NARS as Amber List (moderate evidence)
Severe microcephaly v2.53 NARS Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag)
Severe microcephaly v2.53 NARS Arina Puzriakova Gene: nars has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.52 NARS Arina Puzriakova gene: NARS was added
gene: NARS was added to Severe microcephaly. Sources: Literature
new-gene-name, for-review tags were added to gene: NARS.
Mode of inheritance for gene: NARS was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NARS were set to 32738225; 32788587
Phenotypes for gene: NARS were set to 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
Review for gene: NARS was set to GREEN
Added comment: Associated with relevant phenotype in OMIM, and in Gene2Phenotype with 'confirmed' disease confidence for 'NARS1 Neurodevelopmental Disorder (monoallelic)' and 'probable' for 'NARS1 Neurodevelopmental Disorder (biallelic)'

Total of 24 patients from 13 unrelated families with biallelic variants in the NARS1 gene (PMIDs: 32738225 and 32788587) and 8 unrelated patients with de novo heterozygous variants (PMIDs: 32738225). Microcephaly was observed in the majority of cases (90%), with severity relevant to this panel (≥ 3 SD). These cases predominantly presented with primary microcephaly; however, secondary microcephaly was also noted. Other features include GDD/ID, seizures, ataxia, and dysmorphism. Supportive functional data.
Sources: Literature
Severe microcephaly v2.51 RRP7A Zornitza Stark gene: RRP7A was added
gene: RRP7A was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: RRP7A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RRP7A were set to 33199730
Phenotypes for gene: RRP7A were set to Microcephaly
Review for gene: RRP7A was set to AMBER
Added comment: 10 affected individuals from a single large consanguineous family where bi-allelic variant segregated with severe microcephaly (-6-8SD), variable ID. Supportive functional data from mouse and zebrafish.
Sources: Literature
Severe microcephaly v2.51 YIPF5 Zornitza Stark gene: YIPF5 was added
gene: YIPF5 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: YIPF5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YIPF5 were set to 33164986
Phenotypes for gene: YIPF5 were set to Neonatal diabetes; microcephaly; seizures
Review for gene: YIPF5 was set to GREEN
Added comment: Six individuals from 5 unrelated consanguineous families reported with bi-allelic variants in this gene and neonatal/early-onset diabetes, severe microcephaly, and epilepsy. Functional data supports gene-disease association.
Sources: Literature
Severe microcephaly v2.51 MORC2 Arina Puzriakova Classified gene: MORC2 as Amber List (moderate evidence)
Severe microcephaly v2.51 MORC2 Arina Puzriakova Added comment: Comment on list classification: Though signs suggestive of neuropathy were observed in the cohort presented by Sacoto et al (PMID:32693025), these were not the predominant feature of the disease presentation or the primary indication for diagnostic testing. Inclusion on this panel would be of value for detecting such cases, and so this gene should be promoted to Green at the next GMS panel update (added 'for-review' tag)
Severe microcephaly v2.51 MORC2 Arina Puzriakova Gene: morc2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.50 MORC2 Arina Puzriakova gene: MORC2 was added
gene: MORC2 was added to Severe microcephaly. Sources: Literature
for-review tags were added to gene: MORC2.
Mode of inheritance for gene: MORC2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MORC2 were set to 32693025
Phenotypes for gene: MORC2 were set to Developmental delay; Intellectual disability; Growth retardation; Microcephaly; Craniofacial dysmorphism; Charcot-Marie-Tooth disease, axonal, type 2Z, OMIM:616688
Review for gene: MORC2 was set to GREEN
Added comment: MORC2 variants have commonly been associated with CMT, presenting axonal neuropathy with progressive weakness, muscle cramps and sensory impairment. However, Sacoto et al (2020) (PMID: 32693025) present a cohort of 20 individuals (19 kindreds) with a neurodevelopmental disorder characterised by DD, ID (18/20 - mild to severe), short stature (18/20), microcephaly (15/20) and variable craniofacial dysmorphisms. Severity of microcephaly relevant to this panel (≥ 3 SD) was observed in 7 subjects.
Sources: Literature
Severe microcephaly v2.49 SVBP Arina Puzriakova Phenotypes for gene: SVBP were changed from Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, OMIM #618569 to Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, OMIM:618569; Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, MONDO:0032816
Severe microcephaly v2.48 SVBP Arina Puzriakova Tag for-review tag was added to gene: SVBP.
Severe microcephaly v2.48 SVBP Arina Puzriakova Classified gene: SVBP as Amber List (moderate evidence)
Severe microcephaly v2.48 SVBP Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag).

12 individuals from 5 independent families (PMIDs: 31363758 and 30607023). Phenotypes include severe microcephaly in >3 families. SVBP is associated with a relevant phenotype in OMIM.
Severe microcephaly v2.48 SVBP Arina Puzriakova Gene: svbp has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.47 DNMT3A Sarah Leigh Phenotypes for gene: DNMT3A were changed from Heyn-Sproul-Jackson syndrome 618724 to Heyn-Sproul-Jackson syndrome OMIM:618724; MONDO:0032882
Severe microcephaly v2.46 DNMT3A Sarah Leigh edited their review of gene: DNMT3A: Added comment: Associated with relevant phenotype (Heyn-Sproul-Jackson syndrome 618724) in OMIM and as probable Gen2Phen gene for Microcephalic primordial dwarfism. At least two gain of function variants reported in three unrelated cases, together with supportive functional studies (pmid 30478443).; Changed rating: GREEN
Severe microcephaly v2.46 DNMT3A Sarah Leigh Tag for-review tag was added to gene: DNMT3A.
Severe microcephaly v2.46 DNMT3A Sarah Leigh Phenotypes for gene: DNMT3A were changed from intellectual disability; microcephaly; short stature to Heyn-Sproul-Jackson syndrome 618724
Severe microcephaly v2.45 DNMT3A Sarah Leigh Classified gene: DNMT3A as Amber List (moderate evidence)
Severe microcephaly v2.45 DNMT3A Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Note gain of function variants associated with this phenotype.
Severe microcephaly v2.45 DNMT3A Sarah Leigh Gene: dnmt3a has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.44 LMNB2 Sarah Leigh edited their review of gene: LMNB2: Added comment: Not associated with a relevant phenotype in OMIM or in Gen2Phen. PMID 33033404 reports five individuals with heterozygous variants in LMNB2. One of these cases was de novo for c.160A>C p.N54H (NM_032737.4) and the remaining cases had c.1192G>A, p.Glu398Lys (NM_032737.4), which was shown to be de novo in two cases, inherited from the unaffected mother (who was mosaic for the variant) and the inheritance in the remaining case was not established. All of these cases had moderate to severe developmental delay and microcephaly.; Changed rating: GREEN
Severe microcephaly v2.44 LMNB2 Sarah Leigh Tag for-review tag was added to gene: LMNB2.
Severe microcephaly v2.44 LMNB2 Sarah Leigh Classified gene: LMNB2 as Amber List (moderate evidence)
Severe microcephaly v2.44 LMNB2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Severe microcephaly v2.44 LMNB2 Sarah Leigh Gene: lmnb2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.43 LMNB1 Sarah Leigh changed review comment from: Not associated with relevant phenotype in OMIM (19/11/2020), but as confirmed Gen2Phen gene for LMNB1-associated developmental disorder. At least 7 variants reported in at least 7 unrelated cases. Each variant was associated with intellectual disability and microcephaly (PMID 32910914; 33033404).; to: Not associated with relevant phenotype in OMIM (19/11/2020), but as confirmed Gen2Phen gene for LMNB1-associated developmental disorder. At least 5 variants reported in at least 5 unrelated cases. Each variant was associated with intellectual disability and microcephaly (PMID 32910914; 33033404).
Severe microcephaly v2.43 LMNB1 Sarah Leigh edited their review of gene: LMNB1: Added comment: Not associated with relevant phenotype in OMIM (19/11/2020), but as confirmed Gen2Phen gene for LMNB1-associated developmental disorder. At least 7 variants reported in at least 7 unrelated cases. Each variant was associated with intellectual disability and microcephaly (PMID 32910914; 33033404).; Changed rating: GREEN
Severe microcephaly v2.43 LMNB1 Sarah Leigh Tag for-review tag was added to gene: LMNB1.
Severe microcephaly v2.43 LMNB1 Sarah Leigh Classified gene: LMNB1 as Amber List (moderate evidence)
Severe microcephaly v2.43 LMNB1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Severe microcephaly v2.43 LMNB1 Sarah Leigh Gene: lmnb1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.42 LMNB1 Sarah Leigh Publications for gene: LMNB1 were set to 33033404
Severe microcephaly v2.41 LMNB1 Sarah Leigh Phenotypes for gene: LMNB1 were changed from Congenital microcephaly; Global developmental delay; Intellectual disability to Congenital microcephaly; Global developmental delay; Intellectual disability; LMNB1-associated developmental disorder
Severe microcephaly v2.40 METTL5 Arina Puzriakova Classified gene: METTL5 as Amber List (moderate evidence)
Severe microcephaly v2.40 METTL5 Arina Puzriakova Added comment: Comment on list classification: Borderline Green/Amber gene. Sufficient unrelated cases (3) from literature and supportive animal models, but uncertain functional significance of one variant. Thus METTL5 will be flagged for review of evidence at the next GMS panel update (added 'for-review' tag)
Severe microcephaly v2.40 METTL5 Arina Puzriakova Gene: mettl5 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.39 METTL5 Arina Puzriakova gene: METTL5 was added
gene: METTL5 was added to Severe microcephaly. Sources: Literature
for-review tags were added to gene: METTL5.
Mode of inheritance for gene: METTL5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: METTL5 were set to 29302074; 31564433; https://imgc2019.sciencesconf.org/data/abstract_book_complete.pdf
Phenotypes for gene: METTL5 were set to Intellectual developmental disorder, autosomal recessive 72, 618665
Added comment: Associated with 'Intellectual developmental disorder' in OMIM, and is a 'probable' gene for 'Autosomal-Recessive Intellectual Disability and Microcephaly' in DD-G2P.

Gene added and expert reviewed on Intellectual Disability panel: https://panelapp.genomicsengland.co.uk/panels/285/gene/METTL5/

Distinct biallelic variants reported in 3 unrelated families (total 9 individuals) with severe microcephaly (OFC -2.8 to -8 SD) and intellectual disability. Mouse and zebrafish models appeared to recapitulate relevant human phenotypes (microcephaly, ID and growth retardation).

However, the Gly61Asp variant found in the PMID:29302074 siblings is currently classified VUS as localisation and expression studies failed to demonstrate a functional impact on the encoded protein.
Sources: Literature
Severe microcephaly v2.38 MFSD2A Arina Puzriakova Phenotypes for gene: MFSD2A were changed from Microcephaly 15, primary, autosomal recessive, 616486 to Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain imaging abnormalities, 616486
Severe microcephaly v2.37 MFSD2A Arina Puzriakova Added comment: Comment on publications: Added publications to support this gene-disease association
Severe microcephaly v2.37 MFSD2A Arina Puzriakova Publications for gene: MFSD2A were set to 12046007
Severe microcephaly v2.36 ZNF335 Arina Puzriakova Publications for gene: ZNF335 were set to 25951892; 25548773; 23178126
Severe microcephaly v2.35 ZNF335 Arina Puzriakova Phenotypes for gene: ZNF335 were changed from Autosomal recessive primary microcephaly (MCPH) ; ?Microcephaly 10, primary, autosomal recessive, 615095 to Microcephaly 10, primary, autosomal recessive, 615095
Severe microcephaly v2.34 ZNF335 Arina Puzriakova Classified gene: ZNF335 as Amber List (moderate evidence)
Severe microcephaly v2.34 ZNF335 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated Green at the next GMS panel update (added 'for-review' tag).
Severe microcephaly v2.34 ZNF335 Arina Puzriakova Gene: znf335 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.33 ZNF335 Arina Puzriakova Tag for-review tag was added to gene: ZNF335.
Severe microcephaly v2.33 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
Severe microcephaly v2.33 TTC5 Sarah Leigh Deleted their comment
Severe microcephaly v2.33 CEP55 Arina Puzriakova Classified gene: CEP55 as Amber List (moderate evidence)
Severe microcephaly v2.33 CEP55 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Severe microcephaly v2.33 CEP55 Arina Puzriakova Gene: cep55 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.32 CEP55 Arina Puzriakova Tag for-review tag was added to gene: CEP55.
Severe microcephaly v2.32 TMX2 Arina Puzriakova Classified gene: TMX2 as Amber List (moderate evidence)
Severe microcephaly v2.32 TMX2 Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Severe microcephaly v2.32 TMX2 Arina Puzriakova Gene: tmx2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.31 TMX2 Arina Puzriakova Tag for-review tag was added to gene: TMX2.
Severe microcephaly v2.31 UBE3A Sarah Leigh Phenotypes for gene: UBE3A were changed from Angelman syndrome MIM#105830 to Angelman syndrome 105830
Severe microcephaly v2.30 UBE3A Sarah Leigh Publications for gene: UBE3A were set to
Severe microcephaly v2.29 UBE3A Sarah Leigh Classified gene: UBE3A as Amber List (moderate evidence)
Severe microcephaly v2.29 UBE3A Sarah Leigh Gene: ube3a has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.28 UBE3A Sarah Leigh Tag for-review tag was added to gene: UBE3A.
Severe microcephaly v2.28 UBE3A Sarah Leigh edited their review of gene: UBE3A: Added comment: Postnatal microcephaly has been reported in Angelman syndrome patients, mostly amonst those with deletions rather than UPD of 15q.; Changed rating: AMBER; Changed publications: 2012134, 9182785, 10861661, 10861661; Changed phenotypes: Angelman syndrome 105830; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Severe microcephaly v2.28 UBE3A Sarah Leigh Added comment: Comment on mode of inheritance: In accordance with http://igc.otago.ac.nz/home.html
Severe microcephaly v2.28 UBE3A Sarah Leigh Mode of inheritance for gene: UBE3A was changed from MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed) to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Severe microcephaly v2.27 LMNB2 Konstantinos Varvagiannis gene: LMNB2 was added
gene: LMNB2 was added to Severe microcephaly. 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
Severe microcephaly v2.27 LMNB1 Konstantinos Varvagiannis gene: LMNB1 was added
gene: LMNB1 was added to Severe microcephaly. 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 33033404
Phenotypes for gene: LMNB1 were set to Congenital microcephaly; Global developmental delay; Intellectual disability
Penetrance for gene: LMNB1 were set to Complete
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: 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
Severe microcephaly v2.27 DNMT3A Rachel Jones reviewed gene: DNMT3A: 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: PID: 30478443; Phenotypes: 618724 HEYN-SPROUL-JACKSON SYNDROME, HESJAS; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe microcephaly v2.27 YIF1B Arina Puzriakova Tag for-review was removed from gene: YIF1B.
Tag watchlist tag was added to gene: YIF1B.
Severe microcephaly v2.27 YIF1B Arina Puzriakova Tag for-review tag was added to gene: YIF1B.
Severe microcephaly v2.27 YIF1B Arina Puzriakova Classified gene: YIF1B as Amber List (moderate evidence)
Severe microcephaly v2.27 YIF1B Arina Puzriakova Added comment: Comment on list classification: Although 5/6 individuals described in PMID:32006098 had microcephaly, 4 of these share the same founder variant and the severity of microcephaly is not specified. Therefore, rating Amber until further cases are reported (added to watchlist).
Severe microcephaly v2.27 YIF1B Arina Puzriakova Gene: yif1b has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.26 NUP188 Arina Puzriakova Phenotypes for gene: NUP188 were changed from microcephaly; ID; cataract; structural brain abnormalities; hypoventilation to Sandestig-Stefanova syndrome, 618804
Severe microcephaly v2.25 NUP188 Arina Puzriakova Classified gene: NUP188 as Amber List (moderate evidence)
Severe microcephaly v2.25 NUP188 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next major review - progressive microcephaly reported in at least 5 affected individuals due to biallelic truncating variants in NUP188.
Severe microcephaly v2.25 NUP188 Arina Puzriakova Gene: nup188 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.24 NUP188 Arina Puzriakova Tag for-review tag was added to gene: NUP188.
Severe microcephaly v2.24 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
Severe microcephaly v2.24 RAD50 Arina Puzriakova Tag watchlist tag was added to gene: RAD50.
Severe microcephaly v2.24 RAD50 Arina Puzriakova Phenotypes for gene: RAD50 were changed from Nijmegen breakage syndrome-like disorder, MIM# 613078 to Nijmegen breakage syndrome-like disorder, 613078
Severe microcephaly v2.23 RAD50 Arina Puzriakova Publications for gene: RAD50 were set to 19409520; 32212377
Severe microcephaly v2.22 RAD50 Arina Puzriakova Classified gene: RAD50 as Amber List (moderate evidence)
Severe microcephaly v2.22 RAD50 Arina Puzriakova Added comment: Comment on list classification: Relevant phenotype (two unrelated cases with severe congenital microcephaly) but additional cases required before inclusion of RAD50 on a diagnostic panel.

