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| Malformations of cortical development v7.55 | WDR91 |
Ida Ertmanska gene: WDR91 was added gene: WDR91 was added to Malformations of cortical development. Sources: Literature Q2_26_promote_green tags were added to gene: WDR91. Mode of inheritance for gene: WDR91 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: WDR91 were set to 32732226; 34028500; 34791078; 38041506; 40550703 Phenotypes for gene: WDR91 were set to Abnormal brain morphology, HP:0012443 Review for gene: WDR91 was set to GREEN Added comment: PMID: 32732226 Lefebvre et al., 2021 Homozygous variant WDR91 c.240C>G, p.(Tyr80*) detected in a male fetus with hygroma, macrocephaly, abnormal ears, cerebellar hypoplasia, and hydrocephaly. Concordant segregation among 4 affected fetus, 2 healthy sibs, and both parents. PMID: 34791078 Kurul et al., 2022 Large study, trio exome seq of consanguineous families with neurogenetic diseases. FMAL006_01 - female patient with 'brain malformation' was homozygous for WDR91 c.1395+1G>A. No more details provided. PMID: 38041506 Rosina et al., 2024 Case 75 - male, 3yrs 5mo, homozygous for WDR91 NM_014149.4:c.511+1A>G. Phenotype: severe developmental delay, microcephaly, severe microlissencephaly, agenesis of corpus callosum, epilepsy, spastic tetraparesis, laryngomalacia, bicuspid aortic valve, congenital hip dislocation, growth retardation, dysmorphisms. PMID: 40550703 Marinakis et al., 2026 Consanguineous Syrian family. Proband (4mo female) presented with severe microcephaly, dysmorphic features, organomegaly, early onset psychomotor delay, hypotonia, sensorineural hearing impairment, and visual impairment. Brain MRI revealed bilateral cerebral hemisphere hypoplasia with incomplete sulcation, agenesis of the corpus callosum, suspected bilateral periventricular heterotopias. WES identified a homozygous splice site variant, WDR91 NM_014149.4: c.1395+1G>A (same as in PMID: 34791078, but NOT the same patient). Functional: PMID: 34028500 Xing et al., 2021 - Mice lacking Wdr91 specifically in the central nervous system exhibited behavioral defects and marked neuronal loss in the cerebral and cerebellar cortices. At a cellular level, Wdr91 deficiency caused dysfunction of lysosomes, leading to accumulation of autophagic cargoes in mouse neurons. WDR91 is not yet associated with a phenotype in OMIM, G2P, or ClinGen (accessed 22nd Apr 2026). Sources: Literature |
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| Malformations of cortical development v7.52 | FBXO31 | Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated cases reported in literature with a recurrent de novo heterozygous missense variant FBXO31 p.Asp334Asn, presenting with childhood-onset spasticity, dystonia, ID, and cerebral abnormalities on MRI (including CC hypoplasia and white matter abnormalities). There are 2 recessive pedigrees reported, where individuals presented solely with intellectual disability and dysmorphic features. Hence, this gene can be promoted to Green at the next GMS update, with MOI set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Malformations of cortical development v7.51 | FBXO31 |
Ida Ertmanska gene: FBXO31 was added gene: FBXO31 was added to Malformations of cortical development. Sources: Literature Q2_26_promote_green tags were added to gene: FBXO31. Mode of inheritance for gene: FBXO31 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FBXO31 were set to 24623383; 32989326; 33675180; 35019165; 41640354; 41640354 Phenotypes for gene: FBXO31 were set to neurodevelopmental disorder, MONDO:0700092; ?Intellectual developmental disorder, autosomal recessive 45, OMIM:615979 Review for gene: FBXO31 was set to GREEN Added comment: MONOALLELIC CASES: PMID: 32989326 Jin et al., 2020 Report of 2 unrelated patients with the same de novo FBXO31 mutation 16:87367889:C:T, p.Asp334Asn. Disease onset was under age two years. F218-003 - Female, European, presented with spastic diplegia, as well as Esotropia, ID, dysarthria, mixed receptive/expressive language disorder, ADHD, cleft palate, intestinal malrotation and midgut volvulus. F699-003 - Male, European, presented with spastic paraplegia, as well as Ventricular dilation and thin corpus callosum, ID, attention deficit, anxiety, language