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| Intellectual disability - microarray and sequencing v5.548 | IGF1 | Arina Puzriakova Phenotypes for gene: IGF1 were changed from Growth retardation with deafness and mental retardation due to IGF1 deficiency, 608747; INSULIN-LIKE GROWTH FACTOR I DEFICIENCY (IGF1 DEFICIENCY) to Insulin-like growth factor I deficiency, OMIM:608747 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.532 | GTF3C5 |
Zornitza Stark gene: GTF3C5 was added gene: GTF3C5 was added to Intellectual disability - microarray and sequencing. Sources: Literature Mode of inheritance for gene: GTF3C5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GTF3C5 were set to 38520561; 35503477 Phenotypes for gene: GTF3C5 were set to neurodevelopmental disorder MONDO:0700092, GTF3C5-related Review for gene: GTF3C5 was set to GREEN Added comment: 4 families/probands with syndromic ID. Loss of function is the expected mechanism. PMID: 38520561 - Biallelic variants identified (3 missense & 1 stopgain) in 4 individuals from 3 families presenting with multisystem developmental syndrome including the features: growth retardation, developmental delay, intellectual disability, dental anomalies, cerebellar malformations, delayed bone age, skeletal anomalies, and facial dysmorphism. Gene-disease relationship supported by: reduced protein expression in patient cells, yeast assays, and a zebrafish model PMID: 35503477 - 1 proband with biallelic missense variants and hypomelanosis of Ito, seizures, growth retardation, abnormal brain MRI, developmental delay, and facial dysmorphism Sources: Literature |
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| Intellectual disability - microarray and sequencing v5.515 | ASCC3 | Arina Puzriakova Phenotypes for gene: ASCC3 were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to Intellectual developmental disorder, autosomal recessive 81, OMIM:620700 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.497 | SPATA5 | Arina Puzriakova Phenotypes for gene: SPATA5 were changed from Epilepsy, hearing loss, and mental retardation syndrome, 616577 to Neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities, OMIM:616577 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.493 | DYNC2H1 |
Arina Puzriakova commented on gene: DYNC2H1: - PMID: 22589734 (2012) - A 29 Mb deletion encompassing DYNC2H1 was found in one patient with syndromic hirschsprung disease which included moderate mental retardation, mild hydrocephalus, microcephaly, cardiomyopathy and congenital hypotonia. Other candidate genes in this region include CNTN5 and CARD17. Skeletal findings that are typical for DYNC2H1 are not reported. Comment on publications: PMID: 22589734 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques |
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| Intellectual disability - microarray and sequencing v5.490 | SRPX2 | Arina Puzriakova Phenotypes for gene: SRPX2 were changed from Rolandic epilepsy, mental retardation, and speech dyspraxia, 300643 -3; ROLANDIC EPILEPSY WITH SPEECH DYSPRAXIA AND MENTAL RETARDATION X-LINKED (RESDX) to ?Rolandic epilepsy, impaired intellectual development, and speech dyspraxia, OMIM:300643 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.487 | ZFX |
Sarah Leigh changed review comment from: A single ZFX variant has been associated with a neurodevelopmental disorder, that has a Rett syndrome-like phenotype disorder, in a 14 year old male. The ZFX variant was allelic with another X-linked variant in SHROOM4. These variants were inherited from the mother, who had random X inactivation pattern (PMID: 26740508). PMID: 38325380 reports 11 ZFX variants in 18 subjects from 16 unrelated families (14 males and 4 females) with an X-linked neurodevelopmental disorder with recurrent facial gestalt. Seven variants were truncating and the remaining were missense variants within the Zinc finger array. In the pedigree of family 6 (figure 3, PMID: 38325380), it was apparent that there were female carriers of the ZFX variant (GRCh38 chrX: 24229396A>G, c.2438A>G, p.Tyr774Cys) with hyperparathyroidism and two affected males and one affected female, with the neurodevelopmental disorder. It appeared that skewed X-inactivation in the female carriers was responsible for the different phenotypic features. The association between ZFX variants and a novel neurodevelopmental disorder, was further supported by functional studies showing altered transcriptional activity in missense variants and altered behavior in a zebrafish loss-of-function model.; to: To date, germline variants in ZFX have not been associated with a phenotype in OMIM or Gen2Phen. A single ZFX variant has been associated with a neurodevelopmental disorder, that has a Rett syndrome-like phenotype disorder, in a 14 year old male. The ZFX variant was allelic with another X-linked variant in SHROOM4. These variants were inherited from the mother, who had random X inactivation pattern (PMID: 26740508). PMID: 38325380 reports 11 ZFX variants in 18 subjects from 16 unrelated families (14 males and 4 females) with an X-linked neurodevelopmental disorder with recurrent facial gestalt. Seven variants were truncating and the remaining were missense variants within the Zinc finger array. In the pedigree of family 6 (figure 3, PMID: 38325380), it was apparent that there were female carriers of the ZFX variant (GRCh38 chrX: 24229396A>G, c.2438A>G, p.Tyr774Cys) with hyperparathyroidism and two affected males and one affected female, with the neurodevelopmental disorder. It appeared that skewed X-inactivation in the female carriers was responsible for the different phenotypic features. The association between ZFX variants and a novel neurodevelopmental disorder, was further supported by functional studies showing altered transcriptional activity in missense variants and altered behavior in a zebrafish loss-of-function model. |
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| Intellectual disability - microarray and sequencing v5.485 | AFF2 | Arina Puzriakova Phenotypes for gene: AFF2 were changed from Mental retardation, X-linked, FRAXE type, 309548; FRAXE Syndrome; FRAGILE X-E MENTAL RETARDATION SYNDROME (FRAXE) to Intellectual developmental disorder, X-linked 109, OMIM:309548; Fragile XE syndrome (FRAXE) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.480 | NHEJ1 | Arina Puzriakova Phenotypes for gene: NHEJ1 were changed from Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation to Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation, OMIM:611291 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.479 | KIRREL3 |
Arina Puzriakova Added comment: Comment on publications: New publication added - PMID:25902260. This paper was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques Provides review of cases in literature and functional studies demonstrating brain expressed proteins that interact with the KIRREL3 using yeast two-hybrid screening supporting a link to neurological and cognitive disorders. They also show KIRREL3 localisation to the Golgi complex and synaptic secretary vesicles. |
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| Intellectual disability - microarray and sequencing v5.462 | CLIC2 | Arina Puzriakova Phenotypes for gene: CLIC2 were changed from Mental retardation, X-linked, syndromic 32, 300886 to Intellectual developmental disorder, X-linked syndromic 32 , OMIM:300886 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.459 | ARHGEF6 | Arina Puzriakova Phenotypes for gene: ARHGEF6 were changed from Mental retardation, X-linked 46, 300436; Mental Retardation, X-linked; MENTAL RETARDATION X-LINKED TYPE 46 to Intellectual developmental disorder, X-linked 46, OMIM:300436 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.451 | LRRC32 | Achchuthan Shanmugasundram reviewed gene: LRRC32: Rating: AMBER; Mode of pathogenicity: None; Publications: 30976112, 35656379; Phenotypes: Cleft palate, proliferative retinopathy, and developmental delay, OMIM:619074; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.442 | KIRREL3 | Sarah Leigh Phenotypes for gene: KIRREL3 were changed from Mental retardation, autosomal dominant 4, 612581; MENTAL RETARDATION AUTOSOMAL DOMINANT TYPE 4 (MRD4) to Intellectual developmental disorder, autosomal dominant 4, OMIM:612581; intellectual disability, autosomal dominant 4, MONDO:0012947 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.433 | TUSC3 | Arina Puzriakova Phenotypes for gene: TUSC3 were changed from Mental retardation, autosomal recessive 7, 611093; MENTAL RETARDATION AUTOSOMAL RECESSIVE TYPE 7 (MRT7) to Intellectual developmental disorder, autosomal recessive 7, OMIM:611093 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.431 | CC2D1A | Arina Puzriakova Phenotypes for gene: CC2D1A were changed from Mental retardation, autosomal recessive 3, 608443; MENTAL RETARDATION AUTOSOMAL RECESSIVE TYPE 3 (MRT3) to Intellectual developmental disorder, autosomal recessive 3, OMIM:608443 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.429 | LRRC32 | Hannah Knight reviewed gene: LRRC32: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 35656379; Phenotypes: Cleft palate, proliferative retinopathy, and developmental delay; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.424 | WDR62 | Arina Puzriakova Phenotypes for gene: WDR62 were changed from Microcephaly, Cortical Malformations, and Mental Retardation; Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, 604317; MICROCEPHALY CORTICAL MALFORMATIONS AND MENTAL RETARDATION (MCMMR) to Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, OMIM:604317 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.419 | HSD17B10 | Arina Puzriakova Phenotypes for gene: HSD17B10 were changed from 17-beta-hydroxysteroid dehydrogenase X deficiency, 300438Mental retardation, X-linked syndromic 10, 300220Mental retardation, X-linked 17/31, microduplication, 300705; 2-METHYL-3-HYDROXYBUTYRYL-COA DEHYDROGENASE DEFICIENCY (MHBD DEFICIENCY) to HSD10 mitochondrial disease, OMIM:300438 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.399 | RPL10 | Achchuthan Shanmugasundram Phenotypes for gene: RPL10 were changed from Mental retardation, X-linked, syndromic, 35, 300998 to Intellectual developmental disorder, X-linked syndromic 35, OMIM:300998 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.342 | NSD2 | Sarah Leigh Phenotypes for gene: NSD2 were changed from Intrauterine growth retardation; Growth delay; Microcephaly; Muscular hypotonia; Neurodevelopmental delay; Intellectual disability; No OMIM number to Rauch-Steindl syndrome, OMIM:619695; Rauch-Steindl syndrome, MONDO:0859219 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.340 | CASP2 | Achchuthan Shanmugasundram Phenotypes for gene: CASP2 were changed from Autosomal recessive mental retardation to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.337 | CLEC16A |
Dmitrijs Rots gene: CLEC16A was added gene: CLEC16A was added to Intellectual disability - microarray and sequencing. Sources: Literature Mode of inheritance for gene: CLEC16A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CLEC16A were set to PMID: 36538041 Phenotypes for gene: CLEC16A were set to severe neurodevelopmental disorder including microcephaly, brain atrophy, corpus callosum dysgenesis, and growth retardation Penetrance for gene: CLEC16A were set to Complete Review for gene: CLEC16A was set to GREEN Added comment: Two independent cases reported PMID: 36538041with biallelic variants and functional evidence. Sufficient for the green rating. Sources: Literature |
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| Intellectual disability - microarray and sequencing v5.332 | AGPAT3 |
Zornitza Stark gene: AGPAT3 was added gene: AGPAT3 was added to Intellectual disability - microarray and sequencing. Sources: Literature Mode of inheritance for gene: AGPAT3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AGPAT3 were set to 37821758 Phenotypes for gene: AGPAT3 were set to Neurodevelopmental disorder (MONDO#0700092), AGPAT3-related Review for gene: AGPAT3 was set to AMBER Added comment: - Single consanguineous family with four individuals with severe intellectual disability and retinitis pigmentosa - All affected individuals were homozygous for a nonsense variant in AGPAT3, healthy unaffected individuals who were tested were heterozygous for the variant - Overexpression of mutant transcript revealed absence of AGPAT3 protein compared to WT transcript via Western blot analysis - KO AGPAT3 mouse demonstrated impaired neuronal migration Sources: Literature |
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| Intellectual disability - microarray and sequencing v5.305 | ZMYM3 | Arina Puzriakova Phenotypes for gene: ZMYM3 were changed from X-linked mental retardation to Intellectual developmental disorder, X-linked 112, OMIM:301111 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.301 | TAF2 | Arina Puzriakova Phenotypes for gene: TAF2 were changed from Mental retardation, autosomal recessive 40, 615599 to Mental retardation, autosomal recessive 40, OMIM:615599 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.295 | KDM5A | Arina Puzriakova Phenotypes for gene: KDM5A were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION; autism spectrum disorder, MONDO:0005258; intellectual disability, MONDO:0001071 to autism spectrum disorder, MONDO:0005258; intellectual disability, MONDO:0001071 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.294 | IQSEC2 | Arina Puzriakova Phenotypes for gene: IQSEC2 were changed from Mental retardation, X-linked 1, 309530; non-syndromic X-linked intellectual disability; Rett like phenotype in males; MENTAL RETARDATION X-LINKED TYPE 1 (MRX1) to Intellectual developmental disorder, X-linked 1, OMIM:309530 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.253 | CLCNKA | Sarah Leigh Added comment: Comment on mode of inheritance: Digenic CLCNKA & CLCNKB variants are associated with Bartter syndrome, type 4b, digenic (OMIM:613090)(PMID: 15044642;18310267;32488762). The current GMS rare disease bioinformatic pipeline does not allow for interpretation of digenic events. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.252 | CLCNKB | Sarah Leigh Added comment: Comment on mode of inheritance: The mode of inheritance for CLCNKB should be BIALLELIC, autosomal or pseudoautosomal. Although digenic CLCNKB & CLCNKA variants are associated with Bartter syndrome, type 4b, digenic (OMIM:613090), the current GMS rare disease bioinformatic pipeline does not allow for interpretation of digenic events. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.231 | RPS6KA3 | Arina Puzriakova Phenotypes for gene: RPS6KA3 were changed from Coffin-Lowry syndrome, 303600Mental retardation, X-linked 19, 300844; COFFIN-LOWRY SYNDROME (CLS) to Coffin-Lowry syndrome, OMIM:303600; Intellectual developmental disorder, X-linked 19, OMIM:300844 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.110 | GRIN2B | Arina Puzriakova Phenotypes for gene: GRIN2B were changed from Mental Retardation, Dominant; Mental retardation, autosomal dominant 6, 613970; AUTISM to Intellectual developmental disorder, autosomal dominant 6, with or without seizures, OMIM:613970; Developmental and epileptic encephalopathy 27, OMIM:616139 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.57 | TAF2 | Achchuthan Shanmugasundram reviewed gene: TAF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 21937992, 24084144, 34474177; Phenotypes: Mental retardation, autosomal recessive 40, OMIM:615599; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.47 | CLCN4 | Arina Puzriakova Phenotypes for gene: CLCN4 were changed from Mental retardation, X-linked 49-15 300114 to Raynaud-Claes syndrome, OMIM:300114 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.31 | HUWE1 | Achchuthan Shanmugasundram Phenotypes for gene: HUWE1 were changed from Mental retardation, X-linked syndromic, Turner type, 300706; MENTAL RETARDATION SYNDROMIC X-LINKED TURNER TYPE (MRXST) to Intellectual developmental disorder, X-linked syndromic, Turner type, OMIM:309590 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.25 | KDM5A | Achchuthan Shanmugasundram Phenotypes for gene: KDM5A were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION; autism spectrum disorder, MONDO:0005258; intellectual disability, MONDO:0001071 to AUTOSOMAL RECESSIVE MENTAL RETARDATION; autism spectrum disorder, MONDO:0005258; intellectual disability, MONDO:0001071 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.25 | KDM5A | Achchuthan Shanmugasundram Phenotypes for gene: KDM5A were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION; autism spectrum disorder, MONDO:0005258; intellectual disability, MONDO:0001071 to AUTOSOMAL RECESSIVE MENTAL RETARDATION; autism spectrum disorder, MONDO:0005258; intellectual disability, MONDO:0001071 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.25 | KDM5A | Achchuthan Shanmugasundram Phenotypes for gene: KDM5A were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION; autism spectrum disorder, MONDO:0005258; intellectual disability, MONDO:0001071 to AUTOSOMAL RECESSIVE MENTAL RETARDATION; autism spectrum disorder, MONDO:0005258; intellectual disability, MONDO:0001071 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.25 | KDM5A | Achchuthan Shanmugasundram Phenotypes for gene: KDM5A were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to AUTOSOMAL RECESSIVE MENTAL RETARDATION; autism spectrum disorder, MONDO:0005258; intellectual disability, MONDO:0001071 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v4.109 | DEAF1 | Achchuthan Shanmugasundram Phenotypes for gene: DEAF1 were changed from ?Dyskinesia, seizures, and intellectual developmental disorder, 617171; Mental retardation, autosomal dominant 24, 615828 to ?Dyskinesia, seizures, and intellectual developmental disorder, 617171; Mental retardation, autosomal dominant 24, 615828 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v4.110 | DEAF1 | Achchuthan Shanmugasundram Phenotypes for gene: DEAF1 were changed from ?Dyskinesia, seizures, and intellectual developmental disorder, 617171; Mental retardation, autosomal dominant 24, 615828 to ?Dyskinesia, seizures, and intellectual developmental disorder, 617171; Mental retardation, autosomal dominant 24, 615828 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v4.110 | DEAF1 | Achchuthan Shanmugasundram Phenotypes for gene: DEAF1 were changed from ?Dyskinesia, seizures, and intellectual developmental disorder, 617171; Mental retardation, autosomal dominant 24, 615828 to ?Dyskinesia, seizures, and intellectual developmental disorder, 617171; Mental retardation, autosomal dominant 24, 615828 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v4.109 | DEAF1 | Achchuthan Shanmugasundram Phenotypes for gene: DEAF1 were changed from ?Dyskinesia, seizures, and intellectual developmental disorder, 617171; Mental retardation, autosomal dominant 24, 615828 to ?Dyskinesia, seizures, and intellectual developmental disorder, 617171; Mental retardation, autosomal dominant 24, 615828 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v4.109 | DEAF1 | Achchuthan Shanmugasundram Phenotypes for gene: DEAF1 were changed from ?Dyskinesia, seizures, and intellectual developmental disorder, 617171; Mental retardation, autosomal dominant 24, 615828 to ?Dyskinesia, seizures, and intellectual developmental disorder, 617171; Mental retardation, autosomal dominant 24, 615828 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v4.109 | DEAF1 | Achchuthan Shanmugasundram Phenotypes for gene: DEAF1 were changed from ?Dyskinesia, seizures, and intellectual developmental disorder, 617171; Mental retardation, autosomal dominant 24, 615828 to ?Dyskinesia, seizures, and intellectual developmental disorder, 617171; Mental retardation, autosomal dominant 24, 615828 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v4.109 | DEAF1 | Achchuthan Shanmugasundram Phenotypes for gene: DEAF1 were changed from MENTAL RETARDATION, AUTOSOMAL DOMINANT 24; ?Dyskinesia, seizures, and intellectual developmental disorder, 617171; Mental retardation, autosomal dominant 24, 615828 to ?Dyskinesia, seizures, and intellectual developmental disorder, 617171; Mental retardation, autosomal dominant 24, 615828 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v4.92 | NUP214 |
Eleanor Williams changed review comment from: Associated with {Encephalopathy, acute, infection-induced, susceptibility to, 9} 618426 in OMIM and Gene2Phenotype (probable). PMID: 31178128 - Fichtman et al 2019 - report on two families one of Palestinian decent, the other Northern European (not Finnish descent). Each had two affected siblings in which neurological decline was seen after febrile events. The older son in family A, exhibited minor developmental delay from infancy. A homozygous missense variant was identified in NUP214 (p.Arg38Cys) in family A and segregated with the disease in available family members. In family B affected sisters were compound heterozygous for a frameshift and a missense variant in NUP214 (p.Pro387Ser and p.Pro525Leufs∗6). Functional studies with fibroblasts from one patient in family A showed a decrease in NUP214 and NUP88 levels compared to controls, PMID: 30758658 - Shamseldin et al 2019 - describe a multiplex consanguineous family in which four affected members presented with severe neonatal hypotonia, profound global developmental delay, progressive microcephaly and early death (<2 year old). Whole exome sequencing revealed the presence of a novel homozygous missense variant in NUP214, p.D154G. PMID: 29483668 - Egloff et al 2018 - report a 4-year-old girl presenting with developmental delay, growth retardation and facial dysmorphism. She was found to have a 9q deletion inherited from her healthy mother and a hemizygous one-base pair deletion in the NUP214 gene inherited from her father. From patient leukocytes it was found that the expression level of the NUP214 transcript was significantly decreased and close to zero in the patient compared to the controls. ; to: Associated with {Encephalopathy, acute, infection-induced, susceptibility to, 9} 618426 in OMIM and Gene2Phenotype (probable). PMID: 31178128 - Fichtman et al 2019 - report on two families one of Palestinian decent, the other Northern European (not Finnish descent). Each had two affected family members in which neurological decline was seen after febrile events. The older son in family A, exhibited minor developmental delay from infancy. A homozygous missense variant was identified in NUP214 (p.Arg38Cys) in family A and segregated with the disease in available family members. In family B affected sisters were compound heterozygous for a frameshift and a missense variant in NUP214 (p.Pro387Ser and p.Pro525Leufs∗6). Functional studies with fibroblasts from one patient in family A showed a decrease in NUP214 and NUP88 levels compared to controls, PMID: 30758658 - Shamseldin et al 2019 - describe a multiplex consanguineous family in which four affected members presented with severe neonatal hypotonia, profound global developmental delay, progressive microcephaly and early death (<2 year old). Whole exome sequencing revealed the presence of a novel homozygous missense variant in NUP214, p.D154G. PMID: 29483668 - Egloff et al 2018 - report a 4-year-old girl presenting with developmental delay, growth retardation and facial dysmorphism. She was found to have a 9q deletion inherited from her healthy mother and a hemizygous one-base pair deletion in the NUP214 gene inherited from her father. From patient leukocytes it was found that the expression level of the NUP214 transcript was significantly decreased and close to zero in the patient compared to the controls. |
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| Intellectual disability - microarray and sequencing v4.90 | EMC1 | Achchuthan Shanmugasundram Phenotypes for gene: EMC1 were changed from Cerebellar atrophy, visual impairment, and psychomotor retardation, OMIM:616875 to Cerebellar atrophy, visual impairment, and psychomotor retardation, OMIM:616875 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v4.90 | EMC1 | Achchuthan Shanmugasundram Phenotypes for gene: EMC1 were changed from Cerebellar atrophy, visual impairment, and psychomotor retardation, OMIM:616875 to Cerebellar atrophy, visual impairment, and psychomotor retardation, OMIM:616875 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v4.90 | EMC1 | Achchuthan Shanmugasundram Phenotypes for gene: EMC1 were changed from Cerebellar atrophy, visual impairment, and psychomotor retardation, OMIM:616875 to Cerebellar atrophy, visual impairment, and psychomotor retardation, OMIM:616875 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v4.90 | EMC1 | Achchuthan Shanmugasundram Phenotypes for gene: EMC1 were changed from Cerebellar atrophy, visual impairment, and psychomotor retardation, OMIM:616875 to Cerebellar atrophy, visual impairment, and psychomotor retardation, OMIM:616875 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v4.89 | EMC1 | Achchuthan Shanmugasundram Phenotypes for gene: EMC1 were changed from Cerebellar atrophy, visual impairment, and psychomotor retardation, OMIM:616875 to Cerebellar atrophy, visual impairment, and psychomotor retardation, OMIM:616875 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v4.89 | EMC1 | Achchuthan Shanmugasundram Phenotypes for gene: EMC1 were changed from Cerebellar atrophy, visual impairment, and psychomotor retardation, OMIM:616875 to Cerebellar atrophy, visual impairment, and psychomotor retardation, OMIM:616875 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v4.89 | EMC1 | Achchuthan Shanmugasundram Phenotypes for gene: EMC1 were changed from Cerebellar atrophy, visual impairment, and psychomotor retardation, MIM 616875; Cerebellar atrophy, visual impairment, and psychomotor retardation, 616875 to Cerebellar atrophy, visual impairment, and psychomotor retardation, OMIM:616875 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v4.63 | RAB39B | Achchuthan Shanmugasundram Phenotypes for gene: RAB39B were changed from Mental retardation, X-linked 72, 300271; Mental Retardation, X-linked; MENTAL RETARDATION X-LINKED TYPE 72 (MRX72) +/- PARKINSONS to Intellectual developmental disorder, X-linked 72, OMIM:300271; Waisman syndrome, OMIM:311510 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v4.55 | ISCA-37408-Loss | Arina Puzriakova Phenotypes for Region: ISCA-37408-Loss were changed from PMID: 16963482 idiopathic intellectual disability including moderate to severe intellectual disability, autism/autistic features, microcephaly, structural brain anomalies including cortical dysplasia/pachygyria, renal anomalies (multicystic kidney, hydronephrosis), digital camptodactyly, visual impairment, strabismus, neuromotor deficits, communication and attention impairments, and a distinctive pattern of craniofacial features. Dysmorphic craniofacial features include progressive microcephaly, flat occiput, widened inner canthal distance, small palpebral fissures, ptosis, long and straight eyelashes, broad and high nasal root extending to a widened, prominent nasal tip with elongated, smooth philtrum, rounding of the upper vermillion border and everted lower lips. PMID: 18245392 A 32-year-old, mentally retarded male was referred to our centre for further clinical genetic analysis. He was born to non-consanguineous parents after 42 weeks gestation with a birth weight of 3500 g. He had a healthy older brother. In the neonatal period he was hypotonic and at 8 weeks of age he underwent surgery because of an inguinal hernia with removal of an atrophic right testis. His motor development was severely delayed with sitting at 3.5 years and walking at 5 years of age. Speech was poorly developed, characterised by the usage of only a few words. During infancy an optic nerve hypoplasia was diagnosed, and during childhood he frequently suffered from luxations of the patellae, which required surgery. At the age of 32 years his height is 163 cm (_3 SDS) and head circumference 52.5 cm (_2.5 SDS). He has a narrow receding forehead, widened inner canthal distance of 3.5 cm (90th centile), normal outer canthal distance of 8.5 cm (25th centile), telecanthus, short and down slanting palpebral fissures, epicanthal folds, ptosis, long, straight eyelashes, high nasal bridge, low set large ears, flat philtrum, small mouth with high, narrow palate and retrognathia. The thorax is broad with increased internipple distance and slight gynaecomastia. A recent renal ultrasound revealed multiple cysts in the left, dystrophic kidney and two uncomplicated cysts in the enlarged, right kidney. The patient has a normally sized phallus with absent right testis and small left testis. His hands show a simian crease right and tapering fingers with broad proximal interphalangeal joints. He shows sandal gaps on both flat feet with clinodactyly of the fourth and fifth toes (and more); 612513; PMID: 22579565 severe developmental delay, congenital microcephaly, intractable epilepsy, and renal anomalies, as well as a congenital choledochal cyst which has not been previously reported in other patients with this cytogenetic defect to Dysmorphic features, moderate to severe intellectual disability, microcephaly and renal anomalies | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v4.24 | DDX3X | Arina Puzriakova Phenotypes for gene: DDX3X were changed from Intellectual disability, Mental retardation, X-linked 102, 300958 to Intellectual developmental disorder, X-linked syndromic, Snijders Blok type, OMIM:300958 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v4.15 | RPL10 | Dmitrijs Rots reviewed gene: RPL10: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 35876338; Phenotypes: ID, dysmorphic features, progressive postnatal microcephaly, and retinal anomalies; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1757 | CTNNB1 | Arina Puzriakova Phenotypes for gene: CTNNB1 were changed from Mental retardation, autosomal dominant 19, 615075Colorectal cancer, somatic, 114500Pilomatricoma, somatic, 132600Ovarian cancer, somatic, 167000Hepatocellular carcinoma, somatic, 114550; MENTAL RETARDATION, AUTOSOMAL DOMINANT 19 to Neurodevelopmental disorder with spastic diplegia and visual defects, OMIM:615075 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1746 | GNAS | Sarah Leigh Phenotypes for gene: GNAS were changed from Pseudohypoparathyroidism Ia, 103580McCune-Albright syndrome, 174800Pseudohypoparathyroidism Ic, 612462Osseous heteroplasia, progressive, 166350Pseudohypoparathyroidism Ib, 603233Prolonged bleeding time, brachydactyly and mental retardationAcromegaly, 102200Pseudopseudohypoparathyroidism, 612463Prolonged bleeding time, brachydactyly, and mental retardationACTH-independent macronodular adrenal hyperplasia, 219080; ACTH-INDEPENDENT MACRONODULAR ADRENAL HYPERPLASIA (AIMAH) to Pseudohypoparathyroidism Ia, OMIM:103580; pseudohypoparathyroidism type 1A, MONDO:0007078; Pseudohypoparathyroidism Ic, OMIM:612462; pseudohypoparathyroidism type 1C, MONDO:0012911; Pseudopseudohypoparathyroidism, OMIM:612463; pseudopseudohypoparathyroidism, MONDO:0012912 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1713 | ANK3 | Sarah Leigh Phenotypes for gene: ANK3 were changed from ?Mental retardation, autosomal recessive, 37 615493 to Intellectual developmental disorder, autosomal recessive 37, OMIM:615493; intellectual disability-hypotonia-spasticity-sleep disorder syndrome, MONDO:0014210 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1711 | DOCK8 | Sarah Leigh Phenotypes for gene: DOCK8 were changed from Mental retardation, autosomal dominant 2, 614113Hyper-IgE recurrent infection syndrome, autosomal recessive, 243700; HYPERIMMUNOGLOBULIN E RECURRENT INFECTION SYNDROME AUTOSOMAL RECESSIVE (AR-HIES) to Intellectual developmental disorder, autosomal dominant 2, OMIM:614113 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1703 | ST3GAL3 | Sarah Leigh Phenotypes for gene: ST3GAL3 were changed from Mental retardation, autosomal recessive 12, 611090Epileptic encephalopathy, early infantile, 15, 615006; MENTAL RETARDATION, AUTOSOMAL RECESSIVE 12 to Developmental and epileptic encephalopathy 15, OMIM:615006; developmental and epileptic encephalopathy, 15, MONDO:0014003; Intellectual developmental disorder, autosomal recessive 12, OMIM:611090; intellectual disability, autosomal recessive 12, MONDO:0012612 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1662 | TAF4 |
Eleanor Williams commented on gene: TAF4: Not associated with a phenotype in OMIM or Gene2Phenotype. PMID: 33875846 - Bertoli-Avella et al 2021 - identified two de novo LoF variants (splicing and nonsense) in two unrelated patients with dysmorphic features and one with intellectual disability and one with delayed speech and language development with global developmental delay. PMID: 28191890 - Kosmicki et al 2017 - report a child with autism with an indel in TAF4 leading to a frameshift. No phenotypic details provided. PMID: 27026076 - Langer et al 2016 - Taf4a−/− (gene encoding Taf4) mouse embryos survive until E9.5, but show severe growth retardation and specific defects in anterior and ventral patterning and morphogenesis. |
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| Intellectual disability - microarray and sequencing v3.1654 | TAF8 | Arina Puzriakova Phenotypes for gene: TAF8 were changed from severe developmental delay; feeding problems; microcephaly; growth retardation; spasticity; epilepsy to Neurodevelopmental disorder with severe motor impairment, absent language, cerebral hypomyelination, and brain atrophy, OMIM:619972 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1648 | CNNM2 | Eleanor Williams Phenotypes for gene: CNNM2 were changed from Hypomagnesemia, seizures, and mental retardation 616418 to Hypomagnesemia, seizures, and mental retardation, OMIM:616418; Hypomagnesemia, seizures, and mental retardation, MONDO:0014631 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1632 | TAF8 |
Jana Jezkova gene: TAF8 was added gene: TAF8 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: TAF8 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TAF8 were set to PMID: 35759269 Phenotypes for gene: TAF8 were set to severe developmental delay; feeding problems; microcephaly; growth retardation; spasticity; epilepsy Penetrance for gene: TAF8 were set to unknown Review for gene: TAF8 was set to AMBER Added comment: Eight patients reported in total. Six patients are homozygous for a recurrent NM_138572.2, c.781-1G>A variant. In two sibling patients, two novel compound heterozygous TAF8 splice site mutations, c.45+4A > G and c.489G>A were identified, which cause aberrant splicing as well as reduced expression and mislocalization of TAF8. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1628 | SEMA3E |
Sarah Leigh gene: SEMA3E was added gene: SEMA3E was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: SEMA3E was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SEMA3E were set to 35628442 Phenotypes for gene: SEMA3E were set to Severe Intellectual Disability with Cognitive Regression Review for gene: SEMA3E was set to AMBER Added comment: Not associated with a phenotype in OMIM or Gen2Phen. One variant has been reported in a case of Severe Intellectual Disability with Cognitive Regression (PMID: 35628442). PMID: 35628442 also describes functional studies which show that this variant impairs protein secretion and hampers the binding to both embryonic mouse neuronal cells and tissues, furthermore, SEMA3E was revealed to be expressed during human brain development. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1613 | ATP6V0A1 | Sarah Leigh Phenotypes for gene: ATP6V0A1 were changed from Developmental disorder; Rett syndrome-like to ATP6V0A1-related developmental disorder (monoallelic) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1607 | TMEM63C |
Sarah Leigh gene: TMEM63C was added gene: TMEM63C was added to Intellectual disability. Sources: Literature Q3_22_rating tags were added to gene: TMEM63C. Mode of inheritance for gene: TMEM63C was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TMEM63C were set to 35718349 Phenotypes for gene: TMEM63C were set to hereditary spastic paraplegia, MONDO:0019064 Review for gene: TMEM63C was set to GREEN Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID:35718349 reports four TMEM63C variants in seven individuals from three unrelated families with childhood onset hereditary spastic paraplegia, with mild intellectual disability in some cases. Functional studies in PMID:35718349, reveal a role for TMEM63C in regulating both endoplasmic reticulum and mitochondrial morphologies. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1587 | PRPF8 | Sarah Leigh edited their review of gene: PRPF8: Added comment: Associated with Retinitis pigmentosa 13 (OMIM:600059) in OMIM, but not with PRPF8-related developmental disorder (monoallelic) and as a both RD and IF Gen2Phen gene for PRPF8-related developmental disorder (monoallelic). PMID: 35543142 reports 14 PRPF8 variants in unrelated cases (12/14 variants were confirmed as de novo). Intellectual disability was observed in 13/14 of these cases and seizures were evident in 4/14 cases.; Changed rating: GREEN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1587 | PRPF8 | Sarah Leigh Added comment: Comment on phenotypes: Gen2Phen phenotype: PRPF8-related developmental disorder (monoallelic) in addition to Retinitis pigmentosa 13 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1587 | PRPF8 | Sarah Leigh Phenotypes for gene: PRPF8 were changed from Global developmental delay; Intellectual disability; Seizures; Autism; Retinitis pigmentosa 13, OMIM:600059 to PRPF8-related developmental disorder (monoallelic); Retinitis pigmentosa 13, OMIM:600059 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1585 | PRPF8 | Sarah Leigh Phenotypes for gene: PRPF8 were changed from Global developmental delay; Intellectual disability; Seizures; Autism; Retinitis pigmentosa 13, MIM # 600059 to Global developmental delay; Intellectual disability; Seizures; Autism; Retinitis pigmentosa 13, OMIM:600059 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1580 | DROSHA |
Konstantinos Varvagiannis gene: DROSHA was added gene: DROSHA was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: DROSHA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: DROSHA were set to 35405010 Phenotypes for gene: DROSHA were set to Global developmental delay; Intellectual disability; Seizures; Cerebral white matter atrophy; Abnormality of the corpus callosum; Abnormality of movement; Stereotypic behavior; Abnormality of head or neck; Short foot Penetrance for gene: DROSHA were set to unknown Mode of pathogenicity for gene: DROSHA was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: DROSHA was set to AMBER Added comment: Profound DD, ID and seizures have been reported in 2 unrelated subjects with de novo missense variants. The gene has a role in miRNA biogenesis. Both variants described have been shown to have effect on DROSHA's function in Drosophila / C. elegans (partial loss-of-function vs possibility of antimorphic effect discussed || in gnomAD several individuals with LoF alleles / Z=3.98 – pLI : 0.09). There is currently no DROSHA-related phenotype in OMIM, G2P, SysNDD. In PanelApp Australia the gene has amber rating in genetic epilepsy and microcephaly panels (not currently included in the ID one). Consider inclusion in the current panel with amber rating. Also consider inclusion in other possibly relevant panels (given postnatal microcephaly, abn. corpus callosum, progressive white matter atrophy, etc) [ NOT added ] ----- Barish, Senturk, Schoch et al (2022 - PMID: 35405010) describe the phenotype of 2 unrelated individuals with de novo missense DROSHA variants. Features included generalized hypotonia, postnatal microcephaly (-2,6 and -6 SD), feeding difficulties, profound DD and ID, seizures, abnormal movements (choreoathetosis / stereotypic movements), variable respiratory symptoms (in one case episodes of hyperventilation/apnea), cardiovascular or skeletal findings. Brain MRI demonstrated white matter atrophy and thin corpus callosum in both. Brachycephaly with broad face as well as short feet were also among the shared features. Both were investigated by trio ES/GS which were otherwise non diagnostic and without other candidate variants. The 1st individual harbored a de novo htz missense DROSHA variant (c.3656A>G/p.Asp1219Gly) while the 2nd subject had another missense variant (c.4024C>T/p.Arg1342Trp) [NM_013235.4] confirmed by Sanger seq. DROSHA (on 5p13.3) encodes a ribonuclease, subunit of the microprocessor complex, involved in miRNA biogenesis. Specifically, miRNAs are transcribed as part of pri-miRNAs (primary-miRNAs) which are cleaved to pre-miRNAs (precursor-miRNAs) in the nucleus by DROSHA (and its partner DGCR8 or Pasha) and then exported to the cytoplasm for further processing. Cleavage of pre-miRNAs by DICER1 generates mature miRNAs subsequently loaded to the RISC (RNA-induced silencing) complex which uses miRNA as template for recognition and cleavage of complementary mRNA with RNAse. As the authors discuss, miRNA defects have a well-established role in development of model organisms e.g. (several Refs. provided): - in C. elegans miRNA mutants causing lethality, developmental arrest and heterochronicity - in Drosophila playing a role in the development of ovary, eye, nervous system etc. - in mice mRNAs play a role in BMP and TGF-beta signaling while neuronal loss of miRNA processing leads to neurodegeneration/anatomical defects. Feingold syndrome 2 is the single Mendelian disease associated to date with miRNAs, through deletion of a cluster containing 6 MIR genes. miRNA dysregulation is also observed in Rett syndrome - and DROSHA implicated in the pathogenesis of the syndrome - as MECP2 and FOXG1 are cofactors of the microprocessor complex regulating processing of miRNA. One of the individuals here reported had a clinical diagnosis of Rett spectrum while both had overlapping features with Rett s. Studies of DROSHA-dependent miRNAs in fibroblasts from one individual revealed significantly altered expression of mature miRNA (e.g. increased miR98, a miRNA with reduced expression in studies of somatic DROSHA variants) although this was not likely due to processing errors (given only a modest decrease of precursor miRNAs). Previous studies have demonstrated that drosha (the Drosophila ortholog) null mutants die during post-embryonic development with 100% lethality before adulthood (3rd instar larval stage/beginning of pupariation). Mosaic flies with mutant eyes are small-eyed, while viable hypomorphic alleles display synaptic transmission defects (several Refs provided). Here, homozygous flies for null alleles died at the end of 3rd instar larval stage/beginning of pupariation, while loss of drosha resulted in lack of imaginal disc tissue (which surrounds the larval brain) and severely reduced brain size, the latter similar to the microcephaly phenotype. [To the best of my understanding] introduction of a mutated genomic rescue construct (carrying similar substitutions as those observed in human subjects) in eye-specific drosha null (W1123X) flies was partially able to rescue eye/head size for wt or Asp1219Gly (human:Asp1084Gly) suggesting that the latter is a partial LoF allele. Arg1210Trp (corresponding to human Arg1342Trp) was able to rescue the eye phenotype and was not damaging to the function in the specific assay. Drosha expression levels were similar for genomic rescue flies either for wt or for the Asp-Gly variant suggesting that the effect was not due to expression levels (but rather function). Expression of mature miRNAs known to be regulated by Drosha were not affected when comparing wildtype larvae with genomic construct for wt or Asp1084Gly. Upon expression of human cDNA using GAL4/UAS system in drosha mutant (null) eye clones, the reference partially rescued the eye size defect, Asp-Gly behaved as partial loss-of-function allele (~50% function compared to ref), while the Arg-Trp variant was shown to behave as a weaker loss-of-function allele. The authors generated eye-specific drosha mutant clones to study the aging adult eye using ERG recordings. While null mutants display almost no response to light (7- and 20-day old flies), wt genomic rescue was shown to rescue ERG responses, Asp-Gly variant had significant defects (at both 7 and 20 days) and the Arg-Trp had defects approaching statistical significance only at the age of 20 days. Overall these data suggested that Arg-Trp had less severe effect compared to Asp-Gly (as above) while both variants led to progressive neuronal dysfunction. Using CRISPR/Cas9 the authors generated C.elegans knock-ins for a variant analogous to the Asp1219Gly human one. Homozygous animals were inviable at larval stages, displayed a heterochronic phenotype (heterochronicity : development of cells or tissues at an abnormal time relative to other unaffected events in an organism / miRNAs are known to be involved in the heterochronic gene pathway) while this variant was deleterious to the Drosha's ability to process miRNAs. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1580 | SOX11 | Sarah Leigh Added comment: Comment on phenotypes: Described as MENTAL RETARDATION, AUTOSOMAL DOMINANT, 27 by Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=405). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1580 | SOX11 | Sarah Leigh Phenotypes for gene: SOX11 were changed from MENTAL RETARDATION, AUTOSOMAL DOMINANT, 27 to Coffin-Siris syndrome 9, OMIM:615866 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1576 | PRPF8 |
Konstantinos Varvagiannis gene: PRPF8 was added gene: PRPF8 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PRPF8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: PRPF8 were set to 35543142 Phenotypes for gene: PRPF8 were set to Global developmental delay; Intellectual disability; Seizures; Autism; Retinitis pigmentosa 13, MIM # 600059 Penetrance for gene: PRPF8 were set to unknown Review for gene: PRPF8 was set to AMBER Added comment: A recent study suggests that heterozygous PRPF8 variants are associated with a syndromic form of DD/ID, in some cases epilepsy with heterogeneous other clinical findings. However the authors acknowledge that not all variants within their cohort may be pathogenic (5 VUSs using ACMG criteria) and that conclusive evidence may necessitate functional studies. Heterozygous variants (typically clustering in exon 42) have been reported to cause a non-syndromic form of RP with variable expressivity and incomplete penetrance (Retinitis pigmentosa 13, MIM # 600059) . Overall consider inclusion with amber rating. ------ O'Grady et al. (2022 - PMID: 35543142) describe the phenotype of 14 unrelated individuals with heterozygous, mostly de novo, missense and pLoF variants in PRPF8. Nearly all had some degree of global developmental delay or ID (13/14). 6/14 had a diagnosis of ASD. Seizures were reported in 4 or 5 subjects. Other features included short stature (6/14), abnormal gait, cardiac anomalies and somewhat overlapping facial features (11/14). Ages ranged from 4 - 19 years (median : 9y). PRPF8 encodes a component of the spliceosomes which in turn are involved in removal of introns from mRNA precursors. The gene is ubiquitously expressed with expression within brain being highest in cerebral cortex, basal ganglia and cerebellum (Refs. provided). Individuals were investigated with exome sequencing (12/14) or an autism/ID panel of >2500 genes (likely application of virtual panel on exome data). 13 individuals harbored a missense SNV and 1 further had a frameshift variant. In 12 individuals the variant had occurred de novo. 1 individual had inherited the variant from a possibly mosaic parent, while for 1 further a single parental sample was available. PRPF8 is intolerant to both missense (Z = 8.28) and pLoF variants (pLI : 1). Variants in 5 individuals were formally classified as VUS while 2 variants were present in gnomAD. Additional findings (CNVs/SNVs) were reported, in some cases possibly of relevance. As the authors discuss, heterozygous pathogenic missense SNVs cause (and account for ~2-3% of) non-syndromic AD retinitis pigmentosa with variable expressivity and incomplete penetrance. Variants for this phenotype are typically missense - although nonsense ones have also been reported - clustering within ex42 (of 43) encoding the MPN domain (aa 2103-2335 / NP_006436) and weakening interaction with 2 other spliceosomal proteins. Variants in the present study occurred throughout the gene. Although not universally assessed within the cohort, only one participant had RP (in this case variant within the MPN domain). There were no variant studies performed. Animal models: the authors cite a study by Graziotto et al (2011 - PMID: 20811066) where knock-in mice for a missense variant in ex42 displayed defects of the retinal pigment epithelium. A zebrafish ko model also cited (Keightley et al, 2013 - PMID: 23714367) displayed widespread apoptosis in brain and spinal cord. The authors cite a previous bioinformatic study identifying PRPF8 as a major hub connecting gene-interaction networks for NDDs (Casanova et al, 2018 - PMID: 30420816) as well as 2 studies demonstrating enrichment of variants in individuals with NDDs compared to controls (da Silva Montenegro et al, 2020 - PMID: 31696658, Karczewski et al, 2020 - PMID: 32461654). Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1564 | BUB1 |
Konstantinos Varvagiannis gene: BUB1 was added gene: BUB1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: BUB1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: BUB1 were set to 35044816 Phenotypes for gene: BUB1 were set to Congenital microcephaly; Global developmental delay; Intellectual disability; Abnormal heart morphology; Growth delay Penetrance for gene: BUB1 were set to Complete Review for gene: BUB1 was set to AMBER Added comment: A recent study provides evidence that this gene (biallelic variants) is relevant for inclusion in the DD/ID panel likely with amber / green rating (2 unrelated individuals with similar phenotype, 3 variants, role of this gene, extensive variant studies and demonstrated effects on cohesion and chromosome segregation, similarities with other disorders caused by mutations in mitosis-associated genes at the clinical and cellular level || number of affected subjects/families, different protein levels/kinase activity likely underlying few differences observed, role of monoallelic variants unclear). This gene could probably be included in other panels e.g. for microcephaly (not added). There is no BUB1-related phenotype in OMIM, G2P, SysID, PanelApp Australia. ------ Carvalhal, Bader et al (2022 - PMID: 35044816) describe the phenotype of 2 unrelated individuals with biallelic BUB1 pathogenic variants and provide evidence for the underlying mechanism for this condition. Common features comprised congenital microcephaly (2/2 | -2,8 and -2.9 SDs respectively / -7 and -4,9 SDs on last evaluation), DD/ID (2/2 - in one case with formal evaluation mild), some degree of growth retardation (2/2) and cardiovascular findings (2/2 - small ASD type II). Other findings limited to one subject included Pierre-Robin sequence, Axenfeld-Rieger anomaly, choanal stenosis, hypospadias, tracheal stenosis, etc. Initial genetic testing was normal (incl. CMA in both, metabolic testing and individual genes incl. PITX2, GREM1, FOXD3, FOXC1 for one proband). Exome sequencing revealed homozygosity for a start-lost variant (NM_004336.4:c.2T>G / p.?) in the first subject (P1). The variant lied within a 14-Mb region of homozygosity (no reported consanguinity). The second individual (P2) was compound htz for a splice-site and a frameshift variant (c.2625+1G>A and c.2197dupG) with Sanger sequencing used for confirmation and segregation studies. BUB1 encodes BUB1 Mitotic checkpoint serine/threonine kinase (/Budding uninhibited by benzimidazoles 1, s. cerevisiae, homolog of) a multifunctional component of the segregation machinery contributing to multiple mitotic processes. The protein has a kinetochore localization domain, multiple binding motifs and a C-terminal kinase domain (aa 784-1085) this structure allowing both kinase dependent/independent activities. cDNA sequencing revealed that the splice variant leads to skipping of ex21 and in-frame deletion of 54 residues in the kinase domain (c.2625+1G>A / p.Val822_Leu875del). Both individuals exhibited normal BUB1 mRNA levels (fibroblasts in both, tracheal tissue in one) but severely reduced protein levels (fibroblasts). A shorter protein product corresponding to the in-frame deletion variant was also detected. The authors performed additional experiments to confirm small amounts of full-length protein produced by the start-lost variant. This was shown in SV40-transformed fibroblasts from the corresponding individual (treatment with a proteasome inhibitor resulted also in higher levels). Upon generation RPE1 cells using CRISPR for the start-lost variant, again, small amounts of full length protein were detected, which was not the case for complete knockout HAP1 cells. No shorter versions could be detected in the patient cells or RPE1 cells, arguing against utilization of an alternative start codon. (Use of non-AUG start codons discussed based on literature). In line with small amounts of full-length protein the authors provided evidence for residual kinase activity for the start-loss variant (through proxy of phosphorylation of its substrate and use of a BUB1 kinase inhibitor). Cells from the individual with the frameshift variant and the splice variant had no residual kinase activity. The authors provide evidence for mitotic defects in cells from both individuals with prolonged mitosis duration and chromosome segregation defects. Some patient-specific findings were thought to be related with BUB1 protein levels (affecting BUB1-mediated kinetochore recruitment of BUBR1, important for chromosome alignment) and others due to residual kinase activity [->phosphorylation of H2A at Threonine 120-> affecting centromeric recruitment of Aurora B, SGO1 (role in protection of centromeric cohesion), TOP2A (a protein preventing DNA breakage during sister chromatid separation), these correlated with high anaphase bridges (in P2), aneuploidy observed in lymphoblasts and primary fibroblasts from P2 but not P2's lymphocytes or lymphocytes from P1) and defective sister chromatid cohesion defects (in primary fibroblasts from P2, milder effect for P1). Overall the authors provide evidence for overlapping clinical and cellular phenotype for this condition with primary microcephalies (MCPH - mutations in genes for mitotic regulators incl. kinetochore proteins or regulators of chromosome organization), mosaic variegated aneuploidy (biallelic variants in genes for kinetochore proteins, with random aneuploidies occurring in >5% cells of different tissues) and cohesinopathies (mostly Roberts or Warsaw breakage syndromes - characterized by cohesion loss and/or spontaneous railroad chromosomes). Mouse model: Hmz disruption in mice is lethal shortly after E3.5 (cited PMID: 19772675), while a hypomorphic mutant mouse (lacking exons 2-3, expressing <5% of wt protein levels) is viable but exhibits increased tumorigenesis with aging and aneuploidy (cited PMID: 19117986). Mutant mice that lack kinase activity though with preserved Bub1 protein abundance, did not display increased susceptibility, despite substantial segregation errors and aneuploidies (cited PMID: 23209306). The authors note that monoallelic germline BUB1 variants have been described in small number of individuals with CRC, exhibiting reduced expression levels and variegated aneuploidy in multiple tissues (cited PMID: 23747338) although the role of BUB1 is debated (cited PMIDs: 27713038, 29448935). Based on the discussion, complete loss of BUB1 activity is presumed to be embryonically lethal based on the mouse study (PMID: 19772675) and reduced BUB1 expression associated with spontaneous miscarriages (cited PMID: 20643875, to my understanding in this study mRNA levels remained relatively constant despite reduced Bub1 protein levels, mRNA RT-PCR followed by sequencing revealed only 2 synonymous BUB1 variants). Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1561 | DPH5 |
Konstantinos Varvagiannis gene: DPH5 was added gene: DPH5 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: DPH5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DPH5 were set to 35482014 Phenotypes for gene: DPH5 were set to Abnormality of prenatal development or birth; Neonatal hypotonia; Global developmental delay; Intellectual disability; Seizures; Abnormality of the cardiovascular system; Abnormality of the globe; Feeding difficulties; Short stature; Abnormality of head or neck Penetrance for gene: DPH5 were set to unknown Review for gene: DPH5 was set to AMBER Added comment: Shankar et al (2022 - PMID: 35482014) present evidence for a diphthamide-deficiency syndrome due to biallelic DPH5 pathogenic variants. As the authors summarize, DPH5 encodes a methyltransferase critical to the biosynthesis of diphthamide. Diphthamide is a post translationally modified histidine residue found in eukaryotic elongation factor 2 (eEF2). eEF2 is essential for mRNA translation and protein synthesis. The role of diphthamide is not clear, although it serves as a target for ADP-ribosylation, the latter resulting in inactivation of the eEF2 (inhibition of its translocation activity) and arrest of protein synthesis. Biosynthesis of diphthamide is complex involving multiple components (DPH1-DPH7) and the methylating co-factor S-adenosyl methionine, with 2 diphthamide-deficiency disorders due to biallelic DPH1 or DPH2 pathogenic variants and a NDD phenotype reported to date. The authors describe a phenotypic spectrum associated with biallelic DPH5 variants ranging from a prenatally lethal presentation to profound neurodevelopmental disorder. Details are provided on 5 individuals from 3 unrelated families. While one subject died at the age of few days due to multisystem complications, the phenotype appeared to be relatively consistent with prenatal findings (decreased fetal movements in 2 from 2 families, polyhydramnios in 2 from 2 families), hypotonia, global DD and ID (4/4 from 2 families - profound in 3), seizures (3/5 from 2 families - abnormal EEG in 4/4), cardiovascular findings (5/5, MVP and regurgitation in 2 from Fam1 || aortic dilatation in 2 sibs from Fam2 || VSD, ASD and hypopl. PA, pericardial effusion in 5th), GI issues (5/5, poor feeding in 4), short stature (4/4). Ocular findings were reported in 3/4 (gray sclerae in 2, ocular melanocytosis in 2). The authors describe some common craniofacial findings incl. broad/prominent forehead (5/5), sparse eyebrows (4/5), downturned corners of mouth or triangular chin (each in 3/5). WES/WGS revealed biallelic DPH5 variants in all affected individuals, namely: homozygosity for a missense variant in 2 sibs (NM_001077394.2:c.779A>G/p.His260Arg). Homozygosity for c.521dupA/p.Asn174LysTer10 for the individual deceased in the neonatal period (for this family there was significant history of spontaneous miscarriages/stillbirth/neonatal death). Two sibs born to non-consanguineous parents were compound htz for a stopgain and a missense SNV (c.619C>T/p.Arg207*, c.329A>G/p.Asn110Ser). In silico modeling revealed that the pLoF variants, not predicted to lead to NMD, likely remove the domain for interaction with eEF2 while the missense ones also affected interaction with eEF2. In recombinant MCF7 breast cancer cell line-derived DPH5-knockouts, transfected with recombinant expr. plasmids encoding wt or the 4 variants, the 2 truncating variants were shown to affect ADP-ribosylation of eEF2's diphthamide (total lack / minimal enzymatic activity for Arg207* and Asn174Lysfs respectively). Asn110Ser and His260Arg had residual activities which was thought to be explained by high expression levels compensating partial inactivation (given the multicopy plasmid-driven expression). ADP-ribosylation assays in S. cerevisiae demonstrated loss of function for the 2 truncating variants. Although the 2 missense variants retained sufficient activity to produce diphthamide (assayed through toxin induced ADP-ribosylation of eEF2), more sensitive assays indicated that diphthamide synthesis was also partially compromised for both variants. Generation of a knockin mouse model for His260Arg, appeared to recapitulate the human phenotypes with craniofacial, ophthalmologic, cardiac and visceral abnormalities and hmz mice being subviable. A single homozygous liveborn mouse had low birthweight, FTT, craniofacial dysmorphology, polydactyly, abnormal grooming behavior and early death. Few heterozygous embryos had craniofacial features, decreased body weight, reduced neuromuscular function without other abnormalities, either due to their inbred background or in the context of milder phenotype of heterozygosity in mice. DPH5 is ubiquitously expressed in all human tissues. The gene has a pLI of 0 and LOEUF score of 0.77 (0.48-1.27) in gnomAD. The authors refer to unpublished data, noting that complete absence of DPH5 is incompatible with life with embryonic lethality of a Dph5(ko/ko) line. The phenotype bears similarities to DPH1- and DPH2- related NDDs (both AR / green and amber respectively in ID panel) and appears to be more severe compared to the phenotype of de novo EEF2 variants (cited PMID: 33355653). Please consider inclusion in the ID panel with amber (4 individuals from 2 families with ID) / green rating (rather consistent phenotype in 3 families probably representing a continuous spectrum, variant studies, mouse model, similarities with diphthamide-deficiency syndromes). Also consider amber rating in the epilepsy panel (3 individuals from 2 families reported). The gene may be also relevant in other gene panels e.g. for congenital heart disease, short stature, etc (not added). Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1561 | CDK9 |