Rating Amber in anticipation of additional publications/clinical evidence (added to watchlist).
Severe microcephaly v2.22 RAD50 Arina Puzriakova Gene: rad50 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.21 RAD50 Zornitza Stark gene: RAD50 was added
gene: RAD50 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: RAD50 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RAD50 were set to 19409520; 32212377
Phenotypes for gene: RAD50 were set to Nijmegen breakage syndrome-like disorder, MIM# 613078
Review for gene: RAD50 was set to GREEN
gene: RAD50 was marked as current diagnostic
Added comment: Two individuals reported with bi-allelic variants in this gene showing dysmorphic facial features similar to NBS, short stature, microcephaly, and mild/moderate intellectual disability. Fibroblasts established from one of the individuals showed chromosomal instability and abnormal radioresistant DNA synthesis. The MRE11/RAD50/NBN (MRN) complex is involved in signaling processes inducing the repair of DNA double-strand breaks. Variants in NBN and MRE11 are associated with Nijmegen breakage syndrome (NBS) and ataxia telangiectasia (AT)‐like disorder, respectively, so this gene is a strong biological candidate for this phenotype.
Sources: Literature
Severe microcephaly v2.21 EXOC7 Arina Puzriakova Classified gene: EXOC7 as Amber List (moderate evidence)
Severe microcephaly v2.21 EXOC7 Arina Puzriakova Added comment: Comment on list classification: Though mild microcephaly reported in 5/8 cases (-0.5 to -2.6 SD), rating Amber as severity of presentation is not within the scope of this panel.
Severe microcephaly v2.21 EXOC7 Arina Puzriakova Gene: exoc7 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.20 YIF1B Zornitza Stark gene: YIF1B was added
gene: YIF1B was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: YIF1B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YIF1B were set to 32006098; 26077767
Phenotypes for gene: YIF1B were set to Central hypotonia; Failure to thrive; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Spasticity; Abnormality of movement
Review for gene: YIF1B was set to GREEN
gene: YIF1B was marked as current diagnostic
Added comment: 6 individuals (from 5 families) with biallelic YIF1B truncating variants reported. Presenting features: hypotonia, failure to thrive, microcephaly (5/6), severe global DD and ID 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. 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 KO mice demonstrate a disorganized Golgi architecture in pyramidal hippocampal neurons (Alterio et al 2015 - PMID: 26077767). 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.
Sources: Expert list
Severe microcephaly v2.20 UNC80 Zornitza Stark gene: UNC80 was added
gene: UNC80 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: UNC80 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UNC80 were set to 26708751; 26708753; 26545877; 29572195
Phenotypes for gene: UNC80 were set to Hypotonia, infantile, with psychomotor retardation and characteristic facies 2 MIM#616801
Review for gene: UNC80 was set to GREEN
gene: UNC80 was marked as current diagnostic
Added comment: Summary: Many patients reported as microcephalic. Not all have head circumference < -3SD but there are at least 3 unrelated individuals reported with head circumference smaller than this.

PMID 26708751: 4 individuals from 3 families reported. At 4 years one had OFC -4SD (the others 2nd centile at 4yo, 3rd centile at 15yo, and 10th centile at 9yo).

PMID 26708753: Two 'not directly related' families F1 and F2 identified with the same variant. A third and fourth family had different variants. All affected individuals described were microcephalic (F1: -3.2SD at 4yo; F2: -4SD at 2yo and -2.9SD at 13mo; F3: -2.4SD at 7yo; F4: 9th centile at 4yo and 5th centile at 8yo).

PMID 26545877: 7 affected individuals from 2 distantly related families with the same nonsense variant were all microcephalic (<2nd centile).

PMID 29572195: 2 unrelated individuals reported. Head circumference of patient 1 was -0.5SD at 9yo; Patient 2 -3.7SD at 3yo.
Sources: Expert list
Severe microcephaly v2.20 UGP2 Zornitza Stark gene: UGP2 was added
gene: UGP2 was added to Severe microcephaly. Sources: Expert list
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 Epileptic encephalopathy; intellectual disability; microcephaly
Review for gene: UGP2 was set to GREEN
gene: UGP2 was marked as current diagnostic
Added comment: 22 individuals from 15 families reported with the same homozygous missense variant in this gene, chr2:64083454A > G, which causes a disruption of the start codon in the shorter isoform, which is expressed in brain.
Sources: Expert list
Severe microcephaly v2.20 UBE3A Zornitza Stark gene: UBE3A was added
gene: UBE3A was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: UBE3A was set to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Phenotypes for gene: UBE3A were set to Angelman syndrome MIM#105830
Review for gene: UBE3A was set to GREEN
gene: UBE3A was marked as current diagnostic
Added comment: Microcephaly is a key feature.
Sources: Expert list
Severe microcephaly v2.20 TSEN54 Zornitza Stark gene: TSEN54 was added
gene: TSEN54 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: TSEN54 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TSEN54 were set to 20952379; 20301773
Phenotypes for gene: TSEN54 were set to Pontocerebellar hypoplasia type 2A (MIM#277470) and type 4 (MIM#225753)
Review for gene: TSEN54 was set to GREEN
gene: TSEN54 was marked as current diagnostic
Added comment: Microcephaly is a common feature of TSEN54 pontocerebellar hypoplasia (progressive in type 2, present at birth in type 4).
Sources: Expert list
Severe microcephaly v2.20 TSEN15 Zornitza Stark gene: TSEN15 was added
gene: TSEN15 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: TSEN15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TSEN15 were set to 27392077
Phenotypes for gene: TSEN15 were set to Pontocerebellar hypoplasia, type 2F MIM#617026
Review for gene: TSEN15 was set to GREEN
gene: TSEN15 was marked as current diagnostic
Added comment: PMID 27392077 Reports four individuals from three families with PCH type 2 and different homozygous missense variants, all had progressive microcephaly (between -3SD and -9.7SD). Functional studies indicated that all variants resulted in almost complete lack of in vitro tRNA cleavage activity.
Sources: Expert list
Severe microcephaly v2.20 TRIO Zornitza Stark gene: TRIO was added
gene: TRIO was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: TRIO was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRIO were set to 26721934; 32109419
Phenotypes for gene: TRIO were set to Mental retardation, autosomal dominant 44, MIM# 617061
Review for gene: TRIO was set to GREEN
gene: TRIO was marked as current diagnostic
Added comment: The nonsense mutations are spread along the TRIO sequence, and affected individuals show variable neurodevelopmental phenotypes. In contrast, missense variants cluster into two mutational hotspots in the TRIO sequence, one in the seventh spectrin repeat and one in the RAC1-activating GEFD1. Individuals with a pathogenic variant in the seventh spectrin repeat have a more severe ID associated with macrocephaly than do most individuals with GEFD1 variants, who display milder ID and microcephaly.
Sources: Expert list
Severe microcephaly v2.20 DYNC1I2 Zornitza Stark gene: DYNC1I2 was added
gene: DYNC1I2 was added to Severe microcephaly. Sources: Expert list
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 Neurodevelopmental disorder with microcephaly and structural brain anomalies , MIM#618492
Review for gene: DYNC1I2 was set to GREEN
gene: DYNC1I2 was marked as current diagnostic
Added comment: Five individuals from three unrelated families reported.
Sources: Expert list
Severe microcephaly v2.20 DPM1 Zornitza Stark gene: DPM1 was added
gene: DPM1 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: DPM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DPM1 were set to 16641202; 10642602; 10642597
Phenotypes for gene: DPM1 were set to Congenital disorder of glycosylation, type Ie 608799
Review for gene: DPM1 was set to GREEN
gene: DPM1 was marked as current diagnostic
Added comment: PMID: 16641202 - 2 siblings of consanguineous parents. One patient showed retarded motor skills at 1, 2 and 4 years old, with distal myopathy present at 3 years of age. The younger sister presented at 7 weeks of age with generalized hypotonia. Both had normal CK levels. Both siblings were progressively microcephalic.

PMID: 10642602 - 2 chet siblings with hypotonia within the first year of life. Both had elevated CK. Both siblings were progressively microcephalic

PMID: 10642597 - 2 unrelated patients. One had profound hypotonia at 3 years of age. The other patient was markedly hypotonic in infancy. Both were microcephalic and hd elevated CK levels.
Sources: Expert list
Severe microcephaly v2.20 DNMT3A Zornitza Stark gene: DNMT3A was added
gene: DNMT3A was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: DNMT3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DNMT3A were set to 30478443
Phenotypes for gene: DNMT3A were set to intellectual disability; microcephaly; short stature
Review for gene: DNMT3A was set to GREEN
gene: DNMT3A was marked as current diagnostic
Added comment: Three individuals reported, two with the same de novo missense variant. Postulated to be GOF as opposed to LOF variants in this gene which cause an overgrowth syndrome. Animal model supports pathogenicity.
Sources: Expert list
Severe microcephaly v2.20 DNA2 Zornitza Stark reviewed gene: DNA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24389050, 31045292; Phenotypes: Seckel syndrome 8, MIM#615807; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Severe microcephaly v2.20 CTU2 Zornitza Stark gene: CTU2 was added
gene: CTU2 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: CTU2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTU2 were set to 26633546
Phenotypes for gene: CTU2 were set to Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome (MIM#618142)
Review for gene: CTU2 was set to GREEN
gene: CTU2 was marked as current diagnostic
Added comment: Dysmorphic facies, renal agenesis, ambiguous genitalia, microcephaly, polydactyly and lissencephaly (DREAM-PL) as proposed by authors.

PMID: 26633546
- 3 consanguineous families all with the same splice variant (NM_001012762.1:c.873G>A). Assumed to be founder variant
- all had microcephaly but measurements were not provided

PMID: 27480277
- 2 additional patients from an extended consanguineous family with the same variant as above
- Patient 1: head circumference of -3.5SD at birth, not growing
- Patient 2: head circumference of -4.3 SD

PMID: 31301155
- 5 new patients with microcephaly (no measurements provided)
- 3x PTVs and 1x missense
Sources: Expert list
Severe microcephaly v2.20 CTSF Zornitza Stark gene: CTSF was added
gene: CTSF was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: CTSF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CTSF were set to 23746550; 30893510; 28619046
Phenotypes for gene: CTSF were set to Mental retardation, autosomal dominant 21 (MIM#615502)
Review for gene: CTSF was set to GREEN
gene: CTSF was marked as current diagnostic
Added comment: PMID: 23746550
- 4 probands, 2x PTV, 1x missense, 1x 280kb deletion (all de novo)
- OFCs ranges from -0.8 SD (the proband with the deletion) to -3.51 SD

PMID: 30893510
- 3 probands, de novo 2x PTV and 1x missense
- OFCs ranges from < -2 to < -3 SD

PMID: 28619046
- 1x proband with de novo fs
- head circumference was under 10th centle
Sources: Expert list
Severe microcephaly v2.20 CSNK2A1 Zornitza Stark gene: CSNK2A1 was added
gene: CSNK2A1 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: CSNK2A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CSNK2A1 were set to 29240241
Phenotypes for gene: CSNK2A1 were set to Okur-Chung neurodevelopmental syndrome MIM#617062
Review for gene: CSNK2A1 was set to GREEN
gene: CSNK2A1 was marked as current diagnostic
Added comment: Microcephaly is a feature of the condition in 8/14 cases with de novo variants.
Sources: Expert list
Severe microcephaly v2.20 CHAMP1 Zornitza Stark gene: CHAMP1 was added
gene: CHAMP1 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: CHAMP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHAMP1 were set to 27148580; 26340335
Phenotypes for gene: CHAMP1 were set to Mental retardation, autosomal dominant 40 (MIM#616579)
Review for gene: CHAMP1 was set to GREEN
gene: CHAMP1 was marked as current diagnostic
Added comment: PMID: 27148580;
- 10 patients including 5 from Hempel et al (PMID: 26340335)
- 7 with microcephaly defined as <3rd centile
- all PTVs and de novo