impairments, strabismus, severe constipation. PMID: 33675180 Dzinovic et al., 2021 Report of a 9yo boy of Slovakian descent, with a de novo FBXO31 variant c.1000G>A (p.Asp334Asn) - trio WES. He presented with complex, non‐progressive movement‐disorder syndrome dominated by spasticity and dystonia. Brain MRI showed bilateral occipital and parietal white‐matter volume reduction, irregular white‐matter dysmyelination. Intellectual disability estimated at Moderate severity (no IQ assessment; loss of speech at the age of 1.5 years, receptive language disorder) FBXO31 p.Asp334Asn is not reported in gnomAD v4.1.0. Revel prediction is Uncertain (0.46). PMID: 41858232 Galaz-Montoya et al., 2026 4 additional probands reported, all with the de novo FBXO31 p.Asp334Asn heterozygous variant. Core phenotypes: "cerebral palsy" i.e. mix of spasticity, dystonia, and hypotonia; ID/GDD, and speech impairment. Age of onset: at birth or very early childhood. Brain MRI showed hypoplastic corpus callosum (3/4), ventriculomegaly (2/4), and white matter abnormalitites (2/4). Authors propose the monoallelic disorder could be called "Kruer syndrome". PMID: 41640354 Schierbaum et al., 2026 13yo patient with with spastic diplegia, ID, and abnormal brain MRI findings: "ears of the lynx", thin corpus callosum, and periventricular white matter changes. Trio WGS showed that he had a de novo FBXO31 NM_024735.5, c.1000G>A, p.(Asp334Asn) variant. BIALLELIC CASES: PMID: 24623383 Mir et al., 2014 Consanguineous Pakistani pedigree, FBXO31 p.(Cys283Asnfs*81) segregated with intellectual disability in a recessive manner. Method: autozygosity mapping, WES, Sanger seq. PMID: 35019165 Moudi et al., 2022 Iranian consanguineous pedigree, 2 sibs with a homozygous FBXO31 c.1532G>A, p.Arg511Gln variant (7 alleles in gnomAD v4.1.1, no homozygotes). Heterozygous family members not affected. Phenotype: moderate ID, developmental delay, dysmorphic facial features. FBXO31 is putatively linked to AR ?Intellectual developmental disorder, autosomal recessive 45, OMIM:615979 in OMIM (accessed 13th Apr 2026). Sources: Literature |
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| Malformations of cortical development v7.49 | MYCBP2 |
Ida Ertmanska gene: MYCBP2 was added gene: MYCBP2 was added to Malformations of cortical development. Sources: Literature Q2_26_promote_green tags were added to gene: MYCBP2. Mode of inheritance for gene: MYCBP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MYCBP2 were set to 33875846; 36200388; 41200582; 41543631 Phenotypes for gene: MYCBP2 were set to neurodevelopmental disorder, MONDO:0700092 Review for gene: MYCBP2 was set to GREEN Added comment: PMID: 33875846 Bertoli-Avella et al., 2021 Large WES/WGS cohort. Study detected three de novo variants (one likely affecting splicing and two missense) in three patients with NDD, microcephaly, and seizures. One case presented bilateral bifid thumbs, talipes, and scoliosis, without vaginal or uterine anomalies. No variants details. PMID: 36200388 AlAbdi et al., 2023 Eight patients (7 male, 1 female) with de novo MYCBP2 variants. Phenotypic spectrum: ID (4/8, moderate to severe), GDD (7/8), corpus callosum thinning / dysgenesis / agenesis (4/5). 2 patients had seizures and 1 had abnormal EEG; 1 patient diagnosed with cone dystrophy, one with retinopathy; 2 patients had hearing loss. PMID: 41200582 Kostovska et al., 2025 Family with three affected members (mother and 2 sons aged 3yrs and 9 mo) carrying a novel heterozygous MYCBP2 variant NM_015057.5 c.7311del, p.(Leu2438Trpfs*3). Phenotypes: mild intellectual disability, dev delay, speech impairment, facial dysmorphism, microcephaly, seizures (only in the mother). Brain MRI not done. PMID: 41543631 Pham et al., 2026 Proband with a maternally inherited c.4409dup (p.Leu1470Phefs*7), presented with global developmental delay, autism spectrum disorder (ASD), chronic constipation, sleep disturbances, and aggressive behaviors. Brain MRI showed normal corpus callosum. Mother had generally intact cognition (FSIQ = 103). MYCBP2 is not yet associated with disease in OMIM (accessed 1st Apr 2026). Sources: Literature |
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| Malformations of cortical development v7.47 | RDH11 |