Konstantinos Varvagiannis changed review comment from: There are 4 studies reporting on the phenotype associated with biallelic CDK9 pathogenic variants. DD and ID are part of the phenotype which appears to be relatively consistent. CDK9 encodes Cyclin-dependent kinase 9. There are 4 missense variants reported to date - one of which recurrent (NM_001261.3:c.673C>T / p.Arg225Cys) - with studies for 3 variants suggesting a LoF effect (loss of kinase activity) [Ref4]. Animal models also provide some supporting evidence [discussed Ref4]. Consider inclusion in the current panel (probably with green rating) as well as other possibly relevant ones. Details provided below. [1]----- Shaheen et al (2016 - PMID: 26633546) studied patients with apparently novel phenotypes with positive family history consistent with AR inheritance mode due to consanguinity. After autozygome analysis the authors determined the shared autozygome (ROH >1 Mb / Axiom SNP Chip) in families with multiple affected individuals. This analysis was followed by whole exome/genome sequencing. Using this approach, they managed to map the phenotype of interest to a single novel locus in some families, which was also the case in a large consanguineous family with 2 similarly affected cousins (11DG0424, 11DG1630). Within a 20 Mb region of homozygosity, followed by WES in a single affected individual and Sanger confirmation with compatible segregation studies in parents and 10 unaffected sibs, the authors identified a homozygous CDK9 missense SNV (NM_001261.3:c.673C>T / p.Arg225Cys) responsible for this phenotype. In silico predictions were concordant in favor of a deleterious effect. Features (detailed in the suppl.) included global DD (2/2), severe ID (1/1), cerebral and (mild) cerebellar atrophy (2/2), microcephaly (2/2), ocular anomalies (2/2, coloboma in 2/2, congenital cataract 2/2, etc), heart defects (2/2, PDA in both, ASD), variable genitourinary anomalies (2/2 incl. hydronephrosis, VUR reflux/recurrent UTIs, kidney atrophy, abn. genitalia in 1), abnormalities of the limbs (2/2, bilateral talipes equinovarus : 2/2) or the skeleton (1/2 - butterfly vertebrae). One was reported to have some degree of growth delay (<10th centile for length, <5th for weight and OFC). There was no hearing defect reported (large ears in 1/2). Overall, the authors used the term CHARGE-like phenotype. [2]----- Maddirevula et al (2019 - PMID: 30237576) performed autozygome and exome analysis of individuals with suspected Mendelian disorders. They reported 3 individuals (18DG0161, 18DG0162, 18DG0165) born to 3 different consanguineous families (information in fig2) from Qatar, homozygous for CDK9 p.Arg225Cys. All presented a CHARGE-like phenotype with features ophtalmologic findings (3/3 - abnormal ERG in one, congenital cataracts the other, visual impairment in the 3rd, though NO evidence of coloboma in at least two), heart defect (2/3 had VSD), choanal atresia (3/3), retarded growth/FTT (1/3) or global DD (3/3 - in suppl. table 1), (genito)urinary anomalies (1/3 - dysplastic atrophic kidney) or ear anomalies (3/3 - preauricular tags 2/3, bilateral deafness 1/3, bilat.ossicular anomalies 1/3). Other features incl. epilepsy (2/3), brain MRI abnormalities (2/3), facial asymmetry in one, vertebral segmentation defect in 1/3. [3]----- Hu et al (2019 - PMID: 29302074) performed WES/WGS in 404 consanguineous families from Iran, having 2 or more offspring with ID. In this context they reported 2 females and a male (III:1,4,3 belonging to fam. M9100018 - details in suppl. text) born to first cousin parents from Iran. Features included DD (3/3 - walking at 3y, words at 4y), moderate ID (3/3 - WAIS-IV IQ of 40-43), short stature (3/3 below 3rd %le). Vision and hearing were normal. All three were homozygous for a missense SNV (NM_001261:c.280C>T, p.Arg94Cys) which was ultrarare in ExAC, with severa in silico tools in favor of a deleterious effect. The authors commented that CDK9 is the catalytic core of transcription elongation factor p-TEFb essential for transcription elongation of numerous genes, Cdk9/Cyclin T1 complex may participate in neuronal differentiation, CDK9-cyclinK in maintenance of genomic integrity, with the protein encoded also interacted with AF4/FMR2. In addition the gene was commented to have ubiquitous expression with high protein expression in glial and neuronal cells of the cortex (based on Uniprot and Human Protein Atlas). [4]----- Nishina et al (2021 - PMID: 33640901) described an 8 y.o. male with facial asymmetry, ear/hearing anomalies (microtia, preauricular tags, bilateral hearing loss), ocular/vision anomalies (blepharophimosis, lacrimal obstruction, eyelid dermoids, duane-like anomaly, congenital cataracts, retinal dystrophy), cleft lip and palate, abnormalities of the limbs (finger contractures with associated absence of creases, cutaneous syndactyly, etc). Other features included cardiac dysrhythmia and undescended testes. Development was delayed with associated ID (walking 3y, words 7y, at 10y: could count to 20, 4 word sentences). There was no evidence of coloboma or choanal atresia. Trio exome sequencing revealed that the child was compound htz for 2 missense SNVs (NM_001261.3:c.862G>A / p.Ala288Thr and c.907C>T /p.Arg303Cys) with Sanger confirmation. These were ultrarare/not present in gnomAD. Both lied in the protein kinase catalytic domain of CDK9, with high conservation across different species and in silico predictions in favor of deleterious effect. In vitro studies in HEK293 cells demonstrated that the kinase activity for both variants was significantly reduced compared to wt. Kinase activity was also reduced for the Arg225Cys variant (reported in Refs 1 & 2). The authors briefly discuss evidence from zebrafish (regulates larval morphogenesis incl. brain, heart, eye, blood vessels) and mouse models. In the latter complete LoF is lethal while heterozygous LoF is associated with abnormal morphology of heart, skin and epididymis (PMIDs cited by the authors : 27715402, 30100824). Sources: Literature; to: There are 4 studies reporting on the phenotype associated with biallelic CDK9 pathogenic variants. DD and ID are part of the phenotype which appears to be relatively consistent. CDK9 encodes Cyclin-dependent kinase 9. There are 4 missense variants reported to date - one of which recurrent (NM_001261.3:c.673C>T / p.Arg225Cys) - with studies for 3 variants suggesting a LoF effect (loss of kinase activity) [Ref4]. Animal models also provide some supporting evidence [discussed Ref4]. Consider inclusion in the current panel (probably with green rating) as well as other possibly relevant ones. Details provided below. [1]----- Shaheen et al (2016 - PMID: 26633546) studied patients with apparently novel phenotypes with positive family history consistent with AR inheritance due to consanguinity. Using autozygome analysis the authors determined the shared autozygome (ROH >1 Mb / Axiom SNP Chip) in families with multiple affected individuals. This analysis was followed by whole exome/genome sequencing. Using this approach, they managed to map the phenotype of interest to a single novel locus in some families, which was also the case in a large consanguineous family with 2 similarly affected cousins (11DG0424, 11DG1630). Within a 20 Mb region of homozygosity, followed by WES in a single affected individual and Sanger confirmation with compatible segregation studies in parents and 10 unaffected sibs, the authors identified a homozygous CDK9 missense SNV (NM_001261.3:c.673C>T / p.Arg225Cys) responsible for this phenotype. In silico predictions were concordant in favor of a deleterious effect. Features (detailed in the suppl.) included global DD (2/2), severe ID (1/1), cerebral and (mild) cerebellar atrophy (2/2), microcephaly (2/2), ocular anomalies (2/2, coloboma in 2/2, congenital cataract 2/2, etc), heart defects (2/2, PDA in both, ASD), variable genitourinary anomalies (2/2 incl. hydronephrosis, VUR/recurrent UTIs, kidney atrophy, abn. genitalia in 1), abnormalities of the limbs (2/2, bilateral talipes equinovarus : 2/2) or the skeleton (1/2 - butterfly vertebrae). One was reported to have some degree of growth delay (<10th centile for length, <5th for weight and OFC). There was no hearing defect reported (large ears in one case). Overall, the authors used the term CHARGE-like for this phenotype. [2]----- Maddirevula et al (2019 - PMID: 30237576) performed autozygome and exome analysis of individuals with suspected Mendelian disorders. They reported 3 individuals (18DG0161, 18DG0162, 18DG0165) born to 3 different consanguineous families (information in fig2) from Qatar, homozygous for CDK9 p.Arg225Cys. All presented a CHARGE-like phenotype with ophthalmologic findings (3/3 - abnormal ERG in one, congenital cataracts the other, visual impairment in the 3rd, though NO evidence of coloboma in at least two of them), heart defect (2/3 with VSD), choanal atresia (3/3), retarded growth/FTT (1/3) or global DD (3/3 - in suppl. table 1), (genito)urinary anomalies (1/3 - dysplastic atrophic kidney) or ear anomalies (3/3 - preauricular tags in 2/3, bilateral deafness 1/3, bilateral ossicular anomalies 1/3). Other features incl. epilepsy (2/3), brain MRI abnormalities (2/3), facial asymmetry in one, vertebral segmentation defect in 1/3. [3]----- Hu et al (2019 - PMID: 29302074) performed WES/WGS in 404 consanguineous families from Iran, having 2 or more offspring with ID. In this context they reported 2 females and a male (III:1,4,3 belonging to fam. M9100018 | suppl. text) born to first cousin parents from Iran. Features included DD (3/3 - walking at 3y, words at 4y), moderate ID (3/3 - WAIS-IV IQ of 40-43), short stature (3/3 below 3rd %le). Vision and hearing were normal. All three were homozygous for a missense SNV (NM_001261:c.280C>T, p.Arg94Cys) which was ultrarare in ExAC, with several in silico tools in favor of a deleterious effect. The authors commented that CDK9 is the catalytic core of transcription elongation factor p-TEFb essential for transcription elongation of numerous genes, Cdk9/Cyclin T1 complex may participate in neuronal differentiation, CDK9-cyclinK in maintenance of genomic integrity, with the protein encoded also interacting with AF4/FMR2. In addition the gene was commented to have ubiquitous expression with high protein expression in glial and neuronal cells of the cortex (based on Uniprot and Human Protein Atlas). [4]----- Nishina et al (2021 - PMID: 33640901) described an 8 y.o. male with facial asymmetry, ear/hearing anomalies (microtia, preauricular tags, bilateral hearing loss), ocular/vision anomalies (blepharophimosis, lacrimal obstruction, eyelid dermoids, duane-like anomaly, congenital cataracts, retinal dystrophy), cleft lip and palate, abnormalities of the limbs (finger contractures with associated absence of creases, cutaneous syndactyly, etc). Other features included cardiac dysrhythmia and undescended testes. Development was delayed with ID (walking 3y, words 7y, at 10y: could count to 20, 4 word sentences). There was no evidence of coloboma or choanal atresia. Trio exome revealed that the child was compound htz for 2 missense SNVs (NM_001261.3:c.862G>A / p.Ala288Thr and c.907C>T /p.Arg303Cys) with Sanger confirmation. These were ultrarare/not present in gnomAD. Both lied in the protein kinase catalytic domain of CDK9, with high conservation across different species and in silico predictions in favor of deleterious effect. In vitro studies in HEK293 cells demonstrated that the kinase activity for both variants was significantly reduced compared to wt. Kinase activity was also reduced for the Arg225Cys variant (reported in Refs 1 & 2). The authors briefly discuss evidence from zebrafish (regulates larval morphogenesis incl. brain, heart, eye, blood vessels) and mouse models. In the latter complete LoF is lethal while heterozygous LoF is associated with abnormal morphology of heart, skin and epididymis (PMIDs cited : 27715402, 30100824). Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1561 | CDK9 |
Konstantinos Varvagiannis gene: CDK9 was added gene: CDK9 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CDK9 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CDK9 were set to 26633546; 30237576; 29302074; 33640901 Phenotypes for gene: CDK9 were set to Global developmental delay; Intellectual disability; Abnormality of vision; Congenital cataract; Iris coloboma; Abnormal heart morphology; Choanal atresia; Abnormality of the ear; Preauricular skin tag; Hearing impairment; Abnormality of the genitourinary system; Abnormality of limbs; Abnormality of the vertebrae; Abnormality of nervous system morphology; Seizures Penetrance for gene: CDK9 were set to Complete Review for gene: CDK9 was set to GREEN Added comment: There are 4 studies reporting on the phenotype associated with biallelic CDK9 pathogenic variants. DD and ID are part of the phenotype which appears to be relatively consistent. CDK9 encodes Cyclin-dependent kinase 9. There are 4 missense variants reported to date - one of which recurrent (NM_001261.3:c.673C>T / p.Arg225Cys) - with studies for 3 variants suggesting a LoF effect (loss of kinase activity) [Ref4]. Animal models also provide some supporting evidence [discussed Ref4]. Consider inclusion in the current panel (probably with green rating) as well as other possibly relevant ones. Details provided below. [1]----- Shaheen et al (2016 - PMID: 26633546) studied patients with apparently novel phenotypes with positive family history consistent with AR inheritance mode due to consanguinity. After autozygome analysis the authors determined the shared autozygome (ROH >1 Mb / Axiom SNP Chip) in families with multiple affected individuals. This analysis was followed by whole exome/genome sequencing. Using this approach, they managed to map the phenotype of interest to a single novel locus in some families, which was also the case in a large consanguineous family with 2 similarly affected cousins (11DG0424, 11DG1630). Within a 20 Mb region of homozygosity, followed by WES in a single affected individual and Sanger confirmation with compatible segregation studies in parents and 10 unaffected sibs, the authors identified a homozygous CDK9 missense SNV (NM_001261.3:c.673C>T / p.Arg225Cys) responsible for this phenotype. In silico predictions were concordant in favor of a deleterious effect. Features (detailed in the suppl.) included global DD (2/2), severe ID (1/1), cerebral and (mild) cerebellar atrophy (2/2), microcephaly (2/2), ocular anomalies (2/2, coloboma in 2/2, congenital cataract 2/2, etc), heart defects (2/2, PDA in both, ASD), variable genitourinary anomalies (2/2 incl. hydronephrosis, VUR reflux/recurrent UTIs, kidney atrophy, abn. genitalia in 1), abnormalities of the limbs (2/2, bilateral talipes equinovarus : 2/2) or the skeleton (1/2 - butterfly vertebrae). One was reported to have some degree of growth delay (<10th centile for length, <5th for weight and OFC). There was no hearing defect reported (large ears in 1/2). Overall, the authors used the term CHARGE-like phenotype. [2]----- Maddirevula et al (2019 - PMID: 30237576) performed autozygome and exome analysis of individuals with suspected Mendelian disorders. They reported 3 individuals (18DG0161, 18DG0162, 18DG0165) born to 3 different consanguineous families (information in fig2) from Qatar, homozygous for CDK9 p.Arg225Cys. All presented a CHARGE-like phenotype with features ophtalmologic findings (3/3 - abnormal ERG in one, congenital cataracts the other, visual impairment in the 3rd, though NO evidence of coloboma in at least two), heart defect (2/3 had VSD), choanal atresia (3/3), retarded growth/FTT (1/3) or global DD (3/3 - in suppl. table 1), (genito)urinary anomalies (1/3 - dysplastic atrophic kidney) or ear anomalies (3/3 - preauricular tags 2/3, bilateral deafness 1/3, bilat.ossicular anomalies 1/3). Other features incl. epilepsy (2/3), brain MRI abnormalities (2/3), facial asymmetry in one, vertebral segmentation defect in 1/3. [3]----- Hu et al (2019 - PMID: 29302074) performed WES/WGS in 404 consanguineous families from Iran, having 2 or more offspring with ID. In this context they reported 2 females and a male (III:1,4,3 belonging to fam. M9100018 - details in suppl. text) born to first cousin parents from Iran. Features included DD (3/3 - walking at 3y, words at 4y), moderate ID (3/3 - WAIS-IV IQ of 40-43), short stature (3/3 below 3rd %le). Vision and hearing were normal. All three were homozygous for a missense SNV (NM_001261:c.280C>T, p.Arg94Cys) which was ultrarare in ExAC, with severa in silico tools in favor of a deleterious effect. The authors commented that CDK9 is the catalytic core of transcription elongation factor p-TEFb essential for transcription elongation of numerous genes, Cdk9/Cyclin T1 complex may participate in neuronal differentiation, CDK9-cyclinK in maintenance of genomic integrity, with the protein encoded also interacted with AF4/FMR2. In addition the gene was commented to have ubiquitous expression with high protein expression in glial and neuronal cells of the cortex (based on Uniprot and Human Protein Atlas). [4]----- Nishina et al (2021 - PMID: 33640901) described an 8 y.o. male with facial asymmetry, ear/hearing anomalies (microtia, preauricular tags, bilateral hearing loss), ocular/vision anomalies (blepharophimosis, lacrimal obstruction, eyelid dermoids, duane-like anomaly, congenital cataracts, retinal dystrophy), cleft lip and palate, abnormalities of the limbs (finger contractures with associated absence of creases, cutaneous syndactyly, etc). Other features included cardiac dysrhythmia and undescended testes. Development was delayed with associated ID (walking 3y, words 7y, at 10y: could count to 20, 4 word sentences). There was no evidence of coloboma or choanal atresia. Trio exome sequencing revealed that the child was compound htz for 2 missense SNVs (NM_001261.3:c.862G>A / p.Ala288Thr and c.907C>T /p.Arg303Cys) with Sanger confirmation. These were ultrarare/not present in gnomAD. Both lied in the protein kinase catalytic domain of CDK9, with high conservation across different species and in silico predictions in favor of deleterious effect. In vitro studies in HEK293 cells demonstrated that the kinase activity for both variants was significantly reduced compared to wt. Kinase activity was also reduced for the Arg225Cys variant (reported in Refs 1 & 2). The authors briefly discuss evidence from zebrafish (regulates larval morphogenesis incl. brain, heart, eye, blood vessels) and mouse models. In the latter complete LoF is lethal while heterozygous LoF is associated with abnormal morphology of heart, skin and epididymis (PMIDs cited by the authors : 27715402, 30100824). Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1558 | SLC35B2 |
Konstantinos Varvagiannis gene: SLC35B2 was added gene: SLC35B2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: SLC35B2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC35B2 were set to 35325049 Phenotypes for gene: SLC35B2 were set to Abnormality of the skeletal system; Short long bone; Short stature; Abnormality of epiphysis morphology; Scoliosis; Multiple joint dislocation; Global develpmental delay; Intellectual disability; CNS hypomyelination; Abnormality of the corpus callosum; Cerebral atrophy; Abnormality of the amniotic fluid Penetrance for gene: SLC35B2 were set to Complete Review for gene: SLC35B2 was set to AMBER Added comment: 2 unrelated individuals with biallelic SLC35B2 variants have been reported. DD and ID were part of the phenotype. There is currently no associated phenotype in OMIM/G2P/SysID. The gene has amber rating in the leukodystrophies panel of PanelApp Australia. Consider inclusion in the current panel (or other possibly relevant ones eg. for skeletal disorders, short stature, white matter disorders, corpus callosum, etc) with amber rating. --- Guasto et al (2022 - PMID:35325049) report 2 unrelated individuals with biallelic SLC35B2 variants. SLC35B2 encodes solute carrier family 35 (3'-phosphoadenosine 5'-phosphosulfate (PAPS) transporter), member B2. The protein is located in the Golgi membrane and serves as transporter of the activated nucleotide sulfate PAPS from the cytosol, where it is synthesized to the Golgi lumen. Another PAPS transporter is encoded by SLC35B3. In the Golgi apparatus PAPS serves as substrate of sulfotransferases for the addition sulfate to the covalently attached GAG chains of proteoglycans (PGs). The phenotype corresponded to a chondrodysplasia manifesting as severe pre- and postnatal growth retardation (height <-4 SD and -8 SD), early scoliosis, multiple joint dislocations (in one). There was severe DD affecting motor and expressive language development with associated ID. Brain imaging was suggestive of hypomyelinating leukodystrophy with thin corpus callosum and cerebral atrophy. One individual had a cleft palate in the context of Pierre Robin sequence. Both individuals were investigated with exome sequencing. The first individual - born to consanguineous parents - was homozygous for an in-frame del (NM_178148.3:c.1218_1220del, p.Leu407del) with Sanger sequencing confirming the variants, and heterozygosity in parents and 2 unaffected sibs. There was an initially identified hmz CUL7 variant (for 3M syndrome), which was not felt sufficient to explain the severity of the phenotype and notably ID. The 2nd proband was homozygous for a fs variant (c.1224_1225delAG / p.Arg408SerfsTer18 - leading to loss of the last 8 amino acids) occurring in the context of uniparental isodisomy [iUPD(6)] spanning the complete chr6 based on the exome data. Among the evidence presented for SLC35B2 and the variants : - SLC35B2 has high mRNA expression in fetal and adult mouse brain and other tissues. - Upon qPCR analysis of mRNA expression in human brain samples, the gene had expression across the brain (frontal lobe grey matter, subcortical frontal white matter/cerebellum). - High expression was shown upon analysis of mouse brain single cell RNA data (EMBL) in oligodendrocytes and microglial cells. - RT-PCR on mRNA from skin fibroblasts (both individuals) revealed significant decrease of SCL35B2 mRNA levels compared to controls. - Transfection of C-terminal c-myc tagged wt or mutant proteins in HEK293F cells, followed by western blotting did not reveal significant difference at the protein level. Wt SLC35B2 localized at the Golgi apparatus as suggested by colocalization with GM130 marker. The 2 variants however displayed only partial colocalization (/loss of localization specificity) with diffuse signal in the cell. - Chondroitin sulfate disaccharide sulfation was decreased upon HPLC disaccharide analysis in patient fibroblasts and bikunin (a circulating proteoglycan in blood) electrophoretic pattern in patient sera. - Disorders due to variants in genes implicated in proteoglycan biogenesis (e.g. XYLT1, B3GALT6, CHSY1) are associated with skeletal/connective tissue manifestations with DD/ID. - C-elegans model lacking pst-1 (SLC35B2 ortholog) provides support that the protein is required for migration, axonal guidance, and presynaptic development in a subset of neurons. - dsm-1 - the rat ortholog - is expressed in rat brain in D-serine and NMDA receptor rich regions. When expressed in Xenopus oocytes it accelerated the efflux of D-serine (a co-agonist for NMDA receptor). - Variants in other members of SLC superfamily (e.g. SLC17A5, SLC35A3, SLC29A3, SLC35A2) have been associated with brain-bone phenotypes. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1544 | DTYMK |
Konstantinos Varvagiannis gene: DTYMK was added gene: DTYMK was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: DTYMK was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DTYMK were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Global brain atrophy; Cardiorespiratory arrest Phenotypes for gene: DTYMK were set to 31271740; 34918187; 35346037 Penetrance for gene: DTYMK were set to Complete Review for gene: DTYMK was set to GREEN Added comment: 4 individuals (from 3 families) harboring biallelic DTYMK pathogenic variants have been reported. Consider inclusion in the current panel with green rating given consistent and relevant phenotype and evidence provided to date [effect of variants (LoF), pathogenesis, similar phenotypes in zebrafish model, etc]. Relevant studies are summarized below. ---- Lam et al (2019 - PMID: 31271740) described two siblings aged 25m and 7y, harboring biallelic DTYMK variants. The phenotype consisted of hypotonia, congenital microcephaly, DD, severe ID. Other shared features included raised serum lactate, pyruvate and alanine. The phenotype was more pronounced in the younger one (epilepticus during febrile illness, epilepsy on multiple anti-convulsants, evidence of regression, etc). Brain MRI revealed marked cerebral atrophy among the findings while a lactate peak was present in spectroscopy. The elder brother developed an episode of sudden onset coma with respiratory failure at the age of 7y. Quartet WES identified compound heterozygosity for a fs and a missense DTYMK variant (NM_012145.3:c.287_320del / p.Asp96Valfs*8 - c.295G>A / p.Ala99Thr). There were no additional findings. Previous genetic panel analysis for epilepsy was unremarkable for the 1st sib. There are two pathways for synthesis of dNTPs, the de novo pathway operating in the cytosol only and the salvage operating in both cytosol and mitochondria. DTYMK encodes (deoxy)thymidylate kinase which catalyzes conversion (phosphorylation) of dTMP to dTDP - a step right after convergence of both pathways - in the dTTP synthesis pathway. Mutations in TK2, an enzyme phosphorylating thymidine in mitochondria to dTMP have been associated with mitochondrial DNA depletion syndrome (MDDS). Given this and as the 2 sibs had raised serum lactate and pyruvate, the authors performed in silico analyses to calculate mtDNA/nDNA ratio dividing the respective read depths for mitochondrial and nuclear DNA obtained from WGS data of the two sibs (blood). This ratio was shown to be reduced in the more severely affected sib (65.5% of control) although this was not the case for the mildly affected brother (114.6%). As a control a non-MDDS mitochondrial cytopathy sample (corresponding to m.8993T>G) was used. The respective ratio which was calculated for a known POLG-related MDDS case was 15.6%. ---- Vanoevelen et al (2022 - PMID: 34918187) describe two unrelated children with hypotonia, absence of developmental progress, microcephaly, seizures (recurrent febrile seizures/myoclonic jerks). Severe cerebral atrophy (with unaffected cerebellum) was observed upon brain imaging. Other findings included puffy body/extremities. Both had complications following respiratory illness leading to demise. CNS pathology in the 1st individual revealed massive neuronal dropout, with sparing of dentate nucleus and brainstem. CMA in both cases was normal. This was also the case for extensive metabolic investigations (which provided no evidence of eventual mitochondrial dysfunction). WES revealed compound heterozygosity for 2 missense variants in the first individual (NM_012145.3:c.382G>A - p.Asp128Asn and c.242C>T - p.Pro81Leu). The second individual, born to consanguineous parents, was homozygous for c.242C>T / p.Pro81Leu. In silico predictions varied although each variant were (mostly) suggestive of a deleterious effect. Variants were both ultrarare without homozygotes in ExAC,. The authors generated a dtymk ko zebrafish model (hmz for a frameshift variant). Zebrafish exhibited markedly smaller eyes and pericardiac edema (3dpf-), twitching movements somewhat reminiscent of epilepsy (at 3dpf), prominent edema of brain and intestine. Head size was significantly smaller at a timepoint prior to brain edema (also after correction for length). Histology provided evidence of empty spaces in brain, suggestive of neurodegeneration, with high amounts of apoptotic cells. dTMPK activity was measured in zebrafish (at 5dpf) as well as in fibroblasts from one individual and in both cases, it was barely detectable and significantly lower compared to wt/htz zebrafish or to the activity in fibroblasts from the parents of the individual tested. In fibroblasts from the same individual with comparison to his parents, the authors demonstrated that DNA replication was impaired (using pulse-EdU staining to quantify cells in S-phase). Assessment of cell proliferation in the brain of dtymk ko zebrafish using phospo-Ser10-Histone H3 (pH3) staining was suggestive of severe proliferation defects in forebrain. Impaired biosynthesis of nucleotides for DNA synthesis/repair would be predicted to result in nucleotide pool imbalance, leading to incorporation of ribonucleotides in genomic DNA with - in turn - impairment of DNA replication and genomic instability (sensitivity to strand breakage). In line with this, genomic DNA of ko zebrafish following alkaline hydrolysis and alkaline gel electrophoresis was shown to migrate at lower position and to be more fragmented indicating increased sensitivity (due to incorporation of ribonucleotides). Visualization of DNA breakage by γH2AX staining, following UV-irradiation of zebrafish embryos revealed persistence of elevated γH2AX levels and DNA damage response signaling, interpreted as increase in unrepaired DNA breaks. mtDNA copy numbers in fibroblasts from the affected individual was somewhat but not significantly lower compared to his parents. Importantly, the copy numbers were similar to controls (N=5) which overall does not support mtDNA depletion as a consequence of DTYMK deficiency. Integrity of mtDNA did not appear to be compromised , with the mitochondrial genome migrating at the expected length of 16,5 kb with no indications of mtDNA deletions for both affected individual and his parents. Activity of the mitochondrial respiratory complexes I-V in fibroblasts from the affected individual was comparable to that of his parents. Overall, there was no evidence for mtDNA depletion (although not studied in muscle biopsy) while functional studies failed to demonstrate mitochondrial dysfunction. The authors discuss other disorders of impaired dTTP metabolism due to mutations in TYMP, RRM2B or CAD. ------ In a recent study using zebrafish model, Hu Frisk et al (2022 - PMID: 35346037) further demonstrate that Dtymk is essential for neurodevelopment providing evidence for expression of a compensatory thymidylate kinase-like enzyme at later stages of development (explaining survival of ko dtymk zebrafish despite the central role of this enzyme in dTTP generation). [Not further reviewed] Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1544 | KDM5B | Arina Puzriakova Phenotypes for gene: KDM5B were changed from neurodevelopment delay and autism spectrum disorder; Mental retardation, autosomal recessive 65, 618109 to Intellectual developmental disorder, autosomal recessive 65, OMIM:618109 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1542 | HEPACAM | Arina Puzriakova Phenotypes for gene: HEPACAM were changed from Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation (AD), 613926; Megalencephalic leukoencephalopathy with subcortical cysts 2A (AR), 613925 to Megalencephalic leukoencephalopathy with subcortical cysts 2A, OMIM:613925; Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation, OMIM:613926 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1530 | MAN2C1 |
Konstantinos Varvagiannis gene: MAN2C1 was added gene: MAN2C1 was added to Intellectual disability. Sources: Literature,Other Mode of inheritance for gene: MAN2C1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MAN2C1 were set to 35045343 Phenotypes for gene: MAN2C1 were set to Global developmental delay; Intellectual disability; Abnormality of nervous system morphology; Abnormality of the corpus callosum; Ventriculomegaly; Polymicrogyria; Abnormality of the face; Macrocephaly Penetrance for gene: MAN2C1 were set to unknown Review for gene: MAN2C1 was set to GREEN Added comment: Biallelic pathogenic MAN2C1 variants cause Congenital disorder of deglycosylation 2 (# 619775). Mild to moderate impairment of intellectual development is a feature in most patients as in the OMIM's clinical synopsis for this disorder. ---- Specifically, Maia et al (2022 - PMID: 35045343) report the clinical features based of 6 relevant individuals (4/6 aged 4-18years and 2/6 fetuses) from 4 families. These individuals had non-specific dysmorphic features (micro/retrognathia being the most common in 5/6), different congenital anomalies, variable degrees of ID (3/4), as well as brain MRI abnormalities (PMG in 3/6 from 3 fam, ventriculomegaly in 3/6 from 2 fam, callosal anomalies in 4/6 from 3 fam, cerebellar hypoplasia 2/6 - 2 fam, vermis hypoplasia 4/6 - 3 fam etc). Macrocephaly was reported for 2/6 individuals (2 fam). While ID was observed in 3/4 individuals of relevant age (mild in 1/4, moderate in 1/4, unk in 1/4), delayed motor and language development was reported for all (4/4). All individuals harbored biallelic MAN2C1 variants following exome sequencing (previous investigations not reported), and Sanger sequencing was used for validation and segregation (parents/sibs). There were no putative pathogenic variants in known disease genes. MAN2C1 encodes mannosidase, alpha, class 2c, member 1, an enzyme playing a role in deglycosylation of free oligosaccharides (fOSs). The latter are generated and released in the cytoplasm or the ER lumen during N-glycosylation of proteins. fOSs are generated from two different pathways (ERAD and LLO) with a defect in an enzyme of the NGLY1 already described to cause a NDD due to defect of deglycosylation. In a later step oligossaccharides are trimmed by the action of ENGase to form fOS containing one GlcNAc (N-Acetylglucosamine) residue (fOSGn1) at the reducing end. Processing of these fOSs by the cytosolic α-mannosidase (MAN2C1) converts Man7-9Gn1 to Man5Gn1 subsequently transported to lysosomes for degradation. Variants incl. 3 missense SNVs incl. c.2612G>C/p.Cys871Ser, c.2303G>A/p.Arg768Gln, c.607G>A/p.Gly203Arg, one splice variant (c.601-2A>G/p.Gly201Profs*10) and one indel (c.2733_2734del/p.His911Glnfs*67). [RefSeq NM_006715.3] Most were present in gnomAD with low AF ranging from 0.013% to 0.11% while c.2303G>A/p.Arg768 has an AF of 0.33% with 5 homozygotes(*) in the database. Conservation and in silico predictions supported their effect. For the variant affecting the splicing acceptor site (c.601-2A>G) studies in patient fibroblasts confirmed skipping of ex6. Fibroblasts from 2 sibs cmp htz for Arg768Gln and c.601-2A>G (Gly201Profs*10) were studied for protein levels, demonstrating 90% reduction in the amount of MAN2C1. There was no truncated protein observed upon immunoblot. Protein abundance was not affected in fibroblasts from the individual who was homozygous for Gly203Arg. Mannosidase activities were studied upon overexpression in a HEK293 model, with Gly203Arg presenting similar activity to WT and Arg768Gln exhibiting only a tiny residual activity. Cys871Ser showed increased activity compared to WT. Using fibroblasts from controls and the same individuals as above, the authors showed that pathogenic MAN2C1 variants caused defects in fOS processing (delayed processing of high oligomannose species, reduced production of M5Gn1 with M8 and M9Gn1/2 species remaining at high levels) supporting a total/partial loss of mannosidase activity for Arg768Gln and Gly203Arg. In MAN2C1-KO HAP1 cell lines, M7-M9Gn1 species accumulated while M5Gn1 - the product of MAN2C1 - were absent. Complementation of KO HAP1 cells with Gly203Arg, Arg768Gln and Cys871Ser suggested impaired fOS processing for Gly203Arg and Arg768Gln (with significant amounts of M7-M9Gn1 species). Cells complemented with Cys871Ser did not exhibit fOS processing defects. The authors speculate that Cys871Ser could affect a non-mannosidase function of the enzyme relevant to brain development or that it might lead to abnormal inter-subunit interactions or tetramer formation. Finally, Maia et al summarize findings in previously described Man2c1-KO mice (cited PMID: 24550399). These appeared normal, did not exhibit differences in growth or lifespan and did not present behavioral alterations. Man2c1-KO mice had CNS involvement with histological analyses in favor of neuronal and glial degeneration with multiple vacuoles in deep neocortical layers and telencephalic white matter tracts. Vacuolization was not observed upon brain histology for the 2 fetuses studied which Maia et al speculate may occur at a later stage. In KO mice there was considerable accumulation of Man8–9GlcNAc oligosaccharides. ---- G2P includes MAN2C1 in it's DD panel (confidence: strong, MAN2C1-associated neurodevelopmental disorder with cerebral malformations). In PanelApp Australia, this gene is rated green in the ID, polymicrogyria, cerebellar hypoplasia and fetal anomalies gene panels. Consider inclusion in the current panel with green (3 individuals/families/variants, role of the gene, NDD phenotype also reported for NGLY1-related disorder of deglycosylation, variant studies) or amber rating (ID not a universal feature, still DD observed in all affected individuals). Please consider adding this gene in other relevant panels (as in PanelApp Australia, also for corpus callosum abnormalities, metabolic disorders, etc). Sources: Literature, Other |
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| Intellectual disability - microarray and sequencing v3.1529 | SLC38A3 |
Konstantinos Varvagiannis gene: SLC38A3 was added gene: SLC38A3 was added to Intellectual disability. Sources: Literature,Other Mode of inheritance for gene: SLC38A3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC38A3 were set to 34605855 Phenotypes for gene: SLC38A3 were set to Infantile axial hypotonia; Global developmental delay; Intellectual disability; Seizures; Spasticity; Microcephaly; Cerebral atrophy; Cerebellar atrophy; Abnormality of the corpus callosum; Dysphagia; Constipation; Increased serum lactate; Hyperammonemia Penetrance for gene: SLC38A3 were set to Complete Review for gene: SLC38A3 was set to GREEN Added comment: Marafi et al (2021 - PMID: 34605855) describe the phenotype of 10 individuals, belonging to 7 families (6/7 consanguineous), harboring biallelic deleterious SLC38A3 variants. One subject (from fam3) was previously reported in the context of a larger cohort of consanguineous families investigated with exome sequencing (2017, PMID: 31130284). The phenotype overall corresponded to a DEE and features included axial hypotonia (10/10), severe global DD or ID (10/10), seizures (8/10, onset : 1w-15m, NOT observed in 2/10 aged 1y3m and 4y | s. types: tonic-clonic in 3/8, tonic 2/8, focal 2/8 with secondary generalization, myoclonic 1/8, gelastic 1/8 | EEG burst-suppression, hypsarrhythmia in few). Microcephaly was observed in (8/10) and was more commonly postnatal and/or progressive. Variable abnormalities were observed upon brain imaging incl. cerebral (5/10) or cerebellar atrophy (2/10) and abnormal CC (6/10), abnormal myelination for age (6/10). Other phenotypes included visual impairment (9/10), peripheral hypertonia (8/9) constipation (8/9) and dysphagia (7/9), FTT (4/8), movement disorder (3/10). Metabolic studies indicated (transient) elevation of lactate (7/8 - also pyruvate in 2) and elevated plasma ammonia (4/7). Individuals from the 1st family were investigated with ES, and the SLC38A3 splice site variant (NM_006841.6:c.855+1G>T) was the most likely candidate, additional SNVs not contributing to the NDD phenotype. Other affected subjects were ascertained through GeneMatcher/collaborations. In total, 3 different missense and 4 pLoF (1 fs, 2 nonsense, 1 splicing) variants were identified with individuals from 2 families being hmz or cmd htz for missense variants. Variants were absent/ultrarare with no homozygotes in public/in-house databases with several in silico predictions in favor of a deleterious effect. Regions of AOH (around SLC38A3/total) are provided for some individuals/families. Sanger sequencing was used for confirmation and segregation studies (apart from carrier parents in 7/7 fam, 11 unaffected sibs tested in 6/7 fam). The solute carrier (SLC) superfamily of transmembrane transporters - highly expressed in mammalian brain - is involved in exchange of amino-acids (AAs), nutrients, ions, neurotransmitters and metabolites etc across biological membranes with >100 SLC-encoding genes associated with NDDs. SLC38A3 specifically encodes SNAT3, a sodium-coupled neutral amino-acid transporter, principal transporter of Asn, His, Gln (precursor for GABA and glutamate), expressed in brain, liver, kidney, retina and pancreas. In the brain, it localizes to peri-synaptic astrocytes playing an important role in glutamate/GABA-glutamine cycle. While the pLoF variants are predicted to undergo NMD or result in non-functional protein, protein modelling suggested that missense ones affect protein activity or stability. Biochemical and metabolic screening was carried out for several individuals with plasma AAs reported normal (10/10), urinary OAs normal in 9/9, CSF AAs (incl. GABA/glutamine) normal in 2 sibs, CSF lactate normal in 1 indiv. studied. As discussed above plasma ammonia was elevated in 4/7 (2 fam), and 7/10 had elevated lactate and/or pyruvate (2/7). Untargeted metabolomic profiles performed in biofluids (plasma from 3 subjects, CSF:1, urine:1) were suggestive of altered AA and nitrogen metabolism. In particular, alterations in levels of AA known to be transported by SNAT3 were found. 676 molecules overall showed deviation in plasma samples, 630 in urine and 241 in CSF (albeit with no consistent pattern). Perturbations in several biochemical pathways were shown to occur (incl. Gln-,Asn- and His- pathways). Slc38a3-/- mice have reductions in brain glutamate and GABA neurotransmitters in homogenized brain tissue (GABA analytes being normal in plasma samples or the single CSF sample available from affected subjects). Snat3-deficient mice had elevation of plasma urea and normal ammonia levels (urea was low in all human samples and ranged from -2 to -3.5 SD in plasma, ammonia was elevated in 4/7). Slc38a3-/- mice have impaired growth, lethargy and ataxic gait, altered plasma AAs, normal glutamine in plasma with abundance in brain and exhibit early lethality. Plasma AAs were normal in 4 affected individuals, impaired growth observed in 4 and gait impairment was observed in 9/10. Hypoglycemia, previously reported in Slc38a3-/- mice, was not observed in any of the patients although this is presumably explained by diet/feeding intervals with abnormalities in pentose phosphate pathway in one individual hypothesized to be reflective of abn. glucose metabolism. The human phenotypes of microcephaly and seizures were not observed in mice. For mouse studies PMIDs cited by the authors : 27362266, 26490457. There is currently no SLC38A3-related phenotype reported in OMIM. In G2P this gene is incl. in the DD panel (biallelic, confidence: strong, SLC38A3-associated epileptic encephalopathy). SLC38A3 is listed among the primary ID genes in SysID. In PanelApp Australia, SLC38A3 is included with green rating in the epilepsy, ID and microcephaly panels. Consider inclusion with green rating (10 individuals, 7 families, 7 variants, role of SLCs and SLC38A3, alterations in AA/nitrogen metabolism etc) or amber rating (if discordances with mouse model considered). Please consider inclusion in other panels e.g. for microcephaly, CC abnormalities, metabolic disorders, etc. Sources: Literature, Other |
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| Intellectual disability - microarray and sequencing v3.1528 | ADAT3 | Arina Puzriakova Phenotypes for gene: ADAT3 were changed from Mental retardation, autosomal recessive 36, 615286; MRT36 to Neurodevelopmental disorder with brain abnormalities, poor growth, and dysmorphic facies, OMIM:615286 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1518 | HEATR3 |
Konstantinos Varvagiannis gene: HEATR3 was added gene: HEATR3 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: HEATR3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HEATR3 were set to 35213692 Phenotypes for gene: HEATR3 were set to Anemia; Thrombocytopenia; Growth delay; Short stature; Abnormality of the skeletal system; Abnormality of finger; Abnormality of the thumb; Intellectual disability; Obesity; Abnormality of the face Penetrance for gene: HEATR3 were set to Complete Review for gene: HEATR3 was set to AMBER Added comment: O'Donohue et al (2022 - PMID: 35213692) describe the clinical features of 6 individuals (from 4 unrelated families) with biallelic pathogenic HEATR3 variants. These included bone marrow failure (anemia/anemia and thrombocytopenia at presentation), short stature/growth retardation (4/6), facial features (5/6 - in some: straight eyebrows, d-s palpebral fissures, synophrys) and skeletal findings incl. disproportionately short fingers/thumb anomaly. ID was reported in 4/6 individuals from 3 families (all: mild ID | 2/6 without ID). The phenotype corresponded overall to a variant form Diamond-Blackfan anemia (DBA, disorder caused by variants in genes encoding for ribosomal proteins) with additional features. The 1st family (2 affected sibs and parents) underwent WES, not diagnostic for DBA. Analysis suggested variants in HEATR3 (prioritized due to its potential role in ribosome biogenesis) and 4 additional genes as candidates. Collaboration in the European DBA consortium and national DBA consortia led to identification of additional families. HEATR3 encodes Heat-repeat-containing protein 3 or symportin, a protein that co-imports uL5 (encoded by RPL11) and uL18 (RPL5) in the nucleus where they assemble with 5S rRNA to form 5S RNP. The 5S RNP complex incorporates with maturing large ribosomal subunits to form the central protuberance. When 5S RNP is not incorporated, it accumulates and associates with Hdm2 ubiquitin ligase, the later normally targeting p53 proteasomal degradation. The following missense and splice variants were identified (NM_182922): - c.1751G>Α/p.(Gly584Glu) hmz - c.1337G>A/p.(Cys446Tyr) hmz - c.399+1G>T in trans with c.719C>T/p.(Pro240Leu) - c.400T>C/p.(Cys134Arg) hmz Variants were confirmed with Sanger sequencing. They were dispersed across HEATR3 without clustering although they affect residues either in the ARM (38-320) or HEAT (415-675) repeat domains, at positions evolutionary conserved, with in silico predictions in favor of a deleterious effect. With the exception of Cys134Arg (AF:4.11x10-6/no hmz), all were absent from gnomAD. Studies in yeast suggested that deletions in symportin gene (syo1) lead to a mild growth defect and accumulation of 40S subunits. Similarly, two yeast strains engineered to test for the effect of the p.Gly584Glu (yeast p.Gly522Glu/Ala) exhibited growth defect and ribosomal subunit imbalance, both restored by wt Syo1. HA-tagged HEATR3 in HeLa cells suggested that the co-translational capture mechanism to chaperone uL18 (RPL5) is conserved in human cells but was not observed upon expression of the p.Cys446Tyr variant. While HEATR3 transcription was not affected in LCLs from individuals hmz for Gly584Glu or Cys446Tyr, protein levels were barely detectable, suggesting destabilization of the protein. While uL18 accumulates in cytoplasm and nucleus with expected enrichment in nucleolus, upon siRNA knockdown of HEATR3 in HeLa cells this enrichment was lost. Studies in fibroblasts (Gly584Glu) demonstrated reduced uL18 nuclear staining. Overall, HEATR3 was suggested to be important for nuclear import of uL18 (though not for uL5). LCL studies demonstrated pre-rRNA processing defects in patient cells with accumulation of 32S and 12S pre-rRNAs, the former being reminiscent of accumulations observed in individuals with RPL5- and RPL11-related DBA. Expression of wt HEATR3 restored processing defects. LCLs from affected individuals revealed loss of free 60S subunits (as in yeast) with expression of wt cDNA restoring Nl levels. Western blots of LCLs demonstrated that the levels of uL5, uL18 and p53 were not affected (the latter also observed in RPL5-related DBA) Studies of bone marrow smears from 2 affected individuals allowed to conclude in a strong defect in erythroid cell proliferation. Currently, there is no HEATR3-associated phenotype in OMIM, PanelApp Australia, G2P or the SysID database. Consider inclusion in the ID panel with amber (mild ID in >3 individuals/families/variants although not universal feature) or green rating. Also consider inclusion in other possibly relevant panels eg. for cytopenias/congenital anemias, short stature, etc. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1513 | NUS1 | Arina Puzriakova Phenotypes for gene: NUS1 were changed from #617082 - ?Congenital disorder of glycosylation, type 1aa; #617831 - Mental retardation, autosomal dominant 55, with seizures; Abnormality of extrapyramidal motor function to Mental retardation, autosomal dominant 55, with seizures, OMIM:617831; Congenital disorder of glycosylation, type 1aa, OMIM:617082 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1506 | PDZD8 |
Konstantinos Varvagiannis changed review comment from: Al-Amri et al (2022 - PMID: 35227461) describe 4 affected individuals, belonging to 2 independent consanguineous families, harboring biallelic pLoF PDZD8 variants. The phenotype corresponded to a syndromic form of ID with autistic features. Animal models provide additional evidence for a role of the gene. Details are provided concerning 3 affected sibs born to consanguineous parents (Fam-A) and a male proband born to first cousin parents (Fam-B) from different countries of the Arabian Peninsula. Features included DD (4/4), ID (4/4 - moderate to severe), autistic features[*](4/4), other behavioral problems (3/4 - 2 families). Variable facial features were observed (4/4 - incl. hypertelorism 4/4, myopathic face, open mouth, low-set ears, ptosis). 3 sibs presented with myopathy[*](3/4 overall - 1 fam - see below), and marfanoid habitus was observed in 2 (2/4 - 1 fam). 2 sibs had epilepsy (2/4 - from 1 family). 1 individual had congenital heart defect. [* -also to consider for MOI]Autistic features were however observed in a parent and a htz sib. Mild myopathy/reduced facial expression was also observed in both parents. Contribution of another variant - also within the region of shared homozygosity - to the phenotype of myopathy was deemed to be possible within this family. Previous genetic testing was not reported. Homozygosity mapping in the 1st family identified 3 homozygous regions (2.57 - 28 Mb) shared by all affected sibs. Singleton WES revealed 2 candidate variants within these regions, a PDZD8 frameshift variant [NM_173791.5:c.2197_2200del;p.(S733*)] lying in the last exon and an ANKRD2 missense one (discussed above). The proband in Fam-B was hmz for a nonsense variant in ex2 (of 5), namely c.894C>G/p.(Y298*) considered to be the most likely cause of his phenotype following singleton WES. Sanger sequencing was used for validation and segregation studies confirming carrier status of the parents and compatible results in unaffected sibs (tested : 2 in Fam-A, 3 in Fam-B). Both variants were absent from gnomAD (the first also from a pool of 50 control individuals of the same origin) where PDZD8 has a pLI of 1 (5 different pLoF variants, none hmz). Expression was not studied for the 2 variants. As a result, it is not known whether they escape NMD (as could be expected for the variant in the last exon). PDZD8 encodes an endoplasmatic reticulum (ER) transmembrane protein (TM). As the authors discuss, it has been previously shown that depletion of PDZD8 in neurons impairs endosomal homeostasis, decreases proximity of ER-mitochondria and decreases Ca+2 uptake mitochondria following synaptic transmission-induced release from the ER (sev. refs. provided). The gene is highly expressed in the human brain (incl. subclasses of GABAergic / glutamatergic neurons in adult primary motor cortex). The authors analyzed RNA-seq data from the BrainSpan project, demonstrating stable expression in human brain from 8 wks after conception to adulthood. The gene is not expressed in blood. The authors performed in vivo functional studies. Knockdown of the orthologous gene (CG10362) in Drosophila via RNA interference was shown to result in impairment of long-term memory. Mice homozygous for a variant introducing a premature termination codon exhibited restricted growth, brain structural alterations (incl. relative reduction of the CC, as in one subject), spontaneous stereotypies, decreased anxiety-like behavior with deficits in spatial memory and impaired hippocampal neurophysiology. Currently, there is no associated phenotype in OMIM, Gene2Phenotype, SysID or PanelApp Australia. Overall, this gene can be considered for inclusion in the ID panel probably with amber rating pending further reports. Sources: Literature; to: Al-Amri et al (2022 - PMID: 35227461) describe 4 affected individuals, belonging to 2 independent consanguineous families, harboring biallelic pLoF PDZD8 variants. The phenotype corresponded to a syndromic form of ID with autistic features. Animal models provide additional evidence for a role of the gene. Details are provided concerning 3 affected sibs born to consanguineous parents (Fam-A) and a male proband born to first cousin parents (Fam-B) from different countries of the Arabian Peninsula. Features included DD (4/4), ID (4/4 - moderate to severe), autistic features[*](4/4), other behavioral problems (3/4 - 2 families). Variable facial features were observed (4/4 - incl. hypertelorism 4/4, myopathic face, open mouth, low-set ears, ptosis). 3 sibs presented with myopathy[*](3/4 overall - 1 fam - see below), and marfanoid habitus was observed in 2 (2/4 - 1 fam). 2 sibs had epilepsy (2/4 - from 1 family). 1 individual had congenital heart defect. [*] (also to consider for MOI) : Autistic features were however observed in a parent and a htz sib. Mild myopathy/reduced facial expression was also observed in both parents. Contribution of another variant - also within the region of shared homozygosity - to the phenotype of myopathy was deemed to be possible within this family. Previous genetic testing was not reported. Homozygosity mapping in the 1st family identified 3 homozygous regions (2.57 - 28 Mb) shared by all affected sibs. Singleton WES revealed 2 candidate variants within these regions, a PDZD8 frameshift variant [NM_173791.5:c.2197_2200del;p.(S733*)] lying in the last exon and an ANKRD2 missense one (discussed above). The proband in Fam-B was hmz for a nonsense variant in ex2 (of 5), namely c.894C>G/p.(Y298*) considered to be the most likely cause of his phenotype following singleton WES. Sanger sequencing was used for validation and segregation studies confirming carrier status of the parents and compatible results in unaffected sibs (tested : 2 in Fam-A, 3 in Fam-B). Both variants were absent from gnomAD (the first also from a pool of 50 control individuals of the same origin) where PDZD8 has a pLI of 1 (5 different pLoF variants, none hmz). Expression was not studied for the 2 variants. As a result, it is not known whether they escape NMD (as could be expected for the variant in the last exon). PDZD8 encodes an endoplasmatic reticulum (ER) transmembrane protein (TM). As the authors discuss, it has been previously shown that depletion of PDZD8 in neurons impairs endosomal homeostasis, decreases proximity of ER-mitochondria and decreases Ca+2 uptake mitochondria following synaptic transmission-induced release from the ER (sev. refs. provided). The gene is highly expressed in the human brain (incl. subclasses of GABAergic / glutamatergic neurons in adult primary motor cortex). The authors analyzed RNA-seq data from the BrainSpan project, demonstrating stable expression in human brain from 8 wks after conception to adulthood. The gene is not expressed in blood. The authors performed in vivo functional studies. Knockdown of the orthologous gene (CG10362) in Drosophila via RNA interference was shown to result in impairment of long-term memory. Mice homozygous for a variant introducing a premature termination codon exhibited restricted growth, brain structural alterations (incl. relative reduction of the CC, as in one subject), spontaneous stereotypies, decreased anxiety-like behavior with deficits in spatial memory and impaired hippocampal neurophysiology. Currently, there is no associated phenotype in OMIM, Gene2Phenotype, SysID or PanelApp Australia. Overall, this gene can be considered for inclusion in the ID panel probably with amber rating pending further reports. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1506 | PDZD8 |
Konstantinos Varvagiannis gene: PDZD8 was added gene: PDZD8 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PDZD8 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PDZD8 were set to 35227461 Phenotypes for gene: PDZD8 were set to Global developmental delay; Intellectual disability; Autistic behavior; Behavioral abnormality; Myopathy; Abnormality of the face; Hypertelorism; Seizures; Disproportionate tall stature Penetrance for gene: PDZD8 were set to Complete Review for gene: PDZD8 was set to AMBER Added comment: Al-Amri et al (2022 - PMID: 35227461) describe 4 affected individuals, belonging to 2 independent consanguineous families, harboring biallelic pLoF PDZD8 variants. The phenotype corresponded to a syndromic form of ID with autistic features. Animal models provide additional evidence for a role of the gene. Details are provided concerning 3 affected sibs born to consanguineous parents (Fam-A) and a male proband born to first cousin parents (Fam-B) from different countries of the Arabian Peninsula. Features included DD (4/4), ID (4/4 - moderate to severe), autistic features[*](4/4), other behavioral problems (3/4 - 2 families). Variable facial features were observed (4/4 - incl. hypertelorism 4/4, myopathic face, open mouth, low-set ears, ptosis). 3 sibs presented with myopathy[*](3/4 overall - 1 fam - see below), and marfanoid habitus was observed in 2 (2/4 - 1 fam). 2 sibs had epilepsy (2/4 - from 1 family). 1 individual had congenital heart defect. [* -also to consider for MOI]Autistic features were however observed in a parent and a htz sib. Mild myopathy/reduced facial expression was also observed in both parents. Contribution of another variant - also within the region of shared homozygosity - to the phenotype of myopathy was deemed to be possible within this family. Previous genetic testing was not reported. Homozygosity mapping in the 1st family identified 3 homozygous regions (2.57 - 28 Mb) shared by all affected sibs. Singleton WES revealed 2 candidate variants within these regions, a PDZD8 frameshift variant [NM_173791.5:c.2197_2200del;p.(S733*)] lying in the last exon and an ANKRD2 missense one (discussed above). The proband in Fam-B was hmz for a nonsense variant in ex2 (of 5), namely c.894C>G/p.(Y298*) considered to be the most likely cause of his phenotype following singleton WES. Sanger sequencing was used for validation and segregation studies confirming carrier status of the parents and compatible results in unaffected sibs (tested : 2 in Fam-A, 3 in Fam-B). Both variants were absent from gnomAD (the first also from a pool of 50 control individuals of the same origin) where PDZD8 has a pLI of 1 (5 different pLoF variants, none hmz). Expression was not studied for the 2 variants. As a result, it is not known whether they escape NMD (as could be expected for the variant in the last exon). PDZD8 encodes an endoplasmatic reticulum (ER) transmembrane protein (TM). As the authors discuss, it has been previously shown that depletion of PDZD8 in neurons impairs endosomal homeostasis, decreases proximity of ER-mitochondria and decreases Ca+2 uptake mitochondria following synaptic transmission-induced release from the ER (sev. refs. provided). The gene is highly expressed in the human brain (incl. subclasses of GABAergic / glutamatergic neurons in adult primary motor cortex). The authors analyzed RNA-seq data from the BrainSpan project, demonstrating stable expression in human brain from 8 wks after conception to adulthood. The gene is not expressed in blood. The authors performed in vivo functional studies. Knockdown of the orthologous gene (CG10362) in Drosophila via RNA interference was shown to result in impairment of long-term memory. Mice homozygous for a variant introducing a premature termination codon exhibited restricted growth, brain structural alterations (incl. relative reduction of the CC, as in one subject), spontaneous stereotypies, decreased anxiety-like behavior with deficits in spatial memory and impaired hippocampal neurophysiology. Currently, there is no associated phenotype in OMIM, Gene2Phenotype, SysID or PanelApp Australia. Overall, this gene can be considered for inclusion in the ID panel probably with amber rating pending further reports. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1501 | NALCN | Arina Puzriakova Phenotypes for gene: NALCN were changed from ?Neuroaxonal neurodegeneration, infantile, with facial dysmophism, 615419; CONGENITAL CONTRACTURES OF THE LIMBS AND FACE, HYPOTONIA, AND DEVELOPMENTAL DELAY to Congenital contractures of the limbs and face, hypotonia, and developmental delay, OMIM:616266; Hypotonia, infantile, with psychomotor retardation and characteristic facies 1, OMIM:615419 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1496 | SLC35F1 |