PMID: 26340335;
- 5 unrelated patients OFC at birth ranges from -0.4 to -3.1 SD
Sources: Expert list
Severe microcephaly v2.20 CEP63 Zornitza Stark reviewed gene: CEP63: Rating: AMBER; Mode of pathogenicity: None; Publications: 21983783, 26158450; Phenotypes: Seckel syndrome 6, MIM#614728; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.20 BUB1B Zornitza Stark gene: BUB1B was added
gene: BUB1B was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: BUB1B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BUB1B were set to 18548531
Phenotypes for gene: BUB1B were set to Mosaic variegated aneuploidy syndrome 1 (MIM#257300)
Review for gene: BUB1B was set to GREEN
gene: BUB1B was marked as current diagnostic
Added comment: Severe microcephaly is a feature of MVAS. PMID: 18548531: review of 13 families with 12 presenting with microcephaly
Sources: Expert list
Severe microcephaly v2.20 BPTF Zornitza Stark gene: BPTF was added
gene: BPTF was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: BPTF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BPTF were set to 28942966
Phenotypes for gene: BPTF were set to Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies, MIM# 617755
Review for gene: BPTF was set to GREEN
gene: BPTF was marked as current diagnostic
Added comment: Microcephaly observed in 7/9 individuals reported.
Sources: Expert list
Severe microcephaly v2.20 AARS Zornitza Stark gene: AARS was added
gene: AARS was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: AARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AARS were set to 28493438; 25817015
Phenotypes for gene: AARS were set to Epileptic encephalopathy, early infantile, 29, MIM# 616339
Review for gene: AARS was set to GREEN
gene: AARS was marked as current diagnostic
Added comment: Bi-allelic variants associated with a severe phenotype comprising leukodystrophy, epilepsy, microcephaly and neurodevelopmental delay reported in three families.
Sources: Expert list
Severe microcephaly v2.20 FOXG1 Zornitza Stark gene: FOXG1 was added
gene: FOXG1 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: FOXG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOXG1 were set to 21441262; 19564653; 19578037
Phenotypes for gene: FOXG1 were set to Rett syndrome, congenital variant, MIM# 613454
Review for gene: FOXG1 was set to GREEN
gene: FOXG1 was marked as current diagnostic
Added comment: More than 20 individuals reported with de novo variants in this gene. Microcephaly is part of the phenotype.
Sources: Expert list
Severe microcephaly v2.20 EXOC7 Zornitza Stark gene: EXOC7 was added
gene: EXOC7 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: EXOC7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOC7 were set to 32103185
Phenotypes for gene: EXOC7 were set to brain atrophy; seizures; developmental delay; microcephaly
Review for gene: EXOC7 was set to GREEN
gene: EXOC7 was marked as current diagnostic
Added comment: 4 families with 8 affected individuals with brain atrophy, seizures, and developmental delay, and in more severe cases microcephaly and infantile death. Four novel homozygous or comp.heterozygous variants found in EXOC7, which segregated with disease in the families. They showed that EXOC7, a member of the mammalian exocyst complex, is highly expressed in developing human cortex. In addition, a zebrafish model of Exoc7 deficiency recapitulates the human disorder with increased apoptosis and decreased progenitor cells during telencephalon development, suggesting that the brain atrophy in human cases reflects neuronal degeneration.
Sources: Expert list
Severe microcephaly v2.20 EIF2S3 Zornitza Stark gene: EIF2S3 was added
gene: EIF2S3 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: EIF2S3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: EIF2S3 were set to 23063529; 27333055; 28055140; 32799315
Phenotypes for gene: EIF2S3 were set to MEHMO syndrome, MIM# 300148
Review for gene: EIF2S3 was set to GREEN
Added comment: 9 families reported (3 had the same variant) with MEHMO syndrome (mental retardation, epileptic seizures, hypogonadism and hypogenitalism, microcephaly, and obesity).
Sources: Expert list
Severe microcephaly v2.20 TRAPPC9 Zornitza Stark gene: TRAPPC9 was added
gene: TRAPPC9 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: TRAPPC9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC9 were set to 22549410; 20004765; 20004763; 30853973
Phenotypes for gene: TRAPPC9 were set to Mental retardation, autosomal recessive 13, MIM# 613192
Review for gene: TRAPPC9 was set to GREEN
gene: TRAPPC9 was marked as current diagnostic
Added comment: Microcephaly is part of the phenotype.
Sources: Expert list
Severe microcephaly v2.20 TRAPPC6B Zornitza Stark gene: TRAPPC6B was added
gene: TRAPPC6B was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: TRAPPC6B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC6B were set to 28626029; 28397838; 31687267
Phenotypes for gene: TRAPPC6B were set to Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, MIM# 617862
Review for gene: TRAPPC6B was set to GREEN
gene: TRAPPC6B was marked as current diagnostic
Added comment: Five unrelated families reported with autosomal recessive neurodegenerative disorder characterised by global developmental delay, severe intellectual disability with poor or absent speech and autistic stereotypic behaviors, microcephaly, early-onset generalized seizures, and hypotonia.
Sources: Expert list
Severe microcephaly v2.20 TRAPPC12 Zornitza Stark gene: TRAPPC12 was added
gene: TRAPPC12 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: TRAPPC12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC12 were set to 32369837; 28777934
Phenotypes for gene: TRAPPC12 were set to Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, MIM# 617669
Review for gene: TRAPPC12 was set to GREEN
gene: TRAPPC12 was marked as current diagnostic
Added comment: Four families reported with a severe progressive encephalopathy characterized by microcephaly, global developmental delay, and hearing loss.
Sources: Expert list
Severe microcephaly v2.20 TPRKB Zornitza Stark gene: TPRKB was added
gene: TPRKB was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: TPRKB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TPRKB were set to 28805828; 30053862
Phenotypes for gene: TPRKB were set to Galloway-Mowat syndrome 5, MIM# 617731
Review for gene: TPRKB was set to GREEN
gene: TPRKB was marked as current diagnostic
Added comment: Three unrelated families reported with renal-neurologic disease characterized by early-onset nephrotic syndrome associated with microcephaly.
Sources: Expert list
Severe microcephaly v2.20 TP53RK Zornitza Stark gene: TP53RK was added
gene: TP53RK was added to Severe microcephaly. Sources: Expert Review
Mode of inheritance for gene: TP53RK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TP53RK were set to 28805828; 30053862
Phenotypes for gene: TP53RK were set to Galloway-Mowat syndrome 4, MIM# 617730
Review for gene: TP53RK was set to GREEN
gene: TP53RK was marked as current diagnostic
Added comment: At least 4 unrelated families reported with renal-neurologic disease characterised by early-onset nephrotic syndrome associated with microcephaly, gyral abnormalities, and delayed psychomotor development. Most individuals have dysmorphic facial features, often including hypertelorism, ear abnormalities, and micrognathia. Other features, such as arachnodactyly and visual impairment, are more variable.
Sources: Expert Review
Severe microcephaly v2.20 TCF4 Zornitza Stark gene: TCF4 was added
gene: TCF4 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: TCF4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TCF4 were set to 18728071; 22934316
Phenotypes for gene: TCF4 were set to Pitt-Hopkins syndrome, MIM# 610954
Review for gene: TCF4 was set to GREEN
gene: TCF4 was marked as current diagnostic
Added comment: Well established gene-disease association. Microcephaly reported in around 60%.
Sources: Expert list
Severe microcephaly v2.20 SVBP Zornitza Stark gene: SVBP was added
gene: SVBP was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: SVBP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SVBP were set to 31363758; 30607023
Phenotypes for gene: SVBP were set to Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, OMIM #618569
Review for gene: SVBP was set to GREEN
Added comment: 5 unrelated families with homozygous mutations in SVBP, microcephaly is part of the phenotype. The mutations segregated with the disorder in all families. In vitro functional cellular expression studies showed that protein levels of the SVBP mutants were barely detectable, suggesting instability, and that the mutant proteins had lost VASH/SVBP catalytic detyrosination activity toward tubulin. Knockdown of about 50% Svbp expression using shRNA in rat hippocampal neurons impaired the formation of excitatory synapses compared to controls.
Sources: Expert list
Severe microcephaly v2.20 SMO Zornitza Stark gene: SMO was added
gene: SMO was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: SMO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMO were set to 32413283
Phenotypes for gene: SMO were set to Microcephaly, congenital heart disease, polydactyly, aganglionosis
Review for gene: SMO was set to GREEN
gene: SMO was marked as current diagnostic
Added comment: Bi-allelic loss-of-function variations in SMO reported in seven individuals from five independent families. Wide phenotypic spectrum of developmental anomalies affecting the brain (hypothalamic hamartoma and microcephaly), heart (atrioventricular septal defect), skeleton (postaxial polydactyly, narrow chest, and shortening of long bones), and enteric nervous system (aganglionosis).
Sources: Expert list
Severe microcephaly v2.20 SLC1A4 Zornitza Stark gene: SLC1A4 was added
gene: SLC1A4 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: SLC1A4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC1A4 were set to 25930971; 26138499; 26041762; 27193218; 29989513
Phenotypes for gene: SLC1A4 were set to Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, MIM# 616657
Review for gene: SLC1A4 was set to GREEN
Added comment: Spastic tetraplegia, thin corpus callosum, and progressive microcephaly is an autosomal recessive neurodevelopmental disorder characterized by onset of those features and severely impaired global development in early infancy. Most patients are unable to achieve independent walking or speech; some patients have seizures. Multiple affected families reported. Note founder variant p.Glu256Lys is a common founder variant in the Ashkenazi Jewish population.
Sources: Expert list
Severe microcephaly v2.20 SASS6 Zornitza Stark reviewed gene: SASS6: Rating: AMBER; Mode of pathogenicity: None; Publications: 24951542, 30639237; Phenotypes: Microcephaly 14, primary, autosomal recessive, MIM# 616402; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.20 RUSC2 Zornitza Stark gene: RUSC2 was added
gene: RUSC2 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: RUSC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RUSC2 were set to 27612186
Phenotypes for gene: RUSC2 were set to Mental retardation, autosomal recessive 61, MIM# 617773
Review for gene: RUSC2 was set to AMBER
Added comment: Two unrelated families reported.
Sources: Expert list
Severe microcephaly v2.20 PUS7 Zornitza Stark gene: PUS7 was added
gene: PUS7 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: PUS7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PUS7 were set to 30526862; 30778726; 31583274
Phenotypes for gene: PUS7 were set to Intellectual developmental disorder with abnormal behavior, microcephaly, and short stature, OMIM #618342
Review for gene: PUS7 was set to GREEN
gene: PUS7 was marked as current diagnostic
Added comment: 11 patients from 6 families with ID, speech delay, short stature, microcephaly, and aggressive behavior, with homozygous PUS7 mutations, which segregated with disease.
Sources: Expert list
Severe microcephaly v2.20 PUF60 Zornitza Stark gene: PUF60 was added
gene: PUF60 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: PUF60 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PUF60 were set to 28327570
Phenotypes for gene: PUF60 were set to Verheij syndrome, MIM# 615583
Review for gene: PUF60 was set to GREEN
gene: PUF60 was marked as current diagnostic
Added comment: Over 15 affected individuals reported. Short stature and dev delay are consistent features. 5/12 in the largest case series had microcephaly in relation to stature (Z-scores −2.48, −4.22, −2.09, −2.99, −2.53 respectively).
Sources: Expert list
Severe microcephaly v2.20 PTPN23 Zornitza Stark gene: PTPN23 was added
gene: PTPN23 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: PTPN23 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPN23 were set to 31395947; 29899372; 29090338; 27848944; 25558065
Phenotypes for gene: PTPN23 were set to Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity, MIM# 618890
Review for gene: PTPN23 was set to GREEN
Added comment: Over 10 families reported with an autosomal recessive neurologic disorder characterised by global developmental delay apparent from early infancy, poor overall growth often with microcephaly (6/10), impaired intellectual development with delayed or absent speech, axial hypotonia, and peripheral spasticity. Additional common but variable features include early-onset seizures, optic atrophy with poor visual fixation, and dysmorphic facial features. Brain imaging shows cerebral atrophy, poor or absent myelination with loss of white matter volume, and often hypoplasia of the corpus callosum and/or cerebellum.
Sources: Expert list
Severe microcephaly v2.20 PPP1R15B Zornitza Stark reviewed gene: PPP1R15B: Rating: AMBER; Mode of pathogenicity: None; Publications: 27640355; Phenotypes: Microcephaly, short stature, and impaired glucose metabolism 2, MIM# 616817; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.20 POGZ Zornitza Stark gene: POGZ was added
gene: POGZ was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: POGZ was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POGZ were set to 26942287
Phenotypes for gene: POGZ were set to White-Sutton syndrome, MIM# 616364
Review for gene: POGZ was set to GREEN
gene: POGZ was marked as current diagnostic
Added comment: Microcephaly is reported in around half of affected individuals.
Sources: Expert list
Severe microcephaly v2.20 PDCD6IP Zornitza Stark gene: PDCD6IP was added
gene: PDCD6IP was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: PDCD6IP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDCD6IP were set to 32286682
Phenotypes for gene: PDCD6IP were set to Primary microcephaly
Review for gene: PDCD6IP was set to AMBER
Added comment: One consanguineous family with 2 affected sibs with primary microcephaly (-4SD), intellectual disability and short stature (-5/6SD), and homozygous frameshift variant in PDCD6IP. The homozygous variant was confirmed in both affected sibs, while the four healthy siblings and parents were heterozygous. The clinical features observed in the patients were similar to the phenotypes observed in mouse and zebrafish models of PDCD6IP mutations in previous studies. Borderline Red/Amber rating in view of the supportive animal model data.
Sources: Expert list
Severe microcephaly v2.20 DPP6 Zornitza Stark reviewed gene: DPP6: Rating: AMBER; Mode of pathogenicity: None; Publications: 23832105; Phenotypes: Mental retardation, autosomal dominant 33 (MIM#616311); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe microcephaly v2.20 PCDH12 Zornitza Stark gene: PCDH12 was added
gene: PCDH12 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: PCDH12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCDH12 were set to 27164683; 22822038; 30178464
Phenotypes for gene: PCDH12 were set to Diencephalic-mesencephalic junction dysplasia syndrome 1, MIM# 251280
Review for gene: PCDH12 was set to GREEN
Added comment: Diencephalic-mesencephalic junction dysplasia syndrome-1 (DMJDS1) is an autosomal recessive neurodevelopmental disorder characterized by progressive microcephaly, severely delayed or even absent psychomotor development with profound intellectual disability, and spasticity or dystonia. Some patients may have seizures and/or visual impairment. Brain imaging shows a characteristic developmental malformation of the midbrain; subtle intracranial calcifications may also be present. At least 12 families reported.
Sources: Expert list
Severe microcephaly v2.20 ERCC5 Zornitza Stark edited their review of gene: ERCC5: Changed publications: 32052936, 24700531
Severe microcephaly v2.20 ERCC5 Zornitza Stark reviewed gene: ERCC5: Rating: AMBER; Mode of pathogenicity: None; Publications: 32052936; Phenotypes: Cerebrooculofacioskeletal syndrome 3 MIM#616570; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.20 COASY Sebastian Lunke reviewed gene: COASY: Rating: GREEN; Mode of pathogenicity: None; Publications: 30089828, 28489334; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.20 ADARB1 Arina Puzriakova Publications for gene: ADARB1 were set to 32220291
Severe microcephaly v2.19 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
Severe microcephaly v2.19 HIST1H4C Zornitza Stark gene: HIST1H4C was added
gene: HIST1H4C was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: HIST1H4C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HIST1H4C were set to 28920961
Phenotypes for gene: HIST1H4C were set to Growth delay, microcephaly and intellectual disability
Review for gene: HIST1H4C was set to GREEN
gene: HIST1H4C was marked as current diagnostic
Added comment: Two families and a zebrafish model reported initially, another case identified through clinical testing internally.
Sources: Expert list
Severe microcephaly v2.19 KIF14 Zornitza Stark gene: KIF14 was added
gene: KIF14 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: KIF14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF14 were set to 28892560; 29343805
Phenotypes for gene: KIF14 were set to Microcephaly 20, primary, autosomal recessive, MIM# 617914
Review for gene: KIF14 was set to GREEN
gene: KIF14 was marked as current diagnostic
Added comment: At least 8 families reported. Microcephaly ranged from -3.6 to -11 SD.
Sources: Expert list
Severe microcephaly v2.19 LAGE3 Zornitza Stark edited their review of gene: LAGE3: Set current diagnostic: yes
Severe microcephaly v2.19 LAGE3 Zornitza Stark gene: LAGE3 was added
gene: LAGE3 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: LAGE3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: LAGE3 were set to 28805828
Phenotypes for gene: LAGE3 were set to Galloway-Mowat syndrome 2, X-linked, MIM# 301006
Review for gene: LAGE3 was set to GREEN
Added comment: Renal-neurologic disease characterized by early-onset nephrotic syndrome associated with microcephaly, gyral abnormalities of the brain, and delayed psychomotor development. At least three unrelated families and a mouse model.
Sources: Expert list
Severe microcephaly v2.19 OSGEP Zornitza Stark gene: OSGEP was added
gene: OSGEP was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: OSGEP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OSGEP were set to 28805828; 28272532
Phenotypes for gene: OSGEP were set to Galloway-Mowat syndrome 3, MIM# 617729
Review for gene: OSGEP was set to GREEN
gene: OSGEP was marked as current diagnostic
Added comment: Early-onset nephrotic syndrome associated with microcephaly, gyral abnormalities of the brain, and delayed psychomotor development. Most individuals have dysmorphic facial features, often including hypertelorism, ear abnormalities, and micrognathia. Other features, such as arachnodactyly and visual impairment, are more variable. Over 25 families reported.
Sources: Expert list
Severe microcephaly v2.19 NUP188 Zornitza Stark gene: NUP188 was added
gene: NUP188 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: NUP188 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP188 were set to 32021605; 28726809; 32275884
Phenotypes for gene: NUP188 were set to microcephaly; ID; cataract; structural brain abnormalities; hypoventilation
Review for gene: NUP188 was set to GREEN
gene: NUP188 was marked as current diagnostic
Added comment: Eight unrelated individuals reported.
Sources: Expert list
Severe microcephaly v2.19 NUP107 Zornitza Stark gene: NUP107 was added
gene: NUP107 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: NUP107 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP107 were set to 28280135; 28117080; 30179222; 25558065
Phenotypes for gene: NUP107 were set to Galloway-Mowat syndrome 7, MIM# 618348
Review for gene: NUP107 was set to GREEN
gene: NUP107 was marked as current diagnostic
Added comment: Autosomal recessive disorder characterised by developmental delay, microcephaly (-5 to -9 SD), and early-onset nephrotic syndrome. Approx 10 families reported. Recurrent variant p.Met101Ile identified in several families, likely represents a South Asian founder allele.
Sources: Expert list
Severe microcephaly v2.19 VRK1 Zornitza Stark gene: VRK1 was added
gene: VRK1 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: VRK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VRK1 were set to 19646678; 24126608; 27281532; 31560180
Phenotypes for gene: VRK1 were set to Pontocerebellar hypoplasia type 1A MIM#607596
Review for gene: VRK1 was set to GREEN
gene: VRK1 was marked as current diagnostic
Added comment: PMID 19646678: A homozygous nonsense variant was identified in an affected Ashkenazi Jewish family with 3 individuals with SMA-PCH. 2 had severe microcephaly (-6SD at 5yo and -7.9SD at 19mo). The third was noted to be microcephalic but no figures given. PMID 24126608: "Three affected individuals from 2 unrelated families presented with a complex neuropathy phenotype characterized by axonal sensorimotor neuropathy and microcephaly". 2 sibs from one family had head circumference -4SD and -6SD and were chet for missense variants. The third unrelated individual was -6SD and hom for a nonsense variant. PMID 27281532: reports another individual with microcephaly but no details provided.
Sources: Expert list
Severe microcephaly v2.19 BRD4 Zornitza Stark gene: BRD4 was added
gene: BRD4 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: BRD4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BRD4 were set to 29379197; 30302754
Phenotypes for gene: BRD4 were set to Cornelia de Lange-like syndrome
Review for gene: BRD4 was set to AMBER
Added comment: A mixture of evidence from SNVs and CNVs. Note the CNVs are large and only some individuals have documented OFC < -3SD.

PMID: 29379197;
- 4x patients reports however only 3 reported with occipitofrontal circumference of < -3 SD
- 1x microdeletion of 1.04Mb, 1x missense and 1x fs. All de novo

PMID: 30302754
- 1x proband with occipitofrontal circumference 28 cm (−2 SD)
- de novo interstitial deletion involving the short arm of a chromosome 19, 1.97 Mb in size, which included BRD4
Sources: Expert list
Severe microcephaly v2.19 WDR4 Zornitza Stark reviewed gene: WDR4: Rating: GREEN; Mode of pathogenicity: None; Publications: 26416026, 28617965, 30079490, 29597095; Phenotypes: Galloway-Mowat syndrome 6 MIM#618347; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Severe microcephaly v2.19 WDR37 Zornitza Stark edited their review of gene: WDR37: Set current diagnostic: yes
Severe microcephaly v2.19 WDR37 Zornitza Stark gene: WDR37 was added
gene: WDR37 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: WDR37 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WDR37 were set to 31327508; 31327510
Phenotypes for gene: WDR37 were set to Neurooculocardiogenitourinary syndrome MIM#618652
Review for gene: WDR37 was set to GREEN
Added comment: Summary: 7/9 individuals reported with neurooculocardiogenitourinary syndrome had microcephaly. 5 had measurements provided and were severe (-3SD).

PMID 31327510: 4 individuals with de novo missense variants reported, with Neurooculocardiogenitourinary syndrome. All four have microcephaly - 49.5cm at 21yo, 40.2cm at 22mo (-4.8SD), 47.4cm at 7.5yo.

PMID 31327508: 5 probands with de novo missense variants, 3 with microcephaly (0th centile, <3rd centile (-5SD), and 11th centile)
Sources: Expert list
Severe microcephaly v2.19 ATP1A2 Zornitza Stark gene: ATP1A2 was added
gene: ATP1A2 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: ATP1A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATP1A2 were set to 30690204; 31608932
Phenotypes for gene: ATP1A2 were set to hydrops fetalis, microcephaly, arthrogryposis and extensive cortical malformations
Review for gene: ATP1A2 was set to GREEN
gene: ATP1A2 was marked as current diagnostic
Added comment: This is a distinct phenotype from the one associated with mono-allelic variants.

PMID: 30690204;
- 2 families with severe microcephaly (-6 to -8 SD)
- both homozygous PTVs

PMID: 31608932;
- 4 patients from 2 families
- Family A, all 3 affecteds had severe microcephaly during ultrasound (-3 to -4 SD)
- Family B, no measurements were reported
- both homozygous PTVs
Sources: Expert list
Severe microcephaly v2.19 ARCN1 Zornitza Stark gene: ARCN1 was added
gene: ARCN1 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: ARCN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARCN1 were set to 27476655
Phenotypes for gene: ARCN1 were set to Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay (MIM#617164)
Review for gene: ARCN1 was set to GREEN
gene: ARCN1 was marked as current diagnostic
Added comment: Borderline Amber/Green. Microcephaly is a key part of the phenotype but few exact measurements actually reported.
Sources: Expert list
Severe microcephaly v2.19 AP4S1 Zornitza Stark gene: AP4S1 was added
gene: AP4S1 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: AP4S1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP4S1 were set to 21620353; 25552650; 27444738
Phenotypes for gene: AP4S1 were set to Spastic paraplegia 52, autosomal recessive (MIM#614067)
Review for gene: AP4S1 was set to GREEN
gene: AP4S1 was marked as current diagnostic
Added comment: Borderline Amber/Green as only one affected individual <-3SD; however, part of same gene family as other spastic paraplegias with microcephaly. Microcephaly in another family -2SD and precise information on the microcephaly not available for third family.
Sources: Expert list
Severe microcephaly v2.19 AP4M1 Zornitza Stark gene: AP4M1 was added
gene: AP4M1 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: AP4M1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP4M1 were set to 28464862; 24700674
Phenotypes for gene: AP4M1 were set to Spastic paraplegia 50, autosomal recessive (MIM#612936)
Review for gene: AP4M1 was set to GREEN
gene: AP4M1 was marked as current diagnostic
Added comment: Despite the OMIM name, this is a complex neurological condition, where microcephaly is an early prominent presenting feature.