Ida Ertmanska changed review comment from: PMID: 41904678 Radio et al., 2026 Report of 16 affected individuals from 9 unrelated families with biallelic LoF RDH11 variants, frequently showing juvenile-onset progressive myopathy with vacuolar degeneration and prodromic asymptomatic hyperCKemia. Common features included: neurodevelopmental impairment (16/16), microcephaly (10/16), retinitis pigmentosa (8/16), juvenile-onset cataracts (11/16), myopathy (8/15), progressive night blindness (9/16), hypoplasia of corpus callosum (8/10 assessed by MRI). Microcephaly and distinct craniofacial traits were also recurrent. Short stature was reported in 4/16 patients. Muscle weakness was reported as slowly progressive, associated with myopathic facies and exercise intolerance with onset in the first or second decade of life. PMID: 41459630 Stephenson et al., 2025 Report of a visually asymptomatic 7-year-old boy carrying a homozygous null variant in RDH11 [NM_016026.4:c.216C>A:p.(Cys72*)] with autism, dysmorphic features, oligodontia, microcephaly (<3rd centile) and a novel inherited retinal dystrophy. This retinopathy consisted of yellow deposits and hyperpigmentation within the RPE with absent autofluorescence and a normal electroretinogram. PMID: 34988992 Liu et al., 2022 Chinese patient with retinitis pigmentosa (RP), juvenile cataracts, intellectual disability, and myopathy. No microcephaly. Trio WES identified variants in RDH11: c.938T>C (p.Leu313Pro) and c.75-3C>A - confirmed in trans. Splice variant shown to cause exon 2 skipping resulting in (p.Lys26Serfs*38) change. Using immunofluorescence, authors found mislocalization of RDH11 protein in muscle cells of the patient. PMID: 24916380 Xie et al., 2014 3 sibs aged 8-19 years (Italian-American family) with juvenile cataracts (onset at 8-10 years old), issues with night vision, and retinitis pigmentosa, as well as other syndromic features: facial dysmorphologies, psychomotor developmental delays, learning disabilities and short stature. WES detected comp het RDH11 mutations c.C199T:p.R67* and c.C322T:p.R108*. No mention of muscle weakness or microcephaly. RDH11 is putatively associated in OMIM with AR Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108 (accessed 1st Apr 2026). Sources: Literature; to: PMID: 41904678 Radio et al., 2026 Report of 16 affected individuals from 9 unrelated families with biallelic LoF RDH11 variants, frequently showing juvenile-onset progressive myopathy with vacuolar degeneration and prodromic asymptomatic hyperCKemia. Common features included: neurodevelopmental impairment (16/16), microcephaly (10/16), retinitis pigmentosa (8/16), juvenile-onset cataracts (11/16), myopathy (8/15), progressive night blindness (9/16), hypoplasia of corpus callosum (8/10 assessed by MRI). Microcephaly and distinct craniofacial traits were also recurrent. Short stature was reported in 4/16 patients. Muscle weakness was reported as slowly progressive, associated with myopathic facies and exercise intolerance with onset in the first or second decade of life. PMID: 41459630 Stephenson et al., 2025 Report of a visually asymptomatic 7-year-old boy carrying a homozygous null variant in RDH11 [NM_016026.4:c.216C>A:p.(Cys72*)] with autism, dysmorphic features, oligodontia, microcephaly (<3rd centile) and a novel inherited retinal dystrophy. This retinopathy consisted of yellow deposits and hyperpigmentation within the RPE with absent autofluorescence and a normal electroretinogram. No mention of brain imaging. PMID: 34988992 Liu et al., 2022 15yo Chinese patient with retinitis pigmentosa (RP), juvenile cataracts, intellectual disability, and myopathy. No microcephaly seen, no abnormalities found on MRI. First admitted to the clinic at 7 years old. Trio WES identified variants in RDH11: c.938T>C (p.Leu313Pro) and c.75-3C>A - confirmed in trans. Splice variant shown to cause exon 2 skipping resulting in (p.Lys26Serfs*38) change. Using immunofluorescence, authors found mislocalization of RDH11 protein in muscle cells of the patient. PMID: 24916380 Xie et al., 2014 3 sibs aged 8-19 years (Italian-American family) with juvenile cataracts (onset at 8-10 years old), issues with night vision, and retinitis pigmentosa, as well as other syndromic features: facial dysmorphologies, psychomotor developmental delays, learning disabilities and short stature. WES detected comp het RDH11 mutations c.C199T:p.R67* and c.C322T:p.R108*. No mention of muscle weakness or microcephaly. No brain imaging done. RDH11 is putatively associated in OMIM with AR Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108 (accessed 1st Apr 2026). Sources: Literature |