Zornitza Stark gene: SLC35F1 was added gene: SLC35F1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: SLC35F1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SLC35F1 were set to 33821533 Phenotypes for gene: SLC35F1 were set to Neruodevelopmental disorder, MONDO:0700092, SLC35F1-associated; Rett-like syndrome Review for gene: SLC35F1 was set to RED Added comment: WES identified a de novo heterozygous c.1037T>C; p.(I346T) (absent in gnomad v2 and v3) in a female described to have Rett-like syndrome. Global developmental delay, generalized tonic andtonic–clonic seizure, never acquired independent walking and developed spastictetraplegia in adulthood and limited speech No functional data Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1468 | GPT2 | Arina Puzriakova Phenotypes for gene: GPT2 were changed from Microcephaly; Mental retardation, autosomal recessive 49, 138210; Intellectual disability; Progressive spasticity to Neurodevelopmental disorder with microcephaly and spastic paraplegia, OMIM:616281 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1453 | FXN | Arina Puzriakova Phenotypes for gene: FXN were changed from Friedreich ataxia 229300; Friedreich ataxia with retained reflexes 229300 to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1379 | CDH15 | Arina Puzriakova Phenotypes for gene: CDH15 were changed from Mental retardation, autosomal dominant 3, 612580; MENTAL RETARDATION AUTOSOMAL DOMINANT TYPE 3 (MRD3) to Mental retardation, autosomal dominant 3, OMIM:612580 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1368 | AP1S2 | Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Mental retardation, X-linked syndromic, Fried type, 300630; MENTAL RETARDATION X-LINKED TYPE 59 (MRX59) to Pettigrew syndrome, OMIM:304340 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1364 | ZDHHC15 | Ivone Leong Added comment: Comment on phenotypes: Previously associated with ?Mental retardation, X-linked 91, OMIM:300577; however, OMIM has removed this | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1364 | ZDHHC15 | Ivone Leong Phenotypes for gene: ZDHHC15 were changed from ?Mental retardation, X-linked 91, 300577 to cerebral palsy; intellectual disability; autism spectrum disorder; epilepsy | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1352 | SNIP1 | Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. A single (founder) variant NM_024700.4:c.1097A>G, p.(Glu366Gly) has been reported in over 30 cases of Psychomotor retardation, epilepsy, and craniofacial dysmorphism OMIM:614501 in the Amish community (PMIDs: 22279524; 34570759). Cases are homozygous for this variant and unaffected members of the families are heterozygous or wt. Overexpression of the equivalent mouse variant in mouse inner medullary collecting duct cells, resulted in a more aggregated appearance in the nucleus compared to wildtype. The variant protein maybe unstable as Western blots showed reduced levels of the variant protein (PMID: 22279524). Whole transcriptomic analysis of patient blood was performed in PMID: 34570759. This revealed 11 upregulated and 32 downregulated genes, of which 24 had previously been associated with neurological disease. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1350 | SNIP1 | Sarah Leigh Phenotypes for gene: SNIP1 were changed from Psychomotor retardation, epilepsy, and craniofacial dysmorphism, 614501; severe developmental delay to Psychomotor retardation, epilepsy, and craniofacial dysmorphism OMIM:614501; psychomotor retardation, epilepsy, and craniofacial dysmorphism MONDO:0013787 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1342 | GRIK2 | Ivone Leong Phenotypes for gene: GRIK2 were changed from Mental retardation, autosomal recessive, 6, OMIM:611092; on-syndromic neurodevelopmental disorder (NDD), autosomal dominant to Mental retardation, autosomal recessive, 6, OMIM:611092; non-syndromic neurodevelopmental disorder (NDD), autosomal dominant | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1340 | GRIK2 | Ivone Leong Phenotypes for gene: GRIK2 were changed from Mental retardation, autosomal recessive, 6, 611092; MENTAL RETARDATION AUTOSOMAL RECESSIVE TYPE 6 (MRT6) to Mental retardation, autosomal recessive, 6, OMIM:611092; on-syndromic neurodevelopmental disorder (NDD), autosomal dominant | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1335 | ZDHHC15 | Zornitza Stark reviewed gene: ZDHHC15: Rating: RED; Mode of pathogenicity: None; Publications: 34345675; Phenotypes: Mental retardation, X-linked 91, 300577, cerebral palsy, intellectual disability, autism spectrum disorder, epilepsy; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1332 | KIF4A | Zornitza Stark reviewed gene: KIF4A: Rating: GREEN; Mode of pathogenicity: None; Publications: 24812067, 34346154; Phenotypes: Mental retardation, X-linked 100, MIM# 300923; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1332 | TAF2 | Zornitza Stark reviewed gene: TAF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34474177, 21937992, 22633631, 26350204; Phenotypes: Mental retardation, autosomal recessive 40, OMIM # 615599; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1330 | UBE2U | Ivone Leong Phenotypes for gene: UBE2U were changed from Retinoschisis; cataracts; learning disabilities; developmental delay to Retinoschisis, MONDO:0004579; cataracts; learning disability, MONDO:0004681; developmental delay | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1313 | CDH15 | Zornitza Stark reviewed gene: CDH15: Rating: RED; Mode of pathogenicity: None; Publications: 19012874, 12052883, 28422132, 26506440; Phenotypes: Mental retardation, autosomal dominant 3, MIM#612580; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1271 | GRIN1 | Sarah Leigh Phenotypes for gene: GRIN1 were changed from Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive, 617820; NDHMSR; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, 614254; NDHMSD; Mental retardation, autosomal dominant 8, 614254; EPILEPTIC ENCEPHALOPATHY to Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant OMIM:614254; intellectual disability, autosomal dominant 8 MONDO:0013655; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive OMIM:617820; neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive MONDO:0060629 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1269 | GNB1 | Sarah Leigh Phenotypes for gene: GNB1 were changed from Mental retardation, autosomal dominant 42 OMIM:616973; intellectual disability, autosomal dominant 42 MONDO:0014855 to Mental retardation, autosomal dominant 42 OMIM:616973; intellectual disability, autosomal dominant 42 MONDO:0014855 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1269 | GNB1 | Sarah Leigh Phenotypes for gene: GNB1 were changed from Mental retardation, autosomal dominant 42, OMIM:616973 to Mental retardation, autosomal dominant 42 OMIM:616973; intellectual disability, autosomal dominant 42 MONDO:0014855 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1262 | UBE2U |
Zornitza Stark gene: UBE2U was added gene: UBE2U was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: UBE2U was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: UBE2U were set to 33776059 Phenotypes for gene: UBE2U were set to Retinoschisis; cataracts; learning disabilities; developmental delay Review for gene: UBE2U was set to RED Added comment: Single family with 5 individuals reported. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1262 | CACNA1I |
Zornitza Stark gene: CACNA1I was added gene: CACNA1I was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CACNA1I was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CACNA1I were set to 33704440 Phenotypes for gene: CACNA1I were set to Neurodevelopmental disorder Mode of pathogenicity for gene: CACNA1I was set to Other Review for gene: CACNA1I was set to GREEN gene: CACNA1I was marked as current diagnostic Added comment: 4 different missense variants identified and shown to result in a gain of function. 2 individuals with de novo variants (a 3rd also suspected de novo but their father was unavailable for testing) - these patients all had severe neurodevelopmental disorders, involving severe global developmental delay, absence of speech, gross motor delay, muscular hypotonia, early-onset seizures, cortical visual impairment, and feeding difficulties. Variable clinical features include various brain malformations, startle response or seizures, postnatal growth retardation, gastroesophageal reflux, and gastrostomy. 1 family had three affected individuals - variable cognitive impairment in all, involving borderline intellectual functioning or mild or moderate intellectual disability as main clinical feature, with late-onset seizures in the mother and speech retardation in one of the children. This variant had a milder functional effect than the variants in sporadic cases. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1262 | GRIK2 | Zornitza Stark reviewed gene: GRIK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34375587, 17847003, 25039795; Phenotypes: Mental retardation, autosomal recessive, 6 MIM# 611092, Non-syndromic neurodevelopmental disorder (NDD), autosomal dominant; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1256 | CRADD | Arina Puzriakova Phenotypes for gene: CRADD were changed from Mental retardation, autosomal recessive 34, with variant lissencephaly 614499 to Mental retardation, autosomal recessive 34, with variant lissencephaly, OMIM:614499 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1251 | GMPPB | Sarah Leigh Phenotypes for gene: GMPPB were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 615350; Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 14 615351; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 615352 to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 OMIM:615350; muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14 MONDO:0014140; Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 14 OMIM:615351; muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14 MONDO:0014141; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 OMIM:615352; autosomal recessive limb-girdle muscular dystrophy type 2T MONDO:0014142 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1242 | L1CAM | Arina Puzriakova Phenotypes for gene: L1CAM were changed from Hydrocephalus due to aqueductal stenosis, 307000MASA syndrome, 303350CRASH syndrome, 303350Hydrocephalus with Hirschsprung disease, 307000Hydrocephalus with congenital idiopathic intestinal pseudoobstruction, 307000Corpus callosum, partial agenesis of, 304100; MENTAL RETARDATION-APHASIA-SHUFFLING GAIT-ADDUCTED THUMBS SYNDROME (MASA) to Corpus callosum, partial agenesis of, OMIM:304100; CRASH syndrome, OMIM:303350; MASA syndrome, OMIM:303350; Hydrocephalus due to aqueductal stenosis, OMIM:307000; Hydrocephalus with congential idiopathic intestinal pseudoobstruction, OMIM:307000; Hydrocephalus with Hirschsprung disease, OMIM:307000 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1240 | WDR45B | Arina Puzriakova Phenotypes for gene: WDR45B were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION; Neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without seizures, 617977 to Neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without seizures, OMIM:617977 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1232 | KDM5C | Arina Puzriakova Phenotypes for gene: KDM5C were changed from Mental retardation, X-linked, syndromic, Claes-Jensen type, 300534 -3; MENTAL RETARDATION SYNDROMIC X-LINKED JARID1C-RELATED (MRXSJ) to Mental retardation, X-linked, syndromic, Claes-Jensen type, OMIM:300534 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1228 | HNMT | Ivone Leong Phenotypes for gene: HNMT were changed from Mental retardation, autosomal recessive 51, MIM#616739 to Mental retardation, autosomal recessive 51, OMIM:616739 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1224 | ENTPD1 | Arina Puzriakova Phenotypes for gene: ENTPD1 were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to Spastic paraplegia 64, autosomal recessive, OMIM:615683 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1220 | VPS50 |
Konstantinos Varvagiannis gene: VPS50 was added gene: VPS50 was added to Intellectual disability. Sources: Literature 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 Review for gene: VPS50 was set to AMBER Added comment: Schneeberger et al (2021 - PMID: 34037727) describe the phenotype of 2 unrelated individuals with biallelic VPS50 variants. Common features included transient neonatal cholestasis, failure to thrive, severe DD with failure to achieve milestones (last examination at 2y and 2y2m respectively), postnatal microcephaly, seizures (onset at 6m and 25m) and irritability. There was corpus callosum hypoplasia on brain imaging. Both individuals were homozygous for variants private to each family (no/not known consanguinity applying to each case). The first individual was homozygous for a splicing variant (NM_017667.4:c.1978-1G>T) and had a similarly unaffected sister deceased with no available DNA for testing. The other individual was homozygous for an in-frame deletion (c.1823_1825delCAA / p.(Thr608del)). VPS50 encodes a critical component of the endosome-associated recycling protein (EARP) complex, which functions in recycling endocytic vesicles back to the plasma membrane [OMIM based on Schindler et al]. The complex contains VPS50, VPS51, VPS52, VPS53, the three latter also being components of GARP (Golgi-associated-retrograde protein) complex. GARP contains VPS54 instead of VPS50 and is required for trafficking of proteins to the trans-golgi network. Thus VPS50 (also named syndetin) and VPS54 function in the EARP and GARP complexes, to define directional movement of their endocytic vesicles [OMIM based on Schindler et al]. The VPS50 subunit is required for recycling of the transferrin receptor. As discussed by Schneeberger et al (refs provided in text): - VPS50 has a high expression in mouse and human brain as well as throughout mouse brain development. - Mice deficient for Vps50 have not been reported. vps50 knockdown in zebrafish results in severe developmental defects of the body axis. Knockout mice for other proteins of the EARP/GARP complex (e.g. Vps52, 53 and 54) display embryonic lethality. Studies performed by Schneeberger et al included: - Transcript analysis for the 1st variant demonstrated skipping of ex21 (in patient derived fabriblasts) leading to an in frame deletion of 81 bp (r.1978_2058del) with predicted loss of 27 residues (p.Leu660_Leu686del). - Similar VPS50 mRNA levels but significant reduction of protein levels (~5% and ~8% of controls) were observed in fibroblasts from patients 1 and 2. Additionally, significant reductions in the amounts of VPS52 and VPS53 protein levels were observed despite mRNA levels similar to controls. Overall, this suggested drastic reduction of functional EARP complex levels. - Lysosomes appeared to have similar morphology, cellular distribution and likely unaffected function in patient fibroblasts. - Transferrin receptor recycling was shown to be delayed in patient fibroblasts suggestive of compromise of endocytic-recycling function. As the authors comment, the phenotype of both individuals with biallelic VPS50 variants overlaps with the corresponding phenotype reported in 15 subjects with biallelic VPS53 or VPS51 mutations notably, severe DD/ID, microcephaly and early onset epilepsy, CC anomalies. Overall, for this group, they propose the term "GARP and/or EARP deficiency disorders". There is no VPS50-associated phenotype in OMIM or G2P. SysID includes VPS50 among the ID candidate genes. Consider inclusion in other relevant gene panels (e.g. for neonatal cholestasis, epilepsy, microcephaly, growth failure in early infancy, corpus callosum anomalies, etc) with amber rating pending further reports. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1220 | CTC1 | Arina Puzriakova Phenotypes for gene: CTC1 were changed from CEREBRORETINAL MICROANGIOPATHY WITH CALCIFICATIONS AND CYSTS to Cerebroretinal microangiopathy with calcifications and cysts, OMIM:612199 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1216 | CLCN3 |
Zornitza Stark gene: CLCN3 was added gene: CLCN3 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CLCN3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: CLCN3 were set to 34186028 Phenotypes for gene: CLCN3 were set to Neurodevelopmental disorder Mode of pathogenicity for gene: CLCN3 was set to Other Review for gene: CLCN3 was set to GREEN gene: CLCN3 was marked as current diagnostic Added comment: 11 individuals reported, 9 that carried 8 different rare heterozygous missense variants in CLCN3, and 2 siblings that were homozygous for an NMD-predicted frameshift variant likely abolishing ClC-3 function. All missense variants were confirmed to be de novo in eight individuals for whom parental data was available. The 11 individuals in the cohort share clinical features of variable severity. All 11 have GDD or ID and dysmorphic features, and a majority has mood or behavioural disorders and structural brain abnormalities: - Structural brain abnormalities on MRI (9/11) included partial or full agenesis of the corpus callosum (6/9), disorganized cerebellar folia (4/9), delayed myelination (3/9), decreased white matter volume (3/9), pons hypoplasia (3/9), and dysmorphic dentate nuclei (3/9). Six of those with brain abnormalities also presented with seizures. - Nine have abnormal vision, including strabismus in four and inability to fix or follow in the two with homozygous loss-of-function variants. - Hypotonia ranging from mild to severe was reported in 7 of the 11 individuals. - Six have mood or behavioural disorders, particularly anxiety (3/6). - Consistent dysmorphic facial features included microcephaly, prominent forehead, hypertelorism, down-slanting palpebral fissures, full cheeks, and micrognathia. The severity of disease in the two siblings with homozygous disruption of ClC-3 is consistent with the drastic phenotype seen in Clcn3 KO mice. The disease was more severe in two siblings carrying homozygous loss-of-function variants with the presence of GDD, absent speech, seizures, and salt and pepper fundal pigmentation in both individuals, with one deceased at 14 months of age. The siblings also had significant neuroanatomical findings including diffusely decreased white matter volume, thin corpora callosa, small hippocampi, and disorganized cerebellar folia. Supporting biallelic inheritance for LoF variants, disruption of mouse Clcn3 results in drastic neurodegeneration with loss of the hippocampus a few months after birth and early retinal degeneration. Clcn3−/− mice display severe neurodegeneration, whereas heterozygous Clcn3+/− mice appear normal. Patch-clamp studies were used to investigate four of the missense variants. These suggested a gain of function in two variants with increased current in HEK cells, however they also showed reduced rectification of voltage and a loss of transient current, plus decreased current amplitude, glycosylation and surface expression when expressed in oocytes, and were suspected to interfere with channel gating and a negative feedback mechanism. These effects were also shown to vary depending on pH levels. The current of the remaining two variants did not differ from WT. For heterozygous missense variants, the disruption induced may be at least partially conferred to mutant/WT homodimers and mutant/ClC-4 heterodimers. Both loss and gain of function in this gene resulted in the same phenotype. Green for mono-allelic variants, Amber/Red for bi-allelic. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1215 | KIF1A | Arina Puzriakova Phenotypes for gene: KIF1A were changed from Mental Retardation, Dominant; Spastic paraplegia 30, autosomal recessive, 610357Neuropathy, hereditary sensory, type IIC, 614213Mental retardation, autosomal dominant 9, 614255; MENTAL RETARDATION, AUTOSOMAL DOMINANT 9 to NESCAV syndrome, OMIM:614255; Spastic paraplegia 30, autosomal dominant, OMIM:610357 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1213 | COG4 | Arina Puzriakova Added comment: Comment on mode of inheritance: Early developmental delay (speech and motor) can be a feature of Saul-Wilson syndrome (monoallelic inheritance), however cognition is normal. Therefore, the monoallelic form is not pertinent to this panel and the MOI should remain as biallelic only which is associated with CDG-IIj, including psychomotor retardation. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1201 | ATP9A |
Konstantinos Varvagiannis gene: ATP9A was added gene: ATP9A was added to Intellectual disability. Sources: Literature,Other Mode of inheritance for gene: ATP9A was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ATP9A were set to Global developmental delay; Intellectual disability; Postnatal microcephaly; Failure to thrive; Abnormality of the abdomen Penetrance for gene: ATP9A were set to Complete Review for gene: ATP9A was set to AMBER Added comment: Vogt, Verheyen et al (2021 - http://dx.doi.org/10.1136/jmedgenet-2021-107843) report 3 affected individuals from 2 unrelated consanguineous families. Features included DD, variable ID (Fam1: sib1-mild, sib2-possible, Fam2: severe), postnatal microcephaly (-2.33 to -3.58 SD), failure to thrive as well as gastrointestinal symptoms (nausea, vomiting, GE reflux). These subjects were homozygous for pLoF ATP9A variants private to each family. Previous investigations incl. karyotype, aCGH and transferrin electophoresis (CDGs) and were unremarkable. Diagnosis was made by exome sequencing and homozygosity mapping. Affected sibs from the first family were homozygous for a stopgain variant [NM_006045.3:c.868C>Τ / p.(Arg290*)]. The subject from the second family was homozygous for a variant affecting the consensus (donor) splice site [c.642+1G>A - same RefSeq]. Both variants were absent from gnomAD. Sanger sequencing was used to confirm variants, carrier status of the parents and unaffected sibs in both families. Sequencing of cDNA from the individual homozygous for the splicing variant demonstrated skipping of exon 7 with the variant likely leading to frameshift and introduction of a premature stop codon. qPCR in dermal fibroblasts from affected individuals from both families revealed expression downregulation of ATP9A (14% and 4% respectively for the stopgain and splice variant). Study at the protein level was not possible due to absence of antibody against endogenous ATP9A. ATP9A encodes ATPase phospholipid transporting 9A (similarly to ATP9B) belonging to the subclass 2 of the P4-ATPase family. As the authors comment, the protein is mainly expressed in the brain although the precise function or subcellular distribution of endogenous ATP9A are unknown. A previous study showed that overexpressed ATP9A in HeLa cells localizes to early/recycling endosomes and the trans-Golgi network, being required for endocytic recycling of the transferrin receptor to the plasma membrane. ATP9A (in complex with DOP1B and MON2) functionally interacts with the SNX3-retromer. A previous ATP9A knockdown cell line suggested dysregulation of >100 genes with ARPC3 (actin-related protein 2/3 complex subunit 3) being strongly upregulated. Overall ATP9A appears to have a role in endosome trafficking pathways as well as to inhibit secretion of exosomes at the plasma membrane likely due to alteration of the actin cytoskeleton. In line with the role of APT9A in early/recycling endosomes and identified interactions, the authors demonstrated overexpression of ARPC3 and SNX3. Study of genes encoding other known interacting proteins was not possible due to poor expression in fibroblasts. As the authors note, mutations in genes encoding proteins of the Golgi and endosomal trafficking are important for brain development and have been associated with postnatal microcephaly. In OMIM, G2P, SysID there is no associated phenotype. The gene is included in the ID panel of PanelApp AUS with amber rating. Sources: Literature, Other |
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| Intellectual disability - microarray and sequencing v3.1201 | ZDHHC9 | Ivone Leong Phenotypes for gene: ZDHHC9 were changed from Mental retardation, X-linked syndromic, Raymond type, 300799; MENTAL RETARDATION SYNDROMIC X-LINKED ZDHHC9-RELATED (MRXSZ) to Mental retardation, X-linked syndromic, Raymond type, OMIM:300799 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1176 | CAMK2A | Ivone Leong Phenotypes for gene: CAMK2A were changed from Intellectual disability to Mental retardation, autosomal dominant 53, OMIM:617798; ?Mental retardation, autosomal recessive 63, OMIM:618095 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1167 | ERGIC3 |
Zornitza Stark gene: ERGIC3 was added gene: ERGIC3 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: ERGIC3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ERGIC3 were set to 33710394; 31585110 Phenotypes for gene: ERGIC3 were set to Intellectual disability Review for gene: ERGIC3 was set to AMBER Added comment: PMID: 33710394 - two homozygous sibs with mild ID, a novel canonical splice (c.717+1G>A). Absent in gnomAD, no splice studies. Classed as a VUS. PMID: 31585110 - 1 hom (p.Gln233Argfs*10) in a male 8yo with Growth retardation, Microcephaly, Learning disability, Facial dysmorphism, Abnormal pigmentation. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1167 | ZC3H14 | Zornitza Stark reviewed gene: ZC3H14: Rating: AMBER; Mode of pathogenicity: None; Publications: 21734151, 33710394, 28666327; Phenotypes: Mental retardation, autosomal recessive 56 MIM#617125; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1156 | ACSL4 | Ivone Leong Phenotypes for gene: ACSL4 were changed from Mental retardation, X-linked 63, OMIM:300387; ALPORT SYNDROME WITH MENTAL RETARDATION MIDFACE HYPOPLASIA AND ELLIPTOCYTOSIS (ATS-MR) to Mental retardation, X-linked 63, OMIM:300387; Alport syndrome-intellectual disability-midface hypoplasia-elliptocytosis syndrome, MONDO:0010263 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1155 | ACSL4 | Ivone Leong Phenotypes for gene: ACSL4 were changed from Mental retardation, X-linked 63, 300387; ALPORT SYNDROME WITH MENTAL RETARDATION MIDFACE HYPOPLASIA AND ELLIPTOCYTOSIS (ATS-MR) to Mental retardation, X-linked 63, OMIM:300387; ALPORT SYNDROME WITH MENTAL RETARDATION MIDFACE HYPOPLASIA AND ELLIPTOCYTOSIS (ATS-MR) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1128 | EIF3F | Arina Puzriakova Phenotypes for gene: EIF3F were changed from Intellectual disability; Seizures; Behavioral abnormality; Sensorineural hearing impairment to Mental retardation, autosomal recessive 67, OMIM:618295 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1126 | CTC1 | Zornitza Stark reviewed gene: CTC1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebroretinal microangiopathy with calcifications and cysts, MIM# 612199; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1116 | LRRC32 | Arina Puzriakova Phenotypes for gene: LRRC32 were changed from Intellectual disability; cleft palate; proliferative retinopathy to Cleft palate, proliferative retinopathy, and developmental delay, OMIM:619074 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1107 | FOXG1 | Sarah Leigh Phenotypes for gene: FOXG1 were changed from Rett syndrome, congenital variant, 613454; CONGENITAL VARIANT OF RETT SYNDROME (RTTCV) to Rett Syndrome, congenital variant OMIM:613454; Rett syndrome, congenital variant MONDO:0013270 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1091 | CAMK2B | Arina Puzriakova Phenotypes for gene: CAMK2B were changed from Mental retardation, autosomal dominant 54 617799 to Mental retardation, autosomal dominant 54, OMIM:617799 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1088 | UNC80 | Arina Puzriakova Phenotypes for gene: UNC80 were changed from Hypotonia, infantile, with psychomotor retardation and characteristic facies 2 616801 to Hypotonia, infantile, with psychomotor retardation and characteristic facies 2, OMIM:616801 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1079 | TRAPPC9 | Arina Puzriakova Phenotypes for gene: TRAPPC9 were changed from Mental retardation, autosomal recessive 13, 613192; Mental Retardation, Recessive; MENTAL RETARDATION AUTOSOMAL RECESSIVE TYPE 13 (MRT13) to Mental retardation, autosomal recessive 13, OMIM:613192 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1074 | FXN_GAA | Sarah Leigh Phenotypes for STR: FXN_GAA were changed from Friedreich ataxia 229300 to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1069 | PTPN4 |
Zornitza Stark gene: PTPN4 was added gene: PTPN4 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PTPN4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PTPN4 were set to 17953619; 25424712; 30238967; DOI: https://doi.org/10.1016/j.xhgg.2021.100033 Phenotypes for gene: PTPN4 were set to Intellectual disability Review for gene: PTPN4 was set to GREEN gene: PTPN4 was marked as current diagnostic Added comment: >3 unrelated probands and supportive mouse model PMID: 17953619 - knockout mouse model has impaired motor learning and cerebellar synaptic plasticity PMID: 25424712 - twins with a de novo whole gene deletion and a Rett-like neurodevelopmental disorder PMID: 30238967 - mosaic de novo variant (p.Leu72Ser) identified in a child with developmental delay, autistic features, hypotonia, increased immunoglobulin E and dental problems. Also supporting mouse assays demonstrating loss of protein expression in dendritic spines DOI: https://doi.org/10.1016/j.xhgg.2021.100033 - missense and truncating variants in six unrelated individuals with varying degrees of intellectual disability or developmental delay. 5 were able to undergo segregation analysis and found to be de novo. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1069 | CLTC | Arina Puzriakova Phenotypes for gene: CLTC were changed from Mental retardation, autosomal dominant 56, 617854; Autosomal dominant non-syndromic intellectual disability, Epilepsy and intellectual disability to Mental retardation, autosomal dominant 56, OMIM:617854 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1054 | HERC2 | Arina Puzriakova Phenotypes for gene: HERC2 were changed from Mental retardation, autosomal recessive 38 to Mental retardation, autosomal recessive 38, OMIM:615516 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1052 | INPP4A | Arina Puzriakova Phenotypes for gene: INPP4A were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to Intellectual disability; Seizures | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1037 | JMJD1C |
Zornitza Stark gene: JMJD1C was added gene: JMJD1C was added to Intellectual disability. Sources: Expert Review Mode of inheritance for gene: JMJD1C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: JMJD1C were set to 26181491; 32996679 Phenotypes for gene: JMJD1C were set to Intellectual disability Review for gene: JMJD1C was set to GREEN gene: JMJD1C was marked as current diagnostic Added comment: Reported in ID cohort (with Rett-like phenotypic overlap) with supporting functional studies (PMID: 26181491). 7 individuals with rare variants identified, and variants demonstrated to be de novo in 2, one with a Rett-like phenotype and the other with ID. Functional study of the JMJD1C mutant Rett syndrome patient demonstrated that the altered protein had abnormal subcellular localization, diminished activity to demethylate the DNA damage-response protein MDC1, and reduced binding to MECP2. JMJD1C protein shown to be widely expressed in brain regions and that its depletion compromised dendritic activity. Splice-disrupting JMJD1C variant reported in association with learning disability and myoclonic epilepsy (PMID 32996679). Disruption of gene due to balanced translocation (PMID 33591602) implicated in autism spectrum disease phenotype. Sources: Expert Review |
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| Intellectual disability - microarray and sequencing v3.1037 | LAMA1 | Sarah Leigh Phenotypes for gene: LAMA1 were changed from CEREBELLAR DYSPLASIA WITH CYSTS WITH OR WITHOUT RETINAL DYSTROPHY to Poretti-Boltshauser syndrome OMIM:615960; ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome MONDO:0014419 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.998 | ATP8A2 | Sarah Leigh Phenotypes for gene: ATP8A2 were changed from ?Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 615268; intellectual disability to ?Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 OMIM:615268; cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 MONDO:0014104 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.988 | GNB1 | Arina Puzriakova Phenotypes for gene: GNB1 were changed from Intellectual disability; developmental delay; Global developmental delay to Mental retardation, autosomal dominant 42, OMIM:616973 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.980 | SMARCB1 | Arina Puzriakova Phenotypes for gene: SMARCB1 were changed from Rhabdoid tumors, somatic, 609322Rhabdoid predisposition syndrome 1, 609322Mental retardation, autosomal dominant 15, 614608; RHABDOID PREDISPOSITION SYNDROME 1 to Coffin-Siris syndrome 3, OMIM:614608 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.979 | SMARCA4 | Arina Puzriakova Phenotypes for gene: SMARCA4 were changed from Rhabdoid tumor predisposition syndrome 2, 613325Mental retardation, autosomal dominant 16, 614609; COFFIN SIRIS to Coffin-Siris syndrome 4, OMIM:614609 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.973 | ERBB4 | Sarah Leigh changed review comment from: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review depending on the interpretation of structural variants.; to: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review depending on the interpretation of copy number variants. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.973 | ERBB4 | Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review depending on the interpretation of structural variants. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.968 | ACO2 | Arina Puzriakova Phenotypes for gene: ACO2 were changed from INFANTILE CEREBELLAR-RETINAL DEGENERATION to Infantile cerebellar-retinal degeneration, OMIM:614559; Infantile cerebellar-retinal degeneration, MONDO:0013802 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.765 | VPS4A | Arina Puzriakova Phenotypes for gene: VPS4A were changed from developmental delay; intellectual disability; cerebellar hypoplasia; pontine hypoplasia; thin corpus callosum; microcephaly; growth retardation; congenital anaemia; dyserythropeoitic anaemia; dystonia; congenital cataracts; deafness to CIMDAG syndrome | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.751 | VPS4A |
Evan Reid gene: VPS4A was added gene: VPS4A was added to Intellectual disability. Sources: Literature,Research Mode of inheritance for gene: VPS4A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: VPS4A were set to (PMID: 33186545; 33186543; 33460484) Phenotypes for gene: VPS4A were set to developmental delay; intellectual disability; cerebellar hypoplasia; pontine hypoplasia; thin corpus callosum; microcephaly; growth retardation; congenital anaemia; dyserythropeoitic anaemia; dystonia; congenital cataracts; deafness Penetrance for gene: VPS4A were set to Complete Mode of pathogenicity for gene: VPS4A was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: VPS4A was set to GREEN Added comment: Multiple families (now 10) described with a consistent phenotype (we have termed it CIMDAG as an acronym for the major features). All have de novo heterozygous missense mutations of VPS4A, with a distinct mutational hotspot (R284) in many families. Mechanism is likely dominant negative. Haplo-insufficiency of VPS4A is tolerated and present in general population databases, so loss of function mutations likely do not cause this disease. Sources: Literature, Research |
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| Intellectual disability - microarray and sequencing v3.749 | HIRA |
Zornitza Stark gene: HIRA was added gene: HIRA was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: HIRA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: HIRA were set to 33417013; 28135719; 25363760 Phenotypes for gene: HIRA were set to Neurodevelopmental disorder Review for gene: HIRA was set to GREEN gene: HIRA was marked as current diagnostic Added comment: Two unrelated patients with different de novo loss of function variants identified in PMID 33417013: Individual 1: intragenic deletion, phenotype included psychomotor retardation, ID, growth retardation, microcephaly, and facial features reminiscent of 22q deletion syndrome. Individual 2: canonical splice variant, phenotype mostly confined to ASD Another two de novo variants were identified in the literature by the authors of that paper, one stop-gain (DDD study, PMID 28135719) and one missense (large autism cohort, PMID 25363760). PMID 33417013 also showed that HIRA knockdown in mice results in neurodevelopmental abnormalities. Rated Green due to 4 unrelated individuals (albeit 2 in large cohort studies) and a mouse model. NB: HIRA is within the common 22q deletion region. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.748 | MEIS2 | Arina Puzriakova Phenotypes for gene: MEIS2 were changed from Cleft palate, cardiac defects, and mental retardation; Oral cleft; Abnormal heart morphology; Intellectual disability; Cleft palate, cardiac defects, and mental retardation, 600987 to Cleft palate, cardiac defects, and mental retardation, OMIM:600987; Cardiac malformation, cleft lip/palate, microcephaly, and digital anomalies, MONDO:0010970 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.738 | UBR7 | Arina Puzriakova Phenotypes for gene: UBR7 were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to Intellectual disability; epilepsy; hypothyroidism; congenital anomalies; dysmorphic features | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.714 | GLS_GCA |
Arina Puzriakova changed review comment from: Comment on list classification: Early developmental delay, which preceded other progressive neurological concerns, was reported in the three unrelated cases from PMID:30970188. Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that this is sufficient for inclusion on this panel. However, detection of this 5' UTR triplet expansion must first be internally validated for the interpretation pipeline. In the meantime, rating Red but will raise the STR for validation with the Rare Disease team.; to: Comment on list classification: Early developmental delay, which preceded other progressive neurological concerns, was reported in the three unrelated cases from PMID:30970188. Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that this is sufficient for inclusion on this panel. However, detection of this 5' UTR triplet expansion must first be validated within the Genomics England pipeline. In the meantime, rating Red but will raise the STR for validation with the Rare Disease team. |
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| Intellectual disability - microarray and sequencing v3.714 | GLS_GCA |
Arina Puzriakova Added comment: Comment on list classification: Early developmental delay, which preceded other progressive neurological concerns, was reported in the three unrelated cases from PMID:30970188. Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that this is sufficient for inclusion on this panel. However, detection of this 5' UTR triplet expansion must first be internally validated for the interpretation pipeline. In the meantime, rating Red but will raise the STR for validation with the Rare Disease team. |
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| Intellectual disability - microarray and sequencing v3.713 | GLS |
Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Early developmental delay, which preceded other progressive neurological concerns, was reported in the three unrelated cases from PMID:30970188. Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that this is sufficient for inclusion on this panel. However, detection of the 5' UTR triplet expansion must first be internally validated for the interpretation pipeline. In the meantime, rating Amber but will raise the STR for validation with the Rare Disease team. |
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| Intellectual disability - microarray and sequencing v3.700 | TLK2 | Arina Puzriakova Phenotypes for gene: TLK2 were changed from intellectual disability to Mental retardation, autosomal dominant 57, OMIM:618050; Mental retardation, autosomal dominant 57, MONDO:0054837 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.694 | FGF13 |
Zornitza Stark gene: FGF13 was added gene: FGF13 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: FGF13 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: FGF13 were set to 33245860 Phenotypes for gene: FGF13 were set to Intellectual disability; epilepsy Mode of pathogenicity for gene: FGF13 was set to Other Review for gene: FGF13 was set to GREEN gene: FGF13 was marked as current diagnostic Added comment: Two sibling pairs and three unrelated males reported who presented in infancy with intractable focal seizures and severe developmental delay. The variants were located in the N-terminal domain of the A isoform of FGF13/FHF2 (FHF2A). The X-linked FHF2 gene (also known as FGF13) has alternative first exons which produce multiple protein isoforms that differ in their N-terminal sequence. The variants were located at highly conserved residues in the FHF2A inactivation particle that competes with the intrinsic fast inactivation mechanism of Nav channels. Functional characterization of mutant FHF2A co-expressed with wild-type Nav1.6 (SCN8A) revealed that mutant FHF2A proteins lost the ability to induce rapid-onset, long-term blockade of the channel while retaining pro-excitatory properties. These gain-of-function effects are likely to increase neuronal excitability consistent with the epileptic potential of FHF2 variants. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.645 | ISCA-37418-Loss | Arina Puzriakova Phenotypes for Region: ISCA-37418-Loss were changed from Potocki-Lupski syndrome; hypotonia, poor feeding, failure to thrive, developmental delay particularly cognitive and language deficity, mild-moderate intellectual deficit, and neuropsychiatric disorders; Smith-Magenis syndrome; Structural cardiovascular anomalies (dilated aortic root, bicommissural aortic valve, atrial/ventricular and septal defects) and sleep disturbance; 182290; moderate intellectual disability, delayed speech and language skills, distinctive facial features, sleep disturbances, and behavioral problems; hypotonia, failure to thrive, mental retardation, pervasive developmental disorders, congenital anomalies; Dental abnormalities to Smith-Magenis syndrome, OMIM:182290; Smith-Magenis syndrome, MONDO:0008434 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.641 | MORC2 | Arina Puzriakova Phenotypes for gene: MORC2 were changed from Charcot-Marie-Tooth disease, axonal, type 2Z, MIM #616688 to Developmental delay; Intellectual disability; Growth retardation; Microcephaly; Craniofacial dysmorphism; Charcot-Marie-Tooth disease, axonal, type 2Z, OMIM:616688 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.638 | MORC2 | Arina Puzriakova reviewed gene: MORC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32693025; Phenotypes: Developmental delay, Intellectual disability, Growth retardation, Microcephaly, Craniofacial dysmorphism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.636 | SOX3 | Arina Puzriakova Phenotypes for gene: SOX3 were changed from Mental retardation, X-linked, with isolated growth hormone deficiency, 300123Panhypopituitarism, X-linked, 312000; SEX REVERSAL TYPE 3 (SRXX3) to Mental retardation, X-linked, with isolated growth hormone deficiency, OMIM:300123; Intellectual disability, X-linked, with panhypopituitarism, MONDO:0010252 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.583 | FBXO31 | Ivone Leong Phenotypes for gene: FBXO31 were changed from Mental retardation, autosomal recessive 45, MIM#615979; Intellectual disability, autosomal dominant to ?Mental retardation, autosomal recessive 45, OMIM:615979; Intellectual disability, autosomal dominant | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.553 | FAM50A | Arina Puzriakova Phenotypes for gene: FAM50A were changed from Mental retardation syndrome, X-linked, Armfield type (MIM #300261) to Mental retardation syndrome, X-linked, Armfield type, OMIM:300261; Armfield syndrome, MONDO:0010284 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.510 | MAP1B | Arina Puzriakova commented on gene: MAP1B: Only one homozygous case identified in a screening study of a congenital microcephaly cohort. Other features included hypochromic microcytic anaemia, lymphocytic colitis, retinal coloboma, dysmorphic features, and normal brain MRI. As this is only considered a candidate variant and the phenotype is not compatible with other monoallelic reports, the evidence is currently insufficient for a disease association with biallelic variants (PMID:30214071) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.510 | FBXO31 | Zornitza Stark edited their review of gene: FBXO31: Changed phenotypes: Mental retardation, autosomal recessive 45, MIM#615979, Intellectual disability, spasticity, autosomal dominant | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.510 | FBXO31 |
Zornitza Stark gene: FBXO31 was added gene: FBXO31 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: FBXO31 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: FBXO31 were set to 24623383; 32989326 Phenotypes for gene: FBXO31 were set to Mental retardation, autosomal recessive 45, MIM#615979; Intellectual disability, autosomal dominant Review for gene: FBXO31 was set to AMBER Added comment: Bi-allelic variants: Single consanguineous family reported with homozygous truncating variant, limited functional evidence. Mono-allelic variants: 2 unrelated probands reported as part of a 'cerebral palsy' cohort harbouring the same de novo missense variant (p.Asp334Asn). The variant affects the cyclin D interaction site, leading to an apparent gain of function of cyclin D degradation, supported by Western blots from patient fibroblasts which showed decreased cyclin D expression. Patient phenotypes: Spastic diplegia, with esotropia, ID, dysarthria, mixed receptive/expressive language disorder, ADHD, cleft palate, intestinal malrotation and midgut volvulus (patient 1); Spastic paraplegia with ventricular dilation and thin corpus callosum, ID, attention deficit, anxiety, language impairments, strabismus, severe constipation (patient 2). Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.510 | ATP6V0A1 |
Zornitza Stark gene: ATP6V0A1 was added gene: ATP6V0A1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: ATP6V0A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ATP6V0A1 were set to 30842224; 33057194 Phenotypes for gene: ATP6V0A1 were set to Developmental disorder; Rett syndrome-like Review for gene: ATP6V0A1 was set to AMBER Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 11 de novo missense identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating). PMID: 30842224 - identified a de novo missense variant in a single individual with atypical Rett syndrome phenotype Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.500 | MPP5 |
Konstantinos Varvagiannis gene: MPP5 was added gene: MPP5 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: MPP5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: MPP5 were set to 33073849 Phenotypes for gene: MPP5 were set to Global developmental delay; Intellectual disability; Delayed speech and language development; Developmental regression; Behavioral abnormality Penetrance for gene: MPP5 were set to unknown Review for gene: MPP5 was set to GREEN Added comment: Sterling et al (2020 - PMID: 33073849) provide information on the phenotype of 3 individuals with de novo MPP5 variants. Common features included global developmental delay, intellectual disability (3/3 - severe in 2/3), speech delay/regression (the latter in at least 2) and behavioral abnormalities. Variable other features were reported, among others microcephaly (1/3), abnormal vision (1/3 : CVI, retinal dystrophy, nystagmus), brain MRI abnormalities (2/3), late-onset seizures (1/3). These subjects displayed variable and non-specific dysmorphic features. All were investigated by exome sequencing (previous tests not mentioned). One subject was found to harbor a de novo mosaic (5/25 reads) stopgain variant, further confirmed by Sanger sequencing [NM_022474.4:c.1555C>T - p.(Arg519Ter). The specific variant is reported once in gnomAD (1/251338). Two de novo missense variants were identified in the remaining individuals [c.1289A>G - p.Glu430Gly / c.974A>C - p.His325Pro). All variants had in silico predictions in favor of a deleterious effect (CADD score >24). The authors comment that MPP5 encodes an apical complex protein with asymmetric localization to the apical side of polarized cells. It is expressed in brain, peripheral nervous system and other tissues. MPP5 is a member of the membrane-associated guanylate kinase family of proteins (MAGUK, p55 subfamily), determining cell polarity at tight junctions. Previous animal models suggest that complete Mpp5(Pals1) KO in mice leads to near absence of cerebral cortical neurons. Htz KO mice display reduction in size of cerebral cortex and hippocampus. The gene is expressed in proliferating cell populations of cerebellum and important for establishment cerebellar architecture. Conditional KO of Mpp5(Pals1) in retinal progenitor cells mimics the retinal pathology observed in LCA. [Several refs. provided] The authors studied a heterozygous CNS-specific Mpp5 KO mouse model. These mice presented microcephaly, decreased cerebellar volume and cortical thickness, decreased ependymal cells and Mpp5 at the apical surface of cortical vertrical zone. The proportion of cortical cells undergoing apoptotic cell death was increased. Mice displayed behavioral abnormalities (hyperactivity) and visual deficits, with ERG traces further suggesting retinal blindness. Overall the mouse model was thought to recapitulate the behavioral abnormalities observed in affected subjects as well as individual rare features such as microcephaly and abnormal vision. Haploinsufficiency (rather than a dominant negative effect) is favored as the underlying disease mechanism. This is also in line with a dose dependent effect observed in mice. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.432 | C2CD3 |
Arina Puzriakova changed review comment from: - PMID: 24997988 (2014) - Two unrelated cases with OFD syndrome and biallelic variants (p.Arg62* and p.Cys1029Gly; p.Ala1304Valfs*3, respectively) in C2CD3. In a 4-year-old male, additional manifestations included severe microcephaly (-5 SD), severe ID, micropenis, and brain malformations including Molar Tooth Sign. In the second patient, a terminated foetus, severe microcephaly (-4 SD) was combined with canonical OFD symptoms, but assessment of ID was not possible. No functional studies of the variants; however, some data supporting a role of C2CD3 in cilium assembly and function. - PMID: 26092869 (2015) - Two unrelated individuals with biallelic variants in C2CD3. Clinical details are limited but both had features of Joubert syndrome (as JBTS screening study), as well as oral features including oral frenulae and/or cleft palate. No report on ID status, but could possibly be present in view of the JBTS diagnosis. One patient also harboured biallelic variants in TTC21B. - PMID: 26477546 (2015) - Compound het variants identified in two affected sibs with a classic form of JBTS and severe GDD but without any extraneural manifestations, as described in previous cases. - PMID: 27094867 (2016) - Two sibling fetuses with skeletal dysplasia, brain malformations but no microcephaly, in association with compound het variants in C2CD3. Due to termination of pregnancies, ID status could not be established. Analysis of patient-derived fibroblasts showed impaired cilium assembly. - PMID: 30097616 (2018) - Four individuals from three unrelated families with different biallelic variants in C2CD3. Each family exhibited distinct clinical phenotypes and severity of disease: Family 1: two sibs with a diagnosis of OFD including polydactyly, cleft palate and/or incomplete cleft lip, microcephaly, brain malformations and bilateral colobomas. GDD was noted in both sibs. Family 2: fetus with occipital encephalocele and a ventricular septal defect. Similar abnormalities were identified in another sib (also a terminated fetus), but DNA analysis was not performed on the latter. Family 3: one male with various fetal anomalies, and subsequent diagnosis of JBTS following identification of consistent findings on brain MRI. Other features included DD and bilateral retina colobomas.; to: - PMID: 24997988 (2014) - Two unrelated cases with OFD syndrome and biallelic variants (p.Arg62* and p.Cys1029Gly; p.Ala1304Valfs*3, respectively) in C2CD3. In a 4-year-old male, additional manifestations included severe microcephaly (-5 SD), severe ID, micropenis, and brain malformations including Molar Tooth Sign. In the second patient, a terminated foetus, severe microcephaly (-4 SD) was combined with canonical OFD symptoms, but assessment of ID was not possible. No functional studies of the variants; however, some data supporting a role of C2CD3 in cilium assembly and function. - PMID: 26092869 (2015) - Two unrelated individuals with biallelic variants in C2CD3. Clinical details are limited but both had features of Joubert syndrome (as JBTS screening study), as well as oral features including oral frenulae and/or cleft palate. No report on ID status, but could possibly be present in view of the JBTS diagnosis. One patient also harboured biallelic variants in TTC21B. - PMID: 26477546 (2015) - Compound het variants identified in two affected sibs with a classic form of JBTS and severe GDD but without any extraneural manifestations, as described in previous cases. - PMID: 27094867 (2016) - Two sibling fetuses with skeletal dysplasia, brain malformations but no microcephaly, in association with compound het variants in C2CD3. Due to termination of pregnancies, ID status could not be established. Analysis of patient-derived fibroblasts showed impaired cilium assembly. - PMID: 30097616 (2018) - Four individuals from three unrelated families with different biallelic variants in C2CD3. Each family exhibited distinct clinical phenotypes and severity of disease: Family 1: two sibs with a diagnosis of OFD including polydactyly, cleft palate and/or incomplete cleft lip, microcephaly, brain malformations and bilateral colobomas. GDD was noted in both sibs. Family 2: fetus with encephalocele and a ventricular septal defect. Similar abnormalities were identified in a sib (also a terminated fetus), but DNA analysis was not performed on the latter. Family 3: one male with various fetal anomalies, and subsequent diagnosis of JBTS following identification of consistent findings on brain MRI. Other features included DD and bilateral retina colobomas. |
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| Intellectual disability - microarray and sequencing v3.423 | TINF2 |
Arina Puzriakova Added comment: Comment on list classification: Although DD can be a feature, the condition is expected to present in a syndromic manner with cytopenia, cerebellar hypoplasia and retinopathy representing key characteristics. It is expected that these indications should be sufficient for detecting cases - TINF2 is already Green on the relevant panels. Calling variants in this gene in a cohort of ID patients is therefore unlikely to be of benefit and so the rating has been kept Red. |
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| Intellectual disability - microarray and sequencing v3.421 | RETREG1 |
Arina Puzriakova Source Expert Review Red was added to RETREG1. Rating Changed from Amber List (moderate evidence) to Red List (low evidence) |
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| Intellectual disability - microarray and sequencing v3.405 | NUP214 |
Eleanor Williams changed review comment from: Associated with {Encephalopathy, acute, infection-induced, susceptibility to, 9} 618426 in OMIM and Gene2Phenotype (probable). PMID: 31178128 - Fichtman et al 2019 - report on two families one of Palestinian decent, the other Northern European (not Finnish descent). Each had two affected siblings in which neurological decline was seen after febrile events. The older son in family A, exhibited minor developmental delay from infancy. A homozygous missense variant was identified in NUP214 (p.Arg38Cys) in family A and segregated with the disease in available family members. In family B affected sisters were compound heterozygous for a frameshift and a missense variant in NUP214 (p.Pro387Ser and p.Pro525Leufs∗6). Functional studies with fibroblasts from one patient in family A showed a decrease in NUP214 and NUP88 levels compared to controls, PMID: 30758658 - Shamseldin et al 2019 - describe a multiplex consanguineous family in which four affected members presented with severe neonatal hypotonia, profound global developmental delay, progressive microcephaly and early death. Whole exome sequencing revealed the presence of a novel homozygous missense variant in NUP214, p.D154G. PMID: 29483668 - Egloff et al 2018 - report a 4-year-old girl presenting with developmental delay, growth retardation and facial dysmorphism. She was found to have a 9q deletion inherited from her healthy mother and a a hemizygous one-base pair deletion in the NUP214 gene inherited from her father. From patient leukocytes it was found that the expression level of the NUP214 transcript was significantly decreased and close to zero in the patient compared to the controls. ; to: Associated with {Encephalopathy, acute, infection-induced, susceptibility to, 9} 618426 in OMIM and Gene2Phenotype (probable). PMID: 31178128 - Fichtman et al 2019 - report on two families one of Palestinian decent, the other Northern European (not Finnish descent). Each had two affected siblings in which neurological decline was seen after febrile events. The older son in family A, exhibited minor developmental delay from infancy. A homozygous missense variant was identified in NUP214 (p.Arg38Cys) in family A and segregated with the disease in available family members. In family B affected sisters were compound heterozygous for a frameshift and a missense variant in NUP214 (p.Pro387Ser and p.Pro525Leufs∗6). Functional studies with fibroblasts from one patient in family A showed a decrease in NUP214 and NUP88 levels compared to controls, PMID: 30758658 - Shamseldin et al 2019 - describe a multiplex consanguineous family in which four affected members presented with severe neonatal hypotonia, profound global developmental delay, progressive microcephaly and early death (<2 year old). Whole exome sequencing revealed the presence of a novel homozygous missense variant in NUP214, p.D154G. PMID: 29483668 - Egloff et al 2018 - report a 4-year-old girl presenting with developmental delay, growth retardation and facial dysmorphism. She was found to have a 9q deletion inherited from her healthy mother and a hemizygous one-base pair deletion in the NUP214 gene inherited from her father. From patient leukocytes it was found that the expression level of the NUP214 transcript was significantly decreased and close to zero in the patient compared to the controls. |