PMID: 28464862;
- 1x with severe progressive microcephaly (< - 4 SD)
- homozygous nonsense

PMID: 24700674;
- 2x unrelated patients (1 and 3) < -3 SD head circumference
- 2x homozygous nonsense
Sources: Expert list
Severe microcephaly v2.19 NSD2 Zornitza Stark gene: NSD2 was added
gene: NSD2 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: NSD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NSD2 were set to 30345613; 31171569
Phenotypes for gene: NSD2 were set to microcephaly; intellectual disability
Review for gene: NSD2 was set to GREEN
Added comment: Microcephaly reported in 6 of 7 individuals with LOF variants in this gene.
Sources: Expert list
Severe microcephaly v2.19 ZNF335 Zornitza Stark reviewed gene: ZNF335: Rating: GREEN; Mode of pathogenicity: None; Publications: 23178126, 27540107, 29652087; Phenotypes: Microcephaly 10, primary, autosomal recessive (MIM#615095); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Severe microcephaly v2.19 MED17 Zornitza Stark gene: MED17 was added
gene: MED17 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: MED17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED17 were set to 20950787; 30345598; 26004231
Phenotypes for gene: MED17 were set to Microcephaly, postnatal progressive, with seizures and brain atrophy, MIM# 613668
Review for gene: MED17 was set to GREEN
gene: MED17 was marked as current diagnostic
Added comment: Five individuals from four families reported initially, founder effect for p.Leu371Pro. Two additional families reported since with different variants, one family with milder phenotype.
Sources: Expert list
Severe microcephaly v2.19 MECP2 Zornitza Stark gene: MECP2 was added
gene: MECP2 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: MECP2 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes for gene: MECP2 were set to Rett syndrome, MIM# 312750; Encephalopathy, neonatal severe 300673
Review for gene: MECP2 was set to GREEN
gene: MECP2 was marked as current diagnostic
Added comment: Well established gene-disease association, microcephaly is a key phenotypic feature both in Rett syndrome and in males affected by severe neonatal encephalopathy.
Sources: Expert list
Severe microcephaly v2.19 AKT3 Zornitza Stark changed review comment from: Activating variants in AKT2 and micro duplications are associated with macrocephaly/megalencephaly. Note that deletions involving AKT3 have consistently been associated with microcephaly. However, most involve at least one other gene apart from AKT3. One family reported with only AKT3 deleted: deletion was inherited from a phenotypically normal parent, suggesting either additional effects in bigger deletions or incomplete penetrance. You may wish to consider adding the CNV region to this panel rather than AKT3 alone, in which case I suspect the region has enough evidence for a Green rating.
Sources: Expert list; to: Activating variants in AKT3 and micro duplications are associated with macrocephaly/megalencephaly. Note that deletions involving AKT3 have consistently been associated with microcephaly. However, most involve at least one other gene apart from AKT3. One family reported with only AKT3 deleted: deletion was inherited from a phenotypically normal parent, suggesting either additional effects in bigger deletions or incomplete penetrance. You may wish to consider adding the CNV region to this panel rather than AKT3 alone, in which case I suspect the region has enough evidence for a Green rating.
Sources: Expert list
Severe microcephaly v2.19 AKT3 Zornitza Stark gene: AKT3 was added
gene: AKT3 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: AKT3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AKT3 were set to 32827175; 31929334; 30853971; 30053339; 25424989
Phenotypes for gene: AKT3 were set to Microcephaly
Review for gene: AKT3 was set to AMBER
Added comment: Activating variants in AKT2 and micro duplications are associated with macrocephaly/megalencephaly. Note that deletions involving AKT3 have consistently been associated with microcephaly. However, most involve at least one other gene apart from AKT3. One family reported with only AKT3 deleted: deletion was inherited from a phenotypically normal parent, suggesting either additional effects in bigger deletions or incomplete penetrance. You may wish to consider adding the CNV region to this panel rather than AKT3 alone, in which case I suspect the region has enough evidence for a Green rating.
Sources: Expert list
Severe microcephaly v2.19 AP4E1 Zornitza Stark gene: AP4E1 was added
gene: AP4E1 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: AP4E1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP4E1 were set to 20972249; 21620353; 21937992
Phenotypes for gene: AP4E1 were set to Spastic paraplegia 51, autosomal recessive, MIM# 613744
Review for gene: AP4E1 was set to GREEN
gene: AP4E1 was marked as current diagnostic
Added comment: Autosomal recessive neurodevelopmental disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity and severe mental retardation with poor or absent speech development. Microcephaly is a prominent, presenting feature. At least 3 families reported.
Sources: Expert list
Severe microcephaly v2.19 AP4B1 Zornitza Stark gene: AP4B1 was added
gene: AP4B1 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: AP4B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP4B1 were set to 21620353; 22290197; 24700674; 24781758
Phenotypes for gene: AP4B1 were set to Spastic paraplegia 47, autosomal recessive, MIM# 614066
Review for gene: AP4B1 was set to GREEN
gene: AP4B1 was marked as current diagnostic
Added comment: Microcephaly is an early, prominent presenting feature of this progressive neurological disorder. At least 4 unrelated families reported.
Sources: Expert list
Severe microcephaly v2.19 ANKLE2 Zornitza Stark edited their review of gene: ANKLE2: Changed rating: GREEN
Severe microcephaly v2.19 ANKLE2 Zornitza Stark reviewed gene: ANKLE2: Rating: ; Mode of pathogenicity: None; Publications: 25259927, 30214071, 31735666; Phenotypes: Microcephaly 16, primary, autosomal recessive, MIM# 616681; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Severe microcephaly v2.19 AGMO Zornitza Stark reviewed gene: AGMO: Rating: GREEN; Mode of pathogenicity: None; Publications: 31555905; Phenotypes: microcephaly, intellectual disability, epilepsy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Severe microcephaly v2.19 TUBGCP2 Arina Puzriakova Classified gene: TUBGCP2 as Amber List (moderate evidence)
Severe microcephaly v2.19 TUBGCP2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - at least three families with distinct TUBGCP2 variants, presenting progressive severe microcephaly.
Severe microcephaly v2.19 TUBGCP2 Arina Puzriakova Gene: tubgcp2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.18 TUBGCP2 Arina Puzriakova gene: TUBGCP2 was added
gene: TUBGCP2 was added to Severe microcephaly. Sources: Literature
for-review tags were added to gene: TUBGCP2.
Mode of inheritance for gene: TUBGCP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TUBGCP2 were set to 31630790
Phenotypes for gene: TUBGCP2 were set to Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures, 618737
Review for gene: TUBGCP2 was set to GREEN
Added comment: Associated with phenotype in OMIM, and a probable gene for Microcephaly and Lissencephaly Spectrum Disorders in G2P.

PMID: 31630790 (2019) - Five patients from four families with biallelic variants in the TUBGCP2 gene. Affected individuals shared phenotypic features that included progressive severe microcephaly (4/4, Z score: -4.0 to -9.0), developmental delay (5/5, mild-severe), seizures (4/5). All patients exhibited lissencephaly-spectrum phenotypes with varying degrees of cortical malformations on brain imaging including pachygyria and subcortical band heterotopia.

All variants segregated with disease in each family. Analysis of fibroblasts derived from one patient with a splice site variant revealed several abnormal transcripts, predicted to result in LoF. No further functional studies of other variants or patient cells were performed.
Sources: Literature
Severe microcephaly v2.17 NCAPH Arina Puzriakova Tag watchlist tag was added to gene: NCAPH.
Severe microcephaly v2.17 NCAPH Arina Puzriakova Classified gene: NCAPH as Red List (low evidence)
Severe microcephaly v2.17 NCAPH Arina Puzriakova Added comment: Comment on list classification: Additional cases are required to substantiate causation but added to watchlist.
Severe microcephaly v2.17 NCAPH Arina Puzriakova Gene: ncaph has been classified as Red List (Low Evidence).
Severe microcephaly v2.16 NCAPH Arina Puzriakova gene: NCAPH was added
gene: NCAPH was added to Severe microcephaly. Sources: Literature
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
Severe microcephaly v2.15 NCAPD3 Arina Puzriakova Classified gene: NCAPD3 as Amber List (moderate evidence)
Severe microcephaly v2.15 NCAPD3 Arina Puzriakova Added comment: Comment on list classification: Additional cases, as well as a more significant pattern of microcephaly, are required before inclusion of NCAPD3 on a diagnostic panel.
Severe microcephaly v2.15 NCAPD3 Arina Puzriakova Gene: ncapd3 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.14 NCAPD3 Arina Puzriakova gene: NCAPD3 was added
gene: NCAPD3 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: NCAPD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NCAPD3 were set to 27737959
Phenotypes for gene: NCAPD3 were set to Microcephaly 22, primary, autosomal recessive, 617984
Review for gene: NCAPD3 was set to AMBER
Added comment: Associated with Microcephaly 22 in OMIM and a possible gene for Microcephaly with short stature in G2P.

PMID: 27737959 (2016) - Two unrelated cases. Compound heterozygous variants ([c.1783_1784delG, p.Val595Serfs*34];[c.382+14A>G, p.Ser129Metfs*1]) were detected in a 6-years-5-month-old male with microcephaly (OFC -5.4 SD). The second patient (aged 6-years-11-months-old) was less severely microcephalic (OFC -2.7 SD) but additionally had moderate developmental delay, seizures and lower limb hypertonia, and also harboured a homozygous missense variant in NCAPD3 (c.3458T>G, p.Glu1153Ala).

Functional studies indicated that both variants 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
Severe microcephaly v2.13 NCAPD2 Arina Puzriakova Tag for-review tag was added to gene: NCAPD2.
Severe microcephaly v2.13 NCAPD2 Arina Puzriakova Classified gene: NCAPD2 as Amber List (moderate evidence)
Severe microcephaly v2.13 NCAPD2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - at least three unrelated pedigrees with the relevant phenotype.
Severe microcephaly v2.13 NCAPD2 Arina Puzriakova Gene: ncapd2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.12 NCAPD2 Arina Puzriakova gene: NCAPD2 was added
gene: NCAPD2 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: NCAPD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NCAPD2 were set to 27737959; 28097321; 31056748
Phenotypes for gene: NCAPD2 were set to Microcephaly 21, primary, autosomal recessive, 617983
Review for gene: NCAPD2 was set to GREEN
Added comment: Associated with phenotype in OMIM and a possible gene for Microcephaly with short stature in G2P.

PMID: 27737959 (2016) - A homozygous splice site variant (c.4120+2T>C, p.Asp1374Glyfs*29) in NCAPD2 was detected in a 3-year-old male with severe microcephaly (OFC -11.9 SD), severe ID, autistic-like behaviours, and no speech. The variant was found in a heterozygous state in both unaffected parents and was not present in the ExAC database. Functional studies indicated that the variant disrupted condensin-dependent mitotic chromosome integrity, providing supporting evidence for pathogenicity.

PMID: 28097321 (2017) - In two affected cousins from a consanguineous family with mild ID, intrauterine growth retardation, short stature, and microcephaly. Homozygous missense variants were found in NCAPD2 (c.23T>C, p.Phe8Ser), but also in ENO2 (c.710C>T, p.Thr237Met). Variants segregated with disease in the family, but no further functional studies were undertaken of the variants or patient cells.

PMID: 31056748 (2019) - In a 13-year-old female with severe microcephaly (OFC < -3), mild ID (IQ 59), poor learning performance, sloping forehead and reduced cerebral cortex size, exome sequencing revealed a homozygous variant in NCAPD2 (c.3477+2T>C, p.Gly1160Valfs*16). Progressive microcephaly was also apparent in a sibling of the proband, a male fetus which was terminated at 34 weeks of pregnancy. The same homozygous variant was identified in the fetus, while parents were heterozygotes and an unaffected brother was homozygous for the other allele. No further functional studies of the variant or patient cells were performed.
Sources: Literature
Severe microcephaly v2.11 ADARB1 Arina Puzriakova changed review comment from: Variants reported in four unrelated individuals with severe/profound intellectual disability, microcephaly, and seizures. Affected individuals were microcephalic at birth or developed postnatal microcephaly ranging from -3.6 to -4.0 SD. Functional studies demonstrate variants result in reduction of ADARB1 product activity or changes in splicing (PMID: 32220291). Homozygous knockout mice presented with seizures and early death, supporting the role of ADARB1 in brain function (PMID: 10894545).

Gene is associated with phenotype in OMIM and G2P.
Sources: Literature; to: Gene is associated with phenotype in OMIM and G2P.

PMID: 32220291 - Bi-allelic variants reported in four unrelated individuals with severe/profound intellectual disability, microcephaly, and seizures. Functional studies demonstrate variants result in reduction in ADARB1 product activity or changes in splicing.
PMID: 10894545 - Homozygous knockout mice presented with siezures and early death, supporting the role of ADARB1 in brain function

This gene has also been added to the Genetic Epilepsy and Intellectual Disability panels with a suggested Green classification at the next major review.
Severe microcephaly v2.11 ADARB1 Sarah Leigh Tag for-review tag was added to gene: ADARB1.
Severe microcephaly v2.11 ADARB1 Sarah Leigh Classified gene: ADARB1 as Amber List (moderate evidence)
Severe microcephaly v2.11 ADARB1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Severe microcephaly v2.11 ADARB1 Sarah Leigh Gene: adarb1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.10 ADARB1 Arina Puzriakova gene: ADARB1 was added
gene: ADARB1 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: ADARB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADARB1 were set to 32220291
Phenotypes for gene: ADARB1 were set to Neurodevelopmental disorder with hypotonia, microcephaly, and seizures, 618862
Review for gene: ADARB1 was set to GREEN
Added comment: Variants reported in four unrelated individuals with severe/profound intellectual disability, microcephaly, and seizures. Affected individuals were microcephalic at birth or developed postnatal microcephaly ranging from -3.6 to -4.0 SD. Functional studies demonstrate variants result in reduction of ADARB1 product activity or changes in splicing (PMID: 32220291). Homozygous knockout mice presented with seizures and early death, supporting the role of ADARB1 in brain function (PMID: 10894545).