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| Malformations of cortical development v7.47 | RDH11 |
Ida Ertmanska gene: RDH11 was added gene: RDH11 was added to Malformations of cortical development. Sources: Literature Q2_26_promote_green tags were added to gene: RDH11. Mode of inheritance for gene: RDH11 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RDH11 were set to 24916380; 34988992; 41459630; 41904678 Phenotypes for gene: RDH11 were set to ?Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108; Neurodevelopmental delay, HP:0012758; Juvenile cataract, HP:0001118 Review for gene: RDH11 was set to GREEN Added comment: PMID: 41904678 Radio et al., 2026 Report of 16 affected individuals from 9 unrelated families with biallelic LoF RDH11 variants, frequently showing juvenile-onset progressive myopathy with vacuolar degeneration and prodromic asymptomatic hyperCKemia. Common features included: neurodevelopmental impairment (16/16), microcephaly (10/16), retinitis pigmentosa (8/16), juvenile-onset cataracts (11/16), myopathy (8/15), progressive night blindness (9/16), hypoplasia of corpus callosum (8/10 assessed by MRI). Microcephaly and distinct craniofacial traits were also recurrent. Short stature was reported in 4/16 patients. Muscle weakness was reported as slowly progressive, associated with myopathic facies and exercise intolerance with onset in the first or second decade of life. PMID: 41459630 Stephenson et al., 2025 Report of a visually asymptomatic 7-year-old boy carrying a homozygous null variant in RDH11 [NM_016026.4:c.216C>A:p.(Cys72*)] with autism, dysmorphic features, oligodontia, microcephaly (<3rd centile) and a novel inherited retinal dystrophy. This retinopathy consisted of yellow deposits and hyperpigmentation within the RPE with absent autofluorescence and a normal electroretinogram. PMID: 34988992 Liu et al., 2022 Chinese patient with retinitis pigmentosa (RP), juvenile cataracts, intellectual disability, and myopathy. No microcephaly. Trio WES identified variants in RDH11: c.938T>C (p.Leu313Pro) and c.75-3C>A - confirmed in trans. Splice variant shown to cause exon 2 skipping resulting in (p.Lys26Serfs*38) change. Using immunofluorescence, authors found mislocalization of RDH11 protein in muscle cells of the patient. PMID: 24916380 Xie et al., 2014 3 sibs aged 8-19 years (Italian-American family) with juvenile cataracts (onset at 8-10 years old), issues with night vision, and retinitis pigmentosa, as well as other syndromic features: facial dysmorphologies, psychomotor developmental delays, learning disabilities and short stature. WES detected comp het RDH11 mutations c.C199T:p.R67* and c.C322T:p.R108*. No mention of muscle weakness or microcephaly. RDH11 is putatively associated in OMIM with AR Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108 (accessed 1st Apr 2026). Sources: Literature |
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| Malformations of cortical development v7.33 | ZNF865 |
Ida Ertmanska gene: ZNF865 was added gene: ZNF865 was added to Malformations of cortical development. Sources: Literature Q1_26_promote_green tags were added to gene: ZNF865. Mode of inheritance for gene: ZNF865 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ZNF865 were set to 40936200 Phenotypes for gene: ZNF865 were set to neurodevelopmental disorder, MONDO:0700092 Review for gene: ZNF865 was set to GREEN Added comment: PMID: 40936200 Bradbrook et al., 2025 Report of 18 unrelated individuals (Caucasian / Latino ethnicity) with developmental delay and shared dysmorphic features, harbouring heterozygous variants in ZNF865. Method: WGS / WES. Majority described as severely delayed, with speech delay and moderate to severe learning difficulties; avg age of walking = 24 months, 9/18 patients presented with hypotonia, 1 patient diagnosed with epilepsy, 9/15 had digit anomalies. On MRI, 8/14 patients had brain abnormalities, including hypoplasia of corpus callosum and ventriculomegaly. Shared dysmorphic features: broad nasal bridge, hypertelorism, low-set ears. 14 unique variants (nonsense of frameshift) were detected, mostly towards the C-terminus. Variants were confirmed as de novo in 15 individuals. This gene is not yet linked to any phenotype in OMIM (accessed 10th Mar 2026). Sources: Literature |
