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| Polymicrogyria and Schizencephaly v0.177 | RAC3 |
Alison Yeung gene: RAC3 was added gene: RAC3 was added to Polymicrogyria and Schizencephaly. Sources: Literature Mode of inheritance for gene: RAC3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RAC3 were set to 35851598 Phenotypes for gene: RAC3 were set to Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies, MIM#618577 Review for gene: RAC3 was set to GREEN Added comment: Polymicrogyria commonly reported in cohort of 10 patients Sources: Literature |
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| Polymicrogyria and Schizencephaly v0.170 | MAN2C1 |
Michelle Torres gene: MAN2C1 was added gene: MAN2C1 was added to Polymicrogyria and Schizencephaly. Sources: Literature,Research 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 neurodevelopmental disorder MONDO:0700092 MAN2C1-related Review for gene: MAN2C1 was set to GREEN Added comment: Six individuals from four different families, including two fetuses, exhibiting dysmorphic facial features, congenital anomalies such as tongue hamartoma, variable degrees of intellectual disability, and brain anomalies including polymicrogyria, interhemispheric cysts, hypothalamic hamartoma, callosal anomalies, and hypoplasia of brainstem and cerebellar vermis. Variants include PTC and missense. *3 unrelated individuals presented polymicrogyria Sources: Literature, Research |
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| Polymicrogyria and Schizencephaly v0.168 | HSD17B4 |
Krithika Murali changed review comment from: Associated with DBP deficiency - severe phenotype characterized by infantile-onset of hypotonia, seizures, dysmorphic features and most die before age 2 years. Less severe presentations have been termed type IV deficiency or Perrault syndrome. Polymicrogyria has been reported with DBP deficiency (PMID 32904102 and 2921319) Sources: Literature; to: Associated with DBP deficiency - severe phenotype characterized by infantile-onset of hypotonia, seizures, dysmorphic features and most die before age 2 years. Less severe presentations have been termed type IV deficiency or Perrault syndrome. Polymicrogyria has been reported with DBP deficiency (PMID 32904102 and 2921319) Sources: Literature |
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| Polymicrogyria and Schizencephaly v0.168 | HSD17B4 |
Krithika Murali changed review comment from: Associated with DBP deficiency - severe phenotype characterized by infantile-onset of hypotonia, seizures, dysmorphic features and most die before age 2 years. Less severe presentations have been termed type IV deficiency or Perrault syndrome. Polymicrogyria has been reported with DBP deficiency (PMID 32904102) Sources: Literature; to: Associated with DBP deficiency - severe phenotype characterized by infantile-onset of hypotonia, seizures, dysmorphic features and most die before age 2 years. Less severe presentations have been termed type IV deficiency or Perrault syndrome. Polymicrogyria has been reported with DBP deficiency (PMID 32904102 and 2921319) Sources: Literature |
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| Polymicrogyria and Schizencephaly v0.168 | HSD17B4 |
Krithika Murali gene: HSD17B4 was added gene: HSD17B4 was added to Polymicrogyria and Schizencephaly. Sources: Literature Mode of inheritance for gene: HSD17B4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HSD17B4 were set to 27790638; 32904102 Phenotypes for gene: HSD17B4 were set to D-bifunctional protein deficiency - #261515; Perrault syndrome 1 - #233400 Review for gene: HSD17B4 was set to GREEN Added comment: Associated with DBP deficiency - severe phenotype characterized by infantile-onset of hypotonia, seizures, dysmorphic features and most die before age 2 years. Less severe presentations have been termed type IV deficiency or Perrault syndrome. Polymicrogyria has been reported with DBP deficiency (PMID 32904102) Sources: Literature |
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| Polymicrogyria and Schizencephaly v0.167 | ATP1A2 | Zornitza Stark Phenotypes for gene: ATP1A2 were changed from Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, MIM# 619602; Developmental and epileptic encephalopathy, polymicrogyria to Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, MIM# 619602; Developmental and epileptic encephalopathy 98 , MIM#619605 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Polymicrogyria and Schizencephaly v0.166 | ATP1A2 | Zornitza Stark edited their review of gene: ATP1A2: Changed phenotypes: Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, MIM# 619602, Developmental and epileptic encephalopathy 98, MIM# 619605 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Polymicrogyria and Schizencephaly v0.166 | ATP1A2 | Zornitza Stark Phenotypes for gene: ATP1A2 were changed from Hydrops fetalis, microcephaly, arthrogryposis, extensive cortical malformations; Developmental and epileptic encephalopathy, polymicrogyria to Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, MIM# 619602; Developmental and epileptic encephalopathy, polymicrogyria | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Polymicrogyria and Schizencephaly v0.164 | ATP1A2 | Zornitza Stark edited their review of gene: ATP1A2: Changed phenotypes: Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, MIM# 619602, Developmental and epileptic encephalopathy, polymicrogyria | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Polymicrogyria and Schizencephaly v0.153 | SHMT2 |