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| Intellectual disability - microarray and sequencing v3.405 | NUP214 |
Eleanor Williams changed review comment from: Associated with {Encephalopathy, acute, infection-induced, susceptibility to, 9} 618426 in OMIM and Gene2Phenotype (probable). PMID: 31178128 - Fichtman et al 2019 - report on two families. Family A have first-cousin parents of Palestinian descent. The proband exhibited minor developmental delay from infancy, presented with ataxia, mental retardation, and intractable epilepsy and died at 11 years. He suffered deterioration in association with febrile illnesses. His cousin presented at 5.5 months with partially reversible encephalopathy and developmental regression after a febrile illness. Family B were sisters born to non-consanguineous parents of Northern European (non-Finnish) descent. The older sister had nystagmus at 2 months and mild hypotonia, but she was otherwise meeting milestones appropriately . At 15 months of age, she developed a fever that led to a rapid neurological decline, seizures, and abnormal movements. The younger sister presented at 7 months with failure to thrive and hyponatremia but was meeting developmental milestones appropriately. By 24 months of age, she had motor and speech delay, ataxic gait, and occasional very mild head bobbing. In family A a homozygous NUP214 p.Arg38Cys variant segregated with the disease in available family members. In family B the sisters were found to be compound heterozygous for a frameshift and a missense variant in NUP214 (p.Pro387Ser and p.Pro525Leufs∗6).; to: Associated with {Encephalopathy, acute, infection-induced, susceptibility to, 9} 618426 in OMIM and Gene2Phenotype (probable). PMID: 31178128 - Fichtman et al 2019 - report on two families one of Palestinian decent, the other Northern European (not Finnish descent). Each had two affected siblings in which neurological decline was seen after febrile events. The older son in family A, exhibited minor developmental delay from infancy. A homozygous missense variant was identified in NUP214 (p.Arg38Cys) in family A and segregated with the disease in available family members. In family B affected sisters were compound heterozygous for a frameshift and a missense variant in NUP214 (p.Pro387Ser and p.Pro525Leufs∗6). Functional studies with fibroblasts from one patient in family A showed a decrease in NUP214 and NUP88 levels compared to controls, PMID: 30758658 - Shamseldin et al 2019 - describe a multiplex consanguineous family in which four affected members presented with severe neonatal hypotonia, profound global developmental delay, progressive microcephaly and early death. Whole exome sequencing revealed the presence of a novel homozygous missense variant in NUP214, p.D154G. PMID: 29483668 - Egloff et al 2018 - report a 4-year-old girl presenting with developmental delay, growth retardation and facial dysmorphism. She was found to have a 9q deletion inherited from her healthy mother and a a hemizygous one-base pair deletion in the NUP214 gene inherited from her father. From patient leukocytes it was found that the expression level of the NUP214 transcript was significantly decreased and close to zero in the patient compared to the controls. |
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| Intellectual disability - microarray and sequencing v3.352 | KDM6B | Arina Puzriakova Phenotypes for gene: KDM6B were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities, 618505 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.332 | MECP2 | Arina Puzriakova reviewed gene: MECP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32469049; Phenotypes: Rett syndrome, 312750; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.332 | UPF3B | Arina Puzriakova reviewed gene: UPF3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 32667670; Phenotypes: Mental retardation, X-linked, syndromic 14, 300676; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.330 | RAD50 |
Arina Puzriakova changed review comment from: Comment on list classification: Borderline ID in second patient (at age 15 estimated IQ: 85). Therefore, keeping rating Red awaiting further cases to clarify the relevance of ID to the overall phenotype. ; to: Comment on list classification: Note uncertainty regarding ID in the first patient - PMID:1887849 states 'lack of mental retardation', while a later report PMID:19409520 describes 'mild to moderate retardation of psychomotor development'. ID was borderline in the second patient (at age 15 estimated IQ: 85). Therefore, keeping rating Red awaiting further cases to clarify the relevance of ID to the phenotype associated with RAD50 variants. |
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| Intellectual disability - microarray and sequencing v3.327 | WASHC4 | Arina Puzriakova Phenotypes for gene: WASHC4 were changed from Mental retardation, autosomal recessive 43, MIM #615817 to Mental retardation, autosomal recessive 43, 615817 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.325 | WASHC4 | Arina Puzriakova reviewed gene: WASHC4: Rating: ; Mode of pathogenicity: None; Publications: 21498477, 31953988; Phenotypes: Mental retardation, autosomal recessive 43, 615817; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.313 | CAMK2G | Arina Puzriakova Phenotypes for gene: CAMK2G were changed from to Mental retardation, autosomal dominant 59, 618522 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.295 | WASHC4 |
Zornitza Stark gene: WASHC4 was added gene: WASHC4 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: WASHC4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: WASHC4 were set to 31953988; 21498477 Phenotypes for gene: WASHC4 were set to Mental retardation, autosomal recessive 43, MIM #615817 Review for gene: WASHC4 was set to GREEN gene: WASHC4 was marked as current diagnostic Added comment: Three unrelated families reported. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.254 | RETREG1 | Arina Puzriakova commented on gene: RETREG1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.239 | FAM50A |
Konstantinos Varvagiannis gene: FAM50A was added gene: FAM50A was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: FAM50A was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: FAM50A were set to 32703943 Phenotypes for gene: FAM50A were set to Mental retardation syndrome, X-linked, Armfield type (MIM #300261) Penetrance for gene: FAM50A were set to unknown Review for gene: FAM50A was set to GREEN Added comment: Lee et al (2020 - PMID: 32703943) provide evidence that Armfield X-Linked intellectual disability syndrome is caused by monoallelic FAM50A pathogenic variants. The current review is based only on this reference. The authors provide clinical details on 6 affected individuals from 5 families. Features included postnatal growth delay, DD and ID (6/6 - also evident for those without formal IQ assesment), seizures (3/6 from 2 families), prominent forehead with presence of other facial features and variable head circumference (5th to >97th %le), ocular anomalies (5/6 - strabismus/nystagmus/Axenfeld-Rieger), cardiac (3/6 - ASD/Fallot) and genitourinary anomalies (3/6). In the first of these families (Armfield et al 1999 - PMID: 10398235), linkage analysis followed by additional studies (Sanger, NGS of 718 genes on chrX, X-exome NGS - several refs provided) allowed the identification of a FAM50A variant. Variants in other families were identified by singleton (1 fam) or trio-ES (3 fam). In affected individuals from 3 families, the variant had occurred de novo. Carrier females in the other families were unaffected (based on pedigrees and/or the original publication). XCI was rather biased in most obligate carrier females from the 1st family (although this ranged from 95:5 to 60:40). Missense variants were reported in all affected subjects incl. Trp206Gly, Asp255Gly, Asp255Asn (dn), Glu254Gly (dn), Arg273Trp (dn) (NM_004699.3). Previous studies have demonstrated that FAM50A has ubiquitous expression in human fetal and adult tissues (incl. brain in fetal ones). Immunostaining suggests a nuclear localization for the protein (NIH/3T3 cells). Comparison of protein levels in LCLs from affected males and controls did not demonstrate significant differences. Protein localization for 3 variants (transfection of COS-7 cells) was shown to be similar to wt. Complementation studies in zebrafish provided evidence that the identified variants confer partial loss of function (rescue of the morpholino phenotype with co-injection of wt but not mt mRNA). The zebrafish ko model seemed to recapitulate the abnormal development of cephalic structures and was indicative of diminished/defective neurogenesis. Transcriptional dysregulation was demonstrated in zebrafish (altered levels and mis-splicing). Upregulation of spliceosome effectors was demonstrated in ko zebrafish. Similarly, mRNA expression and splicing defects were demonstrated in LCLs from affected individuals. FAM50A pulldown followed by mass spectrometry in transfected HEK293T cells demonstrated enrichment of binding proteins involved in RNA processing and co-immunoprecipitation assays (transfected U-87 cells) suggested that FAM50A interacts with spliceosome U5 and C-complex proteins. Overall aberrant spliceosome C-complex function is suggested as the underlying pathogenetic mechanism. Several other neurodevelopmental syndromes are caused by variants in genes encoding C-complex affiliated proteins (incl. EFTUD2, EIF4A3, THOC2, etc.). Please consider inclusion in the ID panel with green rating and epilepsy panel with amber (seizures in individuals from 2 families). Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.212 | LRRC32 |
Arina Puzriakova changed review comment from: Not associated with phenotype in OMIM or G2P. PMID: 30976112 (2019) - homozygous stop-gain variant in LRRC32 (c.1630C>T; p.Arg544Ter) in three affected individuals from two families with global developmental delay, cleft palate, and proliferative retinopathy. In one family developmental quotient (DQ) varied from borderline low in the female (DQ = 72 at 3 years-2 months) to severely delayed in the male (DQ = 57 at 2 years-11 months). The male in the second family was even more severely delayed (DQ = 23 at 3 years-3 months). Haplotype analysis indicates a founder effect, and therefore further cases are required to substantiate causation.; to: Not associated with phenotype in OMIM or G2P. PMID: 30976112 (2019) - homozygous stop-gain variant in LRRC32 (c.1630C>T; p.Arg544Ter) in three affected individuals from two families with global developmental delay, cleft palate, and proliferative retinopathy. In one family developmental quotient (DQ) varied from borderline low in the female (DQ = 72 at 3 years-2 months) to severely delayed in the male (DQ = 57 at 2 years-11 months). The male in the second family was even more severely delayed (DQ = 23 at 3 years-3 months). Haplotype analysis indicates a founder effect, and therefore further cases are required to substantiate causation (added founder-effect tag). |
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| Intellectual disability - microarray and sequencing v3.211 | LRRC32 | Arina Puzriakova reviewed gene: LRRC32: Rating: RED; Mode of pathogenicity: None; Publications: 30976112; Phenotypes: Global developmental delay, Speech delay, Hypotonia, Cleft palate, Proliferative retinopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.206 | HNMT | Arina Puzriakova reviewed gene: HNMT: Rating: AMBER; Mode of pathogenicity: None; Publications: 26206890; Phenotypes: Intellectual disability, Mental retardation, 616739; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.201 | MORC2 |
Konstantinos Varvagiannis gene: MORC2 was added gene: MORC2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: MORC2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: MORC2 were set to https://doi.org/10.1016/j.ajhg.2020.06.013 Phenotypes for gene: MORC2 were set to Charcot-Marie-Tooth disease, axonal, type 2Z, MIM #616688 Penetrance for gene: MORC2 were set to unknown Mode of pathogenicity for gene: MORC2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: MORC2 was set to GREEN Added comment: The current review is based on a recent report by Sacoto et al (2020 - https://doi.org/10.1016/j.ajhg.2020.06.013). While several previous studies focused on the phenotype of axonal motor and senory neuropathy in individuals with heterozygous MORC2 pathogenic variants (Charcot-Marie-Tooth disease, axonal, type 2Z, MIM #616688) some of them presented among others with hypotonia, muscle weakness, intellectual disability, microcephaly or hearing loss [refs provided by Sacoto et al - learning disabilities (in some patients) also listed in OMIM's clinical synopsis]. Sacoto et al present a cohort of 20 individuals having genetic testing for developmental delay or growth failure (with a single one for a diagnosis of sensorimotor neuropathy). Overlapping features included DD, ID (18/20 - mild to severe), short stature (18/20), microcephaly (15/20) and variable craniofacial dysmorphisms. The authors comment that features suggestive of neuropathy (weakness, hyporeflexia, abnormal EMG/NCS) were frequent but not the predominant complaint. EMG/NCS abnormalities were abnormal in 6 out of 10 subjects investigated in this cohort. Other findings included brain MRI abnormalities (12/18 - in 5/18 Leigh-like lesions), hearing loss (11/19) and pigmentary retinopathy in few (5). Affected subjects were found to harbor in all cases missense variants in the ATPase module of MORC2 [residues 1 to 494 - NM_001303256.1 - the module consists of an ATPase domain (aa 1-265), a transducer S5-like domain (266-494) and a coiled-coiled domain (CC1 - aa 282-361)]. Variants had occured mostly as de novo events although inheritance from a similarly affected parent was also reported. Some of them were recurring within this cohort and/or the literature eg. c.79G>A/p.Glu27Lys (x5), c.260C>T/p.Ser87Leu (x2), c.394C>T/p.Arg132Cys (4x), c.1164C>G/p.Ser388Arg (x2), c.1181A>G/p.Tyr394Cys (x3). MORC2 encodes an ATPase involved in chromatin remodeling, DNA repair and transcriptional regulation. Chromatin remodeling and epigenetic silencing by MORC2 is mediated by the HUSH (Human Silencing Hub) complex. Functional studies (MORC2-knockout HeLa cells harboring a HUSH-sensitive GFP reporter were transduced with wt or mt MORC2 followed by measurement of reporter repression) supported the deleterious effect of most variants known at the time (hyperactivation of HUSH-mediating silencing, in line with previous observations). Overall this gene can be considered for inclusion in the ID panel with green rating. Also other gene panels (e.g. for short stature, microcephaly, hearing loss, pigmentary retinopathy, etc) if it meets the respective criteria for inclusion. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.175 | ATL1 | Sarah Leigh changed review comment from: Associated with phenotype in OMIM, not in G2P. Mild late onset mental retardation in 10 members of a three generation family with Spastic paraplegia 3A, autosomal dominant 182600; to: Associated with phenotype in OMIM, not in G2P. Mild to severe late onset mental retardation in 10 members of a three generation family with Spastic paraplegia 3A, autosomal dominant 182600 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.175 | ATL1 | Sarah Leigh commented on gene: ATL1: Associated with phenotype in OMIM, not in G2P. Mental retardation has been reported in a second family (PMID 31236401). In this publication, the 9 year old proband and his maternal grandfather had hereditary spastic paraplegia and intellectual disability, however, proband's mother had hereditary spastic paraplegia, but no intelectual disability. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.170 | CCDC174 |
Konstantinos Varvagiannis gene: CCDC174 was added gene: CCDC174 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CCDC174 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CCDC174 were set to 26358778 Phenotypes for gene: CCDC174 were set to Hypotonia, infantile, with psychomotor retardation - IHPMR, 616816 Penetrance for gene: CCDC174 were set to Complete Mode of pathogenicity for gene: CCDC174 was set to Other Review for gene: CCDC174 was set to AMBER Added comment: Biallelic pathogenic CCDC174 variants cause Hypotonia, infantile, with psychomotor retardation - IHPMR (MIM 616816). Volodarsky et al [2015 - PMID: 26358778] describe 6 children from 2 unrelated families with - among others - severe hypotonia, psychomotor delay and abducens nerve palsy. All affected subjects were homozygous for a stoploss variant. Evidence from functional studies/animal model is provided supporting the role of the gene in this phenotype. Overall this gene can be considered for inclusion in the ID panel with amber rating (2 families, single founder variant, consistent phenotype, supportive studies) pending further reports. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.170 | HERC2 |
Konstantinos Varvagiannis edited their review of gene: HERC2: Added comment: Please consider upgrading this gene to green in the current panel based on the following updated review (13-07-2020): Biallelic pathogenic HERC2 variants cause Mental retardation, autosomal recessive 38 (MIM 615516). The current review is based mostly on the information provided by Elpidorou et al (2020 - PMID: 32571899) summarizing the findings in several affected individuals as published in the literature. ID was a universal feature among them (27/27) and seizures were reported in some (9/27): - 22 subjects from Amish/Mennonite families were homozygous for p.Pro594Leu [NM_004667.5(HERC2):c.1781C>T] (Puffenberger et al 2012 - PMID: 23065719, Harlalka et al 2013 - PMID: 23243086, Abraham et al - PMID: 30902390) - 2 additional patients were homozygous for another missense SNV [NM_004667.5(HERC2):c.4625G>A - p.Arg1542His] (Abraham et al 2019 - PMID: 30902390) - 3 sibs born to consanguineous parents, homozygous for NM_004667.5:c.13767_13770delTGAA - p.(Asn4589LysTer4598)] as described by Elpidorou et al. - 1 male homozygous 286 kb deletion spanning several 5' exons of HERC2 as well as the first exons of OCA2 was described by Morice-Picard et al (2016 - PMID: 27759030). Despite a neurological presentation (axial hypotonia, peripheral hypertonia, extrapyramidal symptoms and uncoordinated movements) further information was not available. Apart from the cases summarized by Elpidorou et al, there have been few additional ones e.g. : - Trujillano et al (2017 - PMID: 27848944) reported briefly on a patient, homozygous for NM_004667.5:c.4676-1G>A displaying seizures, hypotonia, global DD, "Encephalopathy" and abnormality of the liver. - Yavarna et al (2015 - PMID: 26077850) provided few details with on an individual with primarily 'neurocognitive' phenotype but rather atypical presentation (MRI abnormalities, TGA, VSD, renal anomaly, growth retardation, hearing loss) due to p.Q3164X variant (recessive inheritance was specified). Several lines of evidence support an important role for the protein encoded (an E3 ubiquitin protein ligase, interacting also with UBE3A, involved in several cellular processes incl. cell cycle regulation, spindle formation during mitosis, mitochondrial functions, DNA damage responses by targeting proteins such as XPA) as well as the effect of the reported variants (mRNA studies, Western blot, detection of a fusion transcript in the case of the deletion, etc). Individuals from the Amish families displayed Angelman-like features (in line with HERC2-UBE3A interaction) with - among others - gait instability. Mouse models recapitulate some of these features (e.g. the movement disorder) as extensively discussed by Abraham et al. Overall this gene can be included in the ID and epilepsy panels with green rating. -----; Changed rating: GREEN; Changed publications: 23065719, 23243086, 30902390, 32571899, 27848944, 26077850, 27759030 |
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| Intellectual disability - microarray and sequencing v3.162 | RUSC2 | Sarah Leigh Phenotypes for gene: RUSC2 were changed from Mental retardation, autosomal recessive 61, MIM# 617773 to Mental retardation, autosomal recessive 61 617773 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.149 | CDK19 | Sarah Leigh Phenotypes for gene: CDK19 were changed from microcephaly, congenital bilateral falciform retinal folds, nystagmus, and mental retardation to Epileptic encephalopathy, early infantile, 87 618916 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.144 | YARS | Sarah Leigh changed review comment from: Comment on list classification: Biallelic variants in three families with complex clinical conditions including developmental delay.; to: Comment on list classification: Biallelic variants in three families with complex clinical conditions including developmental delay. PMID 30304524 reports an extended family with microcephaly, expressive language delay, hearing loss, amongst other features. PMID 29232904 reports a proband whose phenotype included hearing loss, retnititis pigmentosa and hypotonia, but did not include intellectual disability. PMID 27633801 reports two sibblings with hypotionia, the older brother at 15 years of age has mild delays, he attends school on an individualized educational program and functions at a grade 3 level. He speaks and understands English and Polish. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.132 | OTUD7A | Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen, Although the region ISCA-46295-Loss, which encompasses the OTUD7A locus, is associated with seizures 20236110, mental retardation 22775350, dysmorphic features, developmental delay and severe epileptic encephalopathy. PMID 31997314 report a homozygous variant in a case of severe global developmental delay, language impairment and epileptic encephalopathy; segregation and functional studies support this gene disease association. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.126 | HARS |
Zornitza Stark changed review comment from: 3 cases from 2 unrelated families with biallelic variants and mild to severe intellectual disability as a feature of the condition. Please note association with Usher syndrome (deafness/retinal phenotypes) has been assessed as 'refuted' by ClinGen, and this gene has a well-established association between heterozygous variants and CMT. Sources: Literature; to: 3 cases from 2 unrelated families with biallelic variants and mild to severe intellectual disability as a feature of the condition. We have also added to paediatric ataxia panel as Amber. Please note association with Usher syndrome (deafness/retinal phenotypes) has been assessed as 'refuted' by ClinGen, and this gene has a well-established association between heterozygous variants and CMT. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.126 | HARS |
Zornitza Stark gene: HARS was added gene: HARS was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: HARS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HARS were set to 32296180 Phenotypes for gene: HARS were set to multisystem ataxic syndrome; mild-severe intellectual disability Review for gene: HARS was set to AMBER Added comment: 3 cases from 2 unrelated families with biallelic variants and mild to severe intellectual disability as a feature of the condition. Please note association with Usher syndrome (deafness/retinal phenotypes) has been assessed as 'refuted' by ClinGen, and this gene has a well-established association between heterozygous variants and CMT. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.87 | DSCR3 |
Zornitza Stark gene: DSCR3 was added gene: DSCR3 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: DSCR3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DSCR3 were set to 31845315 Phenotypes for gene: DSCR3 were set to Intellectual disability, no OMIM # yet Review for gene: DSCR3 was set to RED Added comment: 1 family/2 cousins with cognitive impairment, growth failure, skeletal abnormalities, and distinctive facial features. Both shared the homozygous nonsense variant c.178G>T (p.Glu60*) in the VPS26C gene. This gene encodes VPS26C, a member of the retriever integral membrane protein recycling pathway. The nature of the variant which is predicted to result in loss‐of‐function, expression studies revealing significant reduction in the mutant transcript, and the co‐segregation of the homozygous variant with the phenotype in two affected individuals. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.67 | WDR45B | Rebecca Foulger Phenotypes for gene: WDR45B were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to AUTOSOMAL RECESSIVE MENTAL RETARDATION; Neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without seizures, 617977 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.39 | NR4A2 |
Konstantinos Varvagiannis edited their review of gene: NR4A2: Added comment: Singh et al (2020 - https://doi.org/10.1038/s41436-020-0815-4) provide details on the phenotype of 9 unrelated individuals with NR4A2 pathogenic variants (in almost all cases de novo). Features included hypotonia (in 6/9), DD (9/9), varying levels of ID (mild to severe in 8/8 for whom this information was available), seizures (6/9 - variable epilepsy phenotypes), behavioral problems (5/9 - with autism reported for one). Less frequent features incl. hypermobility (in 3), ataxia/movement disorder (in 3). 8 total pLoF and missense variants were identified as de novo events following trio exome sequencing with Sanger validation (7/8 variants). For 1(/8) individual with a stopgain variant, a single parental sample was available. A 9th individual was found to harbor a ~3.7 Mb 2q deletion spanning also other genes (which might also contribute to his phenotype of epilepsy). Only the effect of a variant affecting the splice-acceptor site was studied (c.865-1_865delGCinsAAAAAGGAGT - NM_006186.3) with RT-PCR demonstrating an out-of-frame skipping of exon 4. Another variant (NM_006186.3:c.325dup) found in a subject with DD, ID and epilepsy had also previously been reported in another individual with similar phenotype of epilepsy and ID (Ramos et al - PMID: 31428396 - the variant was de novo with other causes for his phenotype excluded). As discussed by Singh et al, NR4A2 encodes a steroid-thyroid-retinoid receptor which acts as a nuclear receptor transcription factor. The authors summarize previous reports on NR4A2 haploinsufficiency (NR4A2 has a pLI of 1 and HI score of 1.28% - Z-score is 2.24). The authors comment on mouse models suggesting a role of NR4A2 for dopaminergic neurons, and provide plausible explanations for the phenotype of ID/seizures.; Changed publications: https://doi.org/10.1038/s41436-020-0815-4, 31428396, 29770430, 30504930, 28544326, 27569545, 23554088, 28135719, 27479843, 25363768; Changed phenotypes: Generalized hypotonia, Global developmental delay, Intellectual disability, Seizures, Behavioral abnormality, Abnormality of movement, Joint hypermobility |
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| Intellectual disability - microarray and sequencing v3.33 | LRRC32 |
Zornitza Stark gene: LRRC32 was added gene: LRRC32 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: LRRC32 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LRRC32 were set to 30976112 Phenotypes for gene: LRRC32 were set to Intellectual disability; cleft palate; proliferative retinopathy Review for gene: LRRC32 was set to AMBER Added comment: Three individuals from two consanguineous families segregated the same homozygous bi-allelic variant, c.1630C>T; p.(Arg544Ter), shared haplotype indicative of founder effect. Mouse model has cleft palate and neonatal death. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.3 | CXorf56 | Zornitza Stark reviewed gene: CXorf56: Rating: GREEN; Mode of pathogenicity: None; Publications: 29374277, 31822863; Phenotypes: Mental retardation, X-linked 107, MIM# 301013; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.3 | RUSC2 |
Zornitza Stark gene: RUSC2 was added gene: RUSC2 was added to Intellectual disability. 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 |
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| Intellectual disability - microarray and sequencing v3.3 | RPE65 | Zornitza Stark reviewed gene: RPE65: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Leber congenital amaurosis 2, MIM# 204100, Retinitis pigmentosa 20, MIM# 613794, Retinitis pigmentosa 87 with choroidal involvement, MIM# 618697; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.3 | RETREG1 | Zornitza Stark reviewed gene: RETREG1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuropathy, hereditary sensory and autonomic, type IIB, MIM# 613115; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.3 | NHEJ1 | Zornitza Stark reviewed gene: NHEJ1: Rating: RED; Mode of pathogenicity: None; Publications: 16439204; Phenotypes: Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.3 | SOX17 | Zornitza Stark reviewed gene: SOX17: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Vesicoureteral reflux 3, MIM# 613674; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.3 | SLC9A7 |
Zornitza Stark gene: SLC9A7 was added gene: SLC9A7 was added to Intellectual disability. Sources: Expert list Mode of inheritance for gene: SLC9A7 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: SLC9A7 were set to 30335141 Phenotypes for gene: SLC9A7 were set to Intellectual developmental disorder, X-linked 108; OMIM #301024 Review for gene: SLC9A7 was set to AMBER Added comment: 6 males from 2 unrelated families with hemizygous missense mutation in the SLC9A7 gene. The mutation segregated with the disorder in the family. In vitro functional expression studies in CHO cells (AP-1 cells) showed that the mutation caused decreased levels of protein expression and reduced oligosaccharide maturation/glycosylation compared to wildtype, indicating impaired posttranslational processing. Subcellular localization studies indicated that protein trafficking was unaffected by the mutation. However, examination of the trans-Golgi compartment suggested a gain-of-function effect and a perturbation of glycosylation of secretory cargo. Serum transferrin studies in 1 patient suggested a glycosylation defect. One to watch. Sources: Expert list |
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| Intellectual disability - microarray and sequencing v3.3 | SOX3 | Zornitza Stark reviewed gene: SOX3: Rating: AMBER; Mode of pathogenicity: None; Publications: 29175558, 30125608, 12428212, 15800844; Phenotypes: Mental retardation, X-linked, with isolated growth hormone deficiency, MIM#300123, Panhypopituitarism, X-linked, MIM#312000; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.0 | PDE6G | Zornitza Stark reviewed gene: PDE6G: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Retinitis pigmentosa 57 613582; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.0 | LMAN2L |
Zornitza Stark gene: LMAN2L was added gene: LMAN2L was added to Intellectual disability. Sources: Expert list Mode of inheritance for gene: LMAN2L was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: LMAN2L were set to 31020005; 26566883 Phenotypes for gene: LMAN2L were set to Intellectual disability; epilepsy Review for gene: LMAN2L was set to AMBER Added comment: 1 consanguineous family with 7 individuals with ID and epilepsy, with homozygous LMAN2L missense mutation. Segregated with disease in family, and unaffected family members were heterozygous variant carriers. No functional studies. 1 non-consanguineous family with 4 affected with heterozygous frameshift LMAN2L mutation. Segregates in family. Mutation eliminates LMAN2L's endoplasmic reticulum retention signal and mislocalizes the protein from that compartment to the plasma membrane. Amber or Red. Sources: Expert list |
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| Intellectual disability - microarray and sequencing v3.0 | HNMT |
Zornitza Stark gene: HNMT was added gene: HNMT was added to Intellectual disability. Sources: Expert list Mode of inheritance for gene: HNMT was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HNMT were set to 26206890; 30744146 Phenotypes for gene: HNMT were set to Mental retardation, autosomal recessive 51, MIM#616739 Review for gene: HNMT was set to GREEN Added comment: 7 individuals from two unrelated families, some functional evidence and other circumstantial evidence linking this gene to brain function. Borderline Amber/Green. Sources: Expert list |
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| Intellectual disability - microarray and sequencing v3.0 | HDAC4 | Zornitza Stark reviewed gene: HDAC4: Rating: AMBER; Mode of pathogenicity: None; Publications: 24715439, 20691407, 31209962; Phenotypes: Brachydactyly mental retardation syndrome, Brachydactyly without intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.0 | FLVCR1 | Zornitza Stark reviewed gene: FLVCR1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ataxia, posterior column, with retinitis pigmentosa, MIM#609033; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.0 | C8orf37 | Zornitza Stark changed review comment from: Two unrelated individuals reported with BBS; note gene has an association with retinal ciliopathies.; to: Two unrelated individuals reported with BBS; note gene has an association with retinal ciliopathies. Suggested rating Amber. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.0 | C2orf71 | Zornitza Stark reviewed gene: C2orf71: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Retinitis pigmentosa 54 613428; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.0 | ARHGEF6 | Zornitza Stark reviewed gene: ARHGEF6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: MENTAL RETARDATION X-LINKED TYPE 46; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.0 | MN1 |
Konstantinos Varvagiannis gene: MN1 was added gene: MN1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: MN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: MN1 were set to 31834374; 31839203; 15870292 Phenotypes for gene: MN1 were set to Central hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Hearing impairment; Abnormality of facial skeleton; Craniosynostosis; Abnormality of the face; Abnormality of the cerebellum; Abnormality of the corpus callosum; Polymicrogyria Penetrance for gene: MN1 were set to Complete Review for gene: MN1 was set to GREEN Added comment: Two studies by Mak et al (2019 - PMID: 31834374 / Ref1) and Miyake et al (2019 - PMID: 31839203 / Ref2) provide sufficient evidence for heterozygous MN1 C-terminal truncating variants (predicted to escape NMD - localizing within the last nucleotides of exon 1 or in exon 2) being associated with a distinctive phenotype and DD and ID among the features. Mak et al also discuss on the phenotype of individuals with variants causing N-terminal truncation or with MN1 deletions (discussed at the end of this review). Overlapping features for C-terminal truncating variants included hypotonia, feeding difficulties, global DD and ID, hearing loss, cranial shape defects (/craniosynostosis in few), highly suggestive/distinctive facial features (eg. frontal bossing, hypertelorism, downslanting palpebral-fissures, shallow orbits, short upturned nose, low-set/posteriorly rotated/dysplastic ears, etc) and brain MRI abnormalities (eg. rhomboencephalosynapsis or cerebellar dysplasia, polymicrogyria, dysplastic CC). The majority of the affected individuals were investigated by WES/WGS with a single one tested by targeted MN1 Sanger sequencing due to highly suggestive features. Variable previous investigations incl. CMA in several, gene panel testing (Rasopathies, hearing loss, craniofacial panels, FMR1, etc) and metabolic work were normal in most. In a single case a likely pathogenic ACSL4 also explained part of the phenotype (Ref2). In the majority of these individuals, the variant had occured as a de novo event. Two sibs had inherited the truncating variant from a milder affected mosaic parent. A parental sample was not available for an additional individual. p.(Arg1295*) or NM_002430.2:c.3883C>T was a recurrent variant, seen in several individuals and in both studies. Several lines of evidence are provided for the MN1 variants and the role of the gene including: - For few individuals for whom cell lines were available, variants were shown to escape NMD by cDNA/RT-PCR/RNA-seq [Ref1 & 2]. - The gene has a high expression in fetal brain [Ref2 / fig S2] - MN1 (* 156100 - MN1 protooncogene, transcriptional regulator) has been proposed to play a role in cell proliferation and shown to act as transcription cofactor (increasing its transactivation capacity in synergy with coactivators EP300 and RAC3) [Discussion and Refs provided in Ref2]. - In vitro studies suggested increased protein stability (upon transfection of wt/mut constructs in HEK293T cells), enhanced MN1 aggregation in nuclei (when wt/mut GFP-tagged MN1 was expressed in HeLa cells), increased inhibitory effect on cell growth (MG63 cells - role of MN1 in cell proliferation discussed above) and retained transactivation activity (upon transient MN1 overexpression of wt/mt MN1 in HEK293T cells) for the variants. These seem to support a gain-of-function effect for the C-terminal truncating variants [Ref2]. - The truncating variants are proposed to raise the fraction of Intrinsically disordered regions (IDRs = regions without fixed tertiary structure) probably contributing to the above effects [Ref2]. - Expression of FLAG-tagged MN1 wt/mut MN1 followed by immunoprecipitation and mass spectrometry analysis (mCAT-Hela cells), provided evidence that MN1 is involved in transcriptional regulation: a. through binding ZBTB24 and RING1 E3 ubiquitin ligase (with mutant MN1 displaying impaired interaction with ZBTB24 and no binding to RING1) and/or b. through interaction with DNA-binding transcription factors PBX1 and PKNOX1. Proper MN1 degradation is proposed to mediate precise transcriptional regulation. [Ref2] - Transcriptome analysis in LCLs from an affected individual suggested dysregulation of genes relevant to neuronal development (eg. LAMP, ITGA, etc) and GO analysis suggested enrichment for pathways possibly linked to the observed phenotypes [Ref2]. - Discussed in both Refs1/2, homozygous Mn1-ko mice display abnormal skull bone development and die at/shortly after birth as a result of cleft palate. Heterozygous Mn1-ko mice display hypoplastic membranous bones of the cranial skeleton and cleft palate (CP), the latter with incomplete penetrance [Meester-Smoor et al 2005 - PMID: 15870292]. This is thus compatible with the cranial shape defects observed in C-terminal truncations (while CP has been reported in gene deletions, bifid uvula was reported once in C-terminal and N-terminal truncating variants, in the latter case with submucous CP). ----- The phenotype of other MN1 variants is discussed by Mak et al (Ref1) : - 3 individuals with MN1 N-terminal truncating variants (eg. Ser179*, Pro365Thrfs*120, Ser472*) presented speech delay, mild conductive hearing loss and facial features different from C-terminal truncations. None of these individuals had significant ID. - Microdeletions: One individual (#27) with 130 kb deletion harboring only MN1, presented microcephaly, DD and ID and mildly dysmorphic facial features. Deletions spanning MN1 and other genes (eg a 1.17 Mb deletion in ind. #28) and relevant cases from the literature reviewed, with mild DD/ID, variable palatal defects and/or facial dysmorphisms (distinct from the C-terminal truncating variants) among the frequent findings. [Please consider inclusion in other possibly relevant gene panels eg. for hearing loss (conductive/sensorineural in 16/20 reported by Mak et al) or craniosynostosis, etc]. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.0 | CXorf56 |
Konstantinos Varvagiannis gene: CXorf56 was added gene: CXorf56 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: CXorf56 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: CXorf56 were set to 29374277; 31822863 Phenotypes for gene: CXorf56 were set to ?Mental retardation, X-linked 107, 301013 Penetrance for gene: CXorf56 were set to unknown Review for gene: CXorf56 was set to AMBER Added comment: Verkerk et al (2018 - PMID: 29374277) reported on a three-generation family with five males and one female presenting mild non-syndromic ID. Segregation was compatible with X-linked inheritance. Multipoint linkage analysis with XL microsatellite markers demonstrated a linkage peak at Xq23-24 with LOD score of 3.3. Haplotype analysis and utilization of additional STR markers allowed narrowing to a region of 7.6 Mb containing 92 genes. WGS in 3 affected males (spanning 3 generations) and 1 unaffected male and application of relevant filters for rare protein affecting variants within this region - present only in affected but absent in the unaffected individual - suggested a CXorf56 frameshift variant in exon 2 [NM_022101.3:c.159_160insTA / p.(Asp54*)] as the only relevant for this phenotype. Sanger sequencing was performed for 25 family members with all 5 affected males and 1 affected female harboring this insertion and 8 unaffected females (also) shown to be carriers. X-chromosome inactivation studies demonstrated that unaffected females had skewed inactivation (76-93%) of the variant allele, while the single affected female did not have a skewed XCI pattern (54%). In EBV-transformed lymphoblasts grown with/without cycloheximide, mRNA levels were shown to be significantly lower in the affected female compared to unaffected ones (and corrected upon treatment with cycloheximide). mRNA levels were also significantly lower in cell lines from an affected male, with expression showing significant increase after treatment with cycloheximide. These results confirmed that nonsense-mediated decay applies. The variant was absent from ExAC (where CXorf56 has a pLI of 0.93) and 188 healthy Dutch individuals. The function of CXorf56 is not known. The gene appears to be expressed in brain and a (broad) range of other tissues [ https://gtexportal.org/home/gene/CXORF56 ]. Immunostaining in 8-week old murine brain, showed that the protein is present in the nucleus and cell soma of most neurons in brain cortex and cerebellum. Upon transfection of human CXorf56 cDNA in mouse primary hippocampal neurons, the protein localized in the nucleus, dendrites (co-localizing with Map2) and dendritic spines. As the authors note, the latter may suggest a role in synaptic function. Overexpression in HEK293T cells demonstrated predominantly nuclear localization. Mouse : Based on MGI (and an article by Cox et al. - PMID: 20548051 / both cited by the authors) male chimeras hemizygous for a gene trapped allele have abnormal midbrain-hindbrain boundary morphology, decreased forebrain size, while a subset hemizygous for a different gene trapped allele show growth delay [ http://www.informatics.jax.org/marker/MGI:1924894 ]. ----- Rocha et al (2019 - PMID: 31822863) report on 9 affected individuals with mild to severe ID belonging to 3 unrelated families. Additional features in this cohort - observed in some - included abnormal reflexes, fine tremor, seizures (in 3), abnormal gait, etc. In the 1st family, 3 males presented with (severe/severe/moderate) ID and 2 females with mild ID. Following a normal CMA and FMR1 testing, trio plus exome sequencing revealed a CXorf56 in-frame deletion [NM_022101.3:c.498_503del / p.(Glu167_Glu168del)]. Sanger sequencing in 9 members, confirmed presence of the variant in one unaffected mother, all her affected sons (2) and daughers(2) and an affected grandson and absence in 2 remaining unaffected daughters. Skewing of XCI was seen in blood cells from affected females (97 and 83%) while the unaffected mother had complete inactivation of the carrier X-chromosome. The authors commented that even minor reductions in CXorf56 (suggested by XCI in affected females) may be detrimental and/or that inactivation for this gene may be different than that of AR gene (which was studied instead) or in other tissues. In family 2, an affected mother (with learning difficulties) and her 2 sons - the most severely affected presenting moderate ID - harbored a frameshift variant [c.303_304delCTinsACCC / p.(Phe101Leufs*20)]. A male with ID belonging to a 3rd family, for which no further information was available, was found to harbor the c.498_503del variant (also discussed above) as a de novo event. It has been commented that individuals with Xq24 deletions spanning CXorf56 present with ID, although (all) such deletions reported in the literature also span the neighboring UBE2A gene, associated with Mental retardation, X-linked syndromic, Nascimento-type (MIM #300860). ----- In OMIM, the CXorf56-related phenotype is ?Mental retardation, X-linked 107 (# 301013), based only on the report by Verkerk et al. This gene is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc). ----- Overall, CXorf56 can be considered for inclusion in the ID panel either with amber (function of the gene unknown, skewed XCI also in affected females in the 2nd reference) or with green rating (several individuals from 4 families, compatible segregation studies and females presenting a milder phenotype than males or unaffected, LOD score in the 1st report, studies confirming lower mRNA levels and NMD, gene expressed in human brain, expression in mouse brain cortex and cerebellum, evidence from transfection studies in mouse hippocampal neurons). [Note : penetrance was here set to unknown / It was complete for males, incomplete for females]. Sources: Literature, Radboud University Medical Center, Nijmegen |
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| Intellectual disability - microarray and sequencing v3.0 | KAT8 |
Konstantinos Varvagiannis gene: KAT8 was added gene: KAT8 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: KAT8 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: KAT8 were set to 31794431 Phenotypes for gene: KAT8 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of vision; Feeding difficulties; Abnormality of the cardiovascular system; Autism Penetrance for gene: KAT8 were set to unknown Review for gene: KAT8 was set to GREEN Added comment: Heterozygous pathogenic missense KAT8 variants have been reported in individuals with DD, ID and epilepsy. Variants occurred as de novo events within the chromobarrel or the acetyltransferase domain and were all shown to affect H4K16 acetylation, as would be predicted by the gene's function (lysine acetyltransferase). Evidence from brain specific Kat8 knockout in mouse, supports the role of the gene in brain development. One similarly affected individual compound heterozygous for a nonsense and a missense variant (the former affecting subnuclear localization and the latter H4K16ac) was also reported, with carrier relatives being unaffected. Mutations in genes of the MSL/NSL complexes (with which KAT8 forms multisubunit complexes) or genes in other acetyltransferases of the same subfamily (MYST) as KAT8 cause neurodevelopmental disorders [Details provided below]. ----- Li et al. (2019 - PMID: 31794431) report on 8 unrelated individuals with heterozygous de novo pathogenic KAT8 variants, as well as an additional one compound heterozygous for a nonsense and a missense one. Overlapping phenotype consisted of DD/ID (8/8), seizures/epilepsy (6/8), brain MRI anomalies as well as presence of variable facial dysmorphic features. Less frequent features included abnormal vision (5/8), feeding difficulties (3/8), cardiac anomalies (3/8), autism (in 1). The (9th) individual with biallelic variants had similar phenotype of DD/ID, epilepsy, autism and dysmorphic facial features. Heterozygous parents and sister, the latter carrier for the missense variant, were all unaffected. All individuals had undergone exome sequencing, while extensive other investigations for at least 7/9 had only revealed variants of uncertain significance/contribution to the phenotype or were normal. KAT8 encodes lysine acetyltransferase 8, which acetylates histone H4 at lysine 16 (H4K16). It belongs to the MYST subfamily of lysine acetyltransferases, the other members of which include KAT6A, KAT6B (both involved in neurodevelopmental disorders) and KAT5. KAT8 forms two stoichiometric multisubunitcomplexes, one with the MSL complex and the other with the NSL. Mutations in genes encoding for subunits of the NSL or MSL complex (eg. KANSL1 and MSL3) are associated with neurodevelopmental disorders. Overall 6 missense SNVs were reported among the heterozygous patients, p.Tyr90Cys (NM_032188.2:c.269A>G) being a recurrent one seen in 3. The compound heterozygous patient had a missense (c.973C>T / p.Arg325Cys) and a nonsense variant (c.523A>T / p.Lys175*). All missense variants lied either in the chromobarrel domain or the acetyltransferase domain. Variants in the latter domain localized within the KAT8/Mof-specific region or - in the case of the compound heterozygous individual - within the acetyl-CoA binding motif. FLAG-tagged KAT8 (either wt or for all missense SNVs) was transfected in HEK293 cells with vectors for HA-tagged MSL proteins. While the nonsense variant was difficult to express, missense SNVs were expressed to similar levels to wt, promoted expression of MSL proteins but resulted in defective H4K16 acetylation and to a lesser extent H4K5 acetylation. As a result all missense variants impaired acetylation. This was also the case for chromobarrel domain variants, while expression of a KAT8 lacking the chromobarrel domain confirmed its ability to form complex with the MSL proteins and the impairment of H4K16 acetylation. The nonsense variant demonstrated abnormal subnuclear localization. The mouse model provides extensive evidence for the involvement of KAT8 in cerebral development. Cerebrum-specific Kat8 knockout mice presented postnatal growth retardation, hyperactivity/irritability, pre-weaning lethality, and cerebral hypoplasia upon autopsy. Loss of Kat8 reduced the number of neural stem and progenitor cells available for embryonic cerebrocortical development, impaired cell proliferation and stimulated apoptosis. The article also provides additional evidence from mouse model. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.0 | SUZ12 |
Konstantinos Varvagiannis changed review comment from: ID can be a feature in individuals heterozygous for SUZ12 pathogenic variants. 13 affected individuals (from 12 families) have been reported: [1] PMID 28229514 (Imagawa et al, 2017) : 1 individual [2] PMID 30019515 (Imagawa et al, 2018) : 2 further unrelated subjects [3] PMID 31736240 (Cyrus et al, 2019) : 10 additional subjects (from 9 families) Reviewed by Cyrus et al, features observed in more than half of the (13) affected individuals included prenatal and/or postnatal overgrowth (in some only prenatal, others only postnatal, others did not manifest overgrowth at all), some suggestive facial features (eg. prominent forehead, hypertelorism, downslanting palpebral fissures, round face, broad/low nasal bridge), DD and ID (the latter in 7/13, in most cases mild), advanced bone age, musculoskeletal abnormalities and cryptorchidism. Less frequent features included brain MRI abnormalities (eg. CC hypoplasia/agenesis, etc.), umbilical hernias, respiratory abnormalities, cardiac anomalies (in one). All were diagnosed with WES/WGS/panel testing, with few having additional findings upon this or prior testing (eg. CNVs/SNVs). SUZ12 encodes one of the 4 core proteins of the PRC2 complex (the 3 other being encoded by EZH1/2, EED and RBBP4/7). The complex has a methyltransferase activity, catalyzing addition of up to 3 methyl groups on histone 3 at lysine residue 27 (H3K27), leading to chromatin compaction and further to gene silencing. Mutations in genes encoding 2 other core components of the PRC2 complex - namely EZH2 and EED - cause Weaver and Cohen-Gibson syndrome with overlapping phenotype incl. overgrowth, advanced bone age, craniofacial features and DD/ID. The SET domain of EZH1/2 and EED as well as the VEFS domain of SUZ12 are contributing to the catalytic activity. SUZ12 variants reported to date include missense and pLoF variants (frameshift, nonsense, splice site ones) predicted to disrupt or eliminate the VEFS-box domain [almost all missense within this domain with the exception of one proximal to it (Arg535Gln) / pLoF causing truncation prior or within this domain (Arg654Ter might be an exception)] {NP_056170.2}. Variants either occurred de novo or were inherited (~1/3), on some occasions from a mildly affected parent. Parental mosaicism has also been reported (eg. in ref1, and one or possibly two additional families in ref3). Some preliminary assumptions on possible genotype-phenotype correlations (for overgrowth and ID related to missense/pLoF variants) are discussed in ref3. SUZ12 is also be deleted in some patients with NF1 deletion (and a diagnosis of neurofibromatosis type 1). Deletion of SUZ12 has been proposed to contribute to the phenotype of these individuals (eg. overgrowth, cognitive development, facial features). [Discussed in ref1]. Functional studies have been carried out only in the first report (ref1) and demonstrated decreased trimethylation of H3K27 in the case of a missense variant. Overall a partial loss-of-function mechanism has been proposed for the variants. Mouse models: A study by Pasini et al (PMID: 15385962) did not report phenotypic differences between wt and heterozygous Suz12 knockout mice (gene-trap vector) as for size, morphology and fertility. Total knockout resulted in embryonic lethality, significant growth retardation and several developmental defects. Loss of Suz12 was shown to result in absence of di- and tri-methylated H3K27 in the ko embryos. In another study cited (Miro et al - PMID: 19535498) heterozygous mice (replacement of exons 12-16 with a lacZ gene and neo cassette) displayed variable CNS defects with incomplete penetrance. The role of the PRC2 complex and the phenotypes related to mutations in genes encoding its core components, are discussed in PMID: 31724824 (also by Cyrus et al, 2019). SUZ12 is not associated with any phenotype in OMIM. In G2P it is included in the DD panel associated with Weaver-like overgrowth syndrome (disease confidence : confirmed). The gene is also included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx). Sources: Literature; to: ID can be a feature in individuals heterozygous for SUZ12 pathogenic variants. 13 affected individuals (from 12 families) have been reported: [1] PMID 28229514 (Imagawa et al, 2017) : 1 individual [2] PMID 30019515 (Imagawa et al, 2018) : 2 further unrelated subjects [3] PMID 31736240 (Cyrus et al, 2019) : 10 additional subjects (from 9 families) Reviewed by Cyrus et al, features observed in more than half of the (13) affected individuals included prenatal and/or postnatal overgrowth (in some only prenatal, others only postnatal, others did not manifest overgrowth at all), some suggestive facial features (eg. prominent forehead, hypertelorism, downslanting palpebral fissures, round face, broad/low nasal bridge), DD and ID (the latter in 7/13, in most cases mild), advanced bone age, musculoskeletal abnormalities and cryptorchidism. Less frequent features included brain MRI abnormalities (eg. CC hypoplasia/agenesis, etc.), umbilical hernias, respiratory abnormalities, cardiac anomalies (in one). All were diagnosed with WES/WGS/panel testing, with few having additional findings upon this or prior testing (eg. CNVs/SNVs). SUZ12 encodes one of the 4 core proteins of the PRC2 complex (the 3 other being encoded by EZH1/2, EED and RBBP4/7). The complex has a methyltransferase activity, catalyzing addition of up to 3 methyl groups on histone 3 at lysine residue 27 (H3K27), leading to chromatin compaction and further to gene silencing. Mutations in genes encoding 2 other core components of the PRC2 complex - namely EZH2 and EED - cause Weaver and Cohen-Gibson syndrome with overlapping phenotype incl. overgrowth, advanced bone age, craniofacial features and DD/ID. The SET domain of EZH1/2 and EED as well as the VEFS domain of SUZ12 are contributing to the catalytic activity. SUZ12 variants reported to date include missense and pLoF variants (frameshift, nonsense, splice site ones) predicted to disrupt or eliminate the VEFS-box domain [almost all missense within this domain with the exception of one proximal to it (Arg535Gln) / pLoF causing truncation prior or within this domain (Arg654Ter might be an exception)] {NP_056170.2}. Variants either occurred de novo or were inherited (~1/3), on some occasions from a mildly affected parent. Parental mosaicism has also been reported (eg. in ref1, and one or possibly two additional families in ref3). Some preliminary assumptions on possible genotype-phenotype correlations (for overgrowth and ID related to missense/pLoF variants) are discussed in ref3. SUZ12 may also be deleted in some patients with NF1 deletion (and a diagnosis of neurofibromatosis type 1). Deletion of SUZ12 has been proposed to contribute to the phenotype of these individuals (eg. overgrowth, cognitive development, facial features). [Discussed in ref1]. Functional studies have been carried out only in the first report (ref1) and demonstrated decreased trimethylation of H3K27 in the case of a missense variant. Overall a partial loss-of-function mechanism has been proposed for the variants. Mouse models: A study by Pasini et al (PMID: 15385962) did not report phenotypic differences between wt and heterozygous Suz12 knockout mice (gene-trap vector) as for size, morphology and fertility. Total knockout resulted in embryonic lethality, significant growth retardation and several developmental defects. Loss of Suz12 was shown to result in absence of di- and tri-methylated H3K27 in the ko embryos. In another study cited (Miro et al - PMID: 19535498) heterozygous mice (replacement of exons 12-16 with a lacZ gene and neo cassette) displayed variable CNS defects with incomplete penetrance. The role of the PRC2 complex and the phenotypes related to mutations in genes encoding its core components, are discussed in PMID: 31724824 (also by Cyrus et al, 2019). SUZ12 is not associated with any phenotype in OMIM. In G2P it is included in the DD panel associated with Weaver-like overgrowth syndrome (disease confidence : confirmed). The gene is also included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx). Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.0 | SUZ12 |