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| Malformations of cortical development v7.30 | ATP1A2 |
Ida Ertmanska edited their review of gene: ATP1A2: Added comment: PMID: 37870493 Furukawa et al., 2023 Male individual born at 28 weeks, with respiratory distress and tonic seizures soon after birth. At 10 months presented with hypotonia, cryptorchidism, generalised tonic and facial clonic seizures, no eye contact or social responses. Brain MRI showed a markedly simplified gyral pattern. He was compound heterozygous for ATP1A2: c.1234C>T, p.Arg412* & ATP1A2: c.2288G>T, p.Arg763Leu - confirmed in trans.; Changed rating: GREEN; Changed publications to: 37870493; Changed phenotypes to: Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, OMIM:619602; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal |
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| Malformations of cortical development v7.30 | ATP1A2 | Ida Ertmanska Phenotypes for gene: ATP1A2 were changed from hydrops fetalis; microcephaly; arthrogryposis; extensive cortical malformations to Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, OMIM:619602 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Malformations of cortical development v7.22 | ASTN1 |
Ida Ertmanska gene: ASTN1 was added gene: ASTN1 was added to Malformations of cortical development. Sources: Literature Q1_26_promote_green tags were added to gene: ASTN1. Mode of inheritance for gene: ASTN1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ASTN1 were set to 41544630 Phenotypes for gene: ASTN1 were set to neurodevelopmental disorder, MONDO:0700092 Review for gene: ASTN1 was set to GREEN Added comment: PMID: 41544630 Levine et al., 2026 Report of 18 individuals from 12 unrelated families with biallelic ASTN1 variants and a neurodevelopmental disorder, plus one individual with digenic inheritance with heterozygous variants in ASTN1 and ASTN2. Of these, 6 families are previously unreported (F1-6). Method: exome seq. Phenotypic spectrum: ID/DD (18/18 - mild to severe), seizures and/or epileptiform activity on EEG (10/18), subtle dysmorphic features (11/18), hypotonia (10/18), ataxia (4/18), hyperreflexia (5/18), and other less common findings. Brain MRI was abnormal in 11/15 tested individuals, with callosal dysgenesis (7/15) and dysgenesis of the cerebellum (5/15) being most common findings. Variants included missense, nonsense, and splice type. 2 patients had other candidate variants reported: P1 - KDM3A:c.1639C>T, (p.Arg547Ter) de novo, heterozygous P4 - TRAK2:c.1675C>T, (p.Gln559Ter) homozygous Neither of these genes is linked to disease in OMIM. ASTN1 is not yet associated with disease in OMIM, ClinGen, or Gene2Phenotype (resources accessed 10th Feb 2026). Sources: Literature |
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| Malformations of cortical development v7.14 | KIF26A |
Ida Ertmanska changed review comment from: At least 13 patients from 10 families have been described in literature with biallelic variants in KIF26A and KIF26A‐related disorder (PMIDs: 36228617; 36564622; 39305096). The heterogenous syndromic presentation may include developmental delay / intellectual disability (6/8, mild to moderate), cardiac defects (6/7), neurological features e.g. hypotonia (2), spasticity (2), paediatric intestinal pseudo‐obstruction (PIPO) (3/13). While only 3/13 patients were diagnosed with PIPO, 8/13 patients had gastrointestinal issues, including megacolon, ischemic small bowels, severe ascites, abdominal distension, vomiting, and intestinal obstruction. Note: several individuals died before certain clinical features could be assessed. Brain MRI showed Ventriculomegaly/Hydrocephalus in 12/12 patients and corpus callosum agenesis / hypoplasia in 7/12 cases; unavailable in 1 case. Other malformations noted on MRI: Hypogenesis of septum pellucidum, Brainstem patterning disorder, Long midbrain, Small pons, Brain atrophy, Reduced white matter, Bilateral schizencephaly, Absent hippocampal commissure. PMID: 39305096 Nosrati et al., 2025 Seq method: Trio exome. Case #1 - 8yo Italian male; at birth: axial hypotonia, poor suction, failed to pass meconium, leading to surgery for Hirschsprung's disease. Compound het c.4378C > T, p.