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| Intellectual disability syndromic and non-syndromic v0.5661 | MAX |
Rylee Peters gene: MAX was added gene: MAX was added to Intellectual disability syndromic and non-syndromic. Sources: Literature Mode of inheritance for gene: MAX was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MAX were set to 38141607 Phenotypes for gene: MAX were set to Syndromic disease (MONDO:0002254), MAX-related Review for gene: MAX was set to GREEN Added comment: Three individuals who each share a recurrent de novo germline variant in the MAX gene, resulting in a p.Arg60Gln substitution in the loop of the b-HLH-LZ domain. Affected individuals have a complex disorder consisting primarily of macrocephaly, polydactyly, and delayed ophthalmic development. Other phenotypes reported include intellectual disability, perianal abscesses, pectus carinatum, hypospadias, renal agenesis, single umbilical artery, flattened thoracic vertebrae. Functional analysis of the p.Arg60Gln variant shows a significant increase in CCND2 protein and a more efficient heterodimerization with c-Myc resulting in an increase in transcriptional activity of c-Myc. Sources: Literature |
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| Intellectual disability syndromic and non-syndromic v0.5660 | SOX8 |
Paul De Fazio changed review comment from: Proband presented to genetics clinic at 27 years of age with BMI -3.4SD, height -2.7SD, head circumference -1.8SD. She had mild intellectual delay and clinical features of a congenital, nonprogressive myopathy with moderate proximal and distal weakness. X-rays showed skeletal dysplasia, including cervical thoracic scoliosis and lumbar scoliosis. She was reported as having had weakness at birth with poor suck, micrognathia, hypotonia, and talipes. She was documented to have significant motor delay as a child. MRI of the brain demonstrated large posterior fossa CSF spaces. Biallelic SOX8 variants biallelic (NM_014587.3:c.422+5G>C; c.583dup p.(His195ProfsTer11)) were identified by WGS. The +5 variant was shown to affect splicing, while the frameshift variant resulted in production of low-level truncated protein (not NMD predicted). Sources: Literature; to: Proband presented to genetics clinic at 27 years of age with BMI -3.4SD, height -2.7SD, head circumference -1.8SD. She had mild intellectual delay and clinical features of a congenital, nonprogressive myopathy with moderate proximal and distal weakness. X-rays showed skeletal dysplasia, including cervical thoracic scoliosis and lumbar scoliosis. She was reported as having had weakness at birth with poor suck, micrognathia, hypotonia, and talipes. She was documented to have significant motor delay as a child. MRI of the brain demonstrated large posterior fossa CSF spaces. Biallelic SOX8 variants biallelic (NM_014587.3:c.422+5G>C; c.583dup p.(His195ProfsTer11)) were identified by WGS. The +5 variant was shown to affect splicing, while the frameshift variant resulted in production of low-level truncated protein (not NMD predicted). Functional studies on patient fibroblasts showed misregulation of downstream SOX8 targets. Sources: Literature |
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| Intellectual disability syndromic and non-syndromic v0.5660 | SOX8 |
Paul De Fazio gene: SOX8 was added gene: SOX8 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature Mode of inheritance for gene: SOX8 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SOX8 were set to https://www.neurology.org/doi/full/10.1212/NXG.0000000000200088 Phenotypes for gene: SOX8 were set to Neurodevelopmental disorder (MONDO:0700092), SOX8-related Review for gene: SOX8 was set to RED gene: SOX8 was marked as current diagnostic Added comment: Proband presented to genetics clinic at 27 years of age with BMI -3.4SD, height -2.7SD, head circumference -1.8SD. She had mild intellectual delay and clinical features of a congenital, nonprogressive myopathy with moderate proximal and distal weakness. X-rays showed skeletal dysplasia, including cervical thoracic scoliosis and lumbar scoliosis. She was reported as having had weakness at birth with poor suck, micrognathia, hypotonia, and talipes. She was documented to have significant motor delay as a child. MRI of the brain demonstrated large posterior fossa CSF spaces. Biallelic SOX8 variants biallelic (NM_014587.3:c.422+5G>C; c.583dup p.(His195ProfsTer11)) were identified by WGS. The +5 variant was shown to affect splicing, while the frameshift variant resulted in production of low-level truncated protein (not NMD predicted). Sources: Literature |