Konstantinos Varvagiannis changed review comment from: ID can be a feature in individuals heterozygous for SUZ12 pathogenic variants. 13 affected individuals (from 12 families) have been reported: [1] PMID 28229514 (Imagawa et al, 2017) : 1 individual [2] PMID 30019515 (Imagawa et al, 2018) : 2 further unrelated subjects [3] PMID 31736240 (Cyrus et al, 2019) : 10 newly diagnosed subjects (from 9 families) Reviewed by Cyrus et al, features observed in more than half of the (13) affected individuals included prenatal and/or postnatal overgrowth (in some only prenatal, others only postnatal, others did not manifest overgrowth at all), some suggestive facial features (eg. prominent forehead, hypertelorism, downslanting palpebral fissures, round face, broad/low nasal bridge), DD and ID (the latter in 7/13, in most cases mild), advanced bone age, musculoskeletal abnormalities and cryptorchidism. Less frequent features included brain MRI abnormalities (eg. CC hypoplasia/agenesis, etc.), umbilical hernias, respiratory abnormalities, cardiac anomalies (in one). All were diagnosed with WES/WGS/panel testing, with few having additional findings upon this or prior testing (eg. CNVs/SNVs). SUZ12 encodes one of the 4 core proteins of the PRC2 complex (the 3 other being encoded by EZH1/2, EED and RBBP4/7). The complex has a methyltransferase activity, catalyzing addition of up to 3 methyl groups on histone 3 at lysine residue 27 (H3K27), leading to chromatin compaction and further to gene silencing. Mutations in genes encoding 2 other core components of the PRC2 complex - namely EZH2 and EED - cause Weaver and Cohen-Gibson syndrome with overlapping phenotype incl. overgrowth, advanced bone age, craniofacial features and DD/ID. The SET domain of EZH1/2 and EED as well as the VEFS domain of SUZ12 are contributing to the catalytic activity. SUZ12 variants reported to date include missense and pLoF variants (frameshift, nonsense, splice site ones) predicted to disrupt or eliminate the VEFS-box domain [almost all missense within this domain with the exception of one proximal to it (Arg535Gln) / pLoF causing truncation prior or within this domain (Arg654Ter might be an exception)] {NP_056170.2}. Variants either occurred de novo or were inherited (~1/3), on some occasions from a mildly affected parent. Parental mosaicism has also been reported (eg. in ref1, and one or possibly two additional families in ref3). Some preliminary assumptions on possible genotype-phenotype correlations (for overgrowth and ID related to missense/pLoF variants) are discussed in ref3. SUZ12 is also be deleted in some patients with NF1 deletion (and a diagnosis of neurofibromatosis type 1). Deletion of SUZ12 has been proposed to contribute to the phenotype of these individuals (eg. overgrowth, cognitive development, facial features). [Discussed in ref1]. Functional studies have been carried out only in the first report (ref1) and demonstrated decreased trimethylation of H3K27 in the case of a missense variant. Overall a partial loss-of-function mechanism has been proposed for the variants. Mouse models: An study by Pasini et al (PMID: 15385962) did not report phenotypic differences between wt and heterozygous Suz12 knockout mice (gene-trap vector) as for size, morphology and fertility. Total knockout resulted in embryonic lethality, significant growth retardation and several developmental defects. Loss of Suz12 was shown to result in absence of di- and tri-methylated H3K27 in the ko embryos. In another study cited (Miro et al - PMID: 19535498) heterozygous mice (replacement of exons 12-16 with a lacZ gene and neo cassette) displayed variable CNS defects with incomplete penetrance. The role of the PRC2 complex and the phenotypes related to mutations in genes encoding its core components, are discussed in PMID: 31724824 (also by Cyrus et al, 2019). SUZ12 is not associated with any phenotype in OMIM. In G2P it is included in the DD panel associated with Weaver-like overgrowth syndrome (disease confidence : confirmed). The gene is also included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx). Sources: Literature; to: ID can be a feature in individuals heterozygous for SUZ12 pathogenic variants. 13 affected individuals (from 12 families) have been reported: [1] PMID 28229514 (Imagawa et al, 2017) : 1 individual [2] PMID 30019515 (Imagawa et al, 2018) : 2 further unrelated subjects [3] PMID 31736240 (Cyrus et al, 2019) : 10 additional subjects (from 9 families) Reviewed by Cyrus et al, features observed in more than half of the (13) affected individuals included prenatal and/or postnatal overgrowth (in some only prenatal, others only postnatal, others did not manifest overgrowth at all), some suggestive facial features (eg. prominent forehead, hypertelorism, downslanting palpebral fissures, round face, broad/low nasal bridge), DD and ID (the latter in 7/13, in most cases mild), advanced bone age, musculoskeletal abnormalities and cryptorchidism. Less frequent features included brain MRI abnormalities (eg. CC hypoplasia/agenesis, etc.), umbilical hernias, respiratory abnormalities, cardiac anomalies (in one). All were diagnosed with WES/WGS/panel testing, with few having additional findings upon this or prior testing (eg. CNVs/SNVs). SUZ12 encodes one of the 4 core proteins of the PRC2 complex (the 3 other being encoded by EZH1/2, EED and RBBP4/7). The complex has a methyltransferase activity, catalyzing addition of up to 3 methyl groups on histone 3 at lysine residue 27 (H3K27), leading to chromatin compaction and further to gene silencing. Mutations in genes encoding 2 other core components of the PRC2 complex - namely EZH2 and EED - cause Weaver and Cohen-Gibson syndrome with overlapping phenotype incl. overgrowth, advanced bone age, craniofacial features and DD/ID. The SET domain of EZH1/2 and EED as well as the VEFS domain of SUZ12 are contributing to the catalytic activity. SUZ12 variants reported to date include missense and pLoF variants (frameshift, nonsense, splice site ones) predicted to disrupt or eliminate the VEFS-box domain [almost all missense within this domain with the exception of one proximal to it (Arg535Gln) / pLoF causing truncation prior or within this domain (Arg654Ter might be an exception)] {NP_056170.2}. Variants either occurred de novo or were inherited (~1/3), on some occasions from a mildly affected parent. Parental mosaicism has also been reported (eg. in ref1, and one or possibly two additional families in ref3). Some preliminary assumptions on possible genotype-phenotype correlations (for overgrowth and ID related to missense/pLoF variants) are discussed in ref3. SUZ12 is also be deleted in some patients with NF1 deletion (and a diagnosis of neurofibromatosis type 1). Deletion of SUZ12 has been proposed to contribute to the phenotype of these individuals (eg. overgrowth, cognitive development, facial features). [Discussed in ref1]. Functional studies have been carried out only in the first report (ref1) and demonstrated decreased trimethylation of H3K27 in the case of a missense variant. Overall a partial loss-of-function mechanism has been proposed for the variants. Mouse models: A study by Pasini et al (PMID: 15385962) did not report phenotypic differences between wt and heterozygous Suz12 knockout mice (gene-trap vector) as for size, morphology and fertility. Total knockout resulted in embryonic lethality, significant growth retardation and several developmental defects. Loss of Suz12 was shown to result in absence of di- and tri-methylated H3K27 in the ko embryos. In another study cited (Miro et al - PMID: 19535498) heterozygous mice (replacement of exons 12-16 with a lacZ gene and neo cassette) displayed variable CNS defects with incomplete penetrance. The role of the PRC2 complex and the phenotypes related to mutations in genes encoding its core components, are discussed in PMID: 31724824 (also by Cyrus et al, 2019). SUZ12 is not associated with any phenotype in OMIM. In G2P it is included in the DD panel associated with Weaver-like overgrowth syndrome (disease confidence : confirmed). The gene is also included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx). Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.0 | SUZ12 |
Konstantinos Varvagiannis gene: SUZ12 was added gene: SUZ12 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: SUZ12 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SUZ12 were set to 28229514; 30019515; 31736240; 15385962; 19535498; 31724824 Phenotypes for gene: SUZ12 were set to Overgrowth; Global developmental delay; Intellectual disability; Accelerated skeletal maturation; Abnormality of the skeletal system; Abnormality of the genitourinary system; Abnormality of the corpus callosum; Abnormality of the respiratory system; Abnormality of the abdominal wall Penetrance for gene: SUZ12 were set to unknown Review for gene: SUZ12 was set to GREEN Added comment: ID can be a feature in individuals heterozygous for SUZ12 pathogenic variants. 13 affected individuals (from 12 families) have been reported: [1] PMID 28229514 (Imagawa et al, 2017) : 1 individual [2] PMID 30019515 (Imagawa et al, 2018) : 2 further unrelated subjects [3] PMID 31736240 (Cyrus et al, 2019) : 10 newly diagnosed subjects (from 9 families) Reviewed by Cyrus et al, features observed in more than half of the (13) affected individuals included prenatal and/or postnatal overgrowth (in some only prenatal, others only postnatal, others did not manifest overgrowth at all), some suggestive facial features (eg. prominent forehead, hypertelorism, downslanting palpebral fissures, round face, broad/low nasal bridge), DD and ID (the latter in 7/13, in most cases mild), advanced bone age, musculoskeletal abnormalities and cryptorchidism. Less frequent features included brain MRI abnormalities (eg. CC hypoplasia/agenesis, etc.), umbilical hernias, respiratory abnormalities, cardiac anomalies (in one). All were diagnosed with WES/WGS/panel testing, with few having additional findings upon this or prior testing (eg. CNVs/SNVs). SUZ12 encodes one of the 4 core proteins of the PRC2 complex (the 3 other being encoded by EZH1/2, EED and RBBP4/7). The complex has a methyltransferase activity, catalyzing addition of up to 3 methyl groups on histone 3 at lysine residue 27 (H3K27), leading to chromatin compaction and further to gene silencing. Mutations in genes encoding 2 other core components of the PRC2 complex - namely EZH2 and EED - cause Weaver and Cohen-Gibson syndrome with overlapping phenotype incl. overgrowth, advanced bone age, craniofacial features and DD/ID. The SET domain of EZH1/2 and EED as well as the VEFS domain of SUZ12 are contributing to the catalytic activity. SUZ12 variants reported to date include missense and pLoF variants (frameshift, nonsense, splice site ones) predicted to disrupt or eliminate the VEFS-box domain [almost all missense within this domain with the exception of one proximal to it (Arg535Gln) / pLoF causing truncation prior or within this domain (Arg654Ter might be an exception)] {NP_056170.2}. Variants either occurred de novo or were inherited (~1/3), on some occasions from a mildly affected parent. Parental mosaicism has also been reported (eg. in ref1, and one or possibly two additional families in ref3). Some preliminary assumptions on possible genotype-phenotype correlations (for overgrowth and ID related to missense/pLoF variants) are discussed in ref3. SUZ12 is also be deleted in some patients with NF1 deletion (and a diagnosis of neurofibromatosis type 1). Deletion of SUZ12 has been proposed to contribute to the phenotype of these individuals (eg. overgrowth, cognitive development, facial features). [Discussed in ref1]. Functional studies have been carried out only in the first report (ref1) and demonstrated decreased trimethylation of H3K27 in the case of a missense variant. Overall a partial loss-of-function mechanism has been proposed for the variants. Mouse models: An study by Pasini et al (PMID: 15385962) did not report phenotypic differences between wt and heterozygous Suz12 knockout mice (gene-trap vector) as for size, morphology and fertility. Total knockout resulted in embryonic lethality, significant growth retardation and several developmental defects. Loss of Suz12 was shown to result in absence of di- and tri-methylated H3K27 in the ko embryos. In another study cited (Miro et al - PMID: 19535498) heterozygous mice (replacement of exons 12-16 with a lacZ gene and neo cassette) displayed variable CNS defects with incomplete penetrance. The role of the PRC2 complex and the phenotypes related to mutations in genes encoding its core components, are discussed in PMID: 31724824 (also by Cyrus et al, 2019). SUZ12 is not associated with any phenotype in OMIM. In G2P it is included in the DD panel associated with Weaver-like overgrowth syndrome (disease confidence : confirmed). The gene is also included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.1135 | TRAPPC4 |
Konstantinos Varvagiannis gene: TRAPPC4 was added gene: TRAPPC4 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: TRAPPC4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TRAPPC4 were set to 31794024 Phenotypes for gene: TRAPPC4 were set to Feeding difficulties; Progressive microcephaly; Intellectual disability; Seizures; Spastic tetraparesis; Abnormality of the face; Scoliosis; Cortical visual impairment; Hearing impairment Penetrance for gene: TRAPPC4 were set to Complete Review for gene: TRAPPC4 was set to GREEN Added comment: Van Bergen et al. (2019 - PMID: 31794024) report on 7 affected individuals from 3 famillies (only 1 of which consanguineous), all homozygous for a TRAPPC4 splicing variant. Overlapping features included feeding difficulties, progressive microcephaly, severe to profound developmental disability (7/7 - DD also prior to the onset of seizures / regression also reported in 3), epilepsy (7/7 - onset in the first year), spastic quadriparesis. Other findings in some/few incl. scoliosis, cortical visual and hearing impairment. Some facial features were shared (eg. bitemporal narrowing, long philtrum, open mouth with thin tented upper lip, pointed chin, etc). Brain imaging demonstrated abnormalities in those performed (among others cerebral with/without cerebellar atrophy). Work-up prior to exome sequencing was normal (highly variable incl. metabolic testing, CMA, MECP2, CDKL5, mitochondrial depletion studies, etc). Exome of affected individuals (and parents +/- affected sibs in some families) revealed a homozygous TRAPPC4 splicing variant [NM_016146.5:c.454+3A>G / chr11:g.118890966A>G (hg19)]. Sanger sequencing confirmed variant in affecteds, heterozygosity in parents and compatible genotypes with disease status in sibs/other members. Families were of Caucasian/Turkish and French-Canadian ethnicities. SNP array to compare haplotypes between affecteds in 2 families did not reveal a shared haplotype (/founder effect) and the variant is present in gnomAD (68/281054 - no hmz) in many populations (European/Asian/African/Latino) [https://gnomad.broadinstitute.org/variant/11-118890966-A-G]. mRNA studies in fibroblasts from an affected individual confirmed the splicing defect (2 RT-PCR products corresponding to wt and a shorter due to skipping of exon 3, the latter further confirmed by Sanger sequencing. The shorter transcript is not present in controls). qPCR revealed that the normal transript in patient fibroblasts was present at 6% of the level observed in control fibroblasts (or 54% in the case of a heterozygote parent compared to controls). Western blot in patient fibroblasts, revealed presence of full-length protein in significantly reduced levels compared to fibroblasts from carrier parents or controls. There was no band using an antibody targeting the N-terminal region of the protein prior to exon 3, suggesting that NMD applies (skipping of ex3 is also predicted to lead to frameshift). TRAPPC4 encodes one of the core proteins of the TRAPP complex. Use of different accessory proteins leads to formation of 2 distinct complexes (TRAPPII / III). The complex has an important role in intracellular trafficking. Both TRAPPII & TRAPPIII have a function in the secretory pathway, while complex III has a role also in autophagy. Core proteins are important for the complex stability. The TRAPP complex serves as a GEF for Ypt/Rab GTPases [several refs in article]. Mutations in genes for other proteins of the complex lead to neurodevelopmental disorders with associated ID ('TRAPPopathies' used by the authors / TRAPPC12, C6B, C9 green in the current panel). Western blot suggested that levels of other TRAPP subunits (TRAPPC2 or C12) under denaturing conditions, although PAGE/size exclusion chromatography suggested that the levels of fully-assembled TRAPP complexes were lower in affected individuals. Studies in patient fibroblasts showed a secretory defect (between ER, Golgi and the plasma membrane) which was restored upon lentiviral transduction with wt TRAPPC4 construct. Basal and starvation-induced autophagy were also impaired in patient fibroblasts (increased LC3 marker and LC3-positive structures / impaired co-localization with lysosomes) partly due to defective autophagosome formation (/sealing). TRAPPC4 is the human orthologue of the yeast Trs23. In a yeast model of reduced Trs23 (due to temperature instability) the authors demonstrated impaired assembly of the TRAPP core. The yeast model recapitulated the autophagy as well as well as the secretory defect observed in patient fibroblasts. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.1135 | SNX27 |
Konstantinos Varvagiannis gene: SNX27 was added gene: SNX27 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: SNX27 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SNX27 were set to 25894286; 31721175; 21300787; 23524343 Phenotypes for gene: SNX27 were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures Penetrance for gene: SNX27 were set to Complete Review for gene: SNX27 was set to GREEN gene: SNX27 was marked as current diagnostic Added comment: Evidence from 2 publications suggests that DD, ID and seizures are part of the phenotype of individuals with biallelic SNX27 pathogenic variants : --------- Damseh, Danson et al (2015 - PMID: 25894286) first reported on a consanguineous family with 4 affected sibs, homozygous for an SNX27 pathogenic variant. Features incl. hypotonia soon after birth, failure to thrive, severely delayed psychomotor development with no milestone acquisition, occurrence of myoclonic seizures with 3 individuals deceased early. Exome sequencing in one revealed a few candidate variants, with an SNX27 frameshift one [NM_030918.6:c.515_516del - p.(His172Argfs*6) / absent from ExAC] being the only retained following Sanger segregation studies. Using fibroblasts from an affected individual, Western blot with an antibody which would also bind prior to the truncation site, was consistent with dramatically reduced/absent SNX27 truncated mutant protein. Protein levels of VPS35, a component of the retromer responsible for direct cargo binding (not mediated by a cargo adaptor as SNX27), were normal. --------- Parente et al (2019 - PMID: 31721175) reported on a 13-year-old male with motor and language delay, ADHD, ID (kindergarten academic level at the age of 13) and seizures with onset at the age of 9 years (GTC, with abnormal EEG and postical SV tachycardia). Variable physical findings were reported. White matter hyperintesities were noted upon initial brain MRI (but were less marked in subsequent ones). Initial genetic testing (Alexander's disease, CMA, FMR1) was normal. Exome revealed compound heterozygosity for 2 SNX27 variants (NM_030918.5/NM_001330723.1 both apply c.510C>G - p.Tyr170* and c.1295G>A - p.Cys432Tyr) each inherited from healthy carrier parents. There were no other potentially causative variants. A parental history of - isolated - late onset seizures was reported (so this individual may not be considered for the seizure phenotype here). The authors also reported on a further 31-year old affected male. This individual had infantile hypotonia, poor eye contact with subsequent significant DD, seizures (febrile/afebrile T-C with onset at the age of 14m) and ID estimated in the severe range. Variable - though somewhat different - physical findings were reported. Initial work-up included basic metabolic testing, standard karyotype, FISH for 15q11 and subtelomeric regions and PHF6 genetic testing - all normal. Exome (and subsequent Sanger confirmation/parental studies) revealed compound heterozygosity for a missense and a frameshift variant (c.989G>A / p.Arg330His and c.782dupT / p.Leu262Profs*6 same in NM_001330723.1, NM_030918.6). --------- SNX27 encodes sorting nexin 27, a cargo adaptor for the retromer. The latter is a multi-protein complex essential for regulating the retrieval and recycling of transmembrane cargos from endosomes to the trans-Golgi network or the plasma membrane [Lucas et al 2016 - PMID: 27889239 / McNally et al 2018 - PMID: 30072228]. As summarized by Parente et al, the encoded protein by regulating composition of the cell surface influences several processes eg. neuronal excitability, synaptic plasticity, Wnt signaling etc. It has been shown to interact with surface receptors and their ligands including GIRK channels, 5-HT4, ionotropic glutamate receptors (incl. NMDA- and AMPA-type receptors) and mGluR5 [several refs. provided]. Knockout of Snx27 in mice resulted in embryonic lethality (16% hmz of the 25% expected), severe postnatal growth retardation and death within the first 3 weeks. Snx27(+/-) mice have normal neuroanatomy but exhibit cognitive deficits (in learning and memory) and defects in synaptic function/plasticity with reduced amounts of NMDA and AMPA receptors (Cai et al - PMID: 21300787, Wang et al - PMID: 23524343). --------- The gene is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx) and a current primary ID gene in SysID. There is no associated phenotype in OMIM/G2P. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.1135 | SLC5A6 |
Konstantinos Varvagiannis changed review comment from: SLC5A6 encodes the sodium dependent multivitamin transporter (SMVT), a transporter of biotin, pantothenate and lipoate. The transporter has a major role in vitamin uptake in the digestive system (among others is the sole transporter for intestinal uptake of biotin which is not synthesized and but must be obtained from exogenous sources) as well as transport across the blood-brain barrier (SMVT being responsible for 89% of biotin transport) [several refs provided by Subramanian et al and Byrne et al]. 4 affected individuals from 3 families have been reported. Subramanian et al (2017 - PMID: 27904971) et al reported on a girl with feeding difficulties and failure to thrive (requiring nasogastric tube placement), microcephaly, DD (at 15m developmental age corresponding to 6m with features suggestive of spastic cerebral palsy), occurrence of multiple infections, osteoporosis and pathologic bone fractures. MRIs suggested brain atrophy, thin CC and hypoplasia of the pons. Metabolic (AA, OA) investigations and array-CGH were normal. Whole exome sequencing revealed presence of a missense (Arg123Leu - RefSeq not provided) and a nonsense (Arg94Ter) SLC5A6 variant. Serum biotin was normal although - at the time - the child was on parenteral and G-T nutrition. Following administration of biotin, pantothenic acid and lipoic acid the child demonstrated among others improved motor and verbal skills, head growth and normalization of immunoglobulin levels. Transfection of mutants in human derived intestinal HuTu-80 cells and brain U87 cells was carried out and a 3H-biotin assay showed no induction in biotin uptake confirming impaired functionality of the transporter. While wt protein displayed normal expression/membrane localization, Arg94Ter was poorly expressed with ectopic localization (cytoplasm). Arg123Leu was retained predominantly intracellularly, probably in the ER as was further supported by colocalization with DsRed-ER. Evidence from the literature is provided that deficiencies of the specific vitamins explain the clinical features (DD, microcephaly, immunological defect, osteopenia, etc). Schwantje et al (2019 - PMID: 31392107) described a girl with severe feeding problems, vomiting with blood (suspected Mallory-Weiss syndrome), poor weight gain and delayed gross motor development. The child presented an episode of gastroenteritis associated with reduced consciousness, circulatory insufficiency and metabolic derangement (hypoglycemia, severe metabolic acidosis, hyperammonemia, mild lactate elevation, ketonuria). Investigations some months prior to the admission (?) were suggestive of a metabolic disorder due to elevated plasma C3-carnitine, C5-OH-carnitine and elevated urinary excretion of 3-OH-isovaleric acid (biotinidase deficiency was considered in the DD but enzymatic activity was only marginally decreased). Biotin supplementation was initiated. Trio-exome sequencing (at 3yrs) demonstrated compound heterozygosity for 2 frameshift variants [NM_021095.2:c.422_423del / p.(Val141Alafs*34) and c.1865_1866del]. Following this result, increase of biotin supplementation and introduction of pantothenic acid, GI symptoms (incl. chronic diarrhea) resolved and the child displayed improved appetite and growth, yet a stable motor delay. The authors cite previous studies of conditional ko mice, displaying intestinal mucosal abnormalities and growth defects (similar to the child's problems), prevented by biotin and pantothenic acid supplementation. Byrne et al (2019 - PMID: 31754459) reported on a sibling pair with severe motor/speech developmental regression following a plateau (at 12m and 14m), development of ataxia and dyskinetic movements (both), seizures (one). Feeding difficulties, reflux and failure to thrive required N-G/gastrostomy feeding while both presented GI hemorrhage (in the case of the older sib, lethal). Other features in the youngest sib included brain MRI abnormalities (cerebral/cerebellar atrophy, thin CC, etc) and IgG deficiency. Biochemical, single-gene testing and mtDNA sequencing were not diagnostic. Exome in one, revealed presence of a frameshift [c.422_423del as above] and a missense variant (Arg400Thr). Sanger sequencing confirmed variants in both sibs and heterozygosity in parents. HeLa cells transfected with empty vector, wt or mut expression constructs confirmed significantly decreased 3H-biotin uptake for mut constructs compared to wt (and similar to empty vector). Parenteral triple vitamin replacement at the age of ~7 years resulted in improved overall condition, regain of some milestones, attenuation of vomiting, and resolution of peripheral neuropathy. Seizure were well-controlled (as was the case before treatment) despite persistence of epileptiform discharges. Again the authors cite studies of conditional (intestine-specific) SLC5A6 ko mice, with those viable (~1/3) demonstrating growth retardation, decreased boned density and GI abnormalities (similar to affected individuals). The phenotype could be rescued by oversupplementation of biotin and pantothenic acid (PMIDs cited: 23104561, 29669219). [Please consider inclusion in other relevant panels eg. metabolic disorders] Sources: Literature; to: SLC5A6 encodes the sodium dependent multivitamin transporter (SMVT), a transporter of biotin, pantothenate and lipoate. The transporter has a major role in vitamin uptake in the digestive system (among others is the sole transporter for intestinal uptake of biotin which is not synthesized but must be obtained from exogenous sources) as well as transport across the blood-brain barrier (SMVT being responsible for 89% of biotin transport) [several refs provided by Subramanian et al and Byrne et al]. 4 affected individuals from 3 families have been reported. Subramanian et al (2017 - PMID: 27904971) et al reported on a girl with feeding difficulties and failure to thrive (requiring nasogastric tube placement), microcephaly, DD (at 15m developmental age corresponding to 6m with features suggestive of spastic cerebral palsy), occurrence of multiple infections, osteoporosis and pathologic bone fractures. MRIs suggested brain atrophy, thin CC and hypoplasia of the pons. Metabolic (AA, OA) investigations and array-CGH were normal. Whole exome sequencing revealed presence of a missense (Arg123Leu - RefSeq not provided) and a nonsense (Arg94Ter) SLC5A6 variant. Serum biotin was normal although - at the time - the child was on parenteral and G-T nutrition. Following administration of biotin, pantothenic acid and lipoic acid the child demonstrated among others improved motor and verbal skills, head growth and normalization of immunoglobulin levels. Transfection of mutants in human derived intestinal HuTu-80 cells and brain U87 cells was carried out and a 3H-biotin assay showed no induction in biotin uptake confirming impaired functionality of the transporter. While wt protein displayed normal expression/membrane localization, Arg94Ter was poorly expressed with ectopic localization (cytoplasm). Arg123Leu was retained predominantly intracellularly, probably in the ER as was further supported by colocalization with DsRed-ER. Evidence from the literature is provided that deficiencies of the specific vitamins explain the clinical features (DD, microcephaly, immunological defect, osteopenia, etc). Schwantje et al (2019 - PMID: 31392107) described a girl with severe feeding problems, vomiting with blood (suspected Mallory-Weiss syndrome), poor weight gain and delayed gross motor development. The child presented an episode of gastroenteritis associated with reduced consciousness, circulatory insufficiency and metabolic derangement (hypoglycemia, severe metabolic acidosis, hyperammonemia, mild lactate elevation, ketonuria). Investigations some months prior to the admission (?) were suggestive of a metabolic disorder due to elevated plasma C3-carnitine, C5-OH-carnitine and elevated urinary excretion of 3-OH-isovaleric acid (biotinidase deficiency was considered in the DD but enzymatic activity was only marginally decreased). Biotin supplementation was initiated. Trio-exome sequencing (at 3yrs) demonstrated compound heterozygosity for 2 frameshift variants [NM_021095.2:c.422_423del / p.(Val141Alafs*34) and c.1865_1866del]. Following this result, increase of biotin supplementation and introduction of pantothenic acid, GI symptoms (incl. chronic diarrhea) resolved and the child displayed improved appetite and growth, yet a stable motor delay. The authors cite previous studies of conditional ko mice, displaying intestinal mucosal abnormalities and growth defects (similar to the child's problems), prevented by biotin and pantothenic acid supplementation. Byrne et al (2019 - PMID: 31754459) reported on a sibling pair with severe motor/speech developmental regression following a plateau (at 12m and 14m), development of ataxia and dyskinetic movements (both), seizures (one). Feeding difficulties, reflux and failure to thrive required N-G/gastrostomy feeding while both presented GI hemorrhage (in the case of the older sib, lethal). Other features in the youngest sib included brain MRI abnormalities (cerebral/cerebellar atrophy, thin CC, etc) and IgG deficiency. Biochemical, single-gene testing and mtDNA sequencing were not diagnostic. Exome in one, revealed presence of a frameshift [c.422_423del as above] and a missense variant (Arg400Thr). Sanger sequencing confirmed variants in both sibs and heterozygosity in parents. HeLa cells transfected with empty vector, wt or mut expression constructs confirmed significantly decreased 3H-biotin uptake for mut constructs compared to wt (and similar to empty vector). Parenteral triple vitamin replacement at the age of ~7 years resulted in improved overall condition, regain of some milestones, attenuation of vomiting, and resolution of peripheral neuropathy. Seizure were well-controlled (as was the case before treatment) despite persistence of epileptiform discharges. Again the authors cite studies of conditional (intestine-specific) SLC5A6 ko mice, with those viable (~1/3) demonstrating growth retardation, decreased boned density and GI abnormalities (similar to affected individuals). The phenotype could be rescued by oversupplementation of biotin and pantothenic acid (PMIDs cited: 23104561, 29669219). [Please consider inclusion in other relevant panels eg. metabolic disorders] Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.1135 | SLC5A6 |
Konstantinos Varvagiannis gene: SLC5A6 was added gene: SLC5A6 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: SLC5A6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC5A6 were set to 27904971; 31392107; 31754459; 23104561; 29669219 Phenotypes for gene: SLC5A6 were set to Feeding difficulties; Failure to thrive; Global developmental delay; Developmental regression; Intellectual disability; Seizures; Microcephaly; Cerebral atrophy; Abnormality of the corpus callosum; Vomiting; Chronic diarrhea; Gastrointestinal hemorrhage; Abnormal immunoglobulin level; Osteopenia; Abnormality of metabolism/homeostasis Penetrance for gene: SLC5A6 were set to Complete Review for gene: SLC5A6 was set to GREEN Added comment: SLC5A6 encodes the sodium dependent multivitamin transporter (SMVT), a transporter of biotin, pantothenate and lipoate. The transporter has a major role in vitamin uptake in the digestive system (among others is the sole transporter for intestinal uptake of biotin which is not synthesized and but must be obtained from exogenous sources) as well as transport across the blood-brain barrier (SMVT being responsible for 89% of biotin transport) [several refs provided by Subramanian et al and Byrne et al]. 4 affected individuals from 3 families have been reported. Subramanian et al (2017 - PMID: 27904971) et al reported on a girl with feeding difficulties and failure to thrive (requiring nasogastric tube placement), microcephaly, DD (at 15m developmental age corresponding to 6m with features suggestive of spastic cerebral palsy), occurrence of multiple infections, osteoporosis and pathologic bone fractures. MRIs suggested brain atrophy, thin CC and hypoplasia of the pons. Metabolic (AA, OA) investigations and array-CGH were normal. Whole exome sequencing revealed presence of a missense (Arg123Leu - RefSeq not provided) and a nonsense (Arg94Ter) SLC5A6 variant. Serum biotin was normal although - at the time - the child was on parenteral and G-T nutrition. Following administration of biotin, pantothenic acid and lipoic acid the child demonstrated among others improved motor and verbal skills, head growth and normalization of immunoglobulin levels. Transfection of mutants in human derived intestinal HuTu-80 cells and brain U87 cells was carried out and a 3H-biotin assay showed no induction in biotin uptake confirming impaired functionality of the transporter. While wt protein displayed normal expression/membrane localization, Arg94Ter was poorly expressed with ectopic localization (cytoplasm). Arg123Leu was retained predominantly intracellularly, probably in the ER as was further supported by colocalization with DsRed-ER. Evidence from the literature is provided that deficiencies of the specific vitamins explain the clinical features (DD, microcephaly, immunological defect, osteopenia, etc). Schwantje et al (2019 - PMID: 31392107) described a girl with severe feeding problems, vomiting with blood (suspected Mallory-Weiss syndrome), poor weight gain and delayed gross motor development. The child presented an episode of gastroenteritis associated with reduced consciousness, circulatory insufficiency and metabolic derangement (hypoglycemia, severe metabolic acidosis, hyperammonemia, mild lactate elevation, ketonuria). Investigations some months prior to the admission (?) were suggestive of a metabolic disorder due to elevated plasma C3-carnitine, C5-OH-carnitine and elevated urinary excretion of 3-OH-isovaleric acid (biotinidase deficiency was considered in the DD but enzymatic activity was only marginally decreased). Biotin supplementation was initiated. Trio-exome sequencing (at 3yrs) demonstrated compound heterozygosity for 2 frameshift variants [NM_021095.2:c.422_423del / p.(Val141Alafs*34) and c.1865_1866del]. Following this result, increase of biotin supplementation and introduction of pantothenic acid, GI symptoms (incl. chronic diarrhea) resolved and the child displayed improved appetite and growth, yet a stable motor delay. The authors cite previous studies of conditional ko mice, displaying intestinal mucosal abnormalities and growth defects (similar to the child's problems), prevented by biotin and pantothenic acid supplementation. Byrne et al (2019 - PMID: 31754459) reported on a sibling pair with severe motor/speech developmental regression following a plateau (at 12m and 14m), development of ataxia and dyskinetic movements (both), seizures (one). Feeding difficulties, reflux and failure to thrive required N-G/gastrostomy feeding while both presented GI hemorrhage (in the case of the older sib, lethal). Other features in the youngest sib included brain MRI abnormalities (cerebral/cerebellar atrophy, thin CC, etc) and IgG deficiency. Biochemical, single-gene testing and mtDNA sequencing were not diagnostic. Exome in one, revealed presence of a frameshift [c.422_423del as above] and a missense variant (Arg400Thr). Sanger sequencing confirmed variants in both sibs and heterozygosity in parents. HeLa cells transfected with empty vector, wt or mut expression constructs confirmed significantly decreased 3H-biotin uptake for mut constructs compared to wt (and similar to empty vector). Parenteral triple vitamin replacement at the age of ~7 years resulted in improved overall condition, regain of some milestones, attenuation of vomiting, and resolution of peripheral neuropathy. Seizure were well-controlled (as was the case before treatment) despite persistence of epileptiform discharges. Again the authors cite studies of conditional (intestine-specific) SLC5A6 ko mice, with those viable (~1/3) demonstrating growth retardation, decreased boned density and GI abnormalities (similar to affected individuals). The phenotype could be rescued by oversupplementation of biotin and pantothenic acid (PMIDs cited: 23104561, 29669219). [Please consider inclusion in other relevant panels eg. metabolic disorders] Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.1122 | TMX2 |
Konstantinos Varvagiannis edited their review of gene: TMX2: Added comment: A recent report by Vandervore, Schot et al. following the previous review (Am J Hum Genet. 2019 Nov 12 - PMID: 31735293), provides further evidence that biallelic TMX2 mutations cause malformations of cortical development, microcephaly, DD and ID and epilepsy. As a result this gene should probably be considered for inclusion in the ID/epilepsy panels with green rating. Overall, 14 affected subjects from 10 unrelated families are reported in the aforementioned study. The majority had severe DD/ID (failure to achieve milestones, absent speech/ambulation and signs of cerebral palsy) with few having a somewhat milder impairment. 12 (of the 14) presented with epilepsy (spasms, myoclonic seizures, focal seizures with/without generalization or generalized tonic-clonic seizures) with onset most often in early infancy. Upon brain MRI (in 12 individuals), 5 presented polymicrogyria, 2 others pachygyria, 4 with brain atrophy, etc. All individuals were found to harbor biallelic TMX2 mutations by exome sequencing while previous investigations in several had ruled out alternative causes (infections, metabolic or chromosomal anomalies). Missense variants, an in-frame deletion as well as pLoF (stopgain/frameshift) variants were reported. [NM_015959.3 used as ref below]. The effect of variants was supported by mRNA studies, eg. RT-qPCR/allele specific RT-qPCR. The latter proved reduced expression for a frameshift variant (c.391dup / p.Leu131Profs*6) most likely due to NMD. Total mRNA levels were also 23% lower in an individual compound htz for a missense variant and a stopgain one localized in the last exon (c.757C>T / p.Arg253*). As for the previously reported c.614G>A (p.Arg205Gln), affecting the last nucleotide of exon 6, total mRNA in skin fibroblasts from a homozygous individual was not significantly decreased. RNA-Seq however demonstrated the presence of 4 different transcripts (roughly 25% each), one representing the regular mRNA, one with intron 6 retention (also present at low levels in healthy individuals), one with loss of 11 nucleotides within exon 6 and a fourth one due to in-frame skipping of exon 6. *To the best of my understanding : Thioredoxin (TRX)-related transmembrane proteins (TMX) belong to the broader family of oxidoreductases of protein disulfide isomerase (PDI) having an important role in protein folding. Study of the data from the Allen Human Brain Atlas suggest relevant fetal expression also increasing during postnatal life. As RNA-seq was carried out for 2 individuals, GO analysis suggested that the most deregulated clusters of genes are implicated in post-translational protein modifications (as would be expected for PDIs), membranes and synapse while pathway analysis suggested that relevant categories were inhibited eg. nervous system development/function and cell growth/proliferation/survival. Upon transfection of HEK293T cells, exogenous TMX2 was shown to co-localize with calnexin (CNX) to the (ER) mitochondria-associated-membrane. Mass-spectrometry based analysis of co-immunoprecipitated proteins confirmed interaction with CNX but also other regulators of calcium homeostasis, mitochondrial membrane components and respiratory chain NADH dehydrogenase. Study of the mitochondrial activity of TMX2-deficient fibroblasts suggested reduced respiratory reserve capacity, compensated by increased glycolytic activity. TMX2 occurs in both reduced and oxidized monomeric form. It also forms (homo)dimers with the ratio of dimers/monomers increasing under conditions of oxidative stress. Variant TMX2 increased propensity to form dimers, thus mimicking increased oxidative state. This was observed under stress but also under native conditions. ---------; Changed rating: GREEN |
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| Intellectual disability - microarray and sequencing v2.1102 | DMXL2 |
Konstantinos Varvagiannis changed review comment from: This gene can be considered for upgrade to green rating (ID and epilepsy with >=4 relevant individuals/families/variants and >=2 studies, role of the protein, effect of variants in most cases demonstrated, phenotypic similarities with other disorders affecting autophagy, some evidence from animal models, etc). Rare heterozygous variants disrupting DMXL2 (intragenic losses/gains, SNVs, CNVs affecting also additional genes) have been reported in individuals with variable neurodevelopmental disorders (ASD and ID) or psychiatric phenotypes [Costain et al. 2019 - PMID: 30732576 - summarized in Table 1]. (Highly) variable expressivity and possibly incomplete penetrance were proposed in the respective study. As a result evidence for ID/seizures due to monoallelic variants appears to be relatively limited. DD, ID and (probably) epilepsy appear however to be features in several individuals with biallelic pathogenic variants as summarized in the studies below. OMIM recently added a relevant entry with the DMXL2-associated phenotypes being the following: - Epileptic encephalopathy, early infantile, 81; EIEE81 - 618663 (AD) [based on refs 2,3] - ?Deafness, autosomal dominant 71 - 617605 (AD) [DD/ID/seizures are not part of the phenotype] - ?Polyendocrine-polyneuropathy syndrome - 616113 (AR) [based on ref1] DMXL2 is not associated with any phenotype in G2P. In SysID it is listed as a candidate ID gene based on the report by Tata et al (ref1). This gene is included in some gene panels for ID. [1] Tata el al. (2014 - PMID: 25248098) reported on 3 sibs born to consanguineous Senegalese parents, presenting with a progressive endocrine and neurodevelopmental disorder. Features incl. incomplete puberty, central hypothyroidism, abnormal glucose regulation, moderate ID (3/3) and peripheral polyneuropathy. Seizures were not part of the phenotype. Linkage analysis suggested 2 candidate regions on chromosomes 13 and 15 with a LOD score of 2.5. High throughput sequencing of genes within these regions (~500) in an affected member and parent revealed a 15 bp in-frame deletion of DMXL2 (NM_015263.4:c.5827_5841del / p.Asp1943_Ser1947del). Sanger sequencing of other affected and unaffected members supported AR inheritance. RT-qPCR demonstrated that DMXL2 mRNA levels in blood lymphocytes were significantly lower in homozygous patients compared to heterozygous or wt family members or controls. The authors demonstrated that the encoded protein (rabconnectin-3a) is a synaptic protein (expressed in exocytosis vesicles) at the ends of axons of GnRH producing neurons. Neuron-specific deletion of one allele in mice resulted in delayed puberty and very low fertility. Adult mice had lower number of GnRH neurons in hypothalamus. siRNA-mediated downregulation of Dmxl2 expression in an insulin-secreting cell line resulted in only slight insulin secretion in response to augmenting concentrations of glucose, providing evidence of involvement of the protein in control of regulated insulin secretion. ----------- [2] Maddirevula et al. (2019 - PMID: 30237576) reported briefly on a 36 months old boy, born to consanguineous parents, homozygous for a frameshift DMXL2 variant [individual 17-3220 | NM_001174117.1:c.4349_4350insTTACATGA or p.(Glu1450Aspfs*23)]. Features included focal seizures (onset at the age of 3m) with subsequent global DD, absent eye contact, cerebral atrophy and macrocephaly. This individual was identified following re-evaluation of exome data in a database of ~1550 exomes specifically for homozygous variants that would have been classified earlier as LP/P if the respective gene had sufficient evidence for association with a disorder. The family was not reported to have other affected members. As the authors noted, the boy was not known to have the multi-endocrine abnormalities reported by Tata et al. There are no additional information provided (eg. on confirmation of variants, etc). ----------- [3] Esposito et al. (2019 - PMID: 31688942) report on 3 sibling pairs (all 3 families unrelated) with biallelic DMXL2 mutations and summarize previous evidence on the gene and the DMXL2-related phenotypes. All presented a highly similar phenotype of Ohtahara syndrome (seizures with onset in the first days of life, tonic/myoclonic/occasionaly focal, burst-suppression upon EEG), profound DD/ID, quadriparesis, sensorineural hearing loss and presence of dysmorphic features. Sibs from 2 families presented evidence of peripheral polyneuropathy. Early brain MRIs revealed thin CC and hypomyelination in all, with later scans suggestive of gray and white matter shrinkage with leukoencephalopathy. None achieved developmental skills following birth with 5/6 deceased by the age of 9 years. Exome sequencing revealed biallelic DMXL2 variants in all, with compatible parental segregation studies (NM_015263.3): - Fam1 (2 sibs) : c.5135C>T (p.Ala1712Val) in trans with c.4478C>G (p.Ser1493*) - Fam2 (2 sibs) : homozygosity for c.4478C>A (p.Ser1493*) - Fam3 (2 sibs) : homozygosity for c.7518-1G>A Heterozygous parents (aged 39-59) did not exhibit hearing impairment [report of a single multigenerational family by Chen et al (2017 - PMID: 27657680) where a heterozygous missense variant segregated with hearing loss - respective OMIM entry: ?Deafness, autosomal dominant 71 - 617605]. In patients' fibroblasts, effect of the variants on mRNA/protein expression was demonstrated with mRNA expressed only in a patient from family 1, and degraded/absent for the 2 stopgain SNVs affecting codon 1493. Skipping of ex31 leading to frameshift/introduction of a PTC was shown for the splice variant (p.Trp2508Argfs*4 secondary to c.7518-1G>A). Protein was also absent upon western-blot. DMXL2 encodes a vesicular protein, DmX-Like protein 2 or rabconnectin-3a (cited Tata et al). The gene is expressed in brain ( https://www.gtexportal.org/home/gene/DMXL2 ). As Esposito et al comment, it is known to regulate the trafficking and activity of v-ATPase the latter having a role in acidifying intracellular organelles and promoting endosomal maturation (cited PMIDs : 25248098, 19758563, 22875945, 24802872). In line with this, staining of patients' fibroblasts using the acidotropic dye LysoTracker demonstrated increased signal, reversed by re-expression of DMXL2 protein. Overall an acidic shift in pH with impairment of lysosomal structures and function was suggested. The authors provided additional evidence for altered lysosomal function and associated autophagy with accumulation of autophagy receptors (eg p62) and substrates (polyubiquitinated proteins). Vacuolization and accumulation of atypical fusion-like structures was shown upon ultrastractural analysis. shRNA-mediated downregulation/silencing of Dmxl2 in mouse hippocampal neurons resulted also in altered lysosomal structures and defective autophagy. The neurons exhibited impaired neurite elongation and synapse formation. The authors suggest similarities with Vici syndrome, where biallelic EPG5 mutations result in autophagic defects and clinical manifestations of DD/ID/epilepsy. Dmxl2 homozygous ko mice display embryonic lethality with heterozygous mice displaying macrocephaly and corpus callosum dysplasia (cited PMIDs: 25248098, 30735494) .; to: This gene can be considered for upgrade to green rating (ID and epilepsy with >=4 relevant individuals/families/variants and >=2 studies, role of the protein, effect of variants in most cases demonstrated, phenotypic similarities with other disorders affecting autophagy, some evidence from animal models, etc). Rare heterozygous variants disrupting DMXL2 (intragenic losses/gains, SNVs, CNVs affecting also additional genes) have been reported in individuals with variable neurodevelopmental disorders (ASD and ID) or psychiatric phenotypes [Costain et al. 2019 - PMID: 30732576 - summarized in Table 1]. (Highly) variable expressivity and possibly incomplete penetrance were proposed in the respective study. As a result evidence for ID/seizures due to monoallelic variants appears to be relatively limited. DD, ID and (probably) epilepsy appear however to be features in several individuals with biallelic pathogenic variants as summarized in the studies below. OMIM recently added a relevant entry with the DMXL2-associated phenotypes being the following: - Epileptic encephalopathy, early infantile, 81; EIEE81 - 618663 (AR) [based on refs 2,3] - ?Deafness, autosomal dominant 71 - 617605 (AD) [DD/ID/seizures are not part of the phenotype] - ?Polyendocrine-polyneuropathy syndrome - 616113 (AR) [based on ref1] DMXL2 is not associated with any phenotype in G2P. In SysID it is listed as a candidate ID gene based on the report by Tata et al (ref1). This gene is included in some gene panels for ID. [1] Tata el al. (2014 - PMID: 25248098) reported on 3 sibs born to consanguineous Senegalese parents, presenting with a progressive endocrine and neurodevelopmental disorder. Features incl. incomplete puberty, central hypothyroidism, abnormal glucose regulation, moderate ID (3/3) and peripheral polyneuropathy. Seizures were not part of the phenotype. Linkage analysis suggested 2 candidate regions on chromosomes 13 and 15 with a LOD score of 2.5. High throughput sequencing of genes within these regions (~500) in an affected member and parent revealed a 15 bp in-frame deletion of DMXL2 (NM_015263.4:c.5827_5841del / p.Asp1943_Ser1947del). Sanger sequencing of other affected and unaffected members supported AR inheritance. RT-qPCR demonstrated that DMXL2 mRNA levels in blood lymphocytes were significantly lower in homozygous patients compared to heterozygous or wt family members or controls. The authors demonstrated that the encoded protein (rabconnectin-3a) is a synaptic protein (expressed in exocytosis vesicles) at the ends of axons of GnRH producing neurons. Neuron-specific deletion of one allele in mice resulted in delayed puberty and very low fertility. Adult mice had lower number of GnRH neurons in hypothalamus. siRNA-mediated downregulation of Dmxl2 expression in an insulin-secreting cell line resulted in only slight insulin secretion in response to augmenting concentrations of glucose, providing evidence of involvement of the protein in control of regulated insulin secretion. ----------- [2] Maddirevula et al. (2019 - PMID: 30237576) reported briefly on a 36 months old boy, born to consanguineous parents, homozygous for a frameshift DMXL2 variant [individual 17-3220 | NM_001174117.1:c.4349_4350insTTACATGA or p.(Glu1450Aspfs*23)]. Features included focal seizures (onset at the age of 3m) with subsequent global DD, absent eye contact, cerebral atrophy and macrocephaly. This individual was identified following re-evaluation of exome data in a database of ~1550 exomes specifically for homozygous variants that would have been classified earlier as LP/P if the respective gene had sufficient evidence for association with a disorder. The family was not reported to have other affected members. As the authors noted, the boy was not known to have the multi-endocrine abnormalities reported by Tata et al. There are no additional information provided (eg. on confirmation of variants, etc). ----------- [3] Esposito et al. (2019 - PMID: 31688942) report on 3 sibling pairs (all 3 families unrelated) with biallelic DMXL2 mutations and summarize previous evidence on the gene and the DMXL2-related phenotypes. All presented a highly similar phenotype of Ohtahara syndrome (seizures with onset in the first days of life, tonic/myoclonic/occasionaly focal, burst-suppression upon EEG), profound DD/ID, quadriparesis, sensorineural hearing loss and presence of dysmorphic features. Sibs from 2 families presented evidence of peripheral polyneuropathy. Early brain MRIs revealed thin CC and hypomyelination in all, with later scans suggestive of gray and white matter shrinkage with leukoencephalopathy. None achieved developmental skills following birth with 5/6 deceased by the age of 9 years. Exome sequencing revealed biallelic DMXL2 variants in all, with compatible parental segregation studies (NM_015263.3): - Fam1 (2 sibs) : c.5135C>T (p.Ala1712Val) in trans with c.4478C>G (p.Ser1493*) - Fam2 (2 sibs) : homozygosity for c.4478C>A (p.Ser1493*) - Fam3 (2 sibs) : homozygosity for c.7518-1G>A Heterozygous parents (aged 39-59) did not exhibit hearing impairment [report of a single multigenerational family by Chen et al (2017 - PMID: 27657680) where a heterozygous missense variant segregated with hearing loss - respective OMIM entry: ?Deafness, autosomal dominant 71 - 617605]. In patients' fibroblasts, effect of the variants on mRNA/protein expression was demonstrated with mRNA expressed only in a patient from family 1, and degraded/absent for the 2 stopgain SNVs affecting codon 1493. Skipping of ex31 leading to frameshift/introduction of a PTC was shown for the splice variant (p.Trp2508Argfs*4 secondary to c.7518-1G>A). Protein was also absent upon western-blot. DMXL2 encodes a vesicular protein, DmX-Like protein 2 or rabconnectin-3a (cited Tata et al). The gene is expressed in brain ( https://www.gtexportal.org/home/gene/DMXL2 ). As Esposito et al comment, it is known to regulate the trafficking and activity of v-ATPase the latter having a role in acidifying intracellular organelles and promoting endosomal maturation (cited PMIDs : 25248098, 19758563, 22875945, 24802872). In line with this, staining of patients' fibroblasts using the acidotropic dye LysoTracker demonstrated increased signal, reversed by re-expression of DMXL2 protein. Overall an acidic shift in pH with impairment of lysosomal structures and function was suggested. The authors provided additional evidence for altered lysosomal function and associated autophagy with accumulation of autophagy receptors (eg p62) and substrates (polyubiquitinated proteins). Vacuolization and accumulation of atypical fusion-like structures was shown upon ultrastractural analysis. shRNA-mediated downregulation/silencing of Dmxl2 in mouse hippocampal neurons resulted also in altered lysosomal structures and defective autophagy. The neurons exhibited impaired neurite elongation and synapse formation. The authors suggest similarities with Vici syndrome, where biallelic EPG5 mutations result in autophagic defects and clinical manifestations of DD/ID/epilepsy. Dmxl2 homozygous ko mice display embryonic lethality with heterozygous mice displaying macrocephaly and corpus callosum dysplasia (cited PMIDs: 25248098, 30735494) . |
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| Intellectual disability - microarray and sequencing v2.1098 | SCAMP5 |
Konstantinos Varvagiannis gene: SCAMP5 was added gene: SCAMP5 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: SCAMP5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SCAMP5 were set to 31439720; 20071347 Phenotypes for gene: SCAMP5 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology; Behavioral abnormality Penetrance for gene: SCAMP5 were set to unknown Mode of pathogenicity for gene: SCAMP5 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: SCAMP5 was set to AMBER Added comment: PMID: 31439720 (Hubert et al. 2019) reported on 2 unrelated individuals with severe ID, seizures behavioral and brain MRI abnormalities (white matter hyperintensity and mesial temporal sclorosis), both harboring the same missense SCAMP5 mutation as a de novo event (NM_001178111.1:c.538G>T or p.Gly180Trp). Previously aCGH +/- metabolic workup were non diagnostic. The occurrence of the same de novo variant in both as well as the similar presentation (incl. MRI images) suggested SCAMP5 as the most probable candidate gene, despite presence of few other variants in both. SCAMP5 is highly expressed in brain (https://www.proteinatlas.org/ENSG00000198794-SCAMP5) and previous studies have suggested a role in synaptic vesicle trafficking (PMIDs cited: 29562188, 25057210, etc). Cultured skin fibroblasts from affected individuals failed to express SCAMP5. Scamp is the Drosophila orthologue, with previous studies having demonstrated that mutants display defects in climbing, olfactory-assisted memory and susceptibility to heat induced seizures (PMIDs cited: 25478561, 19144841). Expression of the Scamp Gly302Trp variant in Drosophila ('equivalent' to the SCAMP5 Gly180Trp) revealed strongly reduced levels for the variant compared with wt upon Western Blot, either due to reduced expression or due to increased turnover. Overall the effect of Gly302Trp expression was similar to Scamp knockdown by RNAi (eg. rough eye phenotype, reduced ability to climb the walls of a graded tube after tapping, less/no flies reaching adult stage) but significantly different compared to wt. As a result, a dominant-negative effect was presumed. ---------- PMID: 20071347 (Castermans et al. 2010) is cited as a previous report of a relevant affected individual. In this study a 40 y.o. male with early DD, mild ID (IQ of 63) and ASD was found to harbor a de novo apparently balanced t(1;15) translocation affecting CLIC4 and PPCDC (both not associated with ID). [1-Mb resolution aCGH revealed no relevant CNVs]. Studies were however focused on SCAMP5 given that the gene is located downstream of / proximal to PPCDC, has brain-enriched expression as well as involvement in synaptic trafficking and demonstrated: - Less than 50% expression upon quantitative RT-PCR in patients leukocytes, compared to control. - Silencing and overexpression of Scamp5 in mouse β-TC3 cells resulted in increased and suppressed respectively secretion of large dense-core vesicles (LDCVs). - Given conservation of some components involved in secretion of dense core granules (DCGs) in platelets and LDCVs in neuronal cells, study of patient platelets - where SCAMP5 was confirmed to be expressed - suggested an altered pattern of DCGs. ---------- SCAMP5 is not associated with any phenotype in OMIM/G2P/SysID and not commonly included in gene panels for ID. ---------- Overall, this gene could be considered for inclusion in the ID and epilepsy panels probably with amber (# of unrelated individuals, 1 recurrent de novo variant and 1 regulatory effect, gene expressed in brain with a role in synaptic vesicle trafficking) or red rating (pending further evidence). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.1098 | PDE6D |