(Arg1460Trp); c.5238C > G, p.(Phe1746Leu). Case #2 - 6mo Syrian female; presented with abdominal distension and intestinal obstruction symptoms; imaging revealed dilated bowels without mechanical obstruction; biopsies of small and large intestine showed hypoganglionosis. Homozygous for c.4085dup, p.(Ala1363Glyfs*47). Case #3 - female born to consanguineous parents (Palestinian / Jordanian) - very different presentation: severe spastic quadriplegic cerebral palsy (CP) with epilepsy, hearing problems and cognitive impairments. Homozygous for c.3996C > A, p.(Cys1332*). PMID: 36564622 Almannai et al., 2023 Seq method: clinical WES. Report of 2 families with KIF26A‐related disorder. Family 1: 4 affected individuals, homozygous for c.792dupC, p.(Val265Argfs*5), all presented with persistent abdominal distension and vomiting after birth. 3 individuals died between 2-11 months, 1 patient alive at 3.5 years. Family 2: proband presented at 3 months with symptoms indicating intestinal obstruction and marked abdominal distension. Symptoms persist at 7yo. Homozygous for c.3330delC, p.(Ser1111Alafs*137). 36228617 Qian et al., 2022 Seq method: WES. 5 unrelated subjects with congenital brain malformations who had inherited biallelic mutations in KIF26A A01 - consanguineous Turkish family, microcephaly (−3.45SD) and an MRI suggesting a component of cerebral atrophy, as well as dysmorphic features and ileus with megacolon. Homozygous for c.3440dupC, p.Ala1148Cysfs*20. B01 - diagnosed prenatally with bilateral schizencephaly at 21 weeks; pregnancy terminated; compound heterozygous c.2161C>T, p.Arg721Cys, and c.4676C>T, p.Ala1559Val C01 - male, non-consanguineous parents, presented with mild developmental delay and learning disability. Brain MRI at 18 years demonstrated agenesis of the corpus callosum; compound het KIF26A: c.4676C>T, p.Arg1624Cys, and c.4870C>T, p.Ala1559Val D01 - was diagnosed with polymicrogyria and hydrocephalus, with inherited compound heterozygous variants in KIF26A: c.2845C>T, p.Pro949Ser, and c.4676C>T, p.Ala1559Val E01 - male born to consanguineous parents with growth retardation and developmental delay. Brain MRI performed at 18 months revealed a thin CC, ventriculomegaly and polymicrogyria; homozygous for c.4804C>T; p.Arg1602Trp. KIF26A is associated with Cortical dysplasia, complex, with other brain malformations 11, 620156 in OMIM (accessed 31st Oct 2025). Sources: Other; to: At least 13 patients from 10 families have been described in literature with biallelic variants in KIF26A and KIF26A‐related disorder (PMIDs: 36228617; 36564622; 39305096). The heterogenous syndromic presentation may include developmental delay / intellectual disability (6/8, mild to moderate), cardiac defects (6/7), neurological features e.g. hypotonia (2), spasticity (2), paediatric intestinal pseudo‐obstruction (PIPO) (3/13). While only 3/13 patients were diagnosed with PIPO, 8/13 patients had gastrointestinal issues, including megacolon, ischemic small bowels, severe ascites, abdominal distension, vomiting, and intestinal obstruction. Note: several individuals died before certain clinical features could be assessed. Brain MRI showed Ventriculomegaly/Hydrocephalus in 12/12 patients and corpus callosum agenesis / hypoplasia in 7/12 cases; unavailable in 1 case. Other malformations noted on MRI: Hypogenesis of septum pellucidum, Brainstem patterning disorder, Long midbrain, Small pons, Brain atrophy, Reduced white matter, Bilateral schizencephaly, Absent hippocampal commissure. PMID: 39305096 Nosrati et al., 2025 Seq method: Trio exome. Case #1 - 8yo Italian male; at birth: axial hypotonia, poor suction, failed to pass meconium, leading to surgery for Hirschsprung's disease. Compound het c.4378C > T, p.(Arg1460Trp); c.5238C > G, p.(Phe1746Leu). Case #2 - 6mo Syrian female; presented with abdominal distension and intestinal obstruction symptoms; imaging revealed dilated bowels without mechanical obstruction; biopsies of small and large intestine showed hypoganglionosis. Homozygous for c.4085dup, p.