Gene is associated with phenotype in OMIM and G2P.
Sources: Literature
Severe microcephaly v2.10 TTC5 Sarah Leigh commented on gene: TTC5: There is enough evidence for this gene to be rated GREEN at the next major review.
Severe microcephaly v2.10 TTC5 Sarah Leigh commented on gene: TTC5: There is enough evidence for this gene to be rated GREEN at the next major review.
Severe microcephaly v2.10 TTC5 Sarah Leigh Classified gene: TTC5 as Amber List (moderate evidence)
Severe microcephaly v2.10 TTC5 Sarah Leigh Gene: ttc5 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.9 TTC5 Sarah Leigh gene: TTC5 was added
gene: TTC5 was added to Severe microcephaly. Sources: Literature
for-review tags were added to gene: TTC5.
Mode of inheritance for gene: TTC5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC5 were set to 29302074; 32439809
Phenotypes for gene: TTC5 were set to Central hypotonia; Global developmental delay; Intellectual disability; Abnormality of nervous system morphology; Microcephaly; Abnormality of the face; Behavioral abnormality; Abnormality of the genitourinary system
Review for gene: TTC5 was set to GREEN
Added comment: Not associated with a relevant phenotype in OMIM and as probable Gen2Phen gene for TTC5-associated neurodevelopmental disorder. At least 7 cases with biallelic variants.
Sources: Literature
Severe microcephaly v2.8 TMX2 Sarah Leigh Classified gene: TMX2 as Green List (high evidence)
Severe microcephaly v2.8 TMX2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Primary microcephaly, cortical malformation and epileptic encephalopathy. At least 7 variants reported in at least 9 unrelated cases of Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity 618730 (PMID 31735293; 31270415).
Severe microcephaly v2.8 TMX2 Sarah Leigh Gene: tmx2 has been classified as Green List (High Evidence).
Severe microcephaly v2.7 TMX2 Sarah Leigh gene: TMX2 was added
gene: TMX2 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: TMX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMX2 were set to 31586943; 31735293; 31270415
Phenotypes for gene: TMX2 were set to Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity 618730
Review for gene: TMX2 was set to GREEN
Added comment: Sources: Literature
Severe microcephaly v2.6 C7orf43 Zornitza Stark gene: C7orf43 was added
gene: C7orf43 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: C7orf43 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C7orf43 were set to 30715179
Phenotypes for gene: C7orf43 were set to Microcephaly 25, primary, autosomal recessive, MIM# 618351
Review for gene: C7orf43 was set to AMBER
Added comment: Single family reported: three affected siblings with homozygous truncating variant. Supportive zebrafish model. HGNC approved name: MAP11.
Sources: Literature
Severe microcephaly v2.6 CEP55 Rebecca Foulger Classified gene: CEP55 as Green List (high evidence)
Severe microcephaly v2.6 CEP55 Rebecca Foulger Gene: cep55 has been classified as Green List (High Evidence).
Severe microcephaly v2.5 CEP55 Rebecca Foulger changed review comment from: PMID:32100459 (Barrie et al., 2020) describe 7 living indivduals (5 families) with biallelic CEP55 variants. Four unrelated individuals with microcephaly, speech delays, and bilateral toe syndactyly all have a common CEP55 variant c.70G>A p.(Glu24Lys) in trans with nonsense variants. Three siblings are homozygous for a consensus splice site variant near the end of the gene. These affected girls all have severely delayed development, microcephaly, and varying degrees of lissencephaly/pachygyria. The authors suggest that individuals compound het for missense + nonsense variants in CEP55 have a viable phenotype (compared to lethal MARCH phenotype).; to: PMID:32100459 (Barrie et al., 2020) describe 7 living indivduals (5 families) with biallelic CEP55 variants (compound het, or homozygous splice site variant). Three sisters (Patients 5,6,7) have severe microcephaly (-7.1 SD, -5.5, -5.5). An additional 3 unrelated patients (Patients 1,2,3) have microcephaly scores of -2 SD, -2.7 SD, and Patient 4 has borderline microcephaly. Severe microcephaly (NHS Test Directory) is defined as having an occipitofrontal circumference (OFC) beyond 3 standard deviations below the mean for age. There are 4 unrelated cases which meet this threshold (3 sisters) or are close to this threshold (3 unrelated patients) and therefore on balance have rated as Green awaiting further GLH review.
Severe microcephaly v2.5 CEP55 Rebecca Foulger commented on gene: CEP55: PMID:32100459 (Barrie et al., 2020) describe 7 living indivduals (5 families) with biallelic CEP55 variants. Four unrelated individuals with microcephaly, speech delays, and bilateral toe syndactyly all have a common CEP55 variant c.70G>A p.(Glu24Lys) in trans with nonsense variants. Three siblings are homozygous for a consensus splice site variant near the end of the gene. These affected girls all have severely delayed development, microcephaly, and varying degrees of lissencephaly/pachygyria. The authors suggest that individuals compound het for missense + nonsense variants in CEP55 have a viable phenotype (compared to lethal MARCH phenotype).
Severe microcephaly v2.5 CEP55 Rebecca Foulger gene: CEP55 was added
gene: CEP55 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: CEP55 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP55 were set to 32100459
Phenotypes for gene: CEP55 were set to microcephaly, speech delays, and bilateral toe syndactyly
Review for gene: CEP55 was set to GREEN
Added comment: Added to Microcephaly panel on advice from Helen Brittain, Genomics England Clinical Team. Phenotype of living individuals described in PMID:32100459 (Barrie et al., 2020) includes microcephaly.
Sources: Literature
Severe microcephaly v2.3 Catherine Snow Panel version has been signed off
Severe microcephaly v2.0 Louise Daugherty promoted panel to version 2.0
Severe microcephaly v1.79 Louise Daugherty Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS signed-off
Severe microcephaly v1.78 ZNHIT3 Louise Daugherty edited their review of gene: ZNHIT3: Added comment: Gene rated Red- this rating was suggested in an email to the test group on 6th November after review by Genomics England clinical team review, and indicating if there were no further comments on the rating the gene would rated as per provisional suggestion as per recommended on the current evidence in the literature; Changed rating: RED
Severe microcephaly v1.78 UFC1 Louise Daugherty Classified gene: UFC1 as Green List (high evidence)
Severe microcephaly v1.78 UFC1 Louise Daugherty Added comment: Comment on list classification: Gene rated Green- this rating was suggested in an email to the test group on 6th November after review by Genomics England clinical team review, and indicating if there were no further comments on the rating the gene would rated as per provisional suggestion as per recommended on the current evidence in the literature
Severe microcephaly v1.78 UFC1 Louise Daugherty Gene: ufc1 has been classified as Green List (High Evidence).
Severe microcephaly v1.77 UFM1 Louise Daugherty commented on gene: UFM1: Gene rated Green this rating was suggested in an email to the test group on 6th November after review by Genomics England clinical team review, and indicating if there were no further comments on the rating the gene would rated as per provisional suggestion as per recommended on the current evidence in the literature
Severe microcephaly v1.77 UBA5 Louise Daugherty Deleted their comment
Severe microcephaly v1.77 UBA5 Louise Daugherty Classified gene: UBA5 as Green List (high evidence)
Severe microcephaly v1.77 UBA5 Louise Daugherty Added comment: Comment on list classification: Gene rated Green- this rating was suggested in an email to the test group on 6th November after review by Genomics England clinical team review, and indicating if there were no further comments on the rating the gene would rated as per provisional suggestion as per recommended on the current evidence in the literature
Severe microcephaly v1.77 UBA5 Louise Daugherty Gene: uba5 has been classified as Green List (High Evidence).
Severe microcephaly v1.76 UBA5 Louise Daugherty changed review comment from: Gene rated Red- this rating was suggested in an email to the test group on 6th November after review by Genomics England clinical team review, and indicating if there were no further comments on the rating the gene would rated as per provisional suggestion as per recommended on the current evidence in the literature; to: Gene rated Green- this rating was suggested in an email to the test group on 6th November after review by Genomics England clinical team review, and indicating if there were no further comments on the rating the gene would rated as per provisional suggestion as per recommended on the current evidence in the literature
Severe microcephaly v1.76 UBA5 Louise Daugherty edited their review of gene: UBA5: Changed rating: GREEN
Severe microcephaly v1.76 UBA5 Louise Daugherty edited their review of gene: UBA5: Added comment: Gene rated Red- this rating was suggested in an email to the test group on 6th November after review by Genomics England clinical team review, and indicating if there were no further comments on the rating the gene would rated as per provisional suggestion as per recommended on the current evidence in the literature; Changed rating: RED
Severe microcephaly v1.76 CCDC88A Louise Daugherty edited their review of gene: CCDC88A: Changed rating: AMBER
Severe microcephaly v1.76 PCLO Louise Daugherty edited their review of gene: PCLO: Added comment: Gene rated Red- this rating was suggested in an email to the test group on 6th November after review by Genomics England clinical team review, and indicating if there were no further comments on the rating the gene would rated as per provisional suggestion as per recommended on the current evidence in the literature; Changed rating: RED
Severe microcephaly v1.76 CCDC88A Louise Daugherty Publications for gene: CCDC88A were set to
Severe microcephaly v1.75 CCDC88A Louise Daugherty Classified gene: CCDC88A as Amber List (moderate evidence)
Severe microcephaly v1.75 CCDC88A Louise Daugherty Added comment: Comment on list classification: Gene rated Amber- this rating was suggested in an email to the test group on 6th November after review by Genomics England clinical team review, and indicating if there were no further comments on the rating the gene would rated as per provisional suggestion as per recommended on the current evidence in the literature
Severe microcephaly v1.75 CCDC88A Louise Daugherty Gene: ccdc88a has been classified as Amber List (Moderate Evidence).
Severe microcephaly v1.74 UFC1 Helen Brittain reviewed gene: UFC1: Rating: GREEN; Mode of pathogenicity: ; Publications: 29868776; Phenotypes: Neurodevelopmental disorder with spasticity and poor growth, 618076; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v1.74 ZNHIT3 Helen Brittain reviewed gene: ZNHIT3: Rating: RED; Mode of pathogenicity: ; Publications: 28335020; Phenotypes: PEHO syndrome, 260565; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v1.74 PCLO Helen Brittain reviewed gene: PCLO: Rating: RED; Mode of pathogenicity: ; Publications: 25832664; Phenotypes: ?Pontocerebellar hypoplasia, type 3, 608027; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v1.74 UFM1 Helen Brittain reviewed gene: UFM1: Rating: GREEN; Mode of pathogenicity: ; Publications: 28931644, 29868776, 27545674; Phenotypes: Leukodystrophy, hypomyelinating, 14, 617899; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v1.74 UBA5 Helen Brittain reviewed gene: UBA5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Epileptic encephalopathy, early infantile, 44, 617132; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v1.74 CCDC88A Helen Brittain reviewed gene: CCDC88A: Rating: AMBER; Mode of pathogenicity: ; Publications: 26917597, 30392057; Phenotypes: ?PEHO syndrome-like, 617507; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v1.73 Louise Daugherty List of related panels changed from Primary Microcephaly - Microcephalic Dwarfism Spectrum; Severe microcephaly to Primary Microcephaly - Microcephalic Dwarfism Spectrum; Severe microcephaly; R88
Severe microcephaly v1.72 KIF1BP Louise Daugherty Tag new-gene-name tag was added to gene: KIF1BP.
Severe microcephaly v1.72 KIF1BP Louise Daugherty commented on gene: KIF1BP: Added new-gene-name tag, new approved HGNC gene symbol for KIF1BP is KIFBP
Severe microcephaly v1.72 IARS Louise Daugherty commented on gene: IARS: Added new-gene-name tag, new approved HGNC gene symbol for IARS is IARS1
Severe microcephaly v1.72 QARS Louise Daugherty Tag new-gene-name tag was added to gene: QARS.
Severe microcephaly v1.72 QARS Louise Daugherty commented on gene: QARS: Added new-gene-name tag, new approved HGNC gene symbol for QARS is QARS1
Severe microcephaly v1.72 UFC1 Louise Daugherty Added comment: Comment on publications: review from Geoff Woods: 5 families reported in PMID 30552426 and 29868776
Severe microcephaly v1.72 UFC1 Louise Daugherty Publications for gene: UFC1 were set to 26917597
Severe microcephaly v1.71 ZNHIT3 Louise Daugherty Publications for gene: ZNHIT3 were set to
Severe microcephaly v1.70 PCLO Louise Daugherty Publications for gene: PCLO were set to
Severe microcephaly v1.69 UBA5 Louise Daugherty Publications for gene: UBA5 were set to
Severe microcephaly v1.68 UFC1 Louise Daugherty Publications for gene: UFC1 were set to
Severe microcephaly v1.67 IARS Sarah Leigh Tag new-gene-name tag was added to gene: IARS.
Severe microcephaly v1.67 IARS Sarah Leigh commented on gene: IARS
Severe microcephaly v1.67 ISCA-37501-Loss Louise Daugherty Source NHS GMS was added to Region: ISCA-37501-Loss.
Severe microcephaly v1.66 ISCA-37425-Gain Louise Daugherty Haploinsufficiency Score for ISCA-37425-Gain was changed from to None.
Source NHS GMS was added to Region: ISCA-37425-Gain.
Severe microcephaly v1.65 ISCA-37408-Loss Louise Daugherty Triplosensitivity Score for ISCA-37408-Loss was changed from to None.
Source NHS GMS was added to Region: ISCA-37408-Loss.
Severe microcephaly v1.64 ISCA-37406-Loss Louise Daugherty Triplosensitivity Score for ISCA-37406-Loss was changed from to None.
Source NHS GMS was added to Region: ISCA-37406-Loss.
Severe microcephaly v1.63 ISCA-37390-Loss Louise Daugherty Triplosensitivity Score for ISCA-37390-Loss was changed from to None.
Source NHS GMS was added to Region: ISCA-37390-Loss.
Severe microcephaly v1.62 ISCA-37390-Loss Louise Daugherty reviewed Region: ISCA-37390-Loss: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe microcephaly v1.62 ISCA-37406-Loss Louise Daugherty reviewed Region: ISCA-37406-Loss: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe microcephaly v1.62 ISCA-37408-Loss Louise Daugherty reviewed Region: ISCA-37408-Loss: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe microcephaly v1.62 ISCA-37425-Gain Louise Daugherty reviewed Region: ISCA-37425-Gain: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe microcephaly v1.62 ISCA-37501-Loss Louise Daugherty commented on Region: ISCA-37501-Loss: As discussed with the GMS Neurology Specialist Test Group webex call 11th July 2019: The Specialist Test Group all agreed that there is enough evidence to rate this region Green
Severe microcephaly v1.62 WDFY3 Louise Daugherty reviewed gene: WDFY3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 TUBGCP3 Louise Daugherty reviewed gene: TUBGCP3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 TRMT1 Louise Daugherty reviewed gene: TRMT1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 SASS6 Louise Daugherty reviewed gene: SASS6: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 PPP1R15B Louise Daugherty reviewed gene: PPP1R15B: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 PLAA Louise Daugherty reviewed gene: PLAA: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 PHC1 Louise Daugherty reviewed gene: PHC1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 NSMCE2 Louise Daugherty reviewed gene: NSMCE2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 NIN Louise Daugherty reviewed gene: NIN: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 FANCM Louise Daugherty reviewed gene: FANCM: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 ERCC5 Louise Daugherty reviewed gene: ERCC5: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 EOMES Louise Daugherty reviewed gene: EOMES: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 DNA2 Louise Daugherty reviewed gene: DNA2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 CENPE Louise Daugherty reviewed gene: CENPE: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 CDK6 Louise Daugherty reviewed gene: CDK6: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 CDC6 Louise Daugherty reviewed gene: CDC6: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 ATRIP Louise Daugherty reviewed gene: ATRIP: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 ANKLE2 Louise Daugherty reviewed gene: ANKLE2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 AGMO Louise Daugherty reviewed gene: AGMO: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 ZNF335 Louise Daugherty reviewed gene: ZNF335: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 WDR4 Louise Daugherty edited their review of gene: WDR4: Added comment: As discussed with the GMS Neurology Specialist Test Group webex call 11th July 2019: The Specialist Test Group all agreed that there is only enough evidence to rate this gene Amber; Changed rating: AMBER
Severe microcephaly v1.62 TAF13 Louise Daugherty reviewed gene: TAF13: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 RMI1 Louise Daugherty reviewed gene: RMI1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 RAD51C Louise Daugherty reviewed gene: RAD51C: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 QARS Louise Daugherty reviewed gene: QARS: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 MRE11 Louise Daugherty commented on gene: MRE11: As discussed with the GMS Neurology Specialist Test Group webex call 11th July 2019: The Specialist Test Group all agreed that there is only enough evidence to rate this gene Amber
Severe microcephaly v1.62 CRIPT Louise Daugherty reviewed gene: CRIPT: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 COASY Louise Daugherty commented on gene: COASY: As discussed with the GMS Neurology Specialist Test Group webex call 11th July 2019: The Specialist Test Group all agreed that there is only enough evidence to rate this gene Amber