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| Intellectual disability syndromic and non-syndromic v0.5534 | TMCO1 | Zornitza Stark Phenotypes for gene: TMCO1 were changed from to Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1, MIM# 213980; cerebrofaciothoracic dysplasia MONDO:0008952 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability syndromic and non-syndromic v0.5508 | TMCO1 | Kaitlyn Dianna Weldon reviewed gene: TMCO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 1204988, 1640432, 15326640, 20018682; Phenotypes: obsolete cerebrofaciothoracic dysplasia MONDO:0008952; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability syndromic and non-syndromic v0.4695 | CIC | Ain Roesley Marked gene: CIC as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability syndromic and non-syndromic v0.4695 | CIC | Ain Roesley Gene: cic has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability syndromic and non-syndromic v0.4695 | CIC | Ain Roesley Phenotypes for gene: CIC were changed from to Intellectual developmental disorder, autosomal dominant 45 MIM#617600 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability syndromic and non-syndromic v0.4695 | CIC | Ain Roesley Publications for gene: CIC were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability syndromic and non-syndromic v0.4695 | CIC | Ain Roesley Mode of inheritance for gene: CIC was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability syndromic and non-syndromic v0.4694 | CIC | Ain Roesley reviewed gene: CIC: Rating: GREEN; Mode of pathogenicity: None; Publications: 28288114, 21076407; Phenotypes: Intellectual developmental disorder, autosomal dominant 45 MIM#617600; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability syndromic and non-syndromic v0.4484 | SOD1 |
Naomi Baker gene: SOD1 was added gene: SOD1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature Mode of inheritance for gene: SOD1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SOD1 were set to PMID: 31314961; 31332433; 34788402 Phenotypes for gene: SOD1 were set to Spastic tetraplegia and axial hypotonia, progressive, MIM#618598 Review for gene: SOD1 was set to GREEN Added comment: Phenotypes include one individual with axial hypotonia and loss of gross and fine motor function beginning at 6 months of age, after which severe, progressive spastic tetraparesis developed and Babinski’s sign was present in both feet. MRI of brain detected mild frontoparietal atrophy. The second individual had severe and marked by progressive loss of motor abilities from 9 months of age, tetraspasticity with predominance in the lower extremities, mild cerebellar atrophy, and hyperekplexia-like symptoms. Dysmorphic features such as low set, posteriorly rotated ears, and overlapping toes The third individual is an infant with severe global developmental delay, axial hypotonia and limb spasticity. No dysmorphic facial features were noted, but she had a high arched palate, bilateral 5th finger clinodactyly, partial toe syndactyly of the second and third toes, and a single hyperpigmented macule tongue fasciculations, axial hypotonia with limb spasticity (more pronounced in the lower limbs), ankle clonus, and brisk patellar deep tendon reflexes. Sources: Literature |
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| Intellectual disability syndromic and non-syndromic v0.3128 | PRKAR1B |