(Ala1363Glyfs*47). Case #3 - female born to consanguineous parents (Palestinian / Jordanian) - very different presentation: severe spastic quadriplegic cerebral palsy (CP) with epilepsy, hearing problems and cognitive impairments. Homozygous for c.3996C > A, p.(Cys1332*). PMID: 36564622 Almannai et al., 2023 Seq method: clinical WES. Report of 2 families with KIF26A‐related disorder. Family 1: 4 affected individuals, homozygous for c.792dupC, p.(Val265Argfs*5), all presented with persistent abdominal distension and vomiting after birth. 3 individuals died between 2-11 months, 1 patient alive at 3.5 years. Family 2: proband presented at 3 months with symptoms indicating intestinal obstruction and marked abdominal distension. Symptoms persist at 7yo. Homozygous for c.3330delC, p.(Ser1111Alafs*137). 36228617 Qian et al., 2022 Seq method: WES. 5 unrelated subjects with congenital brain malformations who had inherited biallelic mutations in KIF26A A01 - consanguineous Turkish family, microcephaly (−3.45SD) and an MRI suggesting a component of cerebral atrophy, as well as dysmorphic features and ileus with megacolon. Homozygous for c.3440dupC, p.Ala1148Cysfs*20. B01 - diagnosed prenatally with bilateral schizencephaly at 21 weeks; pregnancy terminated; compound heterozygous c.2161C>T, p.Arg721Cys, and c.4676C>T, p.Ala1559Val C01 - male, non-consanguineous parents, presented with mild developmental delay and learning disability. Brain MRI at 18 years demonstrated agenesis of the corpus callosum; compound het KIF26A: c.4676C>T, p.Arg1624Cys, and c.4870C>T, p.Ala1559Val D01 - was diagnosed with polymicrogyria and hydrocephalus, with inherited compound heterozygous variants in KIF26A: c.2845C>T, p.Pro949Ser, and c.4676C>T, p.Ala1559Val E01 - male born to consanguineous parents with growth retardation and developmental delay. Brain MRI performed at 18 months revealed a thin CC, ventriculomegaly and polymicrogyria; homozygous for c.4804C>T; p.Arg1602Trp. KIF26A is associated with Cortical dysplasia, complex, with other brain malformations 11, 620156 in OMIM (accessed 31st Oct 2025). The association of KIF26A and 'complex cortical dysplasia with other brain malformations' is classified as Strong in ClinGen (March 2024). |
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| Malformations of cortical development v7.13 | KIF26A |
Ida Ertmanska gene: KIF26A was added gene: KIF26A was added to Malformations of cortical development. Sources: Other Q4_25_promote_green tags were added to gene: KIF26A. Mode of inheritance for gene: KIF26A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: KIF26A were set to 36228617; 36564622; 39305096 Phenotypes for gene: KIF26A were set to Cortical dysplasia, complex, with other brain malformations 11, OMIM:620156; cortical dysplasia, complex, with other brain malformations 11 MONDO:0859332 Review for gene: KIF26A was set to GREEN Added comment: At least 13 patients from 10 families have been described in literature with biallelic variants in KIF26A and KIF26A‐related disorder (PMIDs: 36228617; 36564622; 39305096). The heterogenous syndromic presentation may include developmental delay / intellectual disability (6/8, mild to moderate), cardiac defects (6/7), neurological features e.g. hypotonia (2), spasticity (2), paediatric intestinal pseudo‐obstruction (PIPO) (3/13). While only 3/13 patients were diagnosed with PIPO, 8/13 patients had gastrointestinal issues, including megacolon, ischemic small bowels, severe ascites, abdominal distension, vomiting, and intestinal obstruction. Note: several individuals died before certain clinical features could be assessed. Brain MRI showed Ventriculomegaly/Hydrocephalus in 12/12 patients and corpus callosum agenesis / hypoplasia in 7/12 cases; unavailable in 1 case. Other malformations noted on MRI: Hypogenesis of septum pellucidum, Brainstem patterning disorder, Long midbrain, Small pons, Brain atrophy, Reduced white matter, Bilateral schizencephaly, Absent hippocampal commissure. PMID: 39305096 Nosrati et al., 2025 Seq method: Trio exome. Case #1 - 8yo Italian male; at birth: axial hypotonia, poor suction, failed to pass meconium, leading to surgery for Hirschsprung's disease. Compound het c.4378C > T, p.