Konstantinos Varvagiannis gene: PDE6D was added gene: PDE6D was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PDE6D was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PDE6D were set to 24166846; 30423442 Phenotypes for gene: PDE6D were set to ?Joubert syndrome 22 - MIM 615665 Penetrance for gene: PDE6D were set to Complete Review for gene: PDE6D was set to AMBER gene: PDE6D was marked as current diagnostic Added comment: Thomas et al. (2014 - PMID: 24166846) reported on a consanguineous Pakistani family with 3 members presenting variable polydactyly, brain anomalies (incl. molar tooth sign), microphthalmia/coloboma with retinal disease, renal hypoplasia suggestive of Joubert syndrome. Genotyping with a SNP array identified a unique 17-Mb region of homozygosity on chr2 with LOD score of 2.6. The region contained 208 genes, of which 15 present in ciliary gene databases. A homozygous splicing variant appeared to be the only relevant, PDE6D being a ciliary gene within this region [NM_002601.4:c.140-1G>A]. Status of all affected members, parents and 2 unaffected sibs was verified with Sanger sequencing. PDE6D encodes a phosphodiesterase that binds to prenyl groups and has a critical role in ciliogenesis (Humbert et al. - PMID: 23150559 and OMIM). Several lines of evidence provided support a role for PDE6D and the reported variants : - Study of PDE6D expression during human embryogenesis suggests ubiquitous localization and highest levels in organs affected in ciliopathies (CNS, kidney tubules, respiratory tract epitherlial cells). - RT-PCR of mRNA from control/patient fibroblasts and sequencing confirmed the splicing defect leading to an in-frame deletion of exon 3. - Wt and mutant protein both localized in the basal body of primary cilia (patient/control fibroblasts). Cilia in both cases had normal morphology. - Experiments in RPE cells confirmed that INPP5E (involved in Joubert/MORM syndrome) interacts (/is probably a cargo of) PDE6D, a process dependent on prenylation. - Exon 3 deletion was confirmed to disrupt PDE6D binding to INPP5E. - Analysis by immunofluoresence of INPP5E localization using control/patient fibroblasts and renal tissue showed absence of INPP5E from primary cilia in the case of patient cells (but not controls) suggesting that PDE6D is important for trafficking INPP5E to the cilium. - Previous study in mice suggested altered photoreceptor physiology in Pde6d (-/-) animals, resulting in a slowly progressing rod/cone dystrophy. The effect was however limited to the eye. (PMID cited : 17496142 - Zhang et al., 2007). - Morpholino knockdown of pde6d resulted in pericardial edema, eye abnormalities (microphthalmia and disorganized retinal cell layers) and kidney morphogenesis defects (distended, blocked pronephric openings and proximal tubule cysts). Edema was rescued upon coinjection of morpholino with wt (but not mutant) mRNA. Similarly coinjection led to complete or partial rescue of eye development in the case of wt and mutant mRNA respectively supporting pathogenicity and (partial) loss-of-function effect for the variant. --------- Mégarbané et al. (2019 - PMID: 30423442) reported on an affected 6 month-old boy born to Lebanese first-cousin parents. Features included hypotonia, developmental delay, microcephaly, oculomotor apraxia, postaxial polydactyly of hands and feet and presence of a molar tooth sign upon brain MRI. Renal and retinal anomalies were absent (also given his age). Exome sequencing revealed homozygosity for a frameshift PDE6D variant [NM_002601.3:c.367_368insG or p.(Leu123Cysfs*13)]. Sanger sequencing confirmed presence of the variant in the proband and carrier status of the parents. The variant affected the penultimate exon (note : present in only this longest transcript) and was not predicted to trigger NMD but rather lead to elimination of a highly conserved PDZ-interaction domain. --------- The phenotype associated with biallelic PDE6D variants in OMIM is ?Joubert syndrome 22 - MIM 615665 based only on the 1st report ('delayed psychomotor development' among the features). There is no relevant entry in G2P. PDE6D is listed as a Current primary (/confirmed) ID gene in SysID (the aforementioned PMIDs cited). This gene is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx). --------- Overall PDE6D could be considered for inclusion in the ID panel probably with amber rating (2 families/variants, DD but outcome otherwise unknown - evidence for the the gene causing JS seems however sufficient). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.1098 | NTNG2 |
Konstantinos Varvagiannis gene: NTNG2 was added gene: NTNG2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: NTNG2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NTNG2 were set to 31372774; 31668703 Phenotypes for gene: NTNG2 were set to Central hypotonia; Global developmental delay; Intellectual disability; Behavioral abnormality; Microcephaly; Seizures Penetrance for gene: NTNG2 were set to Complete Review for gene: NTNG2 was set to GREEN Added comment: [1] Abu-Libdeh et al. (2019 - PMID: 31372774) reported 8 individuals from 4 unrelated consanguineous families of Arab Muslim origin, all homozygous for NM_032536.3:c.376dup - p.(Ser126PhefsTer241). Common features included hypotonia, failure to achieve milestones and developmental stagnation without regression during the first year (~9m) of life and severe ID. Minimal purposeful hand use (grasping and bringing objects to mouth), hand stereotypies and bruxism were also observed. Microcephaly and impaired growth were almost universal (with the exception of 2 having an OFC at ~10% percentile). Relevant previous investigations were normal in all and included MECP2, SMN1, aCGH, metabolic testing, etc. The variant was identified by exome in all, and Sanger confirmed with compatible segregation studies in parents and sibs. The variant was found within a shared haplotype of ~4.35 Mb, probably due to a founder effect. [2] Dias et al. (2019 - PMID: 31668703) described 16 individuals from 7 unrelated families from Iran, Mexico, Turkey, Egypt and Bangladesh. Parents were known to be consanguineous or shown to be distantly related. All patients were homozygous for missense variants private to each family (7 variants) identified following exome sequencing. Shared features incl. hypotonia, GDD, severe to profound ID and behavioral anomalies incl. autistic features/stereotypies (most), screaming/laughing spells (most), bruxism. Microcephaly (5/14), growth below average/FTT and GI problems were also observed. Epilepsy was reported in 5 individuals belonging to 4 different families in these 2 studies (5/24 overall / 4 variants). Netrin-G2, the encoded protein, is bound to the plasma membrane by GPI-anchors. Netrins-G2 and G1 (another member of the Netrin-G subfamily) are enriched in presynaptic terminals. Interaction with their cognate Netrin-G ligand trans-synaptic partners / receptors (NGL2, NGL1 respectively) has been shown to promote axon outgrowth, induce and maintain excitatory synapse formation. Complementary and non-overlapping expression in the developping and mature CNS has been shown for Netrin-G2/1 in mice (several references provided by Abu-Libdeh / Dias). Variant effect : The frameshift variant was not studied by Abu-Libdeh et al. Variants in the 2nd ref. were all missense, displayed no-specific localization and were suggested to affect protein stability and/or expression at the cell surface as 4/7 involved loss or addition of cystein residues (possibly creating unpaired cysteins) and 2 of the remaining 3 were predicted to affect the hydrophobic core. In line with this, overexpression of wt/variant constructs in HeLa cells demonstrated substantially decreased cell surface expression for all variants. Mouse models/phenotypes : Dias et al. showed that siRNA-mediated Ntng2 knockdown in N2a cells led to significant reduction in neurite number and length. Studied previously, Ntng2 knockout mice display impaired learning, memory, visual and motor functioning (PMID cited : 26746425). NTNG2 is not associated with any phenotype in OMIM/G2P. SysID lists it among the candidate ID genes, citing PMID: 29302074 (not here reviewed & NTNG2 not in the main text). Overall this gene can be considered for inclusion in the ID panel probably as green (>3 individuals/families/variants, consistent phenotype in both reports, role of the gene, in silico and in vitro studies, animal model, etc) or amber. [Please consider inclusion in other panels if relevant eg. ASD panel (many individuals having autistic / Rett-like features or epilepsy) or epilepsy (>3 individuals/families/variants although most families were also consanguineous)] Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.1098 | FDFT1 |
Konstantinos Varvagiannis gene: FDFT1 was added gene: FDFT1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: FDFT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FDFT1 were set to 29909962 Phenotypes for gene: FDFT1 were set to Profound global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology; Cortical visual impairment; Abnormality of the skin; Abnormality of the face Penetrance for gene: FDFT1 were set to Complete Review for gene: FDFT1 was set to AMBER Added comment: Biallelic pathogenic FDFT1 variants cause Squalene synthase deficiency (MIM 618156). 3 individuals from 2 families (and 3 variants) have been reported. DD, ID and seizures are part of the phenotype (3/3). The metabolic profile observed is specific and highly suggestive of disruption of the cholesterol biosynthesis pathway (at the specific level) while the clinical presentation is similar to other disorders of the pathway (SLO). The effect of 2 variants has been studied in detail (in one case mis-splicing demonstrated and in the other regulatory effect). Overall, this gene could be considered for inclusion in the ID/epilepsy panel with amber rating. As the gene is currently present only in the DDG2P panel, please consider adding it to relevant ones (eg. IEMs, undiagnosed metabolic disorders, etc). [Details provided below]. ---- Coman et al. (2018 - PMID: 29909962) reported on 3 relevant individuals from 2 unrelated families. The phenotype consisted of seizures (3/3 - neonatal onset - generalized), profound DD (ID can be inferred from the description in the supplement), variable brain MRI abnormalities (white matter loss, hypoplastic CC), cortical visual impairment, dry skin with photosensitivity as well facial dysmorphic features. Male subjects presented genital anomalies (cryptorchidism/hypospadias). FDFT1 encodes squalene synthase, the enzyme which catalyzes conversion of farnesyl-pyrophosphate to squalene - the first specific step in cholesterol biosynthesis. A specific pattern of metabolites was observed in all, similar to a pattern previously observed in animal models/humans treated with squalene synthase inhibitor or upon loading with farnesol (in animals). Overall the pattern was suggestive of a cholesterol biosynthesis defect at the level of squalene synthase as suggested by increased total farnesol levels (farnesyl-pyrophosphate + free farnesol), reduced/normal squalene, low plasma cholesterol as well as other metabolites. Clinical features also resembled those observed in Smith-Lemli-Opitz syndrome (another disorder of cholesterol biosynthesis). WES was carried out in affected individuals and their parents and revealed for sibs of the first family, compound heterozygosity for a maternally inherited 120-kb deletion spanning exons 6-10 of FDFT1 and CTSB and a paternally inherited FDFT1 variant in intron 8 (TC deletion/AG insertion). Variant studies for the latter included: - Minigene splice assay demonstrating retention of 22 bp in intron 8. - Partial splicing defect with both nl and mis-spliced cDNA (patient fibroblasts) - Reduced protein levels in lymphoblasts/fibroblasts from both sibs upon Western blot. Contribution of the CTSB deletion was considered unlikely (carrier mother was unaffected). As for the 2nd family, WES data allowed identification of a homozygous deep-intronic (although this is transcript-specific) 16-bp deletion in the proband. Parents were carriers. For the specific variant : - cDNA studies failed to detect 3 (of 10) isoforms which are normally present in control fibroblasts. Eventual NMD (which would be predicted if the deletion resulted in splicing defect) was eliminated given the absent effect of cyclohexamide addition, thus suggesting a regulatory effect. - Given a predicted promoter/enhancer effect of the deleted region, a luciferase assay performed, suggested that the sequence had promoter capacity, with the construct containing the 16-bp deletion showing reduced promoter activity. Fdft1 knockout mice demonstrate embryonic lethality around mid-gestation while they exhibit severe growth retardation and defective neural tube closure. In G2P FDFT1 is associated with 'Defect in Cholesterol Biosynthesis' (confidence:possible/biallelic/LoF). The gene belongs to the Current primary ID gene group of SysID. It is not commonly included in gene panels for ID offered by diagnostic laboratories. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.1047 | METTL5 |
Konstantinos Varvagiannis gene: METTL5 was added gene: METTL5 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: METTL5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: METTL5 were set to 29302074; http://doi.org/10.1016/j.ajhg.2019.09.007; https://imgc2019.sciencesconf.org/data/abstract_book_complete.pdf Phenotypes for gene: METTL5 were set to Delayed speech and language development; Intellectual disability; Microcephaly; Behavioral abnormality Penetrance for gene: METTL5 were set to Complete Review for gene: METTL5 was set to GREEN Added comment: [1] - PMID: 29302074 : In a WES/WGS study of 404 consanguineous families with two or more offspring affected by ID, Hu et al. identified two sibs homozygous for a METTL5 missense variant [NM_014168:c.182G>A / p.Gly61Asp]. These 2 subjects, born to first cousin parents from Iran, presented with early learning impairment, aggressive behaviour, severe microcephaly (-7SD and -8SD) and ID formally evaluated to be in the severe range. Sanger confirmation of variants and segregation studies were performed for all available and informative members in families participating in the study. In silico predictions were all in favour of a deleterious effect (PolyPhen2, MutationTaster, SIFT, CADD) and the variant was absent from ExAC. The effect of the specific variant was studied in ref. 2 (below). [2] - DOI: 10.1016/j.ajhg.2019.09.007 : Richard et al. (2019) reported on 5 additional individuals from 2 consanguineous families. Common phenotype consisted of speech delay, moderate/severe ID (4/4), microcephaly (4/4 - though milder than in the first report), behavioral problems (ADHD, aggressiveness, autistic feat.) and possibly some overlapping facial features (nose and ear abnormalities). 3 sibs from the 1st family, from Pakistan, were homozygous for a frameshift variant (NM_014167.2:c.344_345delGA / p.Arg115Asnfs*19) while sibs from the 2nd family, from Yemen, were homozygous for p.Lys191Valfs*1 (c.571_572delAA). Confirmation and segregation studies supported a role for the variants. The authors performed additional studies for METTL5 and all 3 variants reported to date, notably: - Based on RNA-seq data from the Allen Brain Atlas, METTL5 is expressed in the developing and adult human brain (incl. cerebellar cortex, hippocampus and striatum). - Immunostaining in mouse brain demonstrated ubiquitous expression (postnatal day 30). - In rat hippocampal neurons, enrichment of METTL5 was found in the soma, the nucleus and pre- and post- synaptic regions. - Myc-/GFP-tagged METTL5 wt or mutants were transiently expressed in COS7 cells, and were found in the cytoplasm and nucleus. Levels of the 2 frameshift variants were significantly reduced compared with wt, although this was not the case for Gly61Asp. - Upon transfection of rat hippocampal neurons, METTL5-GFP tagged wt and mt proteins showed similar localicalization in nucleus and dendrites. - Western blot on HEK293T cells transfected with Myc-METTL5 wt or mt constructs demonstrated decreased amounts for the frameshift (but not the missense) variants while comparison after addition of a proteasome inhibitor or cyclohexamide suggested that this is not probably due to decreased mutant protein - rather than mRNA (NMD) - stability. - In zebrafish, morpholino knockdown of mettl5 led to reduced head size and head/body ratio (reproducing the microcephaly phenotype) and curved tails. Forebrain and midbrain sizes were also significantly reduced. Based on the ACMG criteria, Gly61Asp is classified as VUS (PM2, PP1, PP3) and the frameshift ones as pathogenic (PS3, PM2, PM4, PP1, PP3). The authors comment that METTL5 is an uncharacterized member of the methyltransferase superfamily (of 33 METTL proteins). Variants in other methyltransferase-like genes (mainly METTL23) have been associated with ID, while various histone-/DNA-/tRNA-/rRNA- methyltransferases such as EHMT1, DNMT3A, NSUN2, FTSJ1, etc have been implicated in ID. Given the role of methyltransferases in neurodevelopment and neuroplasticity, homology comparisons suggesting presence of relevant domain in METTL5 and accumulation of the protein in the nucleus, a role as epigenetic regulator is proposed (see also ref. 3). [3] - Conference abstract by Helmut et al. ["A novel m6A RNA methyltransferase in mammals - characterization of Mettl5 mutant mice in the German Mouse Clinic" - Oral presentation in the 33rd International Mammalian Genome Conference Sept. 2019 - available at : https://imgc2019.sciencesconf.org/data/abstract_book_complete.pdf ] The group using an in vitro methyltransferase assay, identified METTL5 as a m6A RNA methyltransferase. Generation of Mettl5-knockout mice using the CRISPR/Cas technology, suggested that homozygous mice are subviable, with lower body mass and abnormal growth of nasal bones in half. Homozygous mice were hypoactive and hypoexploratory during an open field test at the age of 8 weeks, while further alterations were observed in neurological functions. Phenotypic deviations were absent or very mild in heterozygous animals. As a result, the mouse model appeared to recapitulate relevant human phenotypes (microcephaly, ID and growth retardation). ---- There is no associated entry in OMIM (neither for the gene nor for a related disorder). G2P does not list any phenotype for this gene, either. METTL5 is included in the SysID database as a current primary ID gene (cited: 27457812, 28097321 / Given the shared co-authors with the study by Richard et al. as well as the overlapping variants, these articles probably report on the same individuals recently described in more detail). The gene is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx). ---- Overall, METTL5 could be considered for inclusion in the ID panel probably as green (3 families, 3 variants, segregation, suggested role of the gene, relevant expression patterns, some evidence at the variant-level, zebrafish and mouse models) or amber (underlying effect of Gly61Asp unknown and variant classified as VUS). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.1046 | PMPCA |
Konstantinos Varvagiannis gene: PMPCA was added gene: PMPCA was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: PMPCA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PMPCA were set to 25808372; 26657514; 27148589; 30617178 Phenotypes for gene: PMPCA were set to Spinocerebellar ataxia, autosomal recessive 2 (MIM 213200) Penetrance for gene: PMPCA were set to Complete Review for gene: PMPCA was set to GREEN gene: PMPCA was marked as current diagnostic Added comment: Biallelic pathogenic PMPCA variants cause Spinocerebellar ataxia, autosomal recessive 2 (SCAR2 - MIM 213200). More than 20 individuals from several unrelated families have been reported. At least 6 different pathogenic variants have been identified. Loss of PMPCA function is the suggested mechanism. ID is a feature of the disorder. PMPCA encodes the α-subunit of mitochondrial processing peptidase (αMPP), a heterodimeric enzyme responsible for the cleavage of nuclear-encoded mitochondrial precursor proteins after import in the mitochondria (summary by Jobling et al and OMIM). Arguments for involvement of the gene include the highly similar phenotype, segregation studies, expression of the gene in fetal and relevant adult tissues (in brain/cerebellum/cerebellar vermis), lower protein levels demonstrated for some variants, abnormal processing of frataxin (in line with the role of αMPP) demonstrated in most cases, rescue of the maturation defect upon transduction of wt PMPCA cDNA, disruption of REDOX balance in patient cells, etc. Relevant studies are summarized below. PMPCA is included in gene panels for ID offered by several diagnostic laboratories (incl. Radboud UMC, GeneDx, etc) and listed as a confirmed ID gene in SysID. It is not associated with any phenotype in G2P. As a result, this gene can be considered for inclusion in the current panel probably as green (or amber). ---- [1] - Jobling et al. (2015 - PMID: 25808372) described the phenotype of 17 individuals from 4 families, all presenting with non-progressive cerebellar ataxia and the majority with ID of variable severity (15/17 - relevant to the current panel). Individuals from 3 of the families - all of Lebanese origin - were homozygous for NM_015160.3:c.1129G>A (p.Ala377Thr). A further similarly affected subject was compound heterozygous for c.287C>T (p.Ser96Leu) and c.1543G>A (p.Gly515Arg). The homozygous variant in the first family was found within a 2.85 Mb linkage region on chr 9q34. An additional variant within this region (in CAMSAP1) was discarded following results in other families of the same origin. Semi-quantitative RT-PCR demonstrated fetal expression of the PMPCA as well as relatively higher expression in adult brain, cerebellum and cerebellar vermis. As for Ala377Thr, protein levels were shown to be lowest in affected individuals (LCLs, fibroblasts) and low - though somewhat higher - in carrier parents (LCL) compared to controls. RT-PCR on total RNA from LCLs did not show evidence of abnormal transcripts/additional splicing defect. Localization of mutant protein and morphology of mitochondrial reticulum was similar to controls. Maturation of frataxin - the protein depleted in Friedreich ataxia - was shown to be abnormal in patient lymphoblasts, compatible with the role of αMPP. In line with abnormal mitochondrial function, REDOX balance was increased in patient cells. [2] - Choquet et al. (2016 - PMID: 26657514) reported on 2 sibs - born to distantly related parents. The authors noted a phenotype corresponding to SCAR2 although the presentation was somewhat milder, intellectual disability was not a feature (despite some learning difficulties in one) and ataxia was progressive. WES demonstrated homozygosity for NM_015160:c.766G>A (p.Val256Met). Western blot in patient lymphoblasts showed αMPP levels similar to carriers and controls. Abnormal maturation (accumulation of specific isoforms) was shown for frataxin. [3] - Joshi et al. (2016 - PMID: 27148589) described the phenotype of 2 cousins belonging to a large Lebanese pedigree. Presentation in both was compatible with multisystem involvement incl. profound global DD, severe hypotonia, weakness, respiratory insufficiency, blindness suggestive of mitochondrial disorder. mtDNA, analyses of mitochondrial focused nuclear gene panel and aCGH were non-diagnostic. Both subjects were compound heterozygous for NM_015160.3:c.1066G>A (p.Gly356Ser) and c.1129G>A (p.Ala377Thr) following WES, with compatible segregation studies within the family. Western blot revealed PMPCA levels similar to control. Reduction of PMPCA staining and abnormally enlarged mitochondria were observed upon immunofluorescence in patient fibroblasts. Frataxin processing was abnormal. Lentiviral transduction of patient fibroblasts with wt PMPCA cDNA, led to increased PMPCA levels and correction of frataxin processing. [4] - Rubegni et al. (2019 - PMID: 30617178) report on a 7-y.o. boy with global DD, spastic-ataxic gait and 'low IQ'. MRI images were suggestive of cerebellar atrophy with hyperintensity in the striatum. The child was homozygous for c.553C>T / p.Arg185Trp (reference not specified, although the variant would be compatible with NM_015160.3). Sources: Literature, Radboud University Medical Center, Nijmegen |
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| Intellectual disability - microarray and sequencing v2.1022 | CACNA2D2 |
Konstantinos Varvagiannis gene: CACNA2D2 was added gene: CACNA2D2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CACNA2D2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CACNA2D2 were set to 23339110; 24358150; 30410802; 29997391; 31402629; 11487633; 11756448; 4177347; 14660671; 15331424 Phenotypes for gene: CACNA2D2 were set to Cerebellar atrophy with seizures and variable developmental delay (MIM 618501) Penetrance for gene: CACNA2D2 were set to Complete Review for gene: CACNA2D2 was set to AMBER gene: CACNA2D2 was marked as current diagnostic Added comment: Gene reviewed for the epilepsy panel. Due to the phenotype of EE, with variable GDD (severe in many cases) and/or ID (either specifically commented on or inferred in some cases, although not universal) this gene might also be relevant for the current panel. CACNA2D2 is also included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx) as well as the SysID database. There is no associated phenotype in G2P. Copied from the epilepsy panel: Biallelic pathogenic CACNA2D2 variants cause Cerebellar atrophy with seizures and variable developmental delay (MIM 618501). A recent OMIM update, a subsequent relevant publication by Punatha et al. as well as several additional LP/P variants in ClinVar for the phenotype of epileptic encephalopathy, support possible upgrade to green. The following affected individuals appear to be relevant [NM_006030.3 used as RefSeq unless otherwise specified]: [1] Edvardson et al. (PMID: 23339110) - 3 sibs born to consanguineous parents with EIEE, severe GDD / ID (inferred from the descritpion, at least for the oldest one), cerebellar atrophy and movement abnormalities. A CACNA2D2 variant (c.3137T>C / p.Leu1046Pro) was found in affected individuals by SNP-arrays and WES in one of them. Functional studies (reduction in current density of calcium channels in Xenopus laevis oocytes) supported the deleterious effect of the variant. A role of a rare hmz CESLR3 variant could not be ruled out. [2] Pippucci et al. (PMID: 24358150) - 1 individual born to consanguineous parents, presenting with EE (onset at 1-2 m), severe GDD, cerebellar atrophy and choreiform movements. Homozygosity for a LoF variant (c.1294delA - p.Asn432fs) was found by WES. The role of the variant was further supported by expression studies (80% reduced mRNA levels, protein levels estimated at 3% of control / milder effect in htz parents). The proband was also hmz for a CESLR3 variant. Previous studies incl. 'high-resolution karyotype' and metabolic investigations. [3] Butler et al. (PMID: 30410802) - A 5 y.o. male, with EE (seizure onset at 7m / GDD) and cerebellar atrophy. Compound heterozygosity for c.782C>T (p.Pro261Leu) and c.3137T>C (p.Leu1046Pro) was demonstrated by WES and supported by segregation studies. [4] Valence et al. (PMID: 29997391) - Reported on a 20 y.o. male belonging to a cohort of 20 individuals with congenital ataxia, all from consaguineous families. This individual, who had cerebellar atrophy, ataxia, a single episode of febrile seizures and normal cognitive impairment was homozygosity for c.2971G>A (p.Asp991Asn). RT-PCR revealed presence of a normal length transcript as well as an additional, longer one, due to a concurrent splicing effect (activation of a cryptic donor splice site and retention of 4 bases of intronic sequence). Presence of both nl/abn length transcripts was presumed to explain the mild phenotype (variability also commented in OMIM). [5] Punatha et al. (PMID: 31402629) - 3 affected individuals from 2 consanguineous families presenting with early onset EE (onset 1-7m), GDD/ID, cerebelar atrophy and ataxia. Sibs from the first family were homozygous for c.1778G>C (p.Arg593Pro). An affected 5 y.o. child from the 2nd family was homozygous for c.485_486delAT (p.Tyr162Ter). Mutations were found by WES in regions of AOH. The following variants - not reported in the literature - have been submitted in ClinVar as LP / P for EE: [VCV000645106.1] NM_006030.4:c.1389+2T>C - EIEE with suppression bursts - Likely Pathogenic (Invitae) [VCV000570589.1] NM_006030.4:c.1956_1960del (p.Asn652fs) - EIEE - Pathogenic (Invitae) [VCV000578284.1] NM_006030.4:c.1555C>T (p.Gln519Ter) - EIEE - Pathogenic (Invitae) [VCV000653393.1] NM_006030.4:c.851dup (p.Ala286fs) - EIEE with suppression bursts - Pathogenic (Invitae) [VCV000411003.1] NM_006030.4:c.485_486del (p.Tyr161_Tyr162insTer) - EIEE - Pathogenic (Invitae) Additional ones have been reported as LP / P although the condition is not specified. [VCV000620551.1] NM_006030.4:c.1023C>A (p.Cys341Ter) - Likely pathogenic (GeneDx) [VCV000373439.2] NM_006030.4:c.1846-1G>A - Likely pathogenic (GeneDx) [VCV000423330.2] NM_006030.4:c.200dup (p.His68fs) - Pathogenic (GeneDx). The aforementioned laboratories include CACNA2D2 in gene panels for epilepsy (Invitae) and/or ID (GeneDx). A role for the CACNA2D2 is supported by : - The highly overlapping features (with the exception of the milder phenotype reported by Valence et al.) incl. early onset of seizures, GDD, cerebellar atrophy in all (9/9 incl. the individual reported by Valence, as evaluated Punatha et al). Ataxia was a feature in many (with movement abnormalities also in the remaining ones). - The role of the gene encoding the alpha-2-delta-2 auxiliary subunit of high voltage-gated calcium channels. Auxiliary subunits modulate calcium current and channel activation and inactivation kinetics, and may be involved in proper assembly and membrane localization of the channels (summary by Edvardson and OMIM). - Functional / expression studies for some of the variants (as in Refs 1,2,4). - Relevant expression patterns (notably in cerebellum) [GTEx project] - Mouse models recapitulating the human phenotypes (summarized by Edvardson et al) : The 'ducky' mouse model (due to biallelic Cacna2d2 mutations) presenting absence epilepsy, spike-wave seizures and ataxia. Dysgenesis of the cerebellum is among the neuropathological findings (PMIDs cited : 11487633, 11756448, 4177347). The 'entla' mouse model (also AR due to an in-frame duplication) presents also epilepsy and ataxia (PMID : 14660671). Targeted knockout in another mouse model resulted also in ataxic gait, seizure susceptibility and cerebellar anomalies/degeneration (PMID: 15331424). [Please consider inclusion in other relevant panels eg. for cerebellar anomalies / ataxia]. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.1021 | PAK1 |
Konstantinos Varvagiannis changed review comment from: Horn et al. (2019 - doi.org/10.1093/brain/awz264) report on 4 additional individuals with de novo missense PAK1 pathogenic variants. ID, seizures and macrocephaly and walking difficulties were observed in all (4/4). ASD was reported in 3 (but was not among the features in the study by Harms et al). PAK1 encodes p21 protein-activated kinase 1. The protein has 2 major domains, an autoregulatory and a protein kinase domain. Homodimerization masks the active site of the kinase, leading to autoinhibition (inactive form). PAK1 is activated by dissociation into monomers upon binding of the GTP-bound forms of the Rho GTPases CDC42 and RAC1. TRIO and HACE1 are indirect regulators of PAK1, via RAC1. PAK1 in turn, activates LIMK1 which plays a critical role in dendritic spine morphogenesis and brain function. CDC42, RAC1, TRIO, HACE1 are all associated with neurodevelopmental disorders. Activation of RAC-PAK1-LIMK1 pathway has been demonstrated for Fragile-X syndrome (sharing ID, macrocephaly and seizures). Mutations in PAK3, another member of the group I PAK subfamily with similar activation mechanism to PAK1 (by CDC42 / RAC1), cause Mental retardation, X-linked 30/47 (MIM 300558) (Green rating in the current panel). 4 additional missense variants - further to the 2 previously described ones - were found, all as de novo events: c.397T>C (p.Ser133Pro) / c.361C>T p.(Pro121Ser) / c.328T>A p.(Ser110Thr) / c.1409T>G (p.Leu470Arg) [For the specific variants, cDNA and aa change are the same for both NM_001128620.1 and NM_002576]. The 3 former variants located within the autoinhibitory domain while the latter in the protein kinase domain though - again - close to the autoinhibitory one (in tertiary structure). A gain of function effect by reduced ability of autoinhibition (leading to autophosphorylation) and activation of PAK1 is the suggested mechanism. Gain of function is also supported by the fact that Pak1-/- do not exhibit neurodevelopmental anomalies / abnormal head size. PAK1 is not particularly intolerant to LoF variants as suggested by its pLI of 0.67. The corresponding phenotype in OMIM is Intellectual developmental disorder with macrocephaly, seizures, and speech delay (MIM 618158). The gene is part of the DD panel of G2P, associated with "Neurodevelopmental Disorder" (monoallelic, activating / disease confidence : probable). PAK1 is included in the gene panel for ID offered by Radboudumc.; to: Based on a further recent study, PAK1 can probably be upgraded to green in both ID and epilepsy gene panels: Horn et al. (2019 - doi.org/10.1093/brain/awz264) report on 4 additional individuals with de novo missense PAK1 pathogenic variants. ID, seizures and macrocephaly and walking difficulties were observed in all (4/4). ASD was reported in 3 (but was not among the features in the study by Harms et al). PAK1 encodes p21 protein-activated kinase 1. The protein has 2 major domains, an autoregulatory and a protein kinase domain. Homodimerization masks the active site of the kinase, leading to autoinhibition (inactive form). PAK1 is activated by dissociation into monomers upon binding of the GTP-bound forms of the Rho GTPases CDC42 and RAC1. TRIO and HACE1 are indirect regulators of PAK1, via RAC1. PAK1 in turn, activates LIMK1 which plays a critical role in dendritic spine morphogenesis and brain function. CDC42, RAC1, TRIO, HACE1 are all associated with neurodevelopmental disorders. Activation of RAC-PAK1-LIMK1 pathway has been demonstrated for Fragile-X syndrome (sharing ID, macrocephaly and seizures). Mutations in PAK3, another member of the group I PAK subfamily with similar activation mechanism to PAK1 (by CDC42 / RAC1), cause Mental retardation, X-linked 30/47 (MIM 300558) (Green rating in the current panel). 4 additional missense variants - further to the 2 previously described ones - were found, all as de novo events: c.397T>C (p.Ser133Pro) / c.361C>T p.(Pro121Ser) / c.328T>A p.(Ser110Thr) / c.1409T>G (p.Leu470Arg) [For the specific variants, cDNA and aa change are the same for both NM_001128620.1 and NM_002576]. The 3 former variants located within the autoinhibitory domain while the latter in the protein kinase domain though - again - close to the autoinhibitory one (in tertiary structure). A gain of function effect by reduced ability of autoinhibition (leading to autophosphorylation) and activation of PAK1 is the suggested mechanism. Gain of function is also supported by the fact that Pak1-/- do not exhibit neurodevelopmental anomalies / abnormal head size. PAK1 is not particularly intolerant to LoF variants as suggested by its pLI of 0.67. The corresponding phenotype in OMIM is Intellectual developmental disorder with macrocephaly, seizures, and speech delay (MIM 618158). The gene is part of the DD panel of G2P, associated with "Neurodevelopmental Disorder" (monoallelic, activating / disease confidence : probable). PAK1 is included in the gene panel for ID offered by Radboudumc. (Previous review below) |
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| Intellectual disability - microarray and sequencing v2.1021 | PAK1 |
Konstantinos Varvagiannis edited their review of gene: PAK1: Added comment: Horn et al. (2019 - doi.org/10.1093/brain/awz264) report on 4 additional individuals with de novo missense PAK1 pathogenic variants. ID, seizures and macrocephaly and walking difficulties were observed in all (4/4). ASD was reported in 3 (but was not among the features in the study by Harms et al). PAK1 encodes p21 protein-activated kinase 1. The protein has 2 major domains, an autoregulatory and a protein kinase domain. Homodimerization masks the active site of the kinase, leading to autoinhibition (inactive form). PAK1 is activated by dissociation into monomers upon binding of the GTP-bound forms of the Rho GTPases CDC42 and RAC1. TRIO and HACE1 are indirect regulators of PAK1, via RAC1. PAK1 in turn, activates LIMK1 which plays a critical role in dendritic spine morphogenesis and brain function. CDC42, RAC1, TRIO, HACE1 are all associated with neurodevelopmental disorders. Activation of RAC-PAK1-LIMK1 pathway has been demonstrated for Fragile-X syndrome (sharing ID, macrocephaly and seizures). Mutations in PAK3, another member of the group I PAK subfamily with similar activation mechanism to PAK1 (by CDC42 / RAC1), cause Mental retardation, X-linked 30/47 (MIM 300558) (Green rating in the current panel). 4 additional missense variants - further to the 2 previously described ones - were found, all as de novo events: c.397T>C (p.Ser133Pro) / c.361C>T p.(Pro121Ser) / c.328T>A p.(Ser110Thr) / c.1409T>G (p.Leu470Arg) [For the specific variants, cDNA and aa change are the same for both NM_001128620.1 and NM_002576]. The 3 former variants located within the autoinhibitory domain while the latter in the protein kinase domain though - again - close to the autoinhibitory one (in tertiary structure). A gain of function effect by reduced ability of autoinhibition (leading to autophosphorylation) and activation of PAK1 is the suggested mechanism. Gain of function is also supported by the fact that Pak1-/- do not exhibit neurodevelopmental anomalies / abnormal head size. PAK1 is not particularly intolerant to LoF variants as suggested by its pLI of 0.67. The corresponding phenotype in OMIM is Intellectual developmental disorder with macrocephaly, seizures, and speech delay (MIM 618158). The gene is part of the DD panel of G2P, associated with "Neurodevelopmental Disorder" (monoallelic, activating / disease confidence : probable). PAK1 is included in the gene panel for ID offered by Radboudumc.; Changed rating: GREEN; Changed publications: 30290153, doi.org/10.1093/brain/awz264; Set current diagnostic: yes |
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| Intellectual disability - microarray and sequencing v2.1021 | GABBR2 | Rebecca Foulger Added comment: Comment on list classification: Updated gene from Amber to Green: As noted by Konstantinos Varvagiannis, an additional 2018 study has been published associating a new GABBR2 variant (A707T) with a RETT-like phenotype including intellectual impairment (PMID:29369404). This adds to the previous papers documenting the recurring p.Ala567Thr variant in RETT-like patients from Portugal (PMID:26740508) and Korea (PMID:28856709). Plus OMIM has been updated since the Dec 2017 curation to include neurodevelopmental disorder MIM:617904. Thirdly, email correspondence from J. Evans notes a patient with a relevant phenotype and a previously-published pathogenic variant in GABBR2. Therefore sufficient unrelated cases to support a Green rating. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.1020 | GABBR2 | Rebecca Foulger Phenotypes for gene: GABBR2 were changed from EPILEPTIC ENCEPHALOPATHY; Rett syndrome to EPILEPTIC ENCEPHALOPATHY; Rett syndrome; Neurodevelopmental disorder with poor language and loss of hand skills, 617903 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.996 | POLR2A |
Konstantinos Varvagiannis gene: POLR2A was added gene: POLR2A was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: POLR2A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: POLR2A were set to 31353023 Phenotypes for gene: POLR2A were set to Generalized hypotonia; Global developmental delay; Feeding difficulties Penetrance for gene: POLR2A were set to unknown Review for gene: POLR2A was set to GREEN gene: POLR2A was marked as current diagnostic Added comment: Haijes et al. (2019 - PMID: 31353023) report on 16 individuals with heterozygous de novo POLR2A variants. DD in all domains was observed in all individuals, ranging from mild to severe (in 8/16 moderate or more severe). The developmental scores were stable over time (as for eventual catch-up/decline) supporting relevance to the current panel. POLR2A encodes RPB1, the largest subunit of RNA polymerase II (pol II). Pol II is responsible for the transcription of all protein coding genes as well as several long/short non-coding RNA genes. Missense, in-frame deletions as well as truncating mutations were observed. POLR2A has a pLI of 1 and a Z-score for missense variants of 7.13 (one of the highest ones). The reported variants did not cluster in specific domains of the protein although many were in regions relatively depleted in benign variants in gnomAD (stretches of desert Z-scores). Measures such as the CADD scores did not discriminate between deleterious ones and those in gnomAD. Different layers of structural analyses, functional analyses (impaired growth in S. cerevisiae in genetic background lacking transcr. factors Dst1 / Sub1 - suggesting reduced transcriptional fidelity / reduced HeLa cell viability) or phenotypic overlap were used to classify variants in probably disease causing (11), possibly disease causing (4 - only based on phenotypic overlap) or of unknown effect (1 variant - due to unavailable/incomplete phenotype). Some variants were predicted to act by haploinsufficiency while others (missense ones) by a dominant-negative mechanism, the latter being more likely to result in severe phenotypes. Mutations in genes encoding subunits of pol III (responsible for tRNA synthesis) are associated with leukodystrophy phenotypes with some limited overlap with POLR2A (delayed myelination/white-matter loss/tooth misalignment). Mutations in genes encoding other subunits of pol II (other than RPB1 encoded by POLR2A) have not been implicated in disease though. POLR2A is not associated with any phenotype in OMIM/G2P. This gene is included in panels for ID offered by some diagnostic laboratories [eg. Utrecht UMC - affiliation of many co-authors of this study or GeneDx]. As a result, this gene can be considered for inclusion in the ID panel probably as green, or amber. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.996 | PIGU |
Konstantinos Varvagiannis gene: PIGU was added gene: PIGU was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PIGU was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PIGU were set to 31353022 Phenotypes for gene: PIGU were set to Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis Penetrance for gene: PIGU were set to Complete Review for gene: PIGU was set to GREEN Added comment: Knaus et al. (2019 - PMID: 31353022) report on 5 affected individuals (from 3 unrelated families) with biallelic pathogenic PIGU variants. Common features included tone abnormalities, global DD, ID, seizures, CNS anomalies (cerebral atrophy and/or cerebellar hypoplasia), scoliosis. Affected individuals presented also with facial similarities. DD/ID were universal features and their severity appears to be relevant to the panel. Seizures were also reported in all individuals (myoclonic in 3, for whom this was specified). ALP was normal in all. Three individuals from 2 non-consanguineous families (one from Norway, the other not specified) were homozygous for a missense variant NM_080476.4:c.1149C>A (or p.Asn383Lys) present with an AF of 7/277197 in Europeans. Two individuals born to consanguineous parents from Turkey were homozygous for another missense variant (c.209T>A or p.Ile70Lys - same RefSeq). Segregation analyses in parents and unaffected sibs were carried out. PIGU encodes a subunit of the GPI transaminidase, a heteropentameric complex (other subunits encoded by PIGK, PIGS, PIGT and GPAA1) that mediates attachment in the endoplasmic reticulum of glycosylphosphatidylinositol (GPI) to the C-termini of proteins which are subsequently anchored to the cell surface. Pathogenic variants in 18 of 29 genes implicated in biosynthesis of the GPI anchor have been identified as a cause of GPI biosynthesis disorders, with ID and seizures as principal features. Mutations in other genes encoding components of the GPI transaminidase complex (GPAA1, PIGT and PIGS) lead to neurodevelopmental disorders. Functional impairment of PIGU was supported by flow-cytometric analysis showing significant reduction of cell surface expression of GPI anchored proteins (mainly FLAER, CD16 and CD24) on granulocytes from affected individuals. In addition accumulation of free GPI anchors on the cell surface of B cells from affected individuals further suggested deficiency of the GPI transaminidase. Transient expression of mutant (Asn383Lys) protein failed to rescue expression of GPI-APs to the same extent as wt in a CHO cell line deficient for PIGU. Feature analysis demonstrated similarities among individuals with mutations in other genes of the GPI transamidase complex (GPAA1 and PIGT) as well as with GPI biosynthesis disorders. Facial analysis was also suggestive of facial similarities between individuals with GPAA1 and PIGU mutations. PIGU is not associated with any phenotype in OMIM or G2P. As a result this gene can be considered for inclusion in the ID and epilepsy panels probably as green (3 families, ID of relevant severity and seizures in all affected individuals, known group of disorders and supportive evidence) or amber. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.978 | PUS3 |
Catherine Snow Source Expert Review Green was added to PUS3. Source Expert Review was added to PUS3. Added phenotypes Mental retardation, autosomal recessive 55, 617051 for gene: PUS3 Publications for gene PUS3 were changed from 27055666; 30308082 to 30697592; 30308082; 27055666 Rating Changed from No List (delete) to Green List (high evidence) |
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| Intellectual disability - microarray and sequencing v2.978 | PIGG |
Catherine Snow Source Expert Review Green was added to PIGG. Added phenotypes Mental retardation, autosomal recessive 53, 616917 for gene: PIGG Publications for gene PIGG were changed from 26996948; 28581210 to 28581210; 26996948; 30914295 Rating Changed from No List (delete) to Green List (high evidence) |
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| Intellectual disability - microarray and sequencing v2.978 | GPT2 |
Catherine Snow Source Expert Review Green was added to GPT2. Source Expert Review was added to GPT2. Added phenotypes Mental retardation, autosomal recessive 49, 138210 for gene: GPT2 Publications for gene GPT2 were changed from PMID: 25758935; 27601654; 28130718; 29226631 to 27601654; 28130718; 29226631; 25758935 Rating Changed from No List (delete) to Green List (high evidence) |
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| Intellectual disability - microarray and sequencing v2.978 | EMC1 |
Catherine Snow Source Expert Review Green was added to EMC1. Added phenotypes Cerebellar atrophy, visual impairment, and psychomotor retardation, 616875 for gene: EMC1 Publications for gene EMC1 were changed from 26942288; 29271071 to 29271071; 26942288; 30914295 Rating Changed from No List (delete) to Green List (high evidence) |
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| Intellectual disability - microarray and sequencing v2.959 | ATRX | Rebecca Foulger Added comment: Comment on mode of inheritance: Changed Mode of inheritance from XLR to XLD: Alpha-thalassemia/mental retardation syndrome, 301040 is listed as XLD in OMIM (in addition to Mental retardation-hypotonic facies syndrome, X-linked, 309580 listed as XLR). Although PMID:17503331 report that nearly all female carriers of ATRX syndrome have highly skewed X-chromosome inactivation in favour of cells expressing the normal ATRX allele and are essentially phenotypically normal, PMID:16955409 report a female carrier where the chromosome carrying the mutant allele was active and she therefore showed a phenotype. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.957 | ATRX | Rebecca Foulger Phenotypes for gene: ATRX were changed from Alpha-thalassemia/mental retardation syndrome, 301040Alpha-thalassemia myelodysplasia syndrome, somatic, 300448Mental retardation-hypotonic facies syndrome, X-linked, 309580; MENTAL RETARDATION SYNDROMIC X-LINKED WITH HYPOTONIC FACIES SYNDROME TYPE 1 (MRXSHF1) to Alpha-thalassemia/mental retardation syndrome, 301040; Mental retardation-hypotonic facies syndrome, X-linked, 309580 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.953 | PIGB |
Konstantinos Varvagiannis gene: PIGB was added gene: PIGB was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PIGB was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PIGB were set to 31256876 Phenotypes for gene: PIGB were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Hearing abnormality; Abnormality of vision; Elevated alkaline phosphatase; Abnormality of the head; Abnormality of the hand; Abnormality of the foot Penetrance for gene: PIGB were set to Complete Review for gene: PIGB was set to GREEN Added comment: Murakami et al. (2019 - PMID: 31256876) provide detailed information on 14 individuals from 10 families (4 of which consanguineous) with biallelic pathogenic PIGB variants. Overlapping features included DD/ID (13/13), epilepsy (14/14), deafness (7/14), ophthalmological or brain anomalies, hand and feet anomalies as well as presence of dysmorphic features. ID was common, in those individuals with appropriate age. Some had a previous diagnosis of DOORS syndrome (deafness/onychodystrophy/osteodystrophy,retardation, seizures) and few showed 2-oxoglutatic aciduria which can also be seen in DOORS s. PIGB encodes phosphatidylinositol glycan anchor biosynthesis class B protein. Overall the phenotype was similar to other inherited glycosylphosphatidylinositol (GPI) deficiencies (IGDs). As happens to be the case in some other GPI deficiencies alkaline phosphatase was also elevated in those tested (8/9). 8 missense, 1 stopgain as well as an intronic SNV are reported. All variants were either absent or ultra-rare and with no homozygotes in gnomAD. Affected individuals from 4 families, harbored an intronic SNV in the homozygous state. For this variant - with MAF of 0.0001592 or 6.51x10-5 in ExAC and gnomAD - activation of an aberrant splice acceptor site was shown [NM_004855.4:c.847-10A>G or p.Gln282_Trp283insArgCysGln]. Flow cytometric analysis of blood cells or fibroblasts showed decreased levels for various GPI-AP (GPI-anchored protein) markers in affected individuals. These levels were rescued upon transduction with a PIGB-encoding-Lx304 lentiviral vector of fibroblasts from one affected individual, suggesting that the PIGB defect was responsible. The effect of the variants was evaluated using PIGB-deficient CHO cells, transfected with wt or mutant PIGB cDNAs. FACS analysis and immunoblotting demonstrated that variants were able to restore only slightly/partially - if at all - the surface presence of GPI-APs in the case of variants while the levels of mutant protein were reduced. PIGB is not associated with any phenotype in OMIM/G2P. This gene is not commonly included in gene panels for ID offered by diagnostic laboratories. As a result, this gene can be considered for inclusion in the ID and epilepsy panels probably as green (or amber). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.953 | DEAF1 | Rebecca Foulger Phenotypes for gene: DEAF1 were changed from MENTAL RETARDATION, AUTOSOMAL DOMINANT 24 to MENTAL RETARDATION, AUTOSOMAL DOMINANT 24; ?Dyskinesia, seizures, and intellectual developmental disorder, 617171; Mental retardation, autosomal dominant 24, 615828 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.950 | NEXMIF | Rebecca Foulger Added comment: Comment on mode of inheritance: Changed MOI from XLR to XLD to match the XLD recorded for 'Mental retardation, X-linked 98' in OMIM (MIM:300912) and Gene2Phenotype, which records X-linked dominant inheritance for 'Intellectual disability and epilepsy' in addition to hemizgyous inheritance for 'KIAA2022'. An XLD inheritance is supported by PMID:27358180 which reports 14 female patients who carry a heterozygous de novo NEXMIF (KIAA2022) variant and share a phenotype characterised by intellectual disability and epilepsy. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.926 | CWC27 | Ivone Leong Added comment: Comment on list classification: Promoted from red to green. CWC27 is associated with a phenotype in OMIM and Gene2Phenotype. PMID: 28285769 reported on 7 unrelated families (10 affected individuals) with variants in this gene. 8/10 had neurological problems, which include ID, delayed walking, delayed speech or psychomotor retardation. Two cases (same family) are specified as moderate ID and they have indicated severe psychomotor retardation in others. After consulting the Genomics England Clinical Team, it was decided that there is enough evidence to promote this to green status. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.893 | ITPA | Ivone Leong Added comment: Comment on list classification: Promoted from red to green. ITPA is associated with a phenotype in OMIM but not in Gene2Phenotype. There are 5 unrelated families (PMID: 26224535, 30816001) with affected individuals who have global developmental delay with different variants in ITPA. PMID: 19498443 describes a knockout mouse model of Itpa, which had growth retardation. Therefore, there is enough evidence to promote this gene to green status. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.885 | CWC27 | Ivone Leong Phenotypes for gene: CWC27 were changed from Retinitis pigmentosa with or without skeletal anomalies to Retinitis pigmentosa with or without skeletal anomalies, 250410 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.874 | KMT5B | Eleanor Williams Phenotypes for gene: KMT5B were changed from Mental retardation, autosomal dominant 51 to Mental retardation, autosomal dominant 51, 617788 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.868 | PUF60 | Leanne Baxter reviewed gene: PUF60: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Syndromic intellectual disability, prenatal onset growth failure, bifid uvula, retinal atrophy, congenital microcephaly, short stature, long fingers, deviation of toes, short thorax; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.859 | POLA1 | Rebecca Foulger Phenotypes for gene: POLA1 were changed from Pigmentary disorder, reticulate, with systemic manifestations, X-linked, 301220; XLPDR to Pigmentary disorder, reticulate, with systemic manifestations, X-linked, 301220; XLPDR; X-Linked Intellectual Disability associated with short stature, microcephaly, and hypogonadism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.847 | DYNC1I2 |
Konstantinos Varvagiannis gene: DYNC1I2 was added gene: DYNC1I2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: DYNC1I2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DYNC1I2 were set to 31079899 Phenotypes for gene: DYNC1I2 were set to Microcephaly; Intellectual disability; Abnormality of nervous system morphology; Abnormality of head or neck Penetrance for gene: DYNC1I2 were set to Complete Review for gene: DYNC1I2 was set to AMBER Added comment: Ansar et al. (2019 - PMID: 31079899) report on five individuals from 3 families, with biallelic likely pathogenic DYNC1I2 variants. The phenotype consisted of microcephaly, intellectual disability, cerebral malformations and suggestive facial features. 2/5 individuals, from different families presented seizures. Affected individuals from a consanguineous Pakistani family were homozygous for a splicing variant (c.607+1G>A - RNA was unavailable for further studies). One individual from a futher family was compound heterozygous for a missense variant (c.740A>G or p.Tyr247Cys) and a 374 kb deletion encompassing DYNC1I2 as well as 3 other genes (DCAF17, CYBRD1, SLC25A12). Another individual was found to harbor c.740A>G (p.Tyr247Cys) in trans with c.868C>T (p.Gln290*). [NM_001378.2 used as reference]. DYNC1I2 encodes Dynein Cytoplasmic 1 intermediate chain 2, a component of the cytoplasmic dynein 1 complex. This complex is involved in retrograde cargo transport within the cytoplasmic microtubule network. Emerging evidence suggests a critical role of this complex in neurodevelopment and homeostasis (PMIDs cited by the authors: 25374356, 28395088). Mutations in other genes encoding components of the complex (principally DYNC1H1) give rise to neurological disorders, some of which with ID as a principal feature (eg. Mental retardation, autosomal dominant 13 - MIM 614563). In zebrafish, DYNC1I2 has 2 orthologs - dync1i2a and dync1i2b. The former is suggested to be the functionally relevant DYNC1I2 ortholog as CRISPR-Cas9 dync1i2a disruption and/or suppression with morpholinos resulted in altered craniofacial patterning and reduction in head size (similar to the microcephaly phenotype reported in affected individuals). In vivo complementation studies suggested a loss of function effect for the p.Tyr247Cys variant, similar to the p.Gln290* one. Evidence is provided for a role of increased apoptosis, probably secondary to altered cell cycle progression (prolonged mitosis due to abnormal spindle morphology), to explain the reduced head size/microcephaly phenotype. There is no associated phenotype in OMIM/G2P. As a result, DYNC1I2 could be considered for inclusion in the ID panel probably as amber (ID reported for 5 individuals from 3 families, severity of ID not specified for all, eg. fam. 2 for whom the deletion was also spanning other genes which might contribute to the phenotype). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.845 | ACTL6B | Rebecca Foulger commented on gene: ACTL6B: Bell et al., 2019 (PMID:31031012) identified 11 individuals (from 10 families) with biallelic variants in ACTL6B and global developmental delay, epileptic encephalopathy, and spasticity. They also identified 10 unrelated individuals with de novo heterozygous variants with ID, developmental delay, hypotonia, Rett-like stereotypies (e.g. handwringing), and minor facial dysmorphisms: 9/10 of these individuals had the identical de novo c.1027G>A (p.Gly343Arg) mutation. Engineered knock-out of ACTL6B in wild-type human neurons resulted in profound deficits in dendrite development. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.831 | TTI2 | Rebecca Foulger Phenotypes for gene: TTI2 were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to AUTOSOMAL RECESSIVE MENTAL RETARDATION; Mental retardation, autosomal recessive 39, 615541 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.826 | TRMT1 | Rebecca Foulger Phenotypes for gene: TRMT1 were changed from autosomal recessive intellectual disorder; ARID to autosomal recessive intellectual disorder; ARID; Mental retardation, autosomal recessive 68, 618302; Global developmental delay; Intellectual disability | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.800 | ZNF142 |
Konstantinos Varvagiannis gene: ZNF142 was added gene: ZNF142 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: ZNF142 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZNF142 were set to 31036918 Phenotypes for gene: ZNF142 were set to Global developmental delay; Intellectual disability; Seizures; Tremor; Dystonia Penetrance for gene: ZNF142 were set to unknown Review for gene: ZNF142 was set to GREEN Added comment: Khan et al. (2019 - PMID: 31036918) describe the phenotype of 7 females from 4 families, harboring biallelic likely pathogenic ZNF142 variants. Overlapping features included cognitive impairment (ID in 6/7 from 3 families, borderline intellectual functioning was reported one occasion), speech impairement and motor impairment (7/7), and variably penetrant seizures (5/7), tremor (4/7) and dystonia (3/7). Most individuals (5/7) had experienced at least one episode of seizures (tonic-clonic) though seizures were recurrent in 3 sibs. Other disorders with ID (eg. Angelman syndrome, Rett syndrome, chromosomal disorders) or movement disorders as a feature were previously ruled out for many subjects. 6 individuals were homozygous or compound heterozygous for LoF (stopgain or frameshift) variants. One individual harbored 2 missense SNVs in the compound heterozygous state. Variants reported include (NM_001105537.2): c. 817_818delAA (p.Lys273Glufs*32), c.1292delG (p.Cys431Leufs*11), c.3175C>T (p.Arg1059*), c.4183delC (p.Leu1395*), c.3698G>T (p.Cys1233Phe), c.4498C>T (p.Arg1500Trp) with the LoF variants predicted to result in NMD. Expression or functional studies were not carried out. ZNF142 encodes a C2H2 domain-containing transcription factor. Mutations in other zinc finger proteins (ZNF/zfp) have been reported in several neurodevelopmental disorders impacting the CNS (eg. ZBTB20 and ZBTB11 heterozygous and biallelic mutations, respectively) and/or presenting with movement disorders among their manifestations (eg. YY1). As the authors comment, homozygous ablation of the orthologous (Zfp142) locus in mice results in behavioral and neurological phenotypes [MGI ref.ID: J:211773 cited - http://www.informatics.jax.org/marker/reference/J:211773 (though Zfp142 or its locus do not seem to appear in the list)]. ZNF142 is not - at least commonly - included in gene panels for ID offered by diagnostic laboratories. It is not associated with any phenotype in OMIM, nor in G2P. As a result, this gene can be considered for inclusion in the current panel as probably as green (individuals from 3 families, appropriate degree of ID for the current panel) or amber (if further evidence would be required). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.800 | SNAP25 |