Zornitza Stark gene: SHMT2 was added gene: SHMT2 was added to Polymicrogyria and Schizencephaly. Sources: Literature Mode of inheritance for gene: SHMT2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SHMT2 were set to 33015733 Phenotypes for gene: SHMT2 were set to Congenital microcephaly; Infantile axial hypotonia; Spastic paraparesis; Global developmental delay; Intellectual disability; Abnormality of the corpus callosum; Abnormal cortical gyration; Hypertrophic cardiomyopathy; Abnormality of the face; Proximal placement of thumb; 2-3 toe syndactyly Review for gene: SHMT2 was set to GREEN Added comment: García‑Cazorla et al. (2020 - PMID: 33015733) report 5 individuals (from 4 families) with a novel brain and heart developmental syndrome caused by biallelic SHMT2 pathogenic variants. All affected subjects presented similar phenotype incl. microcephaly at birth (5/5 with OFC < -2 SD though in 2/5 cases N OFC was observed later), DD and ID (1/5 mild-moderate, 1/5 moderate, 3/5 severe), motor dysfunction in the form of spastic (5/5) paraparesis, ataxia/dysmetria (3/4), intention tremor (in 3/?) and/or peripheral neuropathy (2 sibs). They exhibited corpus callosum hypoplasia (5/5) and perisylvian microgyria-like pattern (4/5). Cardiac problems were reported in all, with hypertrophic cardiomyopathy in 4/5 (from 3 families) and atrial-SD in the 5th individual (1/5). Common dysmorphic features incl. long palpebral/fissures, eversion of lateral third of lower eylids, arched eyebrows, long eyelashes, thin upper lip, short Vth finger, fetal pads, mild 2-3 toe syndactyly, proximally placed thumbs. Biallelic variants were identified following exome sequencing in all (other investigations not mentioned). Identified variants were in all cases missense SNVs or in-frame del, which together with evidence from population databases and mouse model might suggest a hypomorphic effect of variants and intolerance/embryonic lethality for homozygous LoF ones. SHMT2 encodes the mitohondrial form of serine hydroxymethyltransferase. The enzyme transfers one-carbon units from serine to tetrahydrofolate (THF) and generates glycine and 5,10,methylene-THF. Mitochondrial defect was suggested by presence of ragged red fibers in myocardial biopsy of one patient. Quadriceps and myocardial biopsies of the same individual were overall suggestive of myopathic changes. While plasma metabolites were within N range and SHMT2 protein levels not significantly altered in patient fibroblasts, the authors provide evidence for impaired enzymatic function eg. presence of the SHMT2 substrate (THF) in patient but not control (mitochondria-enriched) fibroblasts , decrease in glycine/serine ratios, impared folate metabolism. Patient fibroblasts displayed impaired oxidative capacity (reduced ATP levels in a medium without glucose, diminished oxygen consumption rates). Mitochondrial membrane potential and ROS levels were also suggestive of redox malfunction. Shmt2 ko in mice was previously shown to be embryonically lethal attributed to severe mitochondrial respiration defects, although there was no observed brain metabolic defect. The authors performed Shmt2 knockdown in motoneurons in Drosophila, demonstrating neuromuscular junction (# of satellite boutons) and motility defects (climbing distance/velocity). Sources: Literature |
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| Polymicrogyria and Schizencephaly v0.94 | SMO | Zornitza Stark Marked gene: SMO as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Polymicrogyria and Schizencephaly v0.94 | SMO | Zornitza Stark Gene: smo has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Polymicrogyria and Schizencephaly v0.94 | SMO | Zornitza Stark Classified gene: SMO as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Polymicrogyria and Schizencephaly v0.94 | SMO | Zornitza Stark Gene: smo has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Polymicrogyria and Schizencephaly v0.93 | SMO | Zornitza Stark Tag somatic tag was added to gene: SMO. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Polymicrogyria and Schizencephaly v0.92 | SMO |
Paul De Fazio gene: SMO was added gene: SMO was added to Polymicrogyria and Schizencephaly. Sources: Literature Mode of inheritance for gene: SMO was set to Unknown Publications for gene: SMO were set to 27236920; 24859340 Phenotypes for gene: SMO were set to Curry-Jones syndrome, somatic mosaic MIM#601707 Mode of pathogenicity for gene: SMO 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: SMO was set to AMBER gene: SMO was marked as current diagnostic Added comment: PMID 27236920 summarises the clinical and molecular findings in 8 unrelated individuals (including individuals reported previously). All 8 had the same somatic mosaic missense variant c.1234C>T p.(Leu412Phe) (absent from gnomAD). 2 had polymicrogyria. Other brain abnormalities reported include agenesis of the corpus callosum, hemimegalencephaly, ventriculomegaly. 1 individual was reported to have a normal brain. In mouse embryonic fibroblasts, this variant results in constitutive activation (PMID: 24859340). Other, biallelic germline variants in this gene are associated with Pallister-Hall-like syndrome (MIM#241800) but the MRI findings in individuals with this syndrome don't appear to be applicable to this panel. Sources: Literature |
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| Polymicrogyria and Schizencephaly v0.89 | MAP1B | Zornitza Stark Phenotypes for gene: MAP1B were changed from Intellectual disability; seizures; PVNH; dysmorphic features to Intellectual disability; seizures; PVNH; dysmorphic features; Periventricular nodular heterotopia 9, MIM# 618918 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Polymicrogyria and Schizencephaly v0.88 | MAP1B | Zornitza Stark edited their review of gene: MAP1B: Changed phenotypes: Intellectual disability, seizures, PVNH, dysmorphic features, Periventricular nodular heterotopia 9, MIM# 618918 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Polymicrogyria and Schizencephaly v0.14 | MAP1B | Zornitza Stark Phenotypes for gene: MAP1B were changed from to Intellectual disability; seizures; PVNH; dysmorphic features | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Polymicrogyria and Schizencephaly v0.0 | MAP1B | Zornitza Stark reviewed gene: MAP1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 31317654, 30150678, 30214071; Phenotypes: Intellectual disability, seizures, PVNH, dysmorphic features; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||