Severe microcephaly v1.62 ZEB2 Louise Daugherty reviewed gene: ZEB2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 XRCC4 Louise Daugherty reviewed gene: XRCC4: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 WDR73 Louise Daugherty reviewed gene: WDR73: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 WDR62 Louise Daugherty reviewed gene: WDR62: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 TUBGCP6 Louise Daugherty reviewed gene: TUBGCP6: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 TUBGCP4 Louise Daugherty reviewed gene: TUBGCP4: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 TRMT10A Louise Daugherty reviewed gene: TRMT10A: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 TRAIP Louise Daugherty reviewed gene: TRAIP: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 TOP3A Louise Daugherty reviewed gene: TOP3A: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 STIL Louise Daugherty reviewed gene: STIL: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 STAMBP Louise Daugherty reviewed gene: STAMBP: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 SMC3 Louise Daugherty reviewed gene: SMC3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 SMC1A Louise Daugherty reviewed gene: SMC1A: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 SLX4 Louise Daugherty reviewed gene: SLX4: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 SLC9A6 Louise Daugherty reviewed gene: SLC9A6: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 SLC25A19 Louise Daugherty reviewed gene: SLC25A19: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 RTTN Louise Daugherty reviewed gene: RTTN: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 RPL10 Louise Daugherty reviewed gene: RPL10: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 RNU4ATAC Louise Daugherty reviewed gene: RNU4ATAC: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 RBBP8 Louise Daugherty reviewed gene: RBBP8: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 RAD21 Louise Daugherty reviewed gene: RAD21: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 PQBP1 Louise Daugherty reviewed gene: PQBP1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 POC1A Louise Daugherty reviewed gene: POC1A: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 PNKP Louise Daugherty reviewed gene: PNKP: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 PLK4 Louise Daugherty reviewed gene: PLK4: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 PDHA1 Louise Daugherty reviewed gene: PDHA1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 PCNT Louise Daugherty reviewed gene: PCNT: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 PALB2 Louise Daugherty reviewed gene: PALB2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 ORC6 Louise Daugherty reviewed gene: ORC6: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 ORC4 Louise Daugherty reviewed gene: ORC4: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 ORC1 Louise Daugherty reviewed gene: ORC1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 NIPBL Louise Daugherty reviewed gene: NIPBL: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 NHEJ1 Louise Daugherty reviewed gene: NHEJ1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 NDE1 Louise Daugherty reviewed gene: NDE1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 NBN Louise Daugherty reviewed gene: NBN: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 MYCN Louise Daugherty reviewed gene: MYCN: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 MSMO1 Louise Daugherty reviewed gene: MSMO1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 MFSD2A Louise Daugherty reviewed gene: MFSD2A: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 MCPH1 Louise Daugherty reviewed gene: MCPH1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 LIG4 Louise Daugherty reviewed gene: LIG4: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 LARP7 Louise Daugherty reviewed gene: LARP7: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 KIF11 Louise Daugherty reviewed gene: KIF11: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 IGF1R Louise Daugherty reviewed gene: IGF1R: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 IGF1 Louise Daugherty reviewed gene: IGF1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 IER3IP1 Louise Daugherty reviewed gene: IER3IP1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 IARS Louise Daugherty edited their review of gene: IARS: Added comment: As discussed with the GMS Neurology Specialist Test Group webex call 11th July 2019: The Specialist Test Group all agreed that there is enough evidence to rate this gene Green; Changed rating: AMBER
Severe microcephaly v1.62 HDAC8 Louise Daugherty reviewed gene: HDAC8: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 GMNN Louise Daugherty reviewed gene: GMNN: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 FANCL Louise Daugherty reviewed gene: FANCL: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 FANCI Louise Daugherty reviewed gene: FANCI: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 FANCG Louise Daugherty reviewed gene: FANCG: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 FANCF Louise Daugherty reviewed gene: FANCF: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 FANCE Louise Daugherty reviewed gene: FANCE: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 FANCD2 Louise Daugherty reviewed gene: FANCD2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 FANCC Louise Daugherty reviewed gene: FANCC: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 FANCB Louise Daugherty reviewed gene: FANCB: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 FANCA Louise Daugherty reviewed gene: FANCA: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 ERCC8 Louise Daugherty reviewed gene: ERCC8: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 ERCC6 Louise Daugherty reviewed gene: ERCC6: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 ERCC4 Louise Daugherty reviewed gene: ERCC4: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 EFTUD2 Louise Daugherty reviewed gene: EFTUD2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 DYRK1A Louise Daugherty reviewed gene: DYRK1A: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 DPP6 Louise Daugherty reviewed gene: DPP6: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 DONSON Louise Daugherty reviewed gene: DONSON: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 DIAPH1 Louise Daugherty reviewed gene: DIAPH1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 DHCR7 Louise Daugherty reviewed gene: DHCR7: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 DDX11 Louise Daugherty reviewed gene: DDX11: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 CTNNB1 Louise Daugherty reviewed gene: CTNNB1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 CREBBP Louise Daugherty reviewed gene: CREBBP: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 CKAP2L Louise Daugherty reviewed gene: CKAP2L: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 CIT Louise Daugherty reviewed gene: CIT: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 CEP63 Louise Daugherty reviewed gene: CEP63: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 CEP152 Louise Daugherty reviewed gene: CEP152: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 CEP135 Louise Daugherty reviewed gene: CEP135: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 CENPJ Louise Daugherty reviewed gene: CENPJ: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 CENPF Louise Daugherty reviewed gene: CENPF: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 CDT1 Louise Daugherty reviewed gene: CDT1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 CDK5RAP2 Louise Daugherty reviewed gene: CDK5RAP2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 CASK Louise Daugherty reviewed gene: CASK: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 BRIP1 Louise Daugherty reviewed gene: BRIP1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 BRCA2 Louise Daugherty reviewed gene: BRCA2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 BLM Louise Daugherty reviewed gene: BLM: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 ATRX Louise Daugherty reviewed gene: ATRX: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 ATR Louise Daugherty reviewed gene: ATR: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 ASPM Louise Daugherty reviewed gene: ASPM: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 PRUNE1 Louise Daugherty reviewed gene: PRUNE1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 KNL1 Louise Daugherty reviewed gene: KNL1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 KIF1BP Louise Daugherty reviewed gene: KIF1BP: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.61 UFC1 Louise Daugherty Source NHS GMS was added to UFC1.
Severe microcephaly v1.61 ZNHIT3 Louise Daugherty Source NHS GMS was added to ZNHIT3.
Severe microcephaly v1.61 PCLO Louise Daugherty Source NHS GMS was added to PCLO.
Severe microcephaly v1.61 UFM1 Louise Daugherty Source NHS GMS was added to UFM1.
Severe microcephaly v1.61 UBA5 Louise Daugherty Source NHS GMS was added to UBA5.
Severe microcephaly v1.61 CCDC88A Louise Daugherty Source NHS GMS was added to CCDC88A.
Severe microcephaly v1.61 WDFY3 Louise Daugherty Source NHS GMS was added to WDFY3.
Severe microcephaly v1.61 TUBGCP3 Louise Daugherty Source NHS GMS was added to TUBGCP3.
Severe microcephaly v1.61 TRMT1 Louise Daugherty Source NHS GMS was added to TRMT1.
Severe microcephaly v1.61 SASS6 Louise Daugherty Source NHS GMS was added to SASS6.
Severe microcephaly v1.61 PPP1R15B Louise Daugherty Source NHS GMS was added to PPP1R15B.
Severe microcephaly v1.61 PLAA Louise Daugherty Source NHS GMS was added to PLAA.
Severe microcephaly v1.61 PHC1 Louise Daugherty Source NHS GMS was added to PHC1.
Severe microcephaly v1.61 NSMCE2 Louise Daugherty Source NHS GMS was added to NSMCE2.
Severe microcephaly v1.61 NIN Louise Daugherty Source NHS GMS was added to NIN.
Severe microcephaly v1.61 FANCM Louise Daugherty Source NHS GMS was added to FANCM.
Severe microcephaly v1.61 ERCC5 Louise Daugherty Source NHS GMS was added to ERCC5.
Severe microcephaly v1.61 EOMES Louise Daugherty Source NHS GMS was added to EOMES.
Severe microcephaly v1.61 DNA2 Louise Daugherty Source NHS GMS was added to DNA2.
Severe microcephaly v1.61 CENPE Louise Daugherty Source NHS GMS was added to CENPE.
Severe microcephaly v1.61 CDK6 Louise Daugherty Source NHS GMS was added to CDK6.
Severe microcephaly v1.61 CDC6 Louise Daugherty Source NHS GMS was added to CDC6.
Severe microcephaly v1.61 ATRIP Louise Daugherty Source NHS GMS was added to ATRIP.
Severe microcephaly v1.61 ANKLE2 Louise Daugherty Source NHS GMS was added to ANKLE2.
Severe microcephaly v1.61 AGMO Louise Daugherty Source NHS GMS was added to AGMO.
Severe microcephaly v1.61 ZNF335 Louise Daugherty Source NHS GMS was added to ZNF335.
Severe microcephaly v1.61 WDR4 Louise Daugherty Source NHS GMS was added to WDR4.
Severe microcephaly v1.61 TAF13 Louise Daugherty Source NHS GMS was added to TAF13.
Severe microcephaly v1.61 RMI1 Louise Daugherty Source NHS GMS was added to RMI1.
Severe microcephaly v1.61 RAD51C Louise Daugherty Source NHS GMS was added to RAD51C.
Severe microcephaly v1.61 QARS Louise Daugherty Source NHS GMS was added to QARS.
Severe microcephaly v1.61 MRE11 Louise Daugherty Source NHS GMS was added to MRE11.
Severe microcephaly v1.61 CRIPT Louise Daugherty Source NHS GMS was added to CRIPT.
Severe microcephaly v1.61 COASY Louise Daugherty Source NHS GMS was added to COASY.
Severe microcephaly v1.61 ZEB2 Louise Daugherty Source NHS GMS was added to ZEB2.
Severe microcephaly v1.61 XRCC4 Louise Daugherty Source NHS GMS was added to XRCC4.
Severe microcephaly v1.61 WDR73 Louise Daugherty Source NHS GMS was added to WDR73.
Severe microcephaly v1.61 WDR62 Louise Daugherty Source NHS GMS was added to WDR62.
Severe microcephaly v1.61 TUBGCP6 Louise Daugherty Source NHS GMS was added to TUBGCP6.
Severe microcephaly v1.61 TUBGCP4 Louise Daugherty Source NHS GMS was added to TUBGCP4.
Severe microcephaly v1.61 TRMT10A Louise Daugherty Source NHS GMS was added to TRMT10A.
Severe microcephaly v1.61 TRAIP Louise Daugherty Source NHS GMS was added to TRAIP.
Severe microcephaly v1.61 TOP3A Louise Daugherty Source NHS GMS was added to TOP3A.
Severe microcephaly v1.61 STIL Louise Daugherty Source NHS GMS was added to STIL.
Severe microcephaly v1.61 STAMBP Louise Daugherty Source NHS GMS was added to STAMBP.
Severe microcephaly v1.61 SMC3 Louise Daugherty Source NHS GMS was added to SMC3.
Severe microcephaly v1.61 SMC1A Louise Daugherty Source NHS GMS was added to SMC1A.
Severe microcephaly v1.61 SLX4 Louise Daugherty Source NHS GMS was added to SLX4.
Severe microcephaly v1.61 SLC9A6 Louise Daugherty Source NHS GMS was added to SLC9A6.
Severe microcephaly v1.61 SLC25A19 Louise Daugherty Source NHS GMS was added to SLC25A19.
Severe microcephaly v1.61 RTTN Louise Daugherty Source NHS GMS was added to RTTN.
Severe microcephaly v1.61 RPL10 Louise Daugherty Source NHS GMS was added to RPL10.
Severe microcephaly v1.61 RNU4ATAC Louise Daugherty Source NHS GMS was added to RNU4ATAC.
Severe microcephaly v1.61 RBBP8 Louise Daugherty Source NHS GMS was added to RBBP8.
Severe microcephaly v1.61 RAD21 Louise Daugherty Source NHS GMS was added to RAD21.
Severe microcephaly v1.61 PQBP1 Louise Daugherty Source NHS GMS was added to PQBP1.
Severe microcephaly v1.61 POC1A Louise Daugherty Source NHS GMS was added to POC1A.
Severe microcephaly v1.61 PNKP Louise Daugherty Source NHS GMS was added to PNKP.
Severe microcephaly v1.61 PLK4 Louise Daugherty Source NHS GMS was added to PLK4.
Severe microcephaly v1.61 PDHA1 Louise Daugherty Source NHS GMS was added to PDHA1.
Severe microcephaly v1.61 PCNT Louise Daugherty Source NHS GMS was added to PCNT.
Severe microcephaly v1.61 PALB2 Louise Daugherty Source NHS GMS was added to PALB2.
Severe microcephaly v1.61 ORC6 Louise Daugherty Source NHS GMS was added to ORC6.
Severe microcephaly v1.61 ORC4 Louise Daugherty Source NHS GMS was added to ORC4.
Severe microcephaly v1.61 ORC1 Louise Daugherty Source NHS GMS was added to ORC1.
Severe microcephaly v1.61 NIPBL Louise Daugherty Source NHS GMS was added to NIPBL.
Severe microcephaly v1.61 NHEJ1 Louise Daugherty Source NHS GMS was added to NHEJ1.
Severe microcephaly v1.61 NDE1 Louise Daugherty Source NHS GMS was added to NDE1.
Severe microcephaly v1.61 NBN Louise Daugherty Source NHS GMS was added to NBN.
Severe microcephaly v1.61 MYCN Louise Daugherty Source NHS GMS was added to MYCN.
Severe microcephaly v1.61 MSMO1 Louise Daugherty Source NHS GMS was added to MSMO1.
Severe microcephaly v1.61 MFSD2A Louise Daugherty Source NHS GMS was added to MFSD2A.
Severe microcephaly v1.61 MCPH1 Louise Daugherty Source NHS GMS was added to MCPH1.
Severe microcephaly v1.61 LIG4 Louise Daugherty Source NHS GMS was added to LIG4.
Severe microcephaly v1.61 LARP7 Louise Daugherty Source NHS GMS was added to LARP7.
Severe microcephaly v1.61 KIF11 Louise Daugherty Source NHS GMS was added to KIF11.
Severe microcephaly v1.61 IGF1R Louise Daugherty Source NHS GMS was added to IGF1R.
Severe microcephaly v1.61 IGF1 Louise Daugherty Source NHS GMS was added to IGF1.
Severe microcephaly v1.61 IER3IP1 Louise Daugherty Source NHS GMS was added to IER3IP1.
Severe microcephaly v1.61 IARS Louise Daugherty Source NHS GMS was added to IARS.
Severe microcephaly v1.61 HDAC8 Louise Daugherty Source NHS GMS was added to HDAC8.
Severe microcephaly v1.61 GMNN Louise Daugherty Source NHS GMS was added to GMNN.
Severe microcephaly v1.61 FANCL Louise Daugherty Source NHS GMS was added to FANCL.
Severe microcephaly v1.61 FANCI Louise Daugherty Source NHS GMS was added to FANCI.
Severe microcephaly v1.61 FANCG Louise Daugherty Source NHS GMS was added to FANCG.
Severe microcephaly v1.61 FANCF Louise Daugherty Source NHS GMS was added to FANCF.
Severe microcephaly v1.61 FANCE Louise Daugherty Source NHS GMS was added to FANCE.
Severe microcephaly v1.61 FANCD2 Louise Daugherty Source NHS GMS was added to FANCD2.
Severe microcephaly v1.61 FANCC Louise Daugherty Source NHS GMS was added to FANCC.
Severe microcephaly v1.61 FANCB Louise Daugherty Source NHS GMS was added to FANCB.
Severe microcephaly v1.61 FANCA Louise Daugherty Source NHS GMS was added to FANCA.
Severe microcephaly v1.61 ERCC8 Louise Daugherty Source NHS GMS was added to ERCC8.
Severe microcephaly v1.61 ERCC6 Louise Daugherty Source NHS GMS was added to ERCC6.
Severe microcephaly v1.61 ERCC4 Louise Daugherty Source NHS GMS was added to ERCC4.
Severe microcephaly v1.61 EFTUD2 Louise Daugherty Source NHS GMS was added to EFTUD2.
Severe microcephaly v1.61 DYRK1A Louise Daugherty Source NHS GMS was added to DYRK1A.
Severe microcephaly v1.61 DPP6 Louise Daugherty Source NHS GMS was added to DPP6.
Severe microcephaly v1.61 DONSON Louise Daugherty Source NHS GMS was added to DONSON.
Severe microcephaly v1.61 DIAPH1 Louise Daugherty Source NHS GMS was added to DIAPH1.
Severe microcephaly v1.61 DHCR7 Louise Daugherty Source NHS GMS was added to DHCR7.
Severe microcephaly v1.61 DDX11 Louise Daugherty Source NHS GMS was added to DDX11.
Severe microcephaly v1.61 CTNNB1 Louise Daugherty Source NHS GMS was added to CTNNB1.
Severe microcephaly v1.61 CREBBP Louise Daugherty Source NHS GMS was added to CREBBP.
Severe microcephaly v1.61 CKAP2L Louise Daugherty Source NHS GMS was added to CKAP2L.
Severe microcephaly v1.61 CIT Louise Daugherty Source NHS GMS was added to CIT.
Severe microcephaly v1.61 CEP63 Louise Daugherty Source NHS GMS was added to CEP63.
Severe microcephaly v1.61 CEP152 Louise Daugherty Source NHS GMS was added to CEP152.
Severe microcephaly v1.61 CEP135 Louise Daugherty Source NHS GMS was added to CEP135.
Severe microcephaly v1.61 CENPJ Louise Daugherty Source NHS GMS was added to CENPJ.
Severe microcephaly v1.61 CENPF Louise Daugherty Source NHS GMS was added to CENPF.
Severe microcephaly v1.61 CDT1 Louise Daugherty Source NHS GMS was added to CDT1.
Severe microcephaly v1.61 CDK5RAP2 Louise Daugherty Source NHS GMS was added to CDK5RAP2.
Severe microcephaly v1.61 CASK Louise Daugherty Source NHS GMS was added to CASK.
Severe microcephaly v1.61 BRIP1 Louise Daugherty Source NHS GMS was added to BRIP1.
Severe microcephaly v1.61 BRCA2 Louise Daugherty Source NHS GMS was added to BRCA2.
Severe microcephaly v1.61 BLM Louise Daugherty Source NHS GMS was added to BLM.