Konstantinos Varvagiannis gene: PRKAR1B was added gene: PRKAR1B was added to Intellectual disability syndromic and non-syndromic. Sources: Literature Mode of inheritance for gene: PRKAR1B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: PRKAR1B were set to https://doi.org/10.1101/2020.09.10.20190314; 33057194 Phenotypes for gene: PRKAR1B were set to Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Aggressive behavior; Abnormality of movement; Upslanted palpebral fissure Penetrance for gene: PRKAR1B were set to unknown Review for gene: PRKAR1B was set to AMBER Added comment: Please consider inclusion of this gene with amber rating pending publication of the preprint and/or additional evidence. Marbach et al. (2020 - medRxiv : https://doi.org/10.1101/2020.09.10.20190314 - last author : C. Schaaf) report 6 unrelated individuals with heterozygous missense PRKAR1B variants. All presented formal ASD diagnosis (6/6), global developmental delay (6/6) and intellectual disability (all - formal evaluations were lacking though). Additional features included neurologic anomalies (movement disorders : dyspraxia, apraxia, clumsiness in all, with tremor/dystonia or involuntary movements as single occurrences). Three displayed high pain tolerance. Regression in speech was a feature in two. Additional behavior anomalies included ADHD (4-5/6) or aggression (3/6). There was no consistent pattern of malformations, physical anomalies or facial features (with the exception of uplsanted palpebral fissures reported in 4). 3 different missense variants were identified (NM_00116470:c.1003C>T - p.Arg335Trp, c.586G>A - p.Glu196Lys, c.500_501delAAinsTT - p.Gln167Leu) with Arg355Trp being a recurrent one within this cohort (4/6 subjects). A possible splicing effect may apply for the MNV. All variants are absent from gnomAD and the SNVs had CADD scores > 24. In all cases were parental samples were available (5/6), the variant had occurred as a de novo event. Protein kinase A (PKA) is a tetrameric holoenzyme formed by the association of 2 catalytic (C) subunits with a regulatory (R) subunit dimer. Activation of PKA is achieved through binding of 2 cAMP molecules to each R-subunit, and unleashing(/dissociation) of C-subunits to engage substrates. PRKACA/B genes encode the Cα- and Cβ-subunits while the 4 functionally non-redundant regulatory subunits are encoded by PRKAR1A/1B/2A/2B genes. As the authors comment, the RIβ subunit is primarily expressed in brain with higher expression in cortex and hypothalamus. The functional consequences of the variants at cellular level were not studied. Previous studies have demonstrated that downregulation of RIβ in murine hippocampal cultures, reduced phosphorylation of CREB, a transcription factor involved in long-term memory formation. The authors speculate that a similar effect on cAMP/PKA/CREB cascade may mediate the cognitive effects in humans. RIβ deficient mice also display diminished nociceptive pain, similar to the human phenotype. [Several refs provided]. The authors cite the study by Kaplanis et al (2020 - PMID: 33057194), where in a large sample of 31,058 trio exomes of children with developmental disorders, PRKAR1B was among the genes with significant enrichment for de novo missense variants. [The gene has a pLI score of 0.18 in gnomAD / o/e = 0.26 - so pLoF variants may not be deleterious]. Please note that a specific PRKAR1B variant (NM_002735.2:c.149T>G - p.Leu50Arg) has been previous reported to segregate with a late-onset neurodegenerative disorder characterized by dementia and/or parkinsonism within a large pedigree with 12 affected individuals [Wong et al 2014 - PMID: 25414040]. Sources: Literature |
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| Intellectual disability syndromic and non-syndromic v0.2750 | CEP120 |
Konstantinos Varvagiannis gene: CEP120 was added gene: CEP120 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature Mode of inheritance for gene: CEP120 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CEP120 were set to 27208211 Phenotypes for gene: CEP120 were set to Joubert syndrome 31 (MIM 617761); Short-rib thoracic dysplasia 13 with or without polydactyly (MIM 616300) Penetrance for gene: CEP120 were set to Complete Review for gene: CEP120 was set to GREEN Added comment: Pathogenic CEP120 variants have been reported in recessive ciliopathies, namely Short-rib thoracic dysplasia 13 with or without polydactyly (MIM 616300) and Joubert syndrome 31 (MIM 617761). The former is associated with a severe/lethal outcome (4 unrelated infants described by Shaheen et al 2015 - PMID: 25361962, 2 fetuses reported by Roosing et al 2016 - PMID: 27208211). Roosing et al however, also provided details on 4 unrelated subjects with Joubert syndrome diagnosis. All presented with a neurologic phenotype of hypotonia, DD, cognitive impairment and exhibited a molar tooth sign. As a result, this gene can be considered for inclusion in the ID panel with green rating (>3 individuals/variants, consistent ciliopathy phenotype). Sources: Literature |