Konstantinos Varvagiannis gene: SNAP25 was added gene: SNAP25 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: SNAP25 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SNAP25 were set to 29491473; 28135719; 29100083; 25381298; 25003006 Phenotypes for gene: SNAP25 were set to ?Myasthenic syndrome, congenital 18, 616330 Penetrance for gene: SNAP25 were set to Complete Review for gene: SNAP25 was set to GREEN gene: SNAP25 was marked as current diagnostic Added comment: Probably 9 individuals with heterozygous SNAP25 pathogenic variants have been reported to date, most summarized in the first reference (NM_130811.2 used as reference for all variants below): - Fukuda et al. (2018 - PMID: 29491473) 2 sibs (~11 and 2.5 y.o) with seizures and cerebellar ataxia but not ID. harboring c.176G>C (p.Arg59Pro) variant which was inherited from a mosaic unaffected parent. - DDD study (2017 - PMID: 28135719) [also in Heyne et al. 2018 - PMID: 29942082] 3 inividuals (11 m - 7 y of age) with DD and seizures due to c.118A>G (p.Lys40Glu), c.127G>C (p.Gly43Arg) and c.520C>T (p.Gln174*) de novo variants. - Hamdan et al. (2017 - PMID: 29100083) a 23 y.o. male with epilepsy and ID and c.496G>T (p.Asp166Tyr) de novo variant - Shen et al. (2014 - PMID: 25381298) a 11 y.o. female with epilepsy and ID and c.200T>A (p.Ile67Asn) de novo variant - Rohena et al. (2013 - PMID: 25003006) a 15 y.o. female with epilepsy and ID and c.142G>T (p.Val48Phe) de novo variant - Decipher patient 292139, a male with c.212T>C (p.Met71Thr) with hypotonia, DD, poor coordination and additional features (epilepsy not reported). Seizures of variable type [absence seizures, generalized tonic-clonic (most), focal clonic, myoclonic, etc] have been reported for most (8/9) of these individuals. DD was a feature in several subjects and intellectual outcome has been specifically commented on for 5 (2 without and 3 with ID - moderate/severe/not further specified). SNAP25 encodes a (t-)SNARE protein essential for synaptic vesicle exocytosis. Mutations in genes for other components of the SNARE complex (eg. STXBP1) have been associated with epilepsy and/or ID. SNAP25a and SNAP25b are the 2 major protein isoforms [corresponding transcripts: ENST00000304886 (NM_003081) and ENST00000254976 (NM_130811) respectively]. These isoforms are produced by utilization of alternative exons 5 (5a or 5b) though the amino-acid sequence encoded by these exons appears to be identical except for 9 residues. Most variants reported to date affect both transcripts (and protein isoforms) although 2 were specific for ENST00000254976 (or SNAP25b isoform - Fukuda et al. and Shen et al.). Mouse Snap25 has also 2 isoforms. Both are predominantly localized in embryonic and adult mouse brains. Snap25a is produced before Snap25b though the latter becomes the major isoform early postnatally (by the second week) [PMIDs cited: 7878010, 21526988]. Based on the phenotype of some individuals with chromosome 20 deletions in Decipher (note: only 3 deletions spanning SNAP25 however appear currently, the phenotype is not specified and 2 of them are >4.5Mb) or the pLI of 0.96 in gnomAD, haploinsufficiency has been proposed as a likely mechanism. A dominant-negative effect was however suggested for the Ile67Asn studied by Shen et al. Functional studies have not been performed for other variants. Animal models discussed: - Snap25 null drosophila show complete loss of synaptic transmission upon electroretinogram recordings (PMID cited: 12242238). - In mice, elimination of Snap25b expression resulted in developmental defects, seizures and impaired short-term synaptic plasticity (PMID cited: 19043548). - Mice with a 4.6 Mb deletion encompassing 12 genes (incl. Snap25) display seizure predisposition (PMID cited: 23064108). - Heterozygosity for Ile67Thr in (blind-drunk mutant) mice results in impaired vesicle trafficking, impaired sensorimotor gating and ataxia (PMID cited:17283335). In OMIM, heterozygous SNAP25 mutations are associated with ?Myasthenic syndrome, congenital, 18 (with intellectual disability and ataxia). SNAP25 is part of the DD panel, associated with "Epilepsy and intellectual disability" (disease confidence: probable). This gene is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc). SNAP25 is among the genes discussed by Erger et al. (PMID: 30914295) as associated with ID in OMIM/HPO/G2P/SysID but not included in the current panel. As a result SNAP25 can be considered for inclusion in the ID panel probably as green (3 individuals with ID, role of SNARES in "synaptopathies", supportive animal models) or amber (if functional studies for individual variants would be required). Sources: Literature, Radboud University Medical Center, Nijmegen |
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| Intellectual disability - microarray and sequencing v2.798 | P4HTM |
Konstantinos Varvagiannis gene: P4HTM was added gene: P4HTM was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: P4HTM was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: P4HTM were set to 30940925; 25078763 Phenotypes for gene: P4HTM were set to Central hypotonia; Muscular hypotonia; Global developmental delay; Intellectual disability; Seizures; Abnormality of the eye; Hypoventilation; Sleep apnea; Dysautonomia Penetrance for gene: P4HTM were set to Complete Review for gene: P4HTM was set to GREEN Added comment: Rahikkala et al. (2019 - PMID: 30940925) report on 13 individuals from 5 families with biallelic pathogenic P4HTM variants. 6 of these individuals from a large consanguineous family from Finland were previously reported by the same group, although studies at the time had revealed a 11.5 Mb region of homozygosity with 3 genes within this interval considered to be candidate for the patients' phenotype (P4HTM, TKT, USP4) [Kaasinen et al. - PMID: 25078763]. Common features included Hypotonia (13/13), DD and ID (the latter present in 12/13 individuals with appropriate age for evaluation) and Eye Abnormalities, reason why the acronym HIDEA is suggested for the disorder. Epilepsy was observed in 10 individuals (10/13). Hypoventilation, sleep apnea and dysautonomia were additional features reported. Muscle biopsies from 4 individuals had variable findings suggestive of disruption of normal mitochondrial function. Finnish patients were homozygous for a SNV - possibly a founder variant in this population - predicted to lead to a missense change in the canonical transcript (NM_177938.2:c.1073G>A) but causing an in-frame loss of the complete exon 6 of another transcript (NM_177939.2). The latter transcript (encoding a 502 aa protein) is the prevalent one in fibroblasts/myoblasts instead of the canonical one (563 aa). It is not known whether the canonical transcript is the prevalent in brain tissue although northern blot analysis in a previous study suggested presence of a 2.3 kb mRNA in brain instead of a 1.8 kb observed in other tissues, a finding which may be suggestive of expression of the canonical transcript. [Reviewer's note: In gnomAD based on the pext values from the GTEx, the noncanonical transcript appears to be prevalent in brain regions - https://gnomad.broadinstitute.org/gene/ENSG00000178467] All variants reported in affected both transcripts. All 5 variants have been submitted to LOVD ( https://databases.lovd.nl/shared/variants/P4HTM?search_var_status=%3D%22Marked%22%7C%3D%22Public%22 - the first author appearing as the submitter). Overexpression of wt and 3 mutants (His161Pro, Gln352*and Exon6del) in insect cells followed by analysis with SDS-PAGE and western blot revealed severly reduced/abolished fraction of soluble protein for the 3 studied variants suggesting improper protein folding. Knockout of the gene in mice leads to retinal defects and/or visual impairment in line with eye abnormalites (nystagmus, strabismus, achromic retinal fundi or cortical blindness) being a prominent feature in affected individuals. Mouse studies suggest that this gene is also important for renal function, although kidney problems were not reported in any affected individual. Overall loss-of-function is suggested to be the underlying mechanism. P4HTM is not associated with any phenotype in OMIM, nor in G2P. This gene is not (at least commonly) included in gene panels for ID offered by diagnostic laboratories. As a result P4HTM can be considered for inclusion in the ID and epilepsy panels probably as green (several affected individuals, degree of ID relevant) or amber. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.798 | VAMP2 |
Konstantinos Varvagiannis gene: VAMP2 was added gene: VAMP2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: VAMP2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: VAMP2 were set to 30929742 Phenotypes for gene: VAMP2 were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Autistic behavior; Stereotypic behavior; Seizures; Abnormality of movement; Cortical visual impairment Penetrance for gene: VAMP2 were set to unknown Review for gene: VAMP2 was set to GREEN gene: VAMP2 was marked as current diagnostic Added comment: Salpietro et al. (2019 - PMID: 30929742 - DDD study among the co-authors) report on 5 individuals each with private heterozygous de novo variants in VAMP2. The overlapping phenotype consisted among others of hypotonia with DD, moderate/severe ID and ASD (all in 5/5). Other features included the presence of clinical seizures (3/5 - EEG anomalies observed in all individuals), variable Rett-like stereotypies, hyperkinetic movements, central visual impairment. OFC was normal in all subjects. VAMP2 encodes the vesicular SNARE protein synaptobrevin-2 which - along with its partners (syntaxin-1A and synaptosomal-associated protein 25) - mediates fusion of synaptic vesicles for the release of neurotransmitters. A number of synaptic proteins involved in Ca+2-regulated neurotransmitter release (eg. Munc18 encoded by STXBP1) regulate the fusion of synaptic vesicles, although SNAREs alone are sufficient for this process. All variants localized in the v-SNARE domain (aa 31-91 - of 116 total residues - NP_0055047.2) with some phenotypic differences between variants localizing in the C-terminal end of the v-SNARE domain compared to those localizing in its proximal part. The following 3 missense variants and 2 in-frame deletions were reported (using NM_014232 as reference): c.223T>C or p.Ser75Pro - c.233A>C or p.Glu78Ala - c.230T>C or p.Phe77Ser - c.128_130delTGG or p.Val43del and c.135_137delCAT or p.Ile45del. Functional studies were performed for 2 missense variants and were suggestive of impairment in vesicle fusion for the Ser75Pro variant. The fusion profile for Glu78Ala was however similar to wt. Upon Munc18-activated conditions, wt vesicle fusion was 2-fold increased, in contrast to a >90% loss-of-function effect which was observed for the Ser75Pro variant. Munc18 was however able to activate vesicle fusion mediated by the Glu78Ala variant. When using mixed v-liposomes (50:50 Wildtype:Ser75Pro mutant) the fusion profile was identical to the profile of homogeneous samples containing only the mutant protein which was suggestive of dominant interference of the mutant with wildtype. In gnomAD, VAMP2 has a (low) Z-score and pLI of 1.41 and 0.89 respectively. The authors comment that mutations in other genes encoding presynaptic proteins involved in Ca+2-regulated neurotransmitter release (eg SNAP25, STXBP1, etc) have been identified in other neurological disorders (with ID as a feature). VAMP2 is not associated with any phenotype in OMIM or G2P. This gene is included in gene panels for ID offered by some diagnostic laboratories. As a result, VAMP2 can be considered for inclusion in the ID panel probably as green (5 individuals, degree of ID relevant) or amber. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.787 | CDK8 |
Konstantinos Varvagiannis commented on gene: CDK8: Calpena et al. (2019 - PMID: 30905399 - DDD study among the co-authors) report on 12 unrelated individuals with pathogenic CDK8 missense variants. Common features included hypotonia and DD (universal feature). Older children displayed variable degrees of ID (2 mild, 5 moderate, 2 moderate-severe). Other features included feeding difficulties, behavioral disorders, CHD, epilepsy (2 individuals), impaired vision and hearing problems in few. CDK8 (alternatively CDK19) serves a one of the four subunits of a kinase module that reversibly binds to the mediator complex to regulate its activity (in turn, regulation of transcription). Mutations in other genes coding for the 3 other subunits of the kinase module (eg. MED12 or MED13L) lead to syndromic neurodevelopmental disorders. 8 missense CDK8 variants were reported in total. Ser62Leu (NM_001260.2:c.185C>T) was recurrent, observed in 5 subjects. The variants had occurred as de novo events in all cases (10 individuals) where parental samples were available. All variants clustered in the kinase domain (residues 21-335 - of 464 total) around the ATP binding pocket. A thermal stability assay did not reveal gross protein instability in the presence or absence of ATP while the ability to bind ATP was retained for most/all variants. Study of STAT1 phosphorylation was suggestive of attenuated kinase activity for all variants, though to a lesser degree for 2 of them. Given the type of variants (all missense) and the pLI of 0.38 haploinsufficiency appears to be unlikely. A dominant-negative mechanism is favoured. CDK8 is not associated with any phenotype in G2P. As a result, CDK8 can be considered for upgrade to green or amber (if the degree of ID is relevant for the current panel). |
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| Intellectual disability - microarray and sequencing v2.787 | ARHGEF6 |
Richard Scott commented on gene: ARHGEF6: Literature review identifies lack of clarity about published data on this gene. As per note in OMIM entry: ARHGEF6, IVS1AS, T-C, -11 (rs140322310) RCV000012185 This variant, formerly titled MENTAL RETARDATION, X-LINKED 46, has been reclassified based on a review of the ExAC database by Hamosh (2018). In affected males in a large Dutch family with nonspecific X-linked mental retardation (MRX46; 300436), Kutsche et al. (2000) identified a mutation in the ARHGEF6 gene. The base change IVS1-11T-C had a marginal effect on the predicted splicing efficiency but was not detected in 170 control chromosomes. In affected males, RT-PCR amplification demonstrated products of 2 different sizes: a larger amplicon corresponding to the wildtype fragment, and a smaller amplicon in which exon 1 was spliced to exon 3. Thus, all mentally retarded males in the MRX46 family exhibited enhanced skipping of exon 2. Hamosh (2018) found that the IVS1-11T-C variant (rs140322310) was present in 53 hemizygotes in the ExAC database (November 21, 2018), suggesting that the variant is not pathogenic |
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| Intellectual disability - microarray and sequencing v2.773 | TBC1D20 | Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Green. Gene added to panel and reviewed Green by Konstantinos Varvagiannis. 5 unrelated families (7 individuals) reported in PMID:24239381 (Liegel et al, 2013) with 5 different homozygous TBC1D20 loss of function variants, and all with profound or severe mental retardation and developmental delay (Supplementary table S4). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.770 | TBC1D20 | Rebecca Foulger Phenotypes for gene: TBC1D20 were changed from Warburg Micro syndrome 4 (MIM 615663) to Warburg micro syndrome 4, 615663; mental retardation; developmental delay | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.768 | STAG2 | Rebecca Foulger Added comment: Comment on mode of inheritance: PMID:29263825 report syndromic mental retardation in an X-linked recessive pattern (with two healthy female carriers) wheras PMID:28296084 report an 8 year old girl with a heterozygous variant and ID phenotype. Therefore have selected XLD inheritance in PanelApp to catch all cases. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.766 | STAG2 | Rebecca Foulger commented on gene: STAG2: PMID:29263825 (Soardi et al., 2017) report 5 individuals from a pedigree with a STAG2 p.Ser327Asn (c.980 G > A) variant that perfectly cosegregates with a phenotype of syndromic mental retardation in a characteristic X-linked recessive pattern- heterozygous female carriers of the variant (aunt and mother of the proband) were healthy. Other healthy relatives did not have the c.980 G>A variant. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.751 | SMARCC2 | Rebecca Foulger Phenotypes for gene: SMARCC2 were changed from to Global developmental delay; Intellectual disability; neurodevelopmental delay and growth retardation; prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.742 | KDM5B | Ivone Leong Phenotypes for gene: KDM5B were changed from neurodevelopment delay and autism spectrum disorder to neurodevelopment delay and autism spectrum disorder; Mental retardation, autosomal recessive 65, 618109 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.735 | HEPACAM | Ivone Leong Phenotypes for gene: HEPACAM were changed from Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation (AD); Megalencephalic leukoencephalopathy with subcortical cysts 2A (AR) to Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation (AD), 613926; Megalencephalic leukoencephalopathy with subcortical cysts 2A (AR), 613925 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.730 | NSD2 | Ivone Leong Phenotypes for gene: NSD2 were changed from Intrauterine growth retardation; Growth delay; Microcephaly; Muscular hypotonia; Neurodevelopmental delay; Intellectual disability to Intrauterine growth retardation; Growth delay; Microcephaly; Muscular hypotonia; Neurodevelopmental delay; Intellectual disability; No OMIM number | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.728 | FRMPD4 | Louise Daugherty Phenotypes for gene: FRMPD4 were changed from Mental retardation, X-linked 104, 300983 to Mental retardation, X-linked 104, 300983; global developmental delay; intellectual disability | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.726 | FRMPD4 | Louise Daugherty Phenotypes for gene: FRMPD4 were changed from Mental retardation, X-linked 104 300983 to Mental retardation, X-linked 104, 300983 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.710 | ATP8A2 | Louise Daugherty Phenotypes for gene: ATP8A2 were changed from ?Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 615268 to ?Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 615268; intellectual disability | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.709 | ATP8A2 | Louise Daugherty Phenotypes for gene: ATP8A2 were changed from ?Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 615268 to ?Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 615268 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.695 | AGO1 | Louise Daugherty Added comment: Comment on publications: Added publications suggested from external expert review to support upgrading of the gene. Also added PMID: 29726122 (2018) that reports a novel 2.3 Mb, de novo, 1p34.3p34.2 deletion in a patient with who has a history of global developmental delay, mild intellectual disability, delayed bone age, bilateral vesicoureteral reflux, vocal cord paralysis, right aberrant subclavian artery, kyphoscoliosis, bilateral metatarsus adductus, and valgus knee deformity. This adds to the evolving genetic literature that haploinsufficiency of this region and genes other than AGO1, AGO3, GRIK3, SLC2A1, and RIMS3 may lead to the neurocognitive delays | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.691 | ADAT3 | Louise Daugherty Phenotypes for gene: ADAT3 were changed from # 615286. MENTAL RETARDATION, AUTOSOMAL RECESSIVE 36; MRT36 to Mental retardation, autosomal recessive 36, 615286; MRT36 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.681 | METTL23 | Ivone Leong Phenotypes for gene: METTL23 were changed from Mental retardation, autosomal recessive 44 (MIM 615942) to Mental retardation, autosomal recessive 44, 615942 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.677 | MEIS2 | Ivone Leong Phenotypes for gene: MEIS2 were changed from Cleft palate, cardiac defects, and mental retardation to Cleft palate, cardiac defects, and mental retardation; Oral cleft; Abnormal heart morphology; Intellectual disability; Cleft palate, cardiac defects, and mental retardation, 600987 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.654 | CUX1 |
Konstantinos Varvagiannis gene: CUX1 was added gene: CUX1 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: CUX1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: CUX1 were set to 30014507; 20510857; 25059644 Phenotypes for gene: CUX1 were set to Global developmental delay with or without impaired intellectual development, 618330 Penetrance for gene: CUX1 were set to unknown Review for gene: CUX1 was set to GREEN gene: CUX1 was marked as current diagnostic Added comment: Heterozygous pathogenic variants in CUX1 cause Global developmental delay with or without impaired intellectual development (MIM 618330). Platzer et al. (2018 - PMID: 30014507) report on 9 individuals from 7 families with heterozygous null-allele variants in CUX1. All individuals displayed DD (speech delay 9/9 - motor delay 7/9 - hypotonia 3/7 for whom this information was available). Mild/moderate ID was a feature in 5/8. Catch up was observed in 3/8 individuals who - despite a history of previous significant DD - displayed a normal age-related intelligence. For 1/9 individual (Decipher 338131) information on eventual ID was unavailable. Overall the phenotype was compatible with non-syndromic DD with possible ID. CUX1 encodes Cut homebox-1 transcription factor. 5 LoF variants (Gln21*, Gln800Argfs*19, Gln873*, Ala1067Cysfs*3, Leu1262Argfs*10) and 2 intragenic deletions (deletion of exons 9-24 in one subject and 3-24 in another) are reported. In 6/9 individuals the variant (SNV/CNV) had occurred as a de novo event. Mosaic de novo intragenic deletion was reported for the subject from Decipher. In one family 2 sibs with mild ID had inherited a LoF variant from their affected mother with moderate ID (origin of the variant unknown in her case). Leu1262Argfs*10 lies in the penultimate exon (NM_001202543.1 used as ref.) and is presumed to escape NMD. Expression studies (or functional studies) are not performed for any of the variants. As Gln800Argfs*19, found in one subject with mild ID in the present study, has been reported once in gnomAD, and given the presence of 12 individuals overall with LoF variants in the specific database, plausible explanations are discussed (among others : mild phenotype, incomplete penetrance, somatic mosaicism, exclusion of individuals with severe early-onset disorders in gnomAD, etc). Given the reported variants, the probability of LoF intolerance (pLI:1.00), and the haploinsufficiency score (% HI) of 7.19, haploinsufficiency is thought to be the underlying mechanism. CUX1 however appears to be intolerant also to missense SNVs (z-score : 5.05). Mouse models suggest a role for Cux1 in brain development and signaling. As the authors note, Cux1 (similar to its paralog, Cux2) is selectively expressed in layer II to IV cortical neurons. In Cux1-deficient mice, dendrites display a simpler morphology with decrease in dendritic length and number of branches (PMIDs cited: 20510857, 25059644). (MGI db for Cux1 - http://www.informatics.jax.org/marker/MGI:88568 : "Homozygotes for a targeted null mutation exhibit delayed lung development and neonatal mortality. Survivors show growth retardation and hair defects. Homozygotes for a partially deleted protein have curly hair, and females tend to lose their litters"). Finally, heterozygous mutations in CUX2, encoding cut-like homeobox-2 transcription factor, cause Epileptic encephalopathy, early infantile, 67 (MIM 618141 - in all cases reported to date due to a recurrent missense variant. Gene rated green in the current panel). ------- CUX1 is not associated with any phenotype in G2P. This gene is included in panels for ID offered by diagnostic laboratories (incl. Radboudumc). ------- As a result, CUX1 can be considered for inclusion in the ID panel as green (or amber). Sources: Literature, Radboud University Medical Center, Nijmegen |
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| Intellectual disability - microarray and sequencing v2.654 | LINS1 | Ivone Leong Phenotypes for gene: LINS1 were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to AUTOSOMAL RECESSIVE MENTAL RETARDATION; Mental retardation, autosomal recessive 27, 614340 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.633 | SET | Rebecca Foulger Phenotypes for gene: SET were changed from Intellectual disability; SET syndrome to Intellectual disability; SET syndrome; Mental retardation, autosomal dominant 58, 618106 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.632 | LSS |
Konstantinos Varvagiannis gene: LSS was added gene: LSS was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: LSS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LSS were set to 30723320; 30401459 Phenotypes for gene: LSS were set to Alopecia; Abnormality of the skin; Hypotonia; Global developmental delay; Intellectual disability; Seizures; Abnormality of the genital system; Microcephaly Penetrance for gene: LSS were set to Complete Review for gene: LSS was set to GREEN Added comment: DD and ID seem to be among the features observed in some individuals with biallelic LSS mutations, although the clinical presentation appears to be highly variable. PMID: 30723320 [Besnrard et al, 2019] reports on 10 individuals from 6 unrelated families with biallelic LSS variants. One additional subject from a seventh family was found to harbor only a missense SNV (in the maternal allele) while the transcript corresponding to the other (/paternal) allele was less expressed upon RNA studies from patient fibroblasts. The allelic imbalance and the phenotypic overlap with the other individuals of the study were thought to be explained by an LSS defect. The phenotype consisted of total alopecia (11/11) with additional dermatological features in most (9/11), hypotonia (7/11), DD with variable degrees of ID (11/11 both), epilepsy (8/11), microcephaly and genital anomalies in few. Cataracts were not noted in any individuals. The authors suggest that the phenotype corresponds to that observed in a neuroectodermal syndrome previously known as APMR (alopecia with mental retardation - other genes or loci earlier proposed). Variants included: 7 missense SNVs, 1 nonsense, 1 frameshift, 2 splice variants (c.1109+2T>C / c.1194+5G>A - using NM_002340.5). Using a minigene assay the latter variants were confirmhed (both) to affect splicing, at least to some important extent. However the splicing defect for one SNV (c.1194+5G>A - skipping of exon 12) was not confirmed upon RNA studies from blood samples of the respective individuals but an allelic balance in favor of the other allele instead (due to presumed utilisation of an alternative splice site, introduction of a premature stop codon and NMD). Allelic imbalance is discussed for the individual with the single LSS variant but not shown. Variants did not show clustering (also upon 3D modelling). Lanosterol synthase converts (S)-2,3-oxidosqualene to lanosterol in the cholesterol biosynthesis pathway. Quantification of cholesterol and its precursors in affected individuals did not however reveal any important imbalance. As most individuals harbored an allele with missense variant, and mice homozygous for an allele with absent LSS activity show variable lethality, residual LSS activity is suggested for the individuals studied. Several other disorders affecting cholesterol biosynthesis present overlapping features eg. DD/ID in Lathosterolosis, Desmosterolosis, Smith-Lemli-Opitz syndrome (in this case also genital anomalies), etc or cutaneous anomalies in others. A neurodevelopmental phenotype in animal models for LSS deficiency is not commented. ----- Based on the discussion of the current article (and OMIM): Earlier studies [PMIDs : 26200341, 29016354 - Zhao et al 2015 and Chen and Liu 2017 respectively] found biallelic missense in individuals with congenital cataracts. DD/ID were not commented/observed. The subject reported by Chen had baldness and genital defects. Shumiya cataract rats due to mutation in Lss gene recapitulate the specific human phenotype [PMID: 16440058 and OMIM]. Cataract was not a feature in any of the individuals of the present study. The corresponding entry for this phenotype in OMIM is Cataract 44 (#616509). PMID: 30401459 [Romano et al, 2018] reported biallelic LSS mutations in 3 unrelated families with hypotrichosis. Intellectual disability was a feature in 2 sibs from 1 non-consanguineous family (among the three). ID was considered to be coincidental by the authors. The respective entry in OMIM is Hypotrichosis 14 (#618275). ----- LSS is not included in the DD panel of G2P, nor in gene panels for ID offered by diagnostic laboratories. ----- As a result this gene can be considered for inclusion in this panel as green (or amber). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.621 | NECAP1 |
Konstantinos Varvagiannis gene: NECAP1 was added gene: NECAP1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: NECAP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NECAP1 were set to 24399846; 30525121; 30626896 Phenotypes for gene: NECAP1 were set to ?Epileptic encephalopathy, early infantile 21, 615833 Penetrance for gene: NECAP1 were set to Complete Review for gene: NECAP1 was set to GREEN gene: NECAP1 was marked as current diagnostic Added comment: Biallelic pathogenic variants in NECAP1 cause ?Epileptic encephalopathy, early infantile, 21 (MIM 615833). ---- PMID: 24399846 (Alazami et al. 2014) report on 6 individuals from an multigenerational family from Saudi Arabia with biallelic NECAP1 nonsense variant. The common phenotype consisted of hypotonia, profound global developmental delay preceding the onset of intractable seizures (fragmented multifocal clonic and tonic) in early infancy. Initial workup excluded metabolic causes. 4 of these individuals were born to first cousins once removed, while 2 additional affected subjects from the broader pedigree were born to seemingly unrelated parents from the same region. All affected individuals shared a single autozygous 4.78-Mb interval on chromosome 12p. Linkage analysis confirmed involvement of this locus (LOD score : 5.0447). Exome sequencing demonstrated homozygosity for a nonsense variant (NM_015509.3:c.142C>T - p.R48*). mRNA levels in lymphoblast cell lines from affected subjects were significantly reduced when compared to controls, probably due to NMD. Necap1 was shown to be strongly expressed in the developing (E14.5) mouse brain and spinal cord, upon immunohistochemical analysis (part of the current study). NECAP1 has been previously shown to have a functional role in Clathrin-mediated encocytocis (CME), a process which plays a critical role at the site of synapsis (in synaptic vesicle recycling). ---- PMID: 30525121 (Alsahli et al. 2018) report on a 41-month-old girl with hypotonia, profound global developmental delay and onset of seizures at the age of 3 months (generalized tonic and clonic / flexor hemispasms). Initial workup was negative for an eventual metabolic origin. The girl was born to consanguineous Saudi parents and was found to harbor the p.R48* variant in the homozygous state, following trio-WES. ---- PMID: 30626896 (Mizuguchi et al. 2019) report on a 16-month-old boy, born to consanguineous parents from Malaysia. This individual presented with axial hypotonia and profound developmental delay and developed generalized tonic-clonic and clonic seizures at the (corrected) age of 3 months. EEG demonstrated a burst suppression pattern and a clinical diagnosis of Ohtahara syndrome was retained. Metabolic workup was normal. Homozygosity for a splice-site NECAP1 variant (NM_015509.3:c.301+1G>A) was demonstrated following exome sequencing. The variant was shown to result in inclusion of a 44-bp intron, resulting in frameshift and introduction of a premature termination codon (p.Gly101Aspfs*45). The level of abnormal transcript was 2-fold increased in lymphoblast cells trated with cycloheximide when compared to cells treated with DMSO, suggesting involvement of NMD. As also in PMID: 30525121, the present study suggests similarities with the DNM1-related phenotype (Epileptic encephalopathy, early infantile, 31 - #616346 - DNM1 is rated green in the ID panel) as DNM1 also participates in vesicle recycling. The authors of the present study also note that mutations in CLTC (encoding clathrin heavy chain) cause hypotonia with DD/ID with or without epilepsy (Mental retardation, autosomal dominant 56 - #617854 - CLTC is rated green in the ID panel). ---- NECAP1 is not associated with any phenotype in G2P. This gene is included in gene panels for ID offered by some diagnostic laboratories. ---- As a result this gene can be considered for inclusion in this panel as green (or amber). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.617 | FRMPD4 | Konstantinos Varvagiannis reviewed gene: FRMPD4: Rating: GREEN; Mode of pathogenicity: None; Publications: 29267967, 25644381; Phenotypes: Mental retardation, X-linked 104, 300983; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.599 | ISCA-37501-Loss |
Louise Daugherty Region: ISCA-37501-Loss was added Region: ISCA-37501-Loss was added to Intellectual disability. 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 |
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| Intellectual disability - microarray and sequencing v2.598 | ISCA-37396-Loss |
Louise Daugherty Region: ISCA-37396-Loss was added Region: ISCA-37396-Loss was added to Intellectual disability. Sources: Expert list Mode of inheritance for Region: ISCA-37396-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for Region: ISCA-37396-Loss were set to 22180641; 19557438; 19233321 Phenotypes for Region: ISCA-37396-Loss were set to Chromosome 15q24 deletion syndrome, 613406; PMID: 22180641 intellectual disability, growth retardation, unusual facial morphology; developmental delay, severe speech problems; PMID:19557438 Developmental delay, short stature, hypotonia, digital abnormalities, joint laxity, genital abnormalities, characteristic facial features; PMID:614294 Developmental delay, loose connective tissue, digital and genital anomalies, distinct facial gestalt, congenital diaphragmatic hernia Review for Region: ISCA-37396-Loss was set to GREEN Added comment: Sources: Expert list |
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| Intellectual disability - microarray and sequencing v2.595 | NUS1 |
Konstantinos Varvagiannis gene: NUS1 was added gene: NUS1 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: NUS1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: NUS1 were set to 25066056; 29100083; 24824130; 30348779 Phenotypes for gene: NUS1 were set to #617082 - ?Congenital disorder of glycosylation, type 1aa; #617831 - Mental retardation, autosomal dominant 55, with seizures; Abnormality of extrapyramidal motor function Penetrance for gene: NUS1 were set to unknown Review for gene: NUS1 was set to AMBER gene: NUS1 was marked as current diagnostic Added comment: Mutations in NUS1 have been implicated in recessive as well as dominant forms of ID (1 and 3 unrelated individuals respectively). The latter individuals presented with a developmental and epileptic encephalopathy with ID. At least 2 of these individuals had tremor and other movement disorders. A recent study proposes that NUS1 variants contribute to Parkinson's disease (1 individual with de novo variant affecting the canonical splice site, 26 additional individuals with missense variants - for which segregation studies where not however performed). ID is not commented on for these individuals. NUS1 is included in the DD panel of G2P, associated with "Epilepsy and intellectual disability". (Monoallelic LoF variants / Disease confidence : probable). This gene is included in gene panels for ID offered by diagnostic laboratories (incl. Radboudumc). Associated phenotypes in OMIM and others discussed in the literature are summarized below (to my understanding). As a result, NUS1 can be considered for inclusion in the ID panel probably as amber. -------- Recessive - [MIM #617082 - ?Congenital disorder of glycosylation, type 1aa] : Park et al. (2014 - PMID: 25066056) report on an individual homozygous for a NUS1 missense variant (R290H) and suggest that biallelic variants cause a congenital disorder of glycosylation. The authors based in studies in yeast, mice and man provide evidence that NUS1 encodes the Nogo-B receptor (NgBR), a subunit of cis-prenyltransferase (cis-PTase), important for its activation. cis-PTase catalyzes one of the reactions for dolichol biosynthesis. Dolichol, in turn, is a carrier of glycans for N-linked glycosylation, O-mannosylation and GPI anchor biosynthesis. Genetic defects in the dolichol biosynthetic pathway have been linked to other forms of CDG and/or other recessive or dominant neurodevelopmental disorders (eg. SRD5A3- and DHDDS-related disorders). Similarities are provided at the cellular level between different organisms. Heterozygous knockout mice appear normal. Homozygosity is associated with embryonic lethality before E6.5. Conditional knockout in mouse embryonic fibroblasts led to accumulation of free cholesterol, decreased cis-PTase activity, and mannose incorporation in protein (the first & third rescued by transduction with lentiviral human NgBR). In patient fibroblasts protein levels appeared similar to controls. Interaction with Nogo-B (and hCIT - the product of DHDDS) was not affected. As in mice, accumulation of free cholesterol was observed in cells, with decreased cis-PTase activity and mannose incorporation. LAMP-1 and ICAM-1 were hypoglycosylated in patient fibroblasts. Altered dolichol profiles in serum and urine were observed in carriers of the NUS1 variant, similarly to what described in individuals with DHDDS LoF variants. ---------- Dominant - [MIM #617831 - Mental retardation, autosomal dominant 55, with seizures]. Hamdan et al. (2017 - PMID: 29100083) report on 3 unrelated individuals with developmental and epileptic encephalopathy (onset: 10m - 2.5y) and ID. Two individuals harbored de novo LoF variants while a third subject had a deletion of exon 2. Movement disorders were noted in all 3 and included tremor (2 subjects) or ataxia (1 additional subject). The authors cite a previous study on 6q22.1 deletions the critical region of which encompassed only NUS1 and the promoter of SLC35F1 (Szafranski et al. - PMID: 24824130). Haploinsufficiency is discussed as a possible mechanism (pLI of 0.87). A more severe phenotype due to dramatic reduction of NUS1 activity is proposed for the previously reported patient with CDG. ---------- Other: Guo et al. (2018 - PMID: 30348779) suggest that NUS1 pathogenic variants contribute to Parkinson's disease. By performing WES in 39 individuals with early onset Parkinson's disease and their unaffected patients (and sibs) the authors identified 1 individual with de novo insertion affecting a NUS1 canonical splice site. RT-PCR demonstrated increased mRNA levels compared with controls. Skipping of 91 bp of exon 3 was demonstrated. Study in 2 large sporadic PD-patient (N=1852+3237)/control cohorts (N=1565+2858) suggested association between NUS1 non-synonymous variants and PD (P=1.01e-5, OR:11.3). Other genetic causes of PD were excluded in 26 additional individuals with NUS1 missense variants. Phenotypes of all 27 individuals are provided in Dataset_S04. NUS1 has been found to be differentially expressed in PD mouse models. RNAi-mediated knockdown of Tango14 (the Drosophila NUS1) resulted in impaired climbing activity, reduction in brain dopamine levels and abnormal apoptotic signals in brain. Sources: Literature, Radboud University Medical Center, Nijmegen |
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| Intellectual disability - microarray and sequencing v2.595 | STAG2 |
Konstantinos Varvagiannis gene: STAG2 was added gene: STAG2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: STAG2 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: STAG2 were set to 29263825; 28296084; 30158690; 30447054; 19449417; 26443594; 25677961; 23637084; 25450604 Phenotypes for gene: STAG2 were set to Global developmental delay; Intellectual disability; Abnormality of head or neck; Microcephaly; Growth delay; Hearing impairment; Abnormal heart morphology Penetrance for gene: STAG2 were set to unknown Review for gene: STAG2 was set to GREEN gene: STAG2 was marked as current diagnostic Added comment: Several affected individuals (from at least 8 unrelated) families have been reported in the literature. The phenotype consists - among others - of DD/ID. STAG2 is located on long arm of chromosome X (Xq25). Based on these reports, both males and females can be affected. Soardi et al. (2017 - PMID: 29263825) report an affected male belonging to a large pedigree with 4 other similarly affected males. The disorder in this pedigree followed a typical X-linked inheritance pattern. All affected males were hemizygous for a missense variant (NM_001042749.1:c.980G>A or p.Ser327Asn). Common phenotype consisted of moderate ID, short stature, sensory hearing loss and some similar facial features. Unaffected males did not harbor the variant. Heterozygous females were not affected. Co-segragation of the variant with the affected status under an X-linked model, appeared unlikely to have occurred by chance (probability of 1/131,072 - logarithm of odds score of 5.12). Mullegama et al. (2017 - PMID: 28296084) report on an 8-year-old girl harboring a de novo nonsense variant in STAG2 (NM_001042749.1:c.205C>T or p.Arg69Ter). This individual presented - among others with - DD, microcephaly, growth delay, digit anomalies, particular facial features, and anomalies of other systems (eg. hearing loss, cardiac defect, etc). The authors summarize the features of 2 subjects from the DDD study as available in DECIPHER, without additional details. [Variants of these individuals NM_001042749.1:c.1913_1922del10 or p.(A638Vfs*10) / NM_001042749.1:c.1811G>A p.(R604Q)]. Yuan et al. (2018 - PMID: 30158690) report on 4 females with de novo LoF STAG2 variants as well as 1 male subject with a de novo missense one. DD (5/5) and ID (4/4) were features in all individuals for whom this information was available. One additional female had an intragenic STAG2 deletion, although this subject was not reported to have DD or ID (table S6 : microcephaly, seizures and facial phenotype). It is not known whether the deletion was inherited or had occurred as a de novo event. All variants from this study have been submitted in ClinVar (phenotype : STAG2-related disorder). Mullegama et al. (2018 - PMID: 30447054) report on a 4-year-old male with DD, microcephaly, growth delay, digit anomalies due to a de novo missense STAG2 variant (c.3027A>T or p.Lys1009Asn). As discussed by the authors at the time of the study 33 males with Xq25 duplications and ID had been reported (PMIDs cited: 19449417, 26443594, 25677961, 23637084, 25450604). Discussed in these articles : STAG2 (or STAG1) is one of the 4 core proteins of the cohesin complex, the other 3 being SMC1A, SMC3 and RAD21. Mutations in genes encoding these proteins or their interactors (eg. NIBPL, HDAC8, ESCO2, etc) have been associated cohesinopathies, a group of multisystem developmental disorders (eg. Cornelia de Lange syndrome, Roberts/SC phocomelia, etc). It has been commented that the phenotype of STAG2-related disorder presents overlap with other cohesinopathies (eg. DD, microcephaly and growth retardation, craniofacial features, anomalies of the digits, etc). Decreased proportion of nuclei with premature sister chromatid separation compared to controls was found on one occasion (suggestive of tighter sister chromatid cohesion) [Mullegama-A]. Sister chromatid cohesion was not affected in another report [Soardi et al.]. Western blot demonstrated significant reduction of STAG2 levels for a nonsense variant [Mullegama-A]. Levels were not perturbed for a missense variant [Soardi et al.]. Upon immunofluorescence STAG2 presented normal (nuclear) localization for a missense variant for which this was studied [Soardi et al.]. Perturbation of the cell cycle profile (higher percentage of G2/M cells) was demonstrated for patient fibroblasts compared to controls on one occasion where this was studied. [Soardi et al.]. Microarray expression studies in patient fibroblasts demonstrated altered transcription (upregulation) of genes implicated in cell division, mitosis and DNA replication upon comparison with normal fibroblasts [Soardi et al.]. The effect of a missense variant on STAG2 binding to other cohesin subunits (SCC1, SMC1 and SMC3) and regulators was studied. Binding was found to be reduced in vivo (in HeLa cells) for SCC1 (its direct binding partner) as well as SMC1, SMC3 (possibly indirectly). Reduced STAG2 binding to cohesin regulators was also shown in vivo. However, in vitro studies were not suggestive of impaired binding of STAG2 to SCC1 (a finding difficult to explain) [Soardi et al.]. STAG2 appears to be intolerant to LoF variants (pLI of 1 in ExAC). Z-Score for missense variants is 5.11. Mullegama et al. (B) comment that Xq25 duplications in males may be associated with milder phenotypes compared to intragenic variants. They further hypothesize that males are able to survive less damaging variants while females are able to survive more deleterious (eg. LoF) ones though with more severe phenotypes (similarity to the MECP2 model is discussed). ---------- STAG2 is not associated with any phenotype in OMIM. In G2P this gene is associated with STAG2-related developmental delay with microcephaly and congenital anomalies (disease confidence : confirmed / Both DD and ID among the phenotypes assigned to this entry). ---------- STAG2 is included in gene panels for ID offered by some diagnostic laboratories. ---------- As a result, this gene can be considered for inclusion in the ID panel as green (or amber). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.588 | LINS1 | Konstantinos Varvagiannis reviewed gene: LINS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21937992, 23773660, 28181389, 30090841; Phenotypes: Mental retardation, autosomal recessive 27 (MIM 614340); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.588 | RNF13 |
Konstantinos Varvagiannis gene: RNF13 was added gene: RNF13 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: RNF13 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: RNF13 were set to Congenital microcephaly; Feeding difficulties; Failure to thrive; Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; Cortical visual impairment; Sensorineural hearing impairment Penetrance for gene: RNF13 were set to unknown Mode of pathogenicity for gene: RNF13 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: RNF13 was set to GREEN Added comment: Edvardson et al. (doi.org/10.1016/j.ajhg.2018.11.018) report on 3 unrelated individuals with heterozygous de novo missense RNF13 variants. Features included (rather borderline) congenital microcephaly, feeding difficulties, tone abnormalities, DD/ID (3/3), seizures (3/3), hearing loss and cortical visual impairment. One individual harbored the p.Leu311Ser variant while 2 others the p.Leu312Pro. RNF13 encodes a protein known to interact and activate IRE1a, an endoplasmatic reticulum (ER) stress sensor. The 2 variants are predicted in silico not to affect the tertiary structure of the protein. Further to this, RNF13 is tolerant to LoF variants (pLI of 0 in ExAC). Therefore a gain-of-function mechanism was hypothesized for the 2 missense variants and demonstrated for the Leu311Ser: - Protein levels were similar to controls upon Western blotting in patient fibroblasts. - Enhanced IRE1a activation was demonstrated in patient cells when compared to controls, confirming gain-of-function. - Increased activation (/ER stress), in turn, resulted in abnormally increased apoptosis similarly to what is observed in other neurological disorders. Fibroblast/lymphoblast cells were not available from individuals with the Leu312Pro variant although a similar mechanism is presumed. Although neurodegeneration is suggested by the above pathophysiologic mechanism, this is manifested by failure to achieve milestones (rather than eg. regression after a normal period of postnatal development / loss of milestones). --------- RNF13 is not associated with any phenotype in OMIM, nor in G2P. This gene is not commonly included in gene panels for ID offered by diagnostic laboratories. --------- As a result, RNF13 can be considered for inclusion in this panel possibly as green (or amber). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.588 | SLC35A3 |
Konstantinos Varvagiannis gene: SLC35A3 was added gene: SLC35A3 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: SLC35A3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC35A3 were set to 24031089; 28328131; 28777481; 16344554 Phenotypes for gene: SLC35A3 were set to ?Arthrogryposis, mental retardation, and seizures (MIM 615553) Penetrance for gene: SLC35A3 were set to Complete Review for gene: SLC35A3 was set to GREEN gene: SLC35A3 was marked as current diagnostic Added comment: Biallelic pathogenic variants in SLC35A3 cause Arthrogryposis, mental retardation, and seizures (MIM 615553). -------- Edvardson et al. (PMID: 24031089) report on 8 affected individuals from 3 nuclear Ashkenazi Jewish families. All harbored a nonsense [NM_012243.1:c.514C>T / p.(Gln172*)] as well as a missense variant [NM_012243.1:c.886A>G / p.(Ser296Gly)] in the compound heterozygous state. Most of the parents, who were heterozygous for the one or the other variant, were distantly related. Common features included ASD (8/8), arthrogryposis (8/8), seizures (6/8) and intellectual disability (6/8 - variable degrees). Upon cDNA studies, the (predicted) missense variant led to skipping of exon 8 and there was no normal size transcript (as would be expected for a variant of this type). Introduction of a premature stop codon due to this variant as well instability of the mRNA from the Gln172Ter allele was presumed to lead to absence of functional SLC35A3 protein. Testing of 2045 Ashkenazi Jewish individuals revealed a carrier frequency of 1/205 for the missense variant in this community (with no occurrence of the nonsense variant). SLC35A3 is a nucleotide sugar transporter that transports (uniquely) UDP-N-acetylglucosamine (UDP-GlcNAc) from the cytoplasm where it is synthesized to its site of use in the Golgi. Proper function of such transporters is essential for biosynthesis of glycoproteins, glycolipids and proteoglycans. Although the transport of UDP-GlcNAc is mediated also by other less specific transporters, members of the SLC35 family, reduced transport was shown in patient fibroblasts compared to controls. In addition an abnormal N-glycan profile was shown in patient fibroblasts (but was not the case in serum). Biallelic SLC35A3 mutations in cattle were previously shown to cause a Complex Vertebral Malformation (CVM) syndrome characterized by abnormal growth, vertebral and heart malformations as well as arthrogryposis (Thomsen et al. - PMID: 16344554). Arthrogryposis as well as some skeletal features observed in patients were similar to those of the animal model. -------- Marini et al. (PMID: 28328131) report on 2 sibs compound heterozygous for a missense and a frameshift variant [NM_012243.2:c.73C>T or p.(Arg25Cys) and c.899_900delTTinsA or p.(Leu300Glnfs*6)]. Hypotonia, DD with ID, early-onset seizures and arthrogryposis were features in both. Severe scoliosis was also noted in the younger sib. --------- Edmondson et al. (PMID: 28777481) report on a neonate (follow-up till the 21st day of life) with extensive vertebral anomalies (butterfly vertebrae, hemibertebrae, sagittal clefts, scoliosis), heart defects (PFO, PDA) and arthrogryposis. Presence of hypotonia or other neurologic features (eg. seizures) is not commented on. Conventional caryotype and SNP-array analysis were normal apart from the presence of ROH regions due to parental consanguinity. Exome sequencing revealed only a homozygous missense SNV [c.74G>T or p.(Arg25Leu) - NP_036375.1] which was supported by an abnormal N-glycan profile. As proposed for the bovine model (PMID: 16344554) and discussed in this article, similarity of the skeletal/congenital heart defects with those observed in Alagille syndrome might be due to some of the Notch functions being dependent upon N-acetylglucosamine modification. --------- In ClinVar : There is a further submission of p.Ser296Gly as pathogenic (SCV000699337.1 - 2016) apart from the submission by OMIM (SCV000108589.2 - 2013). The associated condition is Arthrogryposis, mental retardation, and seizures. A frameshift variant [NM_012243.2(SLC35A3):c.680dup (p.Asp227Glufs)- SCV000826704.1 - April 2018] as well as an intragenic deletion [NC_000001.10:g.(?_100472570)_(100477109_?)del (GRCh37) - SCV000837123.1 - June 2018] have both been submitted as pathogenic, associated with Arthrogryposis, mental retardation, and seizures. (Note: due to the different submission dates, one can presume that these variants were found in different individuals). --------- SLC35A3 is not associated with any phenotype in OMIM. It is included in gene panels for ID offered by some diagnostic laboratories. --------- As a result, this gene can be considered for inclusion in the ID panel probably as green (or amber) [Consider upgrade of this gene to green in other panels (eg. CDGs, arthrogryposis, IEMs) and/or inclusion in other possibly relevant panels.] Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.584 | LINGO1 |
Konstantinos Varvagiannis gene: LINGO1 was added gene: LINGO1 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: LINGO1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LINGO1 were set to 28837161 Phenotypes for gene: LINGO1 were set to Mental retardation, autosomal recessive 64 (MIM 618103) Penetrance for gene: LINGO1 were set to Complete Review for gene: LINGO1 was set to AMBER gene: LINGO1 was marked as current diagnostic Added comment: Biallelic pathogenic variants in LINGO1 cause Mental retardation, autosomal recessive 64 (MIM 618103). Ansar et al. (PMID: 28837161) report on 5 individuals from 2 consanguineous Pakistani families. Affected individuals from both families presented with similar phenotype consisting of global developmental delay (5/5), intellectual disability (5/5), microcephaly (4/5) as well as abnormal behavior (5/5). Subjects from both families were homozygous for missense variants (private to each family) affecting proximal residues (290 and 288) of the protein (NM_032808.6:c.869G>A or p.Arg290His and c.863A>G or p.Tyr288Cys). All variants were absent in an ethnically matched control cohort (201 individuals) as well as the relevant subpopulation in gnomAD. Functional studies were not performed. LINGO1 is a transmembrane protein predominantly expressed in the CNS. Previous studies suggest that this protein has an important role in myelination, neuronal survival and CNS repair. LINGO1 is rather intolerant to both missense and LoF variants (Z-score of 4 and pLI of 0.95). According to the authors these variants may be hypomorphic, which might in turn suggest that monoallelic heterozygous LoF mutations could cause ID (although this remains an assumption). This gene is not associated with any phenotype in G2P but is included in panels for ID offered by diagnostic laboratories (incl. Radboudumc). As a result, LINGO1 can be considered for inclusion in this panel probably as amber (2 families, no functional studies). Sources: Literature, Radboud University Medical Center, Nijmegen |
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| Intellectual disability - microarray and sequencing v2.579 | PUS3 | Konstantinos Varvagiannis reviewed gene: PUS3: Rating: AMBER; Mode of pathogenicity: None; Publications: 27055666, 30308082; Phenotypes: ?Mental retardation, autosomal recessive 55 (MIM 617051); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.579 | PUS3 |
Konstantinos Varvagiannis gene: PUS3 was added gene: PUS3 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: PUS3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PUS3 were set to 27055666; 30308082 Phenotypes for gene: PUS3 were set to Global developmental delay; Intellectual disability; Microcephaly Penetrance for gene: PUS3 were set to Complete Review for gene: PUS3 was set to AMBER gene: PUS3 was marked as current diagnostic Added comment: PUS3 (Pseudouridylate synthase 3) is proposed as a gene related to ID in a recent publication on PUS7. Biallelic mutations in this gene are associated in OMIM with ?Mental retardation, autosomal recessive 55 (MIM 617051). PMID: 27055666 reports on 3 sisters from a consanguineous Saudi Arabian family with failure to thrive, DD/ID, microcephaly and some common (coarse) facial features. These individuals were homozygous for a stopgain mutation in the last exon of the gene. Pseudouridylation appeared to be defective (as has also been the case with other genes related to ID, eg. PUS7). PMID: 30308082 describes 1 individual born to consanguineous Palestinian parents, homozygous for a further LoF variant. Despite the localisation of this variant (again in the last exon of the gene) qPCR analyses were suggestive of degradation of the abnormal transcript possibly by NMD. The phenotype consisted of DD/ID and microcephaly. In a further publication (http://dx.doi.org/10.7124/bc.0008D6) Gulkovskyi et al. report on 2 siblings with ID, born to non-consanguineous Ukranian parents. Pathogenicity of the variant is disputed. [NM_031307.4:c.212A>G or p.(Tyr71Cys) is found in an apparent homozygous state in the sibs but was only found in their father. De novo occurence in the maternal allele is proposed although the possibility of microdeletion missed by aCGH or other plausible mechanisms are not considered. This variant has maximum pathogenicity scores in silico (not discussed) and has an allele frequency of 0.00006717 in gnomAD. The authors did not perform studies of pseudouridylation but examined for the presence of hypoproteinemia, observed in some disorders affecting this process). PUS3 is not associated with any phenotype in G2P but is associated with disease in OMIM. The gene is included in gene panels for ID offered by various diagnostic laboratories (including Radboudumc). PUS1 is included in the current panel as green and PUS7 has been suggested for inclusion. As a result, these gene can be considered for inclusion as amber (2 families) or green (given the supportive functional studies and/or the proposed role for the gene). Sources: Literature, Radboud University Medical Center, Nijmegen |
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| Intellectual disability - microarray and sequencing v2.579 | METTL23 |
Konstantinos Varvagiannis gene: METTL23 was added gene: METTL23 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: METTL23 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: METTL23 were set to 24501276; 24626631 Phenotypes for gene: METTL23 were set to Mental retardation, autosomal recessive 44 (MIM 615942) Penetrance for gene: METTL23 were set to Complete Review for gene: METTL23 was set to GREEN gene: METTL23 was marked as current diagnostic Added comment: Biallelic pathogenic variants in METTL23 cause Mental retardation, autosomal recessive 44 (MIM 615942). Reiff et al. (PMID: 24501276) report on a consanguineous pedigree of Yemeni origin with 7 individuals presenting intellectual disability. Clinical details are provided for 3 subjects from one branch of the family. Findings included moderate (2/3) or severe (1/3) ID, seizures (2/3) and some common facial features. Seizures were not observed in individuals from other branch of the family. The affected individuals were homozygous for a 4-bp deletion. Bernkopf et al. (PMID: 24626631) report on a consanguineous family from Pakistan with 2 affected sibs as well as a non-consanguineous family from Austria with 4 affected sibs. The parents in the latter family originated from a small - geographically isolated - village. Individuals from the Pakistani family were homozygous for a nonsense variant, while the sibs from the Austrian family for a frameshift variant. Mild ID was noted in all. In total 3 different LoF variants have been reported. Extensive functional studies have been performed in both articles. METTL23 (methyltransferase like 23) is expressed at low-to-moderate levels in the developping human brain. Bernkopf et al. suggest that METTL23 is indeed a methyltransferase. The gene has 7 transcripts of which one is non-coding. 3 transcripts encode isoform 1 and 3 other encode isoform 2. The variant reported by Reiff et al. affects the coding region of 3 (of the 6 coding) transcripts (corresponding to isoform 1) and the 5'-UTR of the other 3 transcripts. It is however shown that this first coding exon (specific to isoform 1) is expressed in the developing human brain, though at lower levels than downstream exons common to both isoforms. In addition, only isoform 1 appears to be conserved in most other species. The variants described by Bernkopf et al. affect all 6 coding trancripts and as a result both isoforms. [However, the individuals reported by Bernkopf et al. were less severely affected compared to those reported by Reiff et al.] Nonsense-mediated decay appeared unlikely since mRNA levels for both isoforms in lymphoblasts from affected individuals were similar to controls (upon qRT-PCR) [The specific nonsense variant tested would be expected to be subject to NMD given its localization]. METTL23 is not associated with any phenotype in G2P. This gene is included in gene panels for intellectual disability offered by various diagnostic laboratories. As a result, METTL23 can be considered for inclusion in the ID panel as green (or amber). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.579 | RPIA |