Severe microcephaly v1.61 ATRX Louise Daugherty Source NHS GMS was added to ATRX.
Severe microcephaly v1.61 ATR Louise Daugherty Source NHS GMS was added to ATR.
Severe microcephaly v1.61 ASPM Louise Daugherty Source NHS GMS was added to ASPM.
Severe microcephaly v1.61 PRUNE1 Louise Daugherty Source NHS GMS was added to PRUNE1.
Severe microcephaly v1.61 KNL1 Louise Daugherty Source NHS GMS was added to KNL1.
Severe microcephaly v1.61 KIF1BP Louise Daugherty Source NHS GMS was added to KIF1BP.
Severe microcephaly v1.60 UFC1 Louise Daugherty changed review comment from: As discussed with the GMS Neurology Specialist Test Group webex call 11th July 2019: New gene recommended to be added to the panel by Astrid Weber during the call (Geoff Woods is one of the authors). it was suggested that Geoff Woods opinion on this gene would be helpful too, in view of the presence on his publication of the UFM1 gene. PanelApp team added gene /phenotype and MOI from OMIM to panel and requested evidence for the proposed rating before gene can be upgraded to Green
Sources: Expert list; to: As discussed with the GMS Neurology Specialist Test Group webex call 11th July 2019: New gene recommended to be added to the panel by Astrid Weber during the call (Geoff Woods is one of the authors). It was suggested that Geoff Woods opinion on this gene would be helpful too, in view of the presence on his publication of the UFM1 gene. PanelApp team added gene /phenotype and MOI from OMIM to panel and requested evidence for the proposed rating before gene can be upgraded to Green
Sources: Expert list
Severe microcephaly v1.60 UFC1 Louise Daugherty edited their review of gene: UFC1: Changed rating: GREEN
Severe microcephaly v1.60 UFC1 Louise Daugherty gene: UFC1 was added
gene: UFC1 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: UFC1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: UFC1 were set to Neurodevelopmental disorder with spasticity and poor growth, 618076; microcephaly
Review for gene: UFC1 was set to AMBER
Added comment: As discussed with the GMS Neurology Specialist Test Group webex call 11th July 2019: New gene recommended to be added to the panel by Astrid Weber during the call (Geoff Woods is one of the authors). it was suggested that Geoff Woods opinion on this gene would be helpful too, in view of the presence on his publication of the UFM1 gene. PanelApp team added gene /phenotype and MOI from OMIM to panel and requested evidence for the proposed rating before gene can be upgraded to Green
Sources: Expert list
Severe microcephaly v1.59 ZNHIT3 Louise Daugherty gene: ZNHIT3 was added
gene: ZNHIT3 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: ZNHIT3 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ZNHIT3 were set to PEHO syndrome, 260565; microcephaly
Review for gene: ZNHIT3 was set to GREEN
Added comment: As discussed with the GMS Neurology Specialist Test Group webex call 11th July 2019: New gene and Green rating recommended to be added to panel by Steve Abbs (Consultant Clinical Scientist, East Anglia Medical Genetics Service) on behalf of Geoff Woods (Cambridge Institute for Medical research). PanelApp team added gene /phenotype and MOI from OMIM to panel and requested evidence for the proposed rating before gene can be upgraded to Green
Sources: Expert list
Severe microcephaly v1.58 UBA5 Louise Daugherty changed review comment from: As discussed with the GMS Neurology Specialist Test Group webex call 11th July 2019: New gene and Green rating recommended to be added to panel by Steve Abbs (Consultant Clinical Scientist, East Anglia Medical Genetics Service) on behalf of Geoff Woods (Cambridge Institute for Medical research). PanelApp team added gene /phenotype and MOI from OMIM to panel and requested evidence for the proposed rating before gene can be upgraded to Green.
Sources: Expert list; to: As discussed with the GMS Neurology Specialist Test Group webex call 11th July 2019: New gene and Green rating recommended to be added to panel by Steve Abbs (Consultant Clinical Scientist, East Anglia Medical Genetics Service) on behalf of Geoff Woods (Cambridge Institute for Medical research). PanelApp team added gene /phenotype and MOI from OMIM to panel and requested evidence for the proposed rating before gene can be upgraded to Green.
Sources: Expert list
Severe microcephaly v1.58 PCLO Louise Daugherty gene: PCLO was added
gene: PCLO was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: PCLO was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PCLO were set to Pontocerebellar hypoplasia, type 3, 608027
Review for gene: PCLO was set to GREEN
Added comment: As discussed with the GMS Neurology Specialist Test Group webex call 11th July 2019: New gene and Green rating recommended to be added to panel by Steve Abbs (Consultant Clinical Scientist, East Anglia Medical Genetics Service) on behalf of Geoff Woods (Cambridge Institute for Medical research). PanelApp team added gene /phenotype and MOI from OMIM to panel and requested evidence for the proposed rating before gene can be upgraded to Green
Sources: Expert list
Severe microcephaly v1.57 UFM1 Louise Daugherty Classified gene: UFM1 as Green List (high evidence)
Severe microcephaly v1.57 UFM1 Louise Daugherty Added comment: Comment on list classification: As discussed with the GMS Neurology Specialist Test Group webex call 11th July 2019: New gene and Green rating recommended to be added to panel by Steve Abbs (Consultant Clinical Scientist, East Anglia Medical Genetics Service) on behalf of Geoff Woods (Cambridge Institute for Medical research). PanelApp team added gene /phenotype and MOI from OMIM to panel and PMIDs as recommended during the call and in light of evidence as evidence to gene can be upgraded to Green
Severe microcephaly v1.57 UFM1 Louise Daugherty Gene: ufm1 has been classified as Green List (High Evidence).
Severe microcephaly v1.56 UFM1 Louise Daugherty Added comment: Comment on publications: As discussed with the GMS Neurology Specialist Test Group webex call 11th July 2019 : added PMIDs as recommended to support rating of gene to be Green
Severe microcephaly v1.56 UFM1 Louise Daugherty Publications for gene: UFM1 were set to
Severe microcephaly v1.55 CCDC88A Louise Daugherty Phenotypes for gene: CCDC88A were changed from PEHO syndrome-like, 617507 to PEHO syndrome-like, 617507; microcephaly
Severe microcephaly v1.54 UFM1 Louise Daugherty Phenotypes for gene: UFM1 were changed from Leukodystrophy, hypomyelinating, 14, 617899 to Leukodystrophy, hypomyelinating, 14, 617899; microcephaly
Severe microcephaly v1.53 UFM1 Louise Daugherty gene: UFM1 was added
gene: UFM1 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: UFM1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: UFM1 were set to Leukodystrophy, hypomyelinating, 14, 617899
Review for gene: UFM1 was set to GREEN
Added comment: As discussed with the GMS Neurology Specialist Test Group webex call 11th July 2019: New gene and Green rating recommended to be added to panel by Steve Abbs (Consultant Clinical Scientist, East Anglia Medical Genetics Service) on behalf of Geoff Woods (Cambridge Institute for Medical research). PanelApp team added gene /phenotype and MOI from OMIM to panel and requested evidence for the proposed rating before gene can be upgraded to Green.
Sources: Expert list
Severe microcephaly v1.52 UBA5 Louise Daugherty gene: UBA5 was added
gene: UBA5 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: UBA5 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: UBA5 were set to Epileptic encephalopathy, early infantile, 44, 617132
Review for gene: UBA5 was set to GREEN
Added comment: As discussed with the GMS Neurology Specialist Test Group webex call 11th July 2019: New gene and Green rating recommended to be added to panel by Steve Abbs (Consultant Clinical Scientist, East Anglia Medical Genetics Service) on behalf of Geoff Woods (Cambridge Institute for Medical research). PanelApp team added gene /phenotype and MOI from OMIM to panel and requested evidence for the proposed rating before gene can be upgraded to Green.
Sources: Expert list
Severe microcephaly v1.51 CCDC88A Louise Daugherty gene: CCDC88A was added
gene: CCDC88A was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: CCDC88A was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CCDC88A were set to PEHO syndrome-like, 617507
Review for gene: CCDC88A was set to GREEN
Added comment: As discussed with the GMS Neurology Specialist Test Group webex call 11th July 2019: New gene and Green rating recommended to be added to panel by Steve Abbs (Consultant Clinical Scientist, East Anglia Medical Genetics Service) on behalf of Geoff Woods (Cambridge Institute for Medical research). PanelApp team added gene /phenotype and MOI from OMIM to panel and requested evidence for the proposed rating before gene can be upgraded to Green.
Sources: Expert list
Severe microcephaly v1.50 PALB2 Helen Brittain Classified gene: PALB2 as Amber List (moderate evidence)
Severe microcephaly v1.50 PALB2 Helen Brittain Added comment: Comment on list classification: As per structural neurological working group webex on 11th July 2019
Severe microcephaly v1.50 PALB2 Helen Brittain Gene: palb2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v1.49 PALB2 Helen Brittain reviewed gene: PALB2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe microcephaly v1.48 TRMT1 Rebecca Foulger gene: TRMT1 was added
gene: TRMT1 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: TRMT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRMT1 were set to 30289604
Phenotypes for gene: TRMT1 were set to Non‐syndromal congenital microcephaly
Review for gene: TRMT1 was set to RED
Added comment: Added TRMT1 to the microcephaly panel based on PMID:30289604 (Blaesius et al., 2018) who report 4 patients from 2 unrelated consanguineous Pakistani families with homozygous variants in TRMT1 and intellectual disability. Non‐syndromal microcephaly was diagnosed at birth in three of the patients (V:2 from Family 1 (OFC -4.9 SD), and III.3 (OFC -4.1 SD) and III.4 (OFC -4 SD) from Family 2). The authors note that the clinical features are reminiscent of autosomal recessive primary microcephaly (MCPH). Rated as Red awaiting further cases.
Sources: Literature
Severe microcephaly v1.47 ISCA-37501-Loss Louise Daugherty Triplosensitivity Score for ISCA-37501-Loss was changed from 2 to None.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Severe microcephaly v1.46 ISCA-37501-Loss Louise Daugherty Classified Region: ISCA-37501-Loss as Green List (high evidence)
Severe microcephaly v1.46 ISCA-37501-Loss Louise Daugherty Region: isca-37501-loss has been classified as Green List (High Evidence).
Severe microcephaly v1.45 ISCA-37501-Loss Louise Daugherty Region: ISCA-37501-Loss was added
Region: ISCA-37501-Loss was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for Region: ISCA-37501-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37501-Loss were set to 20206336; 22052739
Phenotypes for Region: ISCA-37501-Loss were set to Chromosome 17q23.1-q23.2 deletion syndrome, 613355; PMID:20206336 mild to moderate developmental delay (particularly speech delay), microcephaly, postnatal growth retardation, heart defects, hand, foot and limb abnormalities; PMID: 22052739 Developmental delay, heart defects, microcephaly, postnatal growth retardation, hand, foot and limb abnormalities, sensorineural hearing loss
Review for Region: ISCA-37501-Loss was set to GREEN
Added comment: Sources: Expert list
Severe microcephaly v1.44 Louise Daugherty List of related panels changed from Primary Microcephaly - Microcephalic Dwarfism Spectrum; Severe microcephaly; GMS R88 to Primary Microcephaly - Microcephalic Dwarfism Spectrum; Severe microcephaly
Severe microcephaly v1.42 COASY Louise Daugherty Publications for gene: COASY were set to 30089828
Severe microcephaly v1.41 COASY Louise Daugherty commented on gene: COASY: added watchlist tag
Severe microcephaly v1.41 COASY Louise Daugherty Tag watchlist tag was added to gene: COASY.
Severe microcephaly v1.41 COASY Louise Daugherty Classified gene: COASY as Amber List (moderate evidence)
Severe microcephaly v1.41 COASY Louise Daugherty Added comment: Comment on list classification: New gene. Rated Amber until more cases on gene and disease association are reported.
Severe microcephaly v1.41 COASY Louise Daugherty Gene: coasy has been classified as Amber List (Moderate Evidence).
Severe microcephaly v1.40 COASY Louise Daugherty gene: COASY was added
gene: COASY was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: COASY was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COASY were set to 30089828
Phenotypes for gene: COASY were set to Severe prenatal onset pontocerebellar hypoplasia, microcephaly, arthrogryposis
Review for gene: COASY was set to AMBER
Added comment: From Dijk et al. (2018) PMID: 30089828 variants in the gene Coenzyme A (CoA) synthase (COASY) gene, an enzyme essential in CoA synthesis. A single variant was identified in 4 individuals in 2 unrelated families with PCH, prenatal onset microcephaly, and arthrogryposis. In both families, the variant c.[1549_1550delAG]; [1486-3 C>G] segregated wth the phenotype. No CoA synthase protein was detected in patient cells by immunoblot analysis and CoA synthase activity was virtually absent. Partial CoA synthase defects were previously described by Dusi et al. (2014) PMID: 24360804 as a cause of COASY Protein-Associated Neurodegeneration (CoPAN), a type of Neurodegeneration and Brain Iron Accumulation (MIM: 615643). Dijk et al. (2018) PMID: 30089828 demonstrate that near complete loss of function variants in COASY are associated with lethal PCH and arthrogryposis.
Sources: Literature
Severe microcephaly v1.39 Ellen McDonagh List of related panels changed from Primary Microcephaly - Microcephalic Dwarfism Spectrum to Primary Microcephaly - Microcephalic Dwarfism Spectrum; Severe microcephaly; GMS R88
Severe microcephaly v1.38 Ellen McDonagh Panel name changed from Primary Microcephaly - Microcephalic Dwarfism Spectrum to Severe microcephaly
List of related panels changed from to Primary Microcephaly - Microcephalic Dwarfism Spectrum
Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual
Severe microcephaly v1.37 ISCA-37425-Gain Louise Daugherty Region: ISCA-37425-Gain was added
Region: ISCA-37425-Gain was added to Primary Microcephaly - Microcephalic Dwarfism Spectrum. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37425-Gain was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37425-Gain were set to 23913520; 23599694
Phenotypes for Region: ISCA-37425-Gain were set to Microcephaly, short stature and developmental delay; short stature, microcephaly, learning disability or mild to moderate ID, and distinctive facial features comprising periorbital fullness, short palpebral fissures, a long nose with broad or long nasal tip, a smooth philtrum and a thin upper lip vermilion. Behavioral problems, ocular and minor hand anomalies may be associated.
Severe microcephaly v1.37 ISCA-37390-Loss Louise Daugherty Region: ISCA-37390-Loss was added
Region: ISCA-37390-Loss was added to Primary Microcephaly - Microcephalic Dwarfism Spectrum. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37390-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37390-Loss were set to 11238681; 15635506
Phenotypes for Region: ISCA-37390-Loss were set to 123450; PMID 15635506: characteristic cry, speech delay, facial dysmorphology, and level of mental retardation. PMID 11238681: interstitial deletions and one with a small terminal deletion confirmed the existence of two critical regions, one for dysmorphism and mental retardation in p15.2 and the other for the cat cry in p15.3. Results from one patient permitted the cat cry region to be distally narrowed from D5S13 to D5S731, study supports hypothesis of a separate region in p15.3 for the speech delay
Severe microcephaly v1.37 ISCA-37406-Loss Louise Daugherty Region: ISCA-37406-Loss was added
Region: ISCA-37406-Loss was added to Primary Microcephaly - Microcephalic Dwarfism Spectrum. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37406-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37406-Loss were set to 10573006; 16783566
Phenotypes for Region: ISCA-37406-Loss were set to PMID: 10573006 death in infancy, accessory spleens, hypoplastic left heart, abnormal pulmonary lobulation, renal agenesis (patient 1), severe neonatal seizures (patient 2). PMID 16783566: failure to thrive, life-threatening malformations, and/or critical infections, and all died in infancy (5 weeks, 7 months, and 9 months, respectivelyFrom Genetics Home Reference: short stature, moderate to severe intellectual disability, distinctive facial features, and broad thumbs and first toes; 610543
Severe microcephaly v1.37 ISCA-37408-Loss Louise Daugherty Region: ISCA-37408-Loss was added
Region: ISCA-37408-Loss was added to Primary Microcephaly - Microcephalic Dwarfism Spectrum. 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
Severe microcephaly RMI1 Sarah Leigh classified RMI1 as Amber List (moderate evidence)
Severe microcephaly RMI1 Sarah Leigh Added gene to panel
Severe microcephaly TOP3A Sarah Leigh classified TOP3A as Green List (high evidence)
Severe microcephaly TOP3A Sarah Leigh Added gene to panel
Severe microcephaly WDR4 Louise Daugherty classified WDR4 as Amber List (moderate evidence)
Severe microcephaly WDR4 Ellen McDonagh edited their review of WDR4
Severe microcephaly MRE11 Louise Daugherty classified MRE11 as Amber List (moderate evidence)
Severe microcephaly MRE11 Louise Daugherty edited their review of MRE11
Severe microcephaly MRE11 Louise Daugherty Added gene to panel
Severe microcephaly IARS Louise Daugherty classified IARS as Green List (high evidence)
Severe microcephaly IARS Louise Daugherty edited their review of IARS
Severe microcephaly IARS Louise Daugherty Added gene to panel
Severe microcephaly EOMES Ellen McDonagh commented on EOMES
Severe microcephaly EOMES Ellen McDonagh Added gene to panel
Severe microcephaly FANCM Ellen McDonagh reviewed FANCM
Severe microcephaly RPL10 Sarah Leigh classified RPL10 as green
Severe microcephaly RPL10 Sarah Leigh commented on RPL10
Severe microcephaly RPL10 Sarah Leigh added RPL10 to panel
Severe microcephaly RPL10 Sarah Leigh reviewed RPL10
Severe microcephaly DONSON Sarah Leigh classified DONSON as green
Severe microcephaly DONSON Sarah Leigh reviewed DONSON
Severe microcephaly PLAA Rebecca Foulger classified PLAA as red