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| Intellectual disability syndromic and non-syndromic v0.520 | TTC21B |
Chirag Patel Source Genetic Health Queensland was removed from TTC21B. Source Expert list was added to TTC21B. Mode of inheritance for gene TTC21B was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: TTC21B were changed from to Nephronophthisis 12, OMIM #613820; Short-rib thoracic dysplasia 4 with or without polydactyly; OMIM #613819 |
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| Intellectual disability syndromic and non-syndromic v0.519 | TTC21B | Chirag Patel reviewed gene: TTC21B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Nephronophthisis 12, OMIM #613820, Short-rib thoracic dysplasia 4 with or without polydactyly, OMIM #613819; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability syndromic and non-syndromic v0.451 | IFT140 | Zornitza Stark Phenotypes for gene: IFT140 were changed from to Short-rib thoracic dysplasia 9 with or without polydactyly, MIM#266920 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability syndromic and non-syndromic v0.449 | IFT140 | Zornitza Stark reviewed gene: IFT140: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Short-rib thoracic dysplasia 9 with or without polydactyly, MIM#266920; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability syndromic and non-syndromic v0.354 | WDR19 | Chirag Patel reviewed gene: WDR19: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ?Short-rib thoracic dysplasia 5 with or without polydactyly, OMIM #614376, Nephronophthisis 13, OMIM #614377, Senior-Loken syndrome 8, OMIM#616307; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability syndromic and non-syndromic v0.354 | WDR19 | Chirag Patel Phenotypes for gene: WDR19 were changed from ?Short-rib thoracic dysplasia 5 with or without polydactyly; OMIM #614376; AR 3 Nephronophthisis 13 614377 AR 3 Senior-Loken syndrome 8 616307 to ?Short-rib thoracic dysplasia 5 with or without polydactyly, OMIM #614376; Nephronophthisis 13, OMIM #614377; Senior-Loken syndrome 8, OMIM#616307 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability syndromic and non-syndromic v0.353 | WDR19 |
Chirag Patel Source Genetic Health Queensland was removed from WDR19. Source Expert list was added to WDR19. Mode of inheritance for gene WDR19 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: WDR19 were changed from to ?Short-rib thoracic dysplasia 5 with or without polydactyly; OMIM #614376; AR 3 Nephronophthisis 13 614377 AR 3 Senior-Loken syndrome 8 616307 |
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| Intellectual disability syndromic and non-syndromic v0.351 | WDR34 |
Chirag Patel Source Genetic Health Queensland was removed from WDR34. Source Expert list was added to WDR34. Mode of inheritance for gene WDR34 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: WDR34 were changed from to Short-rib thoracic dysplasia 11 with or without polydactyly; OMIM #615633 |
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| Intellectual disability syndromic and non-syndromic v0.350 | WDR34 | Chirag Patel reviewed gene: WDR34: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Short-rib thoracic dysplasia 11 with or without polydactyly, OMIM #615633; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability syndromic and non-syndromic v0.132 | DYNC2H1 | Zornitza Stark Phenotypes for gene: DYNC2H1 were changed from to Short-rib thoracic dysplasia 3 with or without polydactyly, MIM#613091 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability syndromic and non-syndromic v0.129 | DYNC2H1 | Zornitza Stark reviewed gene: DYNC2H1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Short-rib thoracic dysplasia 3 with or without polydactyly, MIM#613091; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability syndromic and non-syndromic v0.0 | CIC |
Zornitza Stark gene: CIC was added gene: CIC was added to Intellectual disability, syndromic and non-syndromic_GHQ. Sources: Expert Review Green,Genetic Health Queensland Mode of inheritance for gene: CIC was set to Unknown |
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