Konstantinos Varvagiannis gene: RPIA was added gene: RPIA was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: RPIA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RPIA were set to 14988808; 20499043; 28801340; 30088433 Phenotypes for gene: RPIA were set to Ribose 5-phosphate isomerase deficiency, MIM 608611. Penetrance for gene: RPIA were set to unknown Review for gene: RPIA was set to GREEN gene: RPIA was marked as current diagnostic Added comment: Biallelic pathogenic variants in RPIA cause Ribose 5-phosphate isomerase deficiency, MIM 608611. PMID: 14988808 is the first report on the disorder with molecular (incl. genetic) confirmation of the diagnosis. A patient initially investigated for early developmental delay, leukoencephalopathy, seizures with onset at 4 years, with subsequent neurologic regression and peripheral neuropathy at the age of 7, was suspected to have a disorder of the pentose phosphate pathway on the basis of highly elevated polyols on brain MRS and body fluid analysis. Reduced ribose 5-phosphate isomerase activity was shown in fibroblasts. Genetic testing demonstrated the presence of a missense (NM_144563.2:c.404C>T / NP_653164.2:p.Ala135Val - previously referred to as A61V) as well as a frameshift variant (NM_144563.2:c.762delG / NP_653164.2:p.Asn255Ilefs). Additional extensive supportive functional studies were published a few years later (PMID: 20499043). [This patient was initially described in PMID: 10589548]. PMID: 28801340 is a report on a second patient. This individual presented with delayed early development (independent walking and speech achieved at 2 and 5 years respectively), seizures and regression at the age of 7 with MRI white matter abnormalities. Review of magnetic resonance spectroscopy (MRS) was suggestive of elevated polyols (arabitol and ribitol). In line with this, genetic testing revealed a homozygous missense variant in RPIA (NM_144563.2:c.592T>C or p.Phe198Leu). Urine analysis confirmed elevated excretion of polyols, thus confirming the diagnosis. PMID: 30088433 reports on a boy with neonatal onset leukoencephalopathy and developmental delay having undergone early metabolic testing and aCGH (the latter at the age of 16 months). Persistance of his delay motivated exome sequencing at the age of approx. 4.5 years which demonstrated 2 RPIA variants (NM_144563.2:c.253G>A or p.Ala85Thr and NM_144563.2:c.347-1G>A). Measurement of ribitol and arabitol in urine demonstrated significant elevations (>20x) consistent with this diagnosis. RPIA is included in gene panels for intellectual disability offered by various diagnostic laboratories. As a result this gene can be considered for inclusion in this panel as green (or amber). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.574 | SET | Konstantinos Varvagiannis reviewed gene: SET: Rating: GREEN; Mode of pathogenicity: None; Publications: 29688601, 25356899, 28135719; Phenotypes: Mental retardation, autosomal dominant 58 (MIM 618106); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.555 | COG6 |
Konstantinos Varvagiannis gene: COG6 was added gene: COG6 was added to Intellectual disability. Sources: Literature,Expert Review Mode of inheritance for gene: COG6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: COG6 were set to 26260076; 20605848; 23430903; 23606727; 28139241; 28742265; 29445937; 29709711 Phenotypes for gene: COG6 were set to Congenital disorder of glycosylation, type IIl, 614576; Shaheen syndrome, 615328 Penetrance for gene: COG6 were set to Complete Review for gene: COG6 was set to GREEN gene: COG6 was marked as current diagnostic Added comment: DD/ID is an almost universal feature of individuals with biallelic COG6 mutations, whether this is associated with a type II transferrin IEF pattern (as in Congenital disorder of glycosylation, type IIl, 614576) or not (as in Shaheen syndrome, 615328). More than 15 patients from several different families have been reported to date. PMID: 26260076 is a collaborative study reporting on new patients as well as on individuals previously described up to 2015 by Lubbehusen et al. (2010 - PMID: 20605848), Huybrechts et al. (2012 - PMID: 23430903) as well as Shaheen et al. (2013 - PMID: 23606727). As summarized in table 1 of this article, developmental disability was a feature in 8/10, although for a further 2/10 this was probably not relevant (both deceased too early). The following articles are additional reports although there might be some overlap (applicable for the Saudi patients) : PMIDs: 28139241 (individuals with diagnosis of CDG from Spain), 28742265 (cohort of CDG patients from Saudi Arabia), 29445937 (case report of Saudi subject), 29709711 (Chinese individual with COG6-CDG). All types of variants have been observed including missense, stopgain and frameshift ones, as well as variants leading to aberrant splicing [eg. positions -2, -9, -24]. The deep intronic variant (position -24) in the individuals reported by Shaheen and others is considered a founder mutation in the Saudi population. Individuals homozygous for the latter variant have detectable levels of the normal transcript, although 75% of the produced transcript (upon RT-PCR analysis) correspond to retention of 37 intronic nucleotides leading to frameshift and introduction of a premature stop codon. This was also confirmed with Western blot. Given the detectable levels of the normal transcript, it has been proposed that Shaheen syndrome represents the mildest end of the spectrum COG6-related disorders. COG6 is included in gene panels for intellectual disability offered by different diagnostic laboratories. As a result this gene can be considered for inclusion in this panel as green. Sources: Literature, Expert Review |
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| Intellectual disability - microarray and sequencing v2.555 | TELO2 |
Konstantinos Varvagiannis gene: TELO2 was added gene: TELO2 was added to Intellectual disability. Sources: Literature,Expert Review Mode of inheritance for gene: TELO2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TELO2 were set to 27132593; 28944240 Phenotypes for gene: TELO2 were set to You-Hoover-Fong syndrome, MIM 616954 Penetrance for gene: TELO2 were set to Complete Review for gene: TELO2 was set to GREEN gene: TELO2 was marked as current diagnostic Added comment: Biallelic mutations in TELO2 cause You-Hoover-Fong syndrome (MIM 616954). // PMID: 27132593 reports on 6 patients (from 4 non-consanguineous families) with biallelic TELO2 variants and a similar phenotype. Intellectual disability and microcephaly were universal features (6/6). Abnormal hearing (3/6), cortical visual impairment (3/6), abnormality of the cardiovascular system (3/6), behavioral problems (laughter outbursts in 3/6) and abnormal balance and movement disorder (6/6) were part of the phenotype. One individual had seizures. 5 missense variants and a complex allele with a stopgain variant localized in cis with a splice-site variant (NM_016111.3:c.514C>T or p.Gln172* in cis with c.2034+1G>A) are reported. As a result heterozygosity for the complex variant may be confounded with compound heterozygous state until segregation studies are performed. Functional studies support pathogenicity of the missense variants (reduced protein steady-state levels of TELO2 as well as TTI1 and TTI2 - the 2 other members of the TTT complex) suggesting loss of function. PMID: 28944240 reports on 2 sisters born to non-consanguineous parents. Both were compound heterozygous for 2 novel variants, a missense and a frameshift one. Severe microcephaly (-8.5 SD and -10.7 SD) and seizures were noted in both. The first sister passed away at the age of 2 months due to a respiratory infection. The other sister demonstrated a compatible, though much more severe phenotype (of ID, dwarfism, retinitis pigmentosa, etc) compared to previously reported patients. // Biallelic mutations in TTI2 (of the same complex) lead to similar phenotypes (gene rated green in the ID panel). // TELO2 is included in gene panels for intellectual disability offered by different diagnostic laboratories. // As a result this gene can be considered for inclusion in this panel as green. Sources: Literature, Expert Review |
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| Intellectual disability - microarray and sequencing v2.555 | MACF1 |
Konstantinos Varvagiannis gene: MACF1 was added gene: MACF1 was added to Intellectual disability. Sources: Literature,Expert Review Mode of inheritance for gene: MACF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: MACF1 were set to Intellectual disability; Seizures; Lissencephaly; Brainstem dysplasia Penetrance for gene: MACF1 were set to unknown Mode of pathogenicity for gene: MACF1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: MACF1 was set to GREEN Added comment: Dobyns et al. (doi.org/10.1016/j.ajhg.2018.10.019) report on 9 individuals (all unrelated appart from a pair of monozygotic twins) with de novo variants in MACF1. All patients presented lissencephaly and brainstem hypoplasia with associated intellectual disability (9/9) and seizures (9/9). Seven of these individuals had de novo missense variants within the GAR domain and an eighth had a deletion of several exons also spanning this domain and leading to an in-frame deletion. A further ninth patient had a de novo missense variant in the spectrin repeat domain and was found to have similar features although the brainstem dysplasia was rather subtle. 5 missense variants (4 of which in the GAR domain) and an intragenic deletion are reported in total. The variants in the GAR domain were predicted to have important effect in the zinc-binding pocket. The spectrin repeat (SR4) is thought to have an important role for the function of MACF1 and further to neuronal migration. Knockdown of Macf1 in mice has been shown to result in developmental defects similar to the human malformation. The authors note that several high-confidence loss-of-function mutations are listed in ExAC and as a result this type of variants could be non-pathogenic (or lead to neurodevelopmental disorders with reduced penetrance). Still MACF1 has a pLI of 1.0. As for the missense variants, the authors suggest either a gain-of-function or dominant negative mechanism. Caution should be taken when interpreting variants as the ENST00000372915.7 (or MACF1-204) transcript is used for the predicted protein changes, although ENST00000361689.6 or MACF1-203 (corresponding to NM_012090.5) has also been used in some tables or figures. As a result, this gene can be considered for inclusion in this panel probably as green. Sources: Literature, Expert Review |
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| Intellectual disability - microarray and sequencing v2.552 | SCAPER | Louise Daugherty Added comment: Comment on phenotypes: added phenotype and MIM from OMIM : Tatour et al. (2017) PMID: 28794130 describes 4 patients from 3 unrelated families with intellectual disability disorder and retinitis pigmentosa and identified homozygosity or compound heterozygosity for mutations in the SCAPER gene. Noting that the retinal phenotype associated with null SCAPER mutations is not congenital but presents around the second decade of life, the authors suggested that in the retina, SCAPER does not play a developmental role, but rather is important for photoreceptor function and/or maintenance. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.552 | SCAPER | Louise Daugherty Phenotypes for gene: SCAPER were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to AUTOSOMAL RECESSIVE MENTAL RETARDATION; Intellectual developmental disorder and retinitis pigmentosa, 618195 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.537 | GNB5 |
Konstantinos Varvagiannis gene: GNB5 was added gene: GNB5 was added to Intellectual disability. Sources: Literature,Expert Review Mode of inheritance for gene: GNB5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GNB5 were set to 27523599; 27677260; 28697420; 29368331 Phenotypes for gene: GNB5 were set to Intellectual developmental disorder with cardiac arrhythmia, 617173; Language delay and ADHD/cognitive impairment with or without cardiac arrhythmia, 617182 Penetrance for gene: GNB5 were set to Complete Review for gene: GNB5 was set to GREEN gene: GNB5 was marked as current diagnostic Added comment: Biallelic GNB5 pathogenic variants cause Intellectual developmental disorder with cardiac arrhythmia (MIM 617173) or language delay and ADHD/cognitive impairment with or without cardiac arrhythmia (MIM 617182). PMID: 27523599 is the first report on the associated phenotype. A total of 9 individuals from 6 different families (from various ethnic backgrounds) are described. The common features included hypotonia (noted in 6 out of 9 patients), intellectual disability (9/9 - in 3 cases mild, in 6 severe), heart rate disturbance (9/9 - in most cases sick sinus syndrome), seizures (4/9), ophthalmological problems (nystagmus in 6 out of 7 for whom this information was available) as well as gastric problems (5/8 with G-E reflux). The 6 variants (summarized in table S1) included : 2 nonsense mutations, 1 synonymous (demonstrated to affect splicing and leading to retention of 25 intronic bp), 2 further splice variants (positions +1 and +3) and a missense one (S81L). Nonsense mediated decay was the case for the product of the synonymous/splice variant as well as for a stopgain one. As noted by the authors, individuals homozygous for the S81L variant had a less severe phenotype - among others - with mild degree of intellectual disability. Functional studies included knockout of gnb5 in zebrafish, which was able to reproduce the human neurological, cardiac and ophthalmological phenotypes. Alternative causes for these phenotypes (incl. chromosomal or metabolic disorders) were ruled out. Affected individuals might benefit interventions for their heart rate disturbance as appears to be the case in the article as well as subsequent studies. PMID: 27677260 describes an extended consanguineous Saudi family with 5 individuals homozygous for the S81L variant. Common features included severe language delay, ADHD, but normal cognition in those available for evaluation. Seizures were not reported. Pathogenicity of the S81L variant is further supported by functional studies. PMID: 28697420 describes in detail 2 individuals from a large consanguineous pedigree confirmed to be homozygous for a single nucleotide deletion in GNB5. The phenotype included severe DD/ID, seizures, sinus bradycardia with frequent sinus pauses and ophthalmological problems. Sinus arrhythmia and or seizures were documented in several other relatives deceased and unavailable for testing. PMID: 28327206 reports on 2 subjects previously included in PMID: 27523599. PMID: 29368331 describes a child with severe developmental delay, nystagmus and sinus arrhythmia necessitating a pacemaker. EEG was abnormal although no frank seizures were observed. The child was compound heterozygous for a novel missense variant (R246Q) as well a 5 basepair deletion. GNB5 is included in diagnostic gene panels for intellectual disability offered by different laboratories. As a result this gene can be considered for inclusion in this panel as green. Sources: Literature, Expert Review |
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| Intellectual disability - microarray and sequencing v2.535 | FUT8 |
Konstantinos Varvagiannis gene: FUT8 was added gene: FUT8 was added to Intellectual disability. Sources: Literature,Expert Review Mode of inheritance for gene: FUT8 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FUT8 were set to 29304374 Phenotypes for gene: FUT8 were set to Congenital disorder of glycosylation with defective fucosylation, 618005 Penetrance for gene: FUT8 were set to Complete Review for gene: FUT8 was set to GREEN Added comment: PMID: 29304374 reports on 3 unrelated individuals with biallelic pathogenic variants in FUT8. Two of the patients were born to consanguineous parents and were found to be homozygous for stopgain variants (p.Arg239* in one family and p.Arg315* in the other). A third patient was compound heterozygous for a missense as well as a splice variant. All three presented with similar phenotype consisting of polyhydramnios (2 out of 3), IUGR and failure to thrive with short stature (3/3), severe developmental delay (3/3) with microcephaly (3/3) and seizures (3/3). Variable respiratory problems were also noted in all. Western blot demonstrated loss of FUT8 protein expression in one individual homozygous for a stopgain mutation as well as the patient who was compound heterozygous for the missense and the splice variant. The splice variant was further shown to produce a shorter transcript due to lack of exon 9, leading to an in-frame deletion of 59 residues critical for the protein function. Additional studies confirmed the fucosylation defect compared to controls. The authors note that while Fut8 knockout mice are born normal, 70% die within the first 3 days due to severe growth retardation and respiratory deficiency (similarly to what is observed in humans, though to a lesser extent). As a result this gene can be considered for inclusion in this panel probably as green (3 unrelated families, strong additional functional data, consistent phenotype) or amber. Sources: Literature, Expert Review |
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| Intellectual disability - microarray and sequencing v2.530 | RHOBTB2 |
Konstantinos Varvagiannis gene: RHOBTB2 was added gene: RHOBTB2 was added to Intellectual disability. Sources: Expert Review,Literature Mode of inheritance for gene: RHOBTB2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: RHOBTB2 were set to 29276004; 29768694; 26740508 Phenotypes for gene: RHOBTB2 were set to Global developmental delay; Intellectual disability; Seizures; Postnatal microcephaly Penetrance for gene: RHOBTB2 were set to unknown Mode of pathogenicity for gene: RHOBTB2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: RHOBTB2 was set to GREEN gene: RHOBTB2 was marked as current diagnostic Added comment: PMID: 29276004 reports on 10 unrelated patients with de novo pathogenic missense variants in RHOBTB2. The phenotype in all individuals was compatible with a developmental and epileptic encephalopathy including early-onset seizures, severe intellectual disability, postnatal onset microcephaly (6/10) and movement disorders (8/10). The variants occured as de novo events and clustered within the BTB-domain encoding region (within and between the 2 BTB domains). Three missense variants were recurrent and/or concerned the same residue (p.Arg483His in 4 individuals, Arg511Gln was reported in 2, and Arg511Trp was was found in another 2 individuals). Functional studies in HEK293 cells suggested increased abundance of the mutant protein secondary to decreased proteasome degradation. Using Drosophila as a model organism, altered expression of RhoBTB (the single ortholog of the 3 vertebrate paralogs, closest to RHOBTB2) was shown to result in neurological phenotypes. RhoBTB overexpression in particular was associated with increased bang sensitivity (which was not the case or milder in the case if knockdown of this gene) and impaired performance upon the negative geotaxis assay, similar to the human neurological phenotypes. Altered RhoBTB dosage was shown to be associated with impaired dendrite development. As commented by the authors, these results as well as the clustering of missense variants and the pLI score of 0.51 reported for RHOBTB2 are consistent with altered protein function (due to the missense variants) rather than haploinsufficiency or loss-of-function. PMID: 29768694 describes 3 additional individuals, all found to harbor de novo missense variants again within the BTB-domain encoding region. Two of the variants had been reported in the previous study (Arg511Gln and Arg483His) while the third was a private one (Arg507Cys). The phenotype was similar to the previous descriptions. Functional studies were suggestive of impaired degradation of the mutant protein by the CUL3 complex although this was not secondary to decreased binding with CUL3. PMID: 26740508 (cited by the two aforementioned publications) reports briefly on an individual with de novo missense variant in the same region of RHOBTB2 (Asn510Asp) and Rett-like phenotype. RHOBTB2 is included in gene panels for intellectual disability offered by different diagnostic laboratories. As a result the gene can be considered for inclusion in the intellectual disability and epilepsy panels as green. Sources: Expert Review, Literature |
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| Intellectual disability - microarray and sequencing v2.510 | EMC1 |
Konstantinos Varvagiannis gene: EMC1 was added gene: EMC1 was added to Intellectual disability. Sources: Expert Review,Literature Mode of inheritance for gene: EMC1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: EMC1 were set to 26942288; 29271071 Phenotypes for gene: EMC1 were set to Cerebellar atrophy, visual impairment, and psychomotor retardation, MIM 616875 Penetrance for gene: EMC1 were set to Complete Review for gene: EMC1 was set to GREEN gene: EMC1 was marked as current diagnostic Added comment: Harel et al. (PMID: 26942288) describe 7 individuals from 3 families with biallelic pathogenic variants in EMC1. In the first family, a single individual (born to non-consanguineous parents) was found to harbor a homozygous frameshift variant in a small (approx. 100 kb) stretch of absence of heterozygosity. The patients in the other two families were homozygous for missense variants (private to each family) in the context of parental consanguinity. The common phenotype was suggestive of a progressive neurodegenerative disorder and consisted of hypotonia, severe developmental delay with marked speech delay, diminished deep tendon reflexes, cerebellar atrophy, vision as well as skeletal problems. Seizures were a feature in one subject. One further patient from an additional (fourth) family was found to have a similar but milder phenotype and was only found to harbor a de novo missense variant in EMC1 following trio exome sequencing. Sanger sequencing of the promoter region as well as CNV calling from the exome data failed to reveal other variants in this specific individual. Similarly to what has been observed in other genes the authors propose that both monoallelic and biallelic pathogenic variants may be causative of the specific phenotype, though the presentation may be more severe in case of biallelic variants. Altogether this study reports 1 homozygous frameshift and 3 missense variants (2 of the latter found in homozygous state and one as a de novo heterozygous mutation). // Geetha et al. (PMID: 29271071) describe an individual born to consanguineous parents presenting with hypotonia, developmental delay, and cerebellar atrophy as well as early onset epilepsy. Exome sequencing demonstrated a homozygous splice variant in EMC1. This variant was demonstrated to result to retention of intron 11 upon RNA sequencing. This was predicted to lead to premature truncation of the protein. // EMC1 is associated in OMIM with Cerebellar atrophy, visual impairment, and psychomotor retardation (MIM 616875) for which an autosomal recessive inheritance mode is retained. // Apart from the variants reported in the previous studies [p.Pro874Argfs*21, p.Thr82Met, p.Gly868Arg, p.Gly471Arg, c.1212+1G>A - NM_015047.2] further variants have been submitted in ClinVar as likely pathogenic (Variation IDs : 521479, 445564). // The gene has been included in intellectual disability gene panels offered by a few other diagnostic labs. // As a result this gene can be considered for inclusion in the panel as green (or amber). Sources: Expert Review, Literature |
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| Intellectual disability - microarray and sequencing v2.510 | ADAT3 |
Konstantinos Varvagiannis gene: ADAT3 was added gene: ADAT3 was added to Intellectual disability. Sources: Expert Review,Literature Mode of inheritance for gene: ADAT3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ADAT3 were set to 23620220; 26842963; 30296593; 29796286 Phenotypes for gene: ADAT3 were set to # 615286. MENTAL RETARDATION, AUTOSOMAL RECESSIVE 36; MRT36 Penetrance for gene: ADAT3 were set to Complete Review for gene: ADAT3 was set to GREEN gene: ADAT3 was marked as current diagnostic Added comment: Initially reported in PMID 23620220, the findings in several individuals with biallelic ADAT3 pathogenic variants (including also those from the first report) are summarized in PMID 26842963. A total of 39 individuals from 19 consanguineous families are described in the two studies. These individuals were homozygous for a specific missense variant (probably a Saudi Arabian founder mutation). The common phenotype consists of intellectual disability (39/39 patients) and strabismus (32/39). Additional features included failure to thrive (33/39), microcephaly (22/39), short stature (11 of 15 individuals for whom this was information was available). Epilepsy was observed in some of these individuals (6/39). A few facial features were more common, although there was no distinct facial gestalt. // PMID 30296593 reports on 2 additional subjects born to consanguineous parents and found to be homozygous for the same missense variant. These individuals presented with features similar to the previous reports (although none of them was reported to have seizures). // Of note, the variant is either referred to as V144M (using NM_138422.2 or NM_138422.3) or as V128M (using NM_138422.1 as a reference / c.382G>A) as in the initial report. [ClinVar : https://www.ncbi.nlm.nih.gov/clinvar/variation/183301/#summary-evidence] PMID 29796286 describes a 6-year-old female, born to consanguineous Iranian parents, investigated for developmental delay,intellectual disability, behavioral difficulties as well as microcephaly. A homozygous 8-basepair duplication in ADAT3 was identified by exome and was further confirmed by Sanger sequencing. This individual did not have seizures. // This gene is included in DD/ID (but not epilepsy) panels offered by different diagnostic labs. // As a result this gene can be considered for inclusion in the intellectual disability panel as green. Sources: Expert Review, Literature |
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| Intellectual disability - microarray and sequencing v2.510 | PIGG |
Konstantinos Varvagiannis gene: PIGG was added gene: PIGG was added to Intellectual disability. Sources: Literature,Expert Review Mode of inheritance for gene: PIGG was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PIGG were set to 26996948; 28581210 Phenotypes for gene: PIGG were set to # 616917 MENTAL RETARDATION, AUTOSOMAL RECESSIVE 53; MRT53 Penetrance for gene: PIGG were set to Complete Review for gene: PIGG was set to GREEN gene: PIGG was marked as current diagnostic Added comment: PMID: 26996948 reports on 5 individuals from 3 families, with biallelic pathogenic variants in PIGG. Individuals from first family, were born to consanguineous parents from Egypt and were homozygous for a stopgain variant [p.(Gln310*)]. The patient from the second family had a rare missense SNV [p.(Arg669Cys)] and a de novo microdeletion affecting PIGG on her other allele. In the third family (consanguineous parents from Pakistan), two affected sibs were found to be homozygous for a splice variant. The phenotype consisted of hypotonia, early-onset seizures and intellectual disability. Ataxia was an additional feature in one of the families. Seizures, were observed in most of patients but do not appear to be a universal feature as they were absent in one of the sibs from the third family (10 years of age), while the other had a single episode by the age of 12 years. In vitro testing of lymphoblastoid cell lines (generated from individuals from the 1st and 3rd family) indicated that the variants abolished completely the function of PIGG, whereas the surface level of GPI anchored proteins was normal. // PMID: 28581210 describes the phenotype of 2 sibs from Palestine, homozygous for a stopgain variant [p.(Trp547*)]. Hypotonia, feeding difficulties, severe non-progressive ataxia (with cerebellar hypoplasia), intellectual disability and seizures were common features. Differences in severity and/or additional features might be explained by other homozygous variants (the girl had a concurrent diagnosis of MCAD deficiency). The authors demonstrated that the PIGG transcript levels were significantly lower (approximately half) in the two siblings compared to their parents, while the transcripts with the mutation in the heterozygous parents were very low due to nonsense-mediated decay. Patient fibroblasts showed decreased surface level of GPI-anchored proteins, in contrast with what was noted in lymphoblastoid cells in the previous study. // PIGG has been included in gene panels for intellectual disability offered by different diagnostic labs. // As a result this gene can be considered for inclusion in this panel as green (or amber). Sources: Literature, Expert Review |
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| Intellectual disability - microarray and sequencing v2.510 | NSD2 |
Konstantinos Varvagiannis gene: NSD2 was added gene: NSD2 was added to Intellectual disability. Sources: Literature,Expert Review Mode of inheritance for gene: NSD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: NSD2 were set to 29892088; 29760529; 29884796; 30244530 Phenotypes for gene: NSD2 were set to Intrauterine growth retardation; Growth delay; Microcephaly; Muscular hypotonia; Neurodevelopmental delay; Intellectual disability Penetrance for gene: NSD2 were set to unknown Review for gene: NSD2 was set to GREEN gene: NSD2 was marked as current diagnostic Added comment: PMID: 29892088 reports on 2 individuals with de novo SNVs affecting NSD2 (WHSC1). Both individuals presented with pre- and postnatal growth retardation, hypotonia, developmental delay / intellectual disability, as well as microcephaly. The authors suggest partial overlap with the phenotype of Wolf-Hirschhorn syndrome (WHS). Seizures are not part of the phenotype.The first subject had a splice site mutation while the second individual had a stopgain variant (affecting the PWWP domain). PMID: 29760529 describes a further patient with de novo nonsense mutation in NSD2. The boy was evaluated for probable growth delay ("low physical development"), hypotonia, psychomotor delay and microcephaly. The variant affected the SET domain. Three individuals with de novo likely loss-of-function (two frameshift and one stop gained) variants in Decipher [ https://decipher.sanger.ac.uk/search?q=NSD2#research-variants/results ]. A further patient with de novo frameshift mutation in NSD2 and a phenotype overlapping WHS reported in ClinVar [ https://www.ncbi.nlm.nih.gov/clinvar/variation/547999/ ] PMID: 29884796 (Zollino M and Doronzio PN) comments that NSD2 (WHSC1) is a neurodevelopmental gene with a role in growth delay, intellectual disability and dysmorphic facial features. PMID: 30244530 describes patients with 4p16.3 microdeletions spanning (exclusively) NSD2 and reviews the literature on patients with small microdeletions reported to date. All relevant individuals present with developmental delay and (rather mild) intellectual disability apart from other characteristics such as microcephaly, growth retardation and some facial features also observed in WHS. In Decipher one individual (286913) with a single CNV spanning exclusively NSD2 presenting with IUGR, failure to thrive, feeding difficulties, postnatal microcephaly, hypotonia, developmental delay as well as possibly relevant facial features. The gene is included in ID gene panels offered by various labs (either as NSD2 or WHSC1). As a result it can be considered for inclusion in the panel as green. Sources: Literature, Expert Review |
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| Intellectual disability - microarray and sequencing v2.463 | KDM1A | Louise Daugherty Phenotypes for gene: KDM1A were changed from Cleft palate, psychomotor retardation, and distinctive facial features, 616728 to Cleft palate, psychomotor retardation, and distinctive facial features, 616728; Developmental delay | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.459 | KDM1A | Louise Daugherty Phenotypes for gene: KDM1A were changed from Cleft palate, psychomotor retardation, and distinctive facial features to Cleft palate, psychomotor retardation, and distinctive facial features, 616728 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.443 | ISCA-46290-Gain |
Louise Daugherty Region: ISCA-46290-Gain was added Region: ISCA-46290-Gain was added to Intellectual disability. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-46290-Gain was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for Region: ISCA-46290-Gain were set to 25425167; 19716111; 21418194 Phenotypes for Region: ISCA-46290-Gain were set to Idiopathic mental retardation, speech delay, and a peculiar electroencephalographic (EEG) pattern in childhood. Autism and epilepsy, severe intellectual disability and dysmorphic facial features. Moderate to severe intellectual disability, early onset of puberty, language impairment, and age related epileptic syndromes such as West syndrome and focal epilepsy with activation during sleep evolving in some patients to continuous spikes-and-waves during slow sleep; 300801 |
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| Intellectual disability - microarray and sequencing v2.443 | ISCA-37431-Loss |
Louise Daugherty Region: ISCA-37431-Loss was added Region: ISCA-37431-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37431-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for Region: ISCA-37431-Loss were set to dysmorphic features, cardiac anomalies and mental retardation; 613675; variable facial dysmorphism, cafe-au-lait spots, neurofibromas and Lisch nodules in the iris, mental retardation, developmental delay, an excessive number of early-onset neurofibromas and an increased risk for malignant peripheral nerve sheath tumors; NEUROFIBROMATOSIS 1 MICRODELETION SYNDROME; NF1 MICRODELETION SYNDROME; Chromosome 17q11.2 deletion syndrome, 1.4Mb |
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| Intellectual disability - microarray and sequencing v2.422 | AP1S1 | Louise Daugherty Phenotypes for gene: AP1S1 were changed from MEDNIK syndrome to MEDNIK syndrome, 609313; MEDNIK syndrome; mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis and keratoderma syndrome | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.402 | ISCA-37433-Gain |
Louise Daugherty 22q11.2 recurrent (DGS/VCFS) region (proximal region, LCR22-A to -B) Gain was changed to 22q11.2 recurrent (DGS/VCFS) region (proximal, A-B) (includes TBX1) Gain Added phenotypes 608363; Chromosome 22q11.2 microduplication syndrome; dysmorphic facial features, cognitive deficits, velopharyngeal insufficiency, congenital heart defects and immunologic derangement; delayed psychomotor development, growth retardation, and/or hypotonia for Region: ISCA-37433-Gain |
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| Intellectual disability - microarray and sequencing v2.401 | ISCA-37404-Gain | Louise Daugherty Phenotypes for Region: ISCA-37404-Gain were changed from chromosome 15q11-q13 duplication syndrome; include autism, mental retardation, ataxia, seizures, developmental delays, and behavioral problems; 608636; elayed development and intellectual disability associated with abnormal behavior and dysmorphic facial features. Additional variable features may include thin corpus callosum on brain imaging and sleep disturbances. Carrier females may be mildly affected to chromosome 15q11-q13 duplication syndrome; include autism, mental retardation, ataxia, seizures, developmental delays, and behavioral problems; 608636; delayed development and intellectual disability associated with abnormal behavior and dysmorphic facial features. Additional variable features may include thin corpus callosum on brain imaging and sleep disturbances. Carrier females may be mildly affected | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.398 | ISCA-37404-Gain |
Louise Daugherty Region: ISCA-37404-Gain was added Region: ISCA-37404-Gain was added to Intellectual disability. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37404-Gain was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for Region: ISCA-37404-Gain were set to 18374305; 16840569; 9106540 Phenotypes for Region: ISCA-37404-Gain were set to chromosome 15q11-q13 duplication syndrome; include autism, mental retardation, ataxia, seizures, developmental delays, and behavioral problems; 608636; elayed development and intellectual disability associated with abnormal behavior and dysmorphic facial features. Additional variable features may include thin corpus callosum on brain imaging and sleep disturbances. Carrier females may be mildly affected |
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| Intellectual disability - microarray and sequencing v2.398 | ISCA-37418-Gain |
Louise Daugherty Region: ISCA-37418-Gain was added Region: ISCA-37418-Gain was added to Intellectual disability. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37418-Gain was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for Region: ISCA-37418-Gain were set to infantile hypotonia, failure to thrive, mental retardation, autistic features, sleep apnea, and structural cardiovascular anomalies; 610883; characterized by hypotonia, poor feeding, failure to thrive, developmental delay, mild-moderate intellectual deficit, and neuropsychiatric disorders. Structural cardiovascular anomalies (dilated aortic root, bicommissural aortic valve, atrial/ventricular and septal defects) and sleep disturbance (obstructive and central sleep apnea) are also frequently associated |
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| Intellectual disability - microarray and sequencing v2.398 | ISCA-37418-Loss |
Louise Daugherty Region: ISCA-37418-Loss was added Region: ISCA-37418-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37418-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for Region: ISCA-37418-Loss were set to Potocki-Lupski syndrome; hypotonia, poor feeding, failure to thrive, developmental delay particularly cognitive and language deficity, mild-moderate intellectual deficit, and neuropsychiatric disorders; Smith-Magenis syndrome; Structural cardiovascular anomalies (dilated aortic root, bicommissural aortic valve, atrial/ventricular and septal defects) and sleep disturbance; 182290; moderate intellectual disability, delayed speech and language skills, distinctive facial features, sleep disturbances, and behavioral problems; hypotonia, failure to thrive, mental retardation, pervasive developmental disorders, congenital anomalies; Dental abnormalities |
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| Intellectual disability - microarray and sequencing v2.398 | ISCA-37421-Loss |
Louise Daugherty Region: ISCA-37421-Loss was added Region: ISCA-37421-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37421-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for Region: ISCA-37421-Loss were set to dysmorphic features; 612474; Moderate mental retardation, microcephaly, cardiac abnormalities, and cataracts; mild to moderate developmental delay |
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| Intellectual disability - microarray and sequencing v2.398 | ISCA-37423-Loss |
Louise Daugherty Region: ISCA-37423-Loss was added Region: ISCA-37423-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37423-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for Region: ISCA-37423-Loss were set to 23239632; 20969981 Phenotypes for Region: ISCA-37423-Loss were set to prenatal and postnatal growth retardation, low birth weight, mild to moderate intellectual deficit, psychomotor retardation, poor speech, seizures, behavioral problems such as hyperactivity and impulsiveness. Frequent craniofacial abnormalities include microcephaly, high and narrow forehead, broad nasal bridge, epicanthic folds, high arched palate, short neck and low set unusually shaped ears. Furthermore congenital heart defects (atrioventricular, septal defects, pulmonary stenosis), congenital diaphragmatic hernia and in boys cryptorchidism and hypospadias have been frequently reported.; congenital heart defects, microcephaly, psychomotor delay and behavioural problems; hyperactivity, craniofacial abnormalities; 8p23.1 microdeletion syndrome; moderate intellectual disability |
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| Intellectual disability - microarray and sequencing v2.398 | ISCA-37430-Loss |
Louise Daugherty Region: ISCA-37430-Loss was added Region: ISCA-37430-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37430-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for Region: ISCA-37430-Loss were set to microcephaly, dysgenesis of the corpus callosum, and cerebellar atrophy, as well as neurobehavioral disorders, including delayed development, mental retardation, and attention deficit-hyperactivity disorder. Patients with duplications of YWHAE tended to have macrosomia, facial dysmorphism, and mild developmental delay; growth restriction, craniofacial dysmorphisms, structural abnormalities of brain and cognitive impairment; Chromosome 17p13.3 duplication syndrome; prominent forehead, bitemporal hollowing, short nose with upturned nares, protuberant upper lip, thin vermilion border, and small jaw; Characteristic facies, pre- and post-natal growth retardation; 247200; classic lissencephaly (pachygyria, incomplete or absent gyration of the cerebrum), microcephaly, wrinkled skin over the glabella and frontal suture, prominent occiput, narrow forehead, downward slanting palpebral fissures, small nose and chin, cardiac malformations, hypoplastic male extrenal genitalia, growth retardation, and mental deficiency with seizures and EEG abnormalities; Miller-Dieker lissencephaly syndrome |
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| Intellectual disability - microarray and sequencing v2.398 | ISCA-37433-Gain |
Louise Daugherty Region: ISCA-37433-Gain was added Region: ISCA-37433-Gain was added to Intellectual disability. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37433-Gain was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for Region: ISCA-37433-Gain were set to 17250668; 20301749; 18414210 Phenotypes for Region: ISCA-37433-Gain were set to delayed psychomotor development, growth retardation, and/or hypotonia; dysmorphic facial features, cognitive deficits, velopharyngeal insufficiency, congenital heart defects and immunologic derangement; Chromosome 22q11.2 microduplication syndrome; 608363 |
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| Intellectual disability - microarray and sequencing v2.398 | ISCA-37434-Loss |
Louise Daugherty Region: ISCA-37434-Loss was added Region: ISCA-37434-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37434-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for Region: ISCA-37434-Loss were set to 17918734; 22766398; 18245432 Phenotypes for Region: ISCA-37434-Loss were set to posteriorly rotated, low-set, abnormal ears; brachycephaly; epicanthus; heart defects; pointed chin; deep-set eyes; microcephaly; hypotonia; seizures; poor/absent speech; central nervous system anomalies; large anterior fontanels; microbrachycephaly; mental retardation; growth impairment; large, late-closing anterior fontanel; flat nose; nasal bridge; developmental delay; hearing impairment; distinct dysmorphic features; 1p36 deletion syndrome; 607872 |
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| Intellectual disability - microarray and sequencing v2.398 | ISCA-37440-Loss |
Louise Daugherty Region: ISCA-37440-Loss was added Region: ISCA-37440-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37440-Loss was set to BIALLELIC, autosomal or pseudoautosomal Publications for Region: ISCA-37440-Loss were set to 11524703; 18234729; 16385448 Phenotypes for Region: ISCA-37440-Loss were set to mild/moderate mental retardation; facial dysmorphism; Hypotonia-cystinuria syndrome (HCS); 2p21 deletion syndrome; rapid weight gain in late childhood; failure to thrive; growth hormone deficiency; 606407; lactic acidemia; respiratory chain complex IV deficiency; hyperphagia; minor facial dysmorphism; severe somatic and developmental delay; nephrolithiasis; cystinuria; neonatal seizures; hypotonia |
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| Intellectual disability - microarray and sequencing v2.398 | ISCA-37441-Loss |
Louise Daugherty Region: ISCA-37441-Loss was added Region: ISCA-37441-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37441-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for Region: ISCA-37441-Loss were set to 15852040; 16319823; 20140962 Phenotypes for Region: ISCA-37441-Loss were set to Potocki-Shaffer syndrome; multiple exostoses; biparietal foramina; intellectual disability; strabismus; minor craniofacial anomalies; myopia; ophthalmologic anomalies; 601224; mental retardation; enlarged anterior fontanel; genital abnormalities in males; parietal foramina; developmental delay |
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| Intellectual disability - microarray and sequencing v2.398 | ISCA-37443-Loss |
Louise Daugherty Region: ISCA-37443-Loss was added Region: ISCA-37443-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37443-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for Region: ISCA-37443-Loss were set to . mild to moderate mental retardation, with only slightly dysmorphic facial features that were similar in most patients: long and narrow face, short philtrum, and high nasal bridge. Autism, gait ataxia, chest wall deformity, and long and tapering fingers were noted in at least 2 of the 6 patients. delayed psychomotor development with mild to moderate mental retardation and/or learning disabilities with speech delay. All had low birth weight, microcephaly, high nasal bridge, and short philtrum, and 3 had clinodactyly of the toes. primary pulmonary hypertension, patent ductus arteriosus (PDA), subvalvular aortic stenosis, and gastroesophageal reflux, and required neonatal intensive care for 57 days after birth due to complications of meconium aspiration. He had mild dysmorphic features, including posteriorly rotated ears, shallow orbits, frontal bossing, prominent nose, long thin lip, and broad face. He also had bilateral sandal gap toes, single palmar creases, and bilateral inguinal hernia. However, he was developmentally normal at age 6 months. delayed psychomotor development with delayed waking and poor motor skills, autism with speech delay, mental retardation, and psychiatric disturbances, including aggression, anxiety, hyperactivity, and bipolar disorder with psychosis in 1. Both had dysmorphic features, including high nasal bridge, asymmetric face, and crowded/dysplastic teeth; 1 had micrognathia and epicanthal folds. Both had tapered fingers. 609425; Chromosome 3q29 microdeletion syndrome |
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| Intellectual disability - microarray and sequencing v2.398 | ISCA-37500-Loss |
Louise Daugherty Region: ISCA-37500-Loss was added Region: ISCA-37500-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37500-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for Region: ISCA-37500-Loss were set to 23166063; 17847001; 24352913 Phenotypes for Region: ISCA-37500-Loss were set to mild to moderate cognitive deficit; Diamond-Blackfan anemia; intellectual disability; 614294; anemia; congenital diaphragmatic hernia; cryptorchidism in males; severe speech and psychomotor delay; mental retardation; postnatal short stature; behavioral problem; mild dysmorphic feature; developmental delay |
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| Intellectual disability - microarray and sequencing v2.398 | ISCA-37400-Loss |
Louise Daugherty Region: ISCA-37400-Loss was added Region: ISCA-37400-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37400-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for Region: ISCA-37400-Loss were set to 21841781; 18184952; 20301775 Phenotypes for Region: ISCA-37400-Loss were set to seizures; intellectual disability; Chiari malformations; cerebellar ectopia; 611913; mental retardation; Macrocephaly; developmental delay; autism spectrum disorder (ASD); vertebral anomalies |
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| Intellectual disability - microarray and sequencing v2.398 | ISCA-37390-Loss |
Louise Daugherty Region: ISCA-37390-Loss was added Region: ISCA-37390-Loss was added to Intellectual disability. 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 |
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| Intellectual disability - microarray and sequencing v2.398 | ISCA-37394-Loss |
Louise Daugherty Region: ISCA-37394-Loss was added Region: ISCA-37394-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37394-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for Region: ISCA-37394-Loss were set to 25402011; 23188045 Phenotypes for Region: ISCA-37394-Loss were set to 2q37 deletion syndrome is a condition that can affect many parts of the body. This condition is characterized by weak muscle tone (hypotonia) in infancy, mild to severe intellectual disability and developmental delay, behavioral problems, characteristic facial features, and other physical abnormalities. PMID 23188045 brachydactyly-mental retardation syndrome, Albright hereditary osteodystrophy-like syndrome, developmental delay and behavioural abnormalities in combination; 600430 |
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| Intellectual disability - microarray and sequencing v2.398 | ISCA-37405-Loss |
Louise Daugherty Region: ISCA-37405-Loss was added Region: ISCA-37405-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37405-Loss was set to BIALLELIC, autosomal or pseudoautosomal Publications for Region: ISCA-37405-Loss were set to 9856524; 15138899; 8852662 Phenotypes for Region: ISCA-37405-Loss were set to juvenile nephronophthisis 1: including growth retardation. Joubert syndrome: multisystem disease characterized by cerebellar vermis hypoplasia with prominent superior cerebellar peduncles (resulting in the 'molar tooth sign,' or MTS, on axial MRI), mental retardation, hypotonia, irregular breathing pattern, and eye movement abnormalities; 266900; 609583 |
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| Intellectual disability - microarray and sequencing v2.398 | ISCA-37408-Loss |
Louise Daugherty Region: ISCA-37408-Loss was added Region: ISCA-37408-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37408-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for Region: ISCA-37408-Loss were set to 16963482; 22579565; 18245392 Phenotypes for Region: ISCA-37408-Loss were set to PMID: 16963482 idiopathic intellectual disability including moderate to severe intellectual disability, autism/autistic features, microcephaly, structural brain anomalies including cortical dysplasia/pachygyria, renal anomalies (multicystic kidney, hydronephrosis), digital camptodactyly, visual impairment, strabismus, neuromotor deficits, communication and attention impairments, and a distinctive pattern of craniofacial features. Dysmorphic craniofacial features include progressive microcephaly, flat occiput, widened inner canthal distance, small palpebral fissures, ptosis, long and straight eyelashes, broad and high nasal root extending to a widened, prominent nasal tip with elongated, smooth philtrum, rounding of the upper vermillion border and everted lower lips. PMID: 18245392 A 32-year-old, mentally retarded male was referred to our centre for further clinical genetic analysis. He was born to non-consanguineous parents after 42 weeks gestation with a birth weight of 3500 g. He had a healthy older brother. In the neonatal period he was hypotonic and at 8 weeks of age he underwent surgery because of an inguinal hernia with removal of an atrophic right testis. His motor development was severely delayed with sitting at 3.5 years and walking at 5 years of age. Speech was poorly developed, characterised by the usage of only a few words. During infancy an optic nerve hypoplasia was diagnosed, and during childhood he frequently suffered from luxations of the patellae, which required surgery. At the age of 32 years his height is 163 cm (_3 SDS) and head circumference 52.5 cm (_2.5 SDS). He has a narrow receding forehead, widened inner canthal distance of 3.5 cm (90th centile), normal outer canthal distance of 8.5 cm (25th centile), telecanthus, short and down slanting palpebral fissures, epicanthal folds, ptosis, long, straight eyelashes, high nasal bridge, low set large ears, flat philtrum, small mouth with high, narrow palate and retrognathia. The thorax is broad with increased internipple distance and slight gynaecomastia. A recent renal ultrasound revealed multiple cysts in the left, dystrophic kidney and two uncomplicated cysts in the enlarged, right kidney. The patient has a normally sized phallus with absent right testis and small left testis. His hands show a simian crease right and tapering fingers with broad proximal interphalangeal joints. He shows sandal gaps on both flat feet with clinodactyly of the fourth and fifth toes (and more); 612513; PMID: 22579565 severe developmental delay, congenital microcephaly, intractable epilepsy, and renal anomalies, as well as a congenital choledochal cyst which has not been previously reported in other patients with this cytogenetic defect |
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| Intellectual disability - microarray and sequencing v2.398 | ISCA-37411-Loss |
Louise Daugherty Region: ISCA-37411-Loss was added Region: ISCA-37411-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37411-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for Region: ISCA-37411-Loss were set to 19289393; 19136953; 18278044 Phenotypes for Region: ISCA-37411-Loss were set to PMID: 19289393 incomplete penetrance for developmental delay, mental retardation, or borderline IQ in most and autistic spectrum disorder (6/14), speech delay, aggressiveness, attention deficit hyperactivity disorder, and other behavioural problems; 612001; PMID: 18278044 mental retardation, epilepsy and variable facial and digital dysmorphisms; PMID: 19136953 idiopathic generalized epilepsy without other features previously associated with 15q13.3 microdeletions, such as intellectual disability, autism or schizophrenia |
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| Intellectual disability - microarray and sequencing v2.398 | ISCA-37415-Loss |
Louise Daugherty Region: ISCA-37415-Loss was added Region: ISCA-37415-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37415-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for Region: ISCA-37415-Loss were set to 19843651; 18550696; 24246141 Phenotypes for Region: ISCA-37415-Loss were set to PMID: 18550696 Phenotypic variability, common features were identified: mental retardation, microcephaly and epilepsy in three patients, two of these had also short stature, and two other deletion carriers ascertained prenatally presented with cleft lip and midline defects |
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| Intellectual disability - microarray and sequencing v2.398 | ISCA-37478-Gain |
Louise Daugherty Region: ISCA-37478-Gain was added Region: ISCA-37478-Gain was added to Intellectual disability. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37478-Gain was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for Region: ISCA-37478-Gain were set to 18374305; 16840569; 9106540 Phenotypes for Region: ISCA-37478-Gain were set to hypotonia and motor delays, intellectual disability, autism spectrum disorder (ASD), and epilepsy including infantile spasms, 608636; chromosome 15q11-q13 duplication syndrome; autism, mental retardation, ataxia, seizures, developmental delays, and behavioral problems |
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| Intellectual disability - microarray and sequencing v2.398 | ISCA-37404-Loss |
Louise Daugherty Region: ISCA-37404-Loss was added Region: ISCA-37404-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37404-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for Region: ISCA-37404-Loss were set to 22045295; 7611294 Phenotypes for Region: ISCA-37404-Loss were set to microcephaly; Developmental delay, muscle weakness; Mental retardation; Angelman syndrome; 176270; Prader-Willi syndrome; 105830 |
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| Intellectual disability - microarray and sequencing v2.398 | ISCA-37425-Loss |
Louise Daugherty Region: ISCA-37425-Loss was added Region: ISCA-37425-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37425-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for Region: ISCA-37425-Loss were set to macrocephaly, overgrowth and advanced bone age; colpocephaly; Sotos syndrome; macrocephaly; 117550; rapid growth, acromegalic features, and a nonprogressive cerebral disorder with mental retardation. High-arched palate and prominent jaw |
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| Intellectual disability - microarray and sequencing v2.398 | ISCA-37493-Loss |
Louise Daugherty Region: ISCA-37493-Loss was added Region: ISCA-37493-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37493-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for Region: ISCA-37493-Loss were set to 21800092; 17603806; 22678713 Phenotypes for Region: ISCA-37493-Loss were set to microcephaly; seizures; agenesis of the corpus callosum; intellectual disability; hand and foot anomalies; 612337; non-specific craniofacial anomalies; hypoplasia; psychomotor retardation; hypogenesis of the corpus callosum |
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| Intellectual disability - microarray and sequencing v2.398 | ISCA-46295-Loss |
Louise Daugherty Region: ISCA-46295-Loss was added Region: ISCA-46295-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-46295-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for Region: ISCA-46295-Loss were set to 19898479; 20236110; 22775350 Phenotypes for Region: ISCA-46295-Loss were set to seizures; 20236110; mental retardation; 22775350; dysmorphic features; developmental delay; severe epileptic encephalopathy |
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| Intellectual disability - microarray and sequencing v2.398 | ISCA-37401-Loss |
Louise Daugherty Region: ISCA-37401-Loss was added Region: ISCA-37401-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37401-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for Region: ISCA-37401-Loss were set to Wilms tumor, aniridia, genitourinary anomalies and mental retardation syndrome; 194072 |
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| Intellectual disability - microarray and sequencing v2.398 | ISCA-37478-Loss |
Louise Daugherty Region: ISCA-37478-Loss was added Region: ISCA-37478-Loss was added to Intellectual disability. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37478-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for Region: ISCA-37478-Loss were set to 22045295; 7611294 Phenotypes for Region: ISCA-37478-Loss were set to microcephaly; Developmental delay, muscle weakness; Mental retardation; Angelman syndrome; 176270; Prader-Willi syndrome; 105830 |
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| Intellectual disability - microarray and sequencing | RET | Ellen McDonagh classified RET as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing | RET | BRIDGE consortium edited their review of RET | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing | RET | BRIDGE consortium edited their review of RET | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing | RET | Louise Daugherty classified RET as amber | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing | RET | Louise Daugherty commented on RET | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing | RET | BRIDGE consortium reviewed RET | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||