Severe microcephaly PLAA Rebecca Foulger commented on PLAA
Severe microcephaly PLAA Rebecca Foulger commented on PLAA
Severe microcephaly PLAA Rebecca Foulger added PLAA to panel
Severe microcephaly PLAA Rebecca Foulger reviewed PLAA
Severe microcephaly TAF13 Ellen McDonagh classified TAF13 as amber
Severe microcephaly TAF13 Ellen McDonagh added TAF13 to panel
Severe microcephaly TAF13 Ellen McDonagh reviewed TAF13
Severe microcephaly WDFY3 Rebecca Foulger classified WDFY3 as red
Severe microcephaly WDFY3 Rebecca Foulger added WDFY3 to panel
Severe microcephaly WDFY3 Rebecca Foulger reviewed WDFY3
Severe microcephaly DONSON Olivia Niblock added DONSON to panel
Severe microcephaly DONSON Olivia Niblock reviewed DONSON
Severe microcephaly PRUNE Ellen McDonagh reviewed PRUNE
Severe microcephaly RAD51C Rebecca Foulger edited their review of RAD51C
Severe microcephaly RAD51C Rebecca Foulger classified RAD51C as amber
Severe microcephaly RAD51C Rebecca Foulger commented on RAD51C
Severe microcephaly MSMO1 Sarah Leigh classified MSMO1 as green
Severe microcephaly MSMO1 Sarah Leigh commented on MSMO1
Severe microcephaly PRUNE Rebecca Foulger commented on PRUNE
Severe microcephaly PDHA1 emma baple edited their review of PDHA1
Severe microcephaly PDHA1 emma baple marked PDHA1 as ready
Severe microcephaly PDHA1 emma baple classified PDHA1 as green
Severe microcephaly PDHA1 emma baple added PDHA1 to panel
Severe microcephaly PDHA1 emma baple reviewed PDHA1
Severe microcephaly PRUNE emma baple marked PRUNE as ready
Severe microcephaly PRUNE emma baple classified PRUNE as green
Severe microcephaly PRUNE emma baple added PRUNE to panel
Severe microcephaly PRUNE emma baple reviewed PRUNE
Severe microcephaly Rebecca Foulger promoted panel to version 1
Severe microcephaly DIAPH1 Rebecca Foulger classified DIAPH1 as green
Severe microcephaly SMC1A Rebecca Foulger classified SMC1A as green
Severe microcephaly SMC1A Rebecca Foulger commented on SMC1A
Severe microcephaly SMC1A Rebecca Foulger edited their review of SMC1A
Severe microcephaly DPP6 Rebecca Foulger classified DPP6 as green
Severe microcephaly HDAC8 Rebecca Foulger classified HDAC8 as green
Severe microcephaly HDAC8 Rebecca Foulger commented on HDAC8
Severe microcephaly HDAC8 Rebecca Foulger commented on HDAC8
Severe microcephaly NIPBL Rebecca Foulger classified NIPBL as green
Severe microcephaly NIPBL Rebecca Foulger commented on NIPBL
Severe microcephaly SMC1A Rebecca Foulger commented on SMC1A
Severe microcephaly SMC3 Rebecca Foulger classified SMC3 as green
Severe microcephaly SMC3 Rebecca Foulger commented on SMC3
Severe microcephaly RAD21 Rebecca Foulger classified RAD21 as green
Severe microcephaly RAD21 Rebecca Foulger commented on RAD21
Severe microcephaly RAD21 Rebecca Foulger commented on RAD21
Severe microcephaly RAD21 Rebecca Foulger commented on RAD21
Severe microcephaly DPP6 Rebecca Foulger commented on DPP6
Severe microcephaly POC1A Rebecca Foulger classified POC1A as green
Severe microcephaly DYRK1A Rebecca Foulger commented on DYRK1A
Severe microcephaly DYRK1A Rebecca Foulger classified DYRK1A as green
Severe microcephaly DYRK1A Rebecca Foulger commented on DYRK1A
Severe microcephaly DYRK1A Rebecca Foulger commented on DYRK1A
Severe microcephaly CTNNB1 Rebecca Foulger classified CTNNB1 as green
Severe microcephaly CTNNB1 Rebecca Foulger commented on CTNNB1
Severe microcephaly RBBP8 Rebecca Foulger classified RBBP8 as green
Severe microcephaly ZNF335 Rebecca Foulger classified ZNF335 as amber
Severe microcephaly ZNF335 Rebecca Foulger commented on ZNF335
Severe microcephaly ZNF335 Rebecca Foulger commented on ZNF335
Severe microcephaly ZNF335 Rebecca Foulger commented on ZNF335
Severe microcephaly WDR4 Rebecca Foulger commented on WDR4
Severe microcephaly TRMT10A Rebecca Foulger classified TRMT10A as green
Severe microcephaly TRMT10A Rebecca Foulger commented on TRMT10A
Severe microcephaly TRMT10A Rebecca Foulger commented on TRMT10A
Severe microcephaly TRMT10A Rebecca Foulger commented on TRMT10A
Severe microcephaly TRMT10A Rebecca Foulger commented on TRMT10A
Severe microcephaly RBBP8 Rebecca Foulger commented on RBBP8
Severe microcephaly RBBP8 Rebecca Foulger commented on RBBP8
Severe microcephaly RBBP8 Rebecca Foulger commented on RBBP8
Severe microcephaly RBBP8 Rebecca Foulger commented on RBBP8
Severe microcephaly POC1A Rebecca Foulger commented on POC1A
Severe microcephaly POC1A Rebecca Foulger commented on POC1A
Severe microcephaly POC1A Rebecca Foulger commented on POC1A
Severe microcephaly POC1A Rebecca Foulger commented on POC1A
Severe microcephaly POC1A Rebecca Foulger commented on POC1A
Severe microcephaly PHC1 Rebecca Foulger commented on PHC1
Severe microcephaly PHC1 Rebecca Foulger commented on PHC1
Severe microcephaly NSMCE2 Rebecca Foulger commented on NSMCE2
Severe microcephaly DPP6 Rebecca Foulger commented on DPP6
Severe microcephaly DDX11 Rebecca Foulger classified DDX11 as green
Severe microcephaly DDX11 Rebecca Foulger commented on DDX11
Severe microcephaly CDC6 Rebecca Foulger commented on CDC6
Severe microcephaly TUBGCP3 Rebecca Foulger commented on TUBGCP3
Severe microcephaly NSMCE2 Rebecca Foulger commented on NSMCE2
Severe microcephaly ERCC5 Rebecca Foulger classified ERCC5 as red
Severe microcephaly ERCC5 Rebecca Foulger commented on ERCC5
Severe microcephaly ERCC5 Rebecca Foulger commented on ERCC5
Severe microcephaly ERCC5 Rebecca Foulger added ERCC5 to panel
Severe microcephaly ERCC5 Rebecca Foulger reviewed ERCC5
Severe microcephaly ERCC4 Rebecca Foulger classified ERCC4 as green
Severe microcephaly ERCC4 Rebecca Foulger commented on ERCC4
Severe microcephaly ERCC4 Rebecca Foulger commented on ERCC4
Severe microcephaly ERCC4 Rebecca Foulger added ERCC4 to panel
Severe microcephaly ERCC4 Rebecca Foulger reviewed ERCC4
Severe microcephaly FANCM Rebecca Foulger classified FANCM as red
Severe microcephaly FANCM Rebecca Foulger commented on FANCM
Severe microcephaly WDR73 Rebecca Foulger classified WDR73 as green
Severe microcephaly CRIPT Rebecca Foulger classified CRIPT as amber
Severe microcephaly CRIPT Rebecca Foulger commented on CRIPT
Severe microcephaly KIAA1279 Rebecca Foulger classified KIAA1279 as green
Severe microcephaly KIAA1279 Rebecca Foulger commented on KIAA1279
Severe microcephaly LARP7 Rebecca Foulger classified LARP7 as green
Severe microcephaly LARP7 Rebecca Foulger edited their review of LARP7
Severe microcephaly LARP7 Rebecca Foulger commented on LARP7
Severe microcephaly ATRX Rebecca Foulger edited their review of ATRX
Severe microcephaly ATRX Rebecca Foulger classified ATRX as green
Severe microcephaly ATRX Rebecca Foulger commented on ATRX
Severe microcephaly CREBBP Rebecca Foulger marked CREBBP as ready
Severe microcephaly MYCN Rebecca Foulger marked MYCN as ready
Severe microcephaly MYCN Rebecca Foulger classified MYCN as green
Severe microcephaly MYCN Rebecca Foulger commented on MYCN
Severe microcephaly CREBBP Rebecca Foulger classified CREBBP as green
Severe microcephaly CREBBP Rebecca Foulger commented on CREBBP
Severe microcephaly MYCN emma baple reviewed MYCN
Severe microcephaly KIAA1279 emma baple reviewed KIAA1279
Severe microcephaly CREBBP emma baple reviewed CREBBP
Severe microcephaly ATRX emma baple reviewed ATRX
Severe microcephaly SLX4 emma baple reviewed SLX4
Severe microcephaly RAD51C emma baple reviewed RAD51C
Severe microcephaly PALB2 emma baple reviewed PALB2
Severe microcephaly FANCL emma baple reviewed FANCL
Severe microcephaly FANCI emma baple reviewed FANCI
Severe microcephaly FANCG emma baple reviewed FANCG
Severe microcephaly FANCF emma baple reviewed FANCF
Severe microcephaly FANCE emma baple reviewed FANCE
Severe microcephaly FANCD2 emma baple reviewed FANCD2
Severe microcephaly FANCC emma baple reviewed FANCC
Severe microcephaly FANCB emma baple reviewed FANCB
Severe microcephaly FANCA emma baple reviewed FANCA
Severe microcephaly ERCC8 emma baple reviewed ERCC8
Severe microcephaly ERCC6 emma baple reviewed ERCC6
Severe microcephaly BRIP1 emma baple reviewed BRIP1
Severe microcephaly BRCA2 emma baple reviewed BRCA2
Severe microcephaly KIAA1279 Rebecca Foulger commented on KIAA1279
Severe microcephaly PNKP Rebecca Foulger classified PNKP as green
Severe microcephaly PNKP Rebecca Foulger commented on PNKP
Severe microcephaly WDR73 Rebecca Foulger commented on WDR73
Severe microcephaly SLC9A6 Rebecca Foulger classified SLC9A6 as green
Severe microcephaly SLC9A6 Rebecca Foulger commented on SLC9A6
Severe microcephaly IER3IP1 Rebecca Foulger classified IER3IP1 as green
Severe microcephaly IER3IP1 Rebecca Foulger commented on IER3IP1
Severe microcephaly TRMT10A Rebecca Foulger commented on TRMT10A
Severe microcephaly PPP1R15B Rebecca Foulger commented on PPP1R15B
Severe microcephaly MSMO1 Rebecca Foulger classified MSMO1 as red
Severe microcephaly MSMO1 Rebecca Foulger commented on MSMO1
Severe microcephaly POC1A Rebecca Foulger classified POC1A as red
Severe microcephaly CRIPT Rebecca Foulger classified CRIPT as amber
Severe microcephaly CRIPT Rebecca Foulger added CRIPT to panel
Severe microcephaly CRIPT Rebecca Foulger reviewed CRIPT
Severe microcephaly QARS Rebecca Foulger classified QARS as amber
Severe microcephaly QARS Rebecca Foulger commented on QARS
Severe microcephaly DIAPH1 Rebecca Foulger classified DIAPH1 as amber
Severe microcephaly DIAPH1 Rebecca Foulger commented on DIAPH1
Severe microcephaly QARS Alice Gardham added QARS to panel
Severe microcephaly QARS Alice Gardham reviewed QARS
Severe microcephaly CKAP2L Alice Gardham marked CKAP2L as ready
Severe microcephaly CKAP2L Alice Gardham classified CKAP2L as green
Severe microcephaly CKAP2L Alice Gardham commented on CKAP2L
Severe microcephaly STAMBP Alice Gardham marked STAMBP as ready
Severe microcephaly STAMBP Alice Gardham classified STAMBP as green
Severe microcephaly STAMBP Alice Gardham added STAMBP to panel
Severe microcephaly STAMBP Alice Gardham reviewed STAMBP
Severe microcephaly NHEJ1 Alice Gardham marked NHEJ1 as ready
Severe microcephaly NHEJ1 Alice Gardham added NHEJ1 to panel
Severe microcephaly NHEJ1 Alice Gardham reviewed NHEJ1
Severe microcephaly DDX11 Alice Gardham added DDX11 to panel
Severe microcephaly DDX11 Alice Gardham reviewed DDX11
Severe microcephaly NBN Alice Gardham marked NBN as ready
Severe microcephaly NBN Alice Gardham added NBN to panel
Severe microcephaly NBN Alice Gardham reviewed NBN
Severe microcephaly ZEB2 Alice Gardham marked ZEB2 as ready
Severe microcephaly ZEB2 Alice Gardham added ZEB2 to panel
Severe microcephaly ZEB2 Alice Gardham reviewed ZEB2
Severe microcephaly DHCR7 Alice Gardham marked DHCR7 as ready
Severe microcephaly DHCR7 Alice Gardham added DHCR7 to panel
Severe microcephaly DHCR7 Alice Gardham reviewed DHCR7
Severe microcephaly CIT Alice Gardham marked CIT as ready
Severe microcephaly CIT Alice Gardham classified CIT as green
Severe microcephaly CIT Alice Gardham reviewed CIT
Severe microcephaly ANKLE2 Alice Gardham marked ANKLE2 as ready
Severe microcephaly ANKLE2 Alice Gardham reviewed ANKLE2
Severe microcephaly MFSD2A Alice Gardham marked MFSD2A as ready
Severe microcephaly MFSD2A Alice Gardham classified MFSD2A as green
Severe microcephaly MFSD2A Alice Gardham reviewed MFSD2A
Severe microcephaly ZNF335 Alice Gardham reviewed ZNF335
Severe microcephaly MCPH1 Alice Gardham marked MCPH1 as ready
Severe microcephaly MCPH1 Alice Gardham commented on MCPH1
Severe microcephaly CDK5RAP2 Alice Gardham marked CDK5RAP2 as ready
Severe microcephaly CDK5RAP2 Alice Gardham commented on CDK5RAP2
Severe microcephaly CASK Alice Gardham marked CASK as ready
Severe microcephaly ASPM Alice Gardham marked ASPM as ready
Severe microcephaly PCNT Alice Gardham marked PCNT as ready
Severe microcephaly PCNT Alice Gardham commented on PCNT
Severe microcephaly RTTN Alice Gardham marked RTTN as ready
Severe microcephaly RTTN Alice Gardham classified RTTN as green
Severe microcephaly RTTN Alice Gardham reviewed RTTN
Severe microcephaly CASC5 Alice Gardham marked CASC5 as ready
Severe microcephaly CASC5 Alice Gardham reviewed CASC5
Severe microcephaly STIL Alice Gardham marked STIL as ready
Severe microcephaly STIL Alice Gardham commented on STIL
Severe microcephaly WDR62 Alice Gardham marked WDR62 as ready
Severe microcephaly WDR62 Alice Gardham commented on WDR62
Severe microcephaly CEP152 Alice Gardham marked CEP152 as ready
Severe microcephaly CEP152 Alice Gardham commented on CEP152
Severe microcephaly CENPJ Alice Gardham marked CENPJ as ready
Severe microcephaly CENPJ Alice Gardham marked CENPJ as ready
Severe microcephaly CENPJ Alice Gardham commented on CENPJ
Severe microcephaly NDE1 Alice Gardham marked NDE1 as ready
Severe microcephaly NDE1 Alice Gardham classified NDE1 as green
Severe microcephaly NDE1 Alice Gardham reviewed NDE1
Severe microcephaly BLM Alice Gardham marked BLM as ready
Severe microcephaly BLM Alice Gardham reviewed BLM
Severe microcephaly LIG4 Alice Gardham marked LIG4 as ready
Severe microcephaly LIG4 Alice Gardham classified LIG4 as green
Severe microcephaly LIG4 Alice Gardham reviewed LIG4
Severe microcephaly XRCC4 Alice Gardham marked XRCC4 as ready
Severe microcephaly XRCC4 Alice Gardham classified XRCC4 as green
Severe microcephaly XRCC4 Alice Gardham reviewed XRCC4
Severe microcephaly CENPF Alice Gardham marked CENPF as ready
Severe microcephaly CENPF Alice Gardham classified CENPF as green
Severe microcephaly CENPF Alice Gardham reviewed CENPF
Severe microcephaly TRAIP Alice Gardham marked TRAIP as ready
Severe microcephaly TRAIP Alice Gardham classified TRAIP as green
Severe microcephaly TRAIP Alice Gardham reviewed TRAIP
Severe microcephaly TUBGCP4 Alice Gardham marked TUBGCP4 as ready
Severe microcephaly TUBGCP4 Alice Gardham marked TUBGCP4 as ready
Severe microcephaly TUBGCP4 Alice Gardham classified TUBGCP4 as green
Severe microcephaly TUBGCP4 Alice Gardham reviewed TUBGCP4
Severe microcephaly PLK4 Alice Gardham marked PLK4 as ready
Severe microcephaly PLK4 Alice Gardham classified PLK4 as green
Severe microcephaly PLK4 Alice Gardham reviewed PLK4
Severe microcephaly TUBGCP6 Alice Gardham marked TUBGCP6 as ready
Severe microcephaly TUBGCP6 Alice Gardham classified TUBGCP6 as green
Severe microcephaly TUBGCP6 Alice Gardham reviewed TUBGCP6
Severe microcephaly PQBP1 Alice Gardham marked PQBP1 as ready
Severe microcephaly PQBP1 Alice Gardham added PQBP1 to panel
Severe microcephaly PQBP1 Alice Gardham reviewed PQBP1
Severe microcephaly RNU4ATAC Alice Gardham marked RNU4ATAC as ready
Severe microcephaly RNU4ATAC Alice Gardham classified RNU4ATAC as green
Severe microcephaly RNU4ATAC Alice Gardham reviewed RNU4ATAC
Severe microcephaly EFTUD2 Alice Gardham marked EFTUD2 as ready
Severe microcephaly EFTUD2 Alice Gardham classified EFTUD2 as green
Severe microcephaly EFTUD2 Alice Gardham added EFTUD2 to panel
Severe microcephaly EFTUD2 Alice Gardham reviewed EFTUD2
Severe microcephaly IGF1R Alice Gardham marked IGF1R as ready
Severe microcephaly IGF1R Alice Gardham reviewed IGF1R
Severe microcephaly IGF1 Alice Gardham marked IGF1 as ready
Severe microcephaly IGF1 Alice Gardham reviewed IGF1
Severe microcephaly KIF11 Alice Gardham marked KIF11 as ready
Severe microcephaly KIF11 Alice Gardham classified KIF11 as green
Severe microcephaly KIF11 Alice Gardham commented on KIF11
Severe microcephaly GMNN Alice Gardham marked GMNN as ready
Severe microcephaly GMNN Alice Gardham classified GMNN as green
Severe microcephaly GMNN Alice Gardham reviewed GMNN
Severe microcephaly CDC6 Alice Gardham reviewed CDC6
Severe microcephaly CDT1 Alice Gardham marked CDT1 as ready
Severe microcephaly CDT1 Alice Gardham classified CDT1 as green
Severe microcephaly CDT1 Alice Gardham reviewed CDT1
Severe microcephaly ORC6 Alice Gardham marked ORC6 as ready
Severe microcephaly ORC6 Alice Gardham classified ORC6 as green
Severe microcephaly ORC6 Alice Gardham reviewed ORC6
Severe microcephaly ORC4 Alice Gardham marked ORC4 as ready
Severe microcephaly ORC4 Alice Gardham classified ORC4 as green
Severe microcephaly ORC4 Alice Gardham reviewed ORC4
Severe microcephaly ORC1 Alice Gardham marked ORC1 as ready
Severe microcephaly ORC1 Alice Gardham classified ORC1 as green
Severe microcephaly ORC1 Alice Gardham classified ORC1 as green
Severe microcephaly ORC1 Alice Gardham reviewed ORC1
Severe microcephaly CEP63 Alice Gardham classified CEP63 as green
Severe microcephaly CEP63 Alice Gardham reviewed CEP63
Severe microcephaly RBBP8 Alice Gardham reviewed RBBP8
Severe microcephaly ATRIP Alice Gardham marked ATRIP as ready
Severe microcephaly ATR Alice Gardham marked ATR as ready
Severe microcephaly ATR Alice Gardham classified ATR as green
Severe microcephaly ATR Alice Gardham reviewed ATR
Severe microcephaly CEP135 Alice Gardham marked CEP135 as ready
Severe microcephaly CEP135 Alice Gardham classified CEP135 as green
Severe microcephaly CEP135 Alice Gardham classified CEP135 as amber
Severe microcephaly CEP135 Alice Gardham reviewed CEP135
Severe microcephaly RNU4ATAC Ellen McDonagh commented on RNU4ATAC
Severe microcephaly DNA2 Rebecca Foulger marked DNA2 as ready
Severe microcephaly DNA2 Rebecca Foulger commented on DNA2
Severe microcephaly DNA2 Rebecca Foulger commented on DNA2
Severe microcephaly NIN Rebecca Foulger marked NIN as ready
Severe microcephaly NIN Rebecca Foulger commented on NIN
Severe microcephaly SLC25A19 Rebecca Foulger commented on SLC25A19
Severe microcephaly CKAP2L Rebecca Foulger commented on CKAP2L
Severe microcephaly KIF11 Rebecca Foulger commented on KIF11
Severe microcephaly CASK Rebecca Foulger commented on CASK
Severe microcephaly PHC1 Rebecca Foulger commented on PHC1
Severe microcephaly DPP6 Rebecca Foulger commented on DPP6
Severe microcephaly WDR4 Rebecca Foulger commented on WDR4
Severe microcephaly CASC5 Rebecca Foulger commented on CASC5
Severe microcephaly CENPE Rebecca Foulger commented on CENPE
Severe microcephaly SASS6 Rebecca Foulger commented on SASS6
Severe microcephaly POC1A Rebecca Foulger commented on POC1A
Severe microcephaly NDE1 Rebecca Foulger commented on NDE1
Severe microcephaly CIT Rebecca Foulger commented on CIT
Severe microcephaly CDK6 Rebecca Foulger commented on CDK6
Severe microcephaly ATRIP Rebecca Foulger commented on ATRIP
Severe microcephaly ASPM Rebecca Foulger commented on ASPM
Severe microcephaly ASPM Rebecca Foulger commented on ASPM
Severe microcephaly AGMO Rebecca Foulger commented on AGMO
Severe microcephaly LARP7 Richard Scott added LARP7 to panel
Severe microcephaly LARP7 Richard Scott reviewed LARP7