(Arg1460Trp); c.5238C > G, p.(Phe1746Leu). Case #2 - 6mo Syrian female; presented with abdominal distension and intestinal obstruction symptoms; imaging revealed dilated bowels without mechanical obstruction; biopsies of small and large intestine showed hypoganglionosis. Homozygous for c.4085dup, p.(Ala1363Glyfs*47). Case #3 - female born to consanguineous parents (Palestinian / Jordanian) - very different presentation: severe spastic quadriplegic cerebral palsy (CP) with epilepsy, hearing problems and cognitive impairments. Homozygous for c.3996C > A, p.(Cys1332*). PMID: 36564622 Almannai et al., 2023 Seq method: clinical WES. Report of 2 families with KIF26A‐related disorder. Family 1: 4 affected individuals, homozygous for c.792dupC, p.(Val265Argfs*5), all presented with persistent abdominal distension and vomiting after birth. 3 individuals died between 2-11 months, 1 patient alive at 3.5 years. Family 2: proband presented at 3 months with symptoms indicating intestinal obstruction and marked abdominal distension. Symptoms persist at 7yo. Homozygous for c.3330delC, p.(Ser1111Alafs*137). 36228617 Qian et al., 2022 Seq method: WES. 5 unrelated subjects with congenital brain malformations who had inherited biallelic mutations in KIF26A A01 - consanguineous Turkish family, microcephaly (−3.45SD) and an MRI suggesting a component of cerebral atrophy, as well as dysmorphic features and ileus with megacolon. Homozygous for c.3440dupC, p.Ala1148Cysfs*20. B01 - diagnosed prenatally with bilateral schizencephaly at 21 weeks; pregnancy terminated; compound heterozygous c.2161C>T, p.Arg721Cys, and c.4676C>T, p.Ala1559Val C01 - male, non-consanguineous parents, presented with mild developmental delay and learning disability. Brain MRI at 18 years demonstrated agenesis of the corpus callosum; compound het KIF26A: c.4676C>T, p.Arg1624Cys, and c.4870C>T, p.Ala1559Val D01 - was diagnosed with polymicrogyria and hydrocephalus, with inherited compound heterozygous variants in KIF26A: c.2845C>T, p.Pro949Ser, and c.4676C>T, p.Ala1559Val E01 - male born to consanguineous parents with growth retardation and developmental delay. Brain MRI performed at 18 months revealed a thin CC, ventriculomegaly and polymicrogyria; homozygous for c.4804C>T; p.Arg1602Trp. KIF26A is associated with Cortical dysplasia, complex, with other brain malformations 11, 620156 in OMIM (accessed 31st Oct 2025). Sources: Other |
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| Malformations of cortical development v7.7 | CDK5 |
Arina Puzriakova gene: CDK5 was added gene: CDK5 was added to Malformations of cortical development. Sources: Literature Q3_25_promote_green tags were added to gene: CDK5. Mode of inheritance for gene: CDK5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CDK5 were set to 25560765; 40186457; 28854363; 8855328 Phenotypes for gene: CDK5 were set to Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342 Review for gene: CDK5 was set to GREEN Added comment: - PMID: 25560765 (2015) - Homozygous splice site variant g.IVS8+1G>A p.V162SfsX19 segregated with a lethal form of lissencephaly with cerebellar hypoplasia in 4 patients and 25 healthy relatives from one consanguineous family. Affected newborns had dysmorphic facial features, HC in normal-low range, lymphedema, arthrogryposis multiplex, and intractable seizures. Functional studies of the variant showed loss-of-function of the gene product. - PMID: 40186457 (2025) - Homozygous missense variant c.149G>A (p.Arg50Gln) in an infant with diffuse agyria, cerebellar hypoplasia, agenesis of the corpus callosum, refractory seizures, pyramidal signs, microcephaly, and growth failure. The disease course and severity were similar to those observed in the patients in the first report. Functional studies support deleterious effect of the variant. Animal models: Brains of Cdk5-null mice lacked cortical laminar structure and cerebellar foliation (PMID: 8855328). Cdk5 knockout in the ferret cerebral cortex also markedly impaired cortical folding (PMID: 28854363). Sources: Literature |
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| Malformations of cortical development v5.4 | COL3A1 |
Eleanor Williams changed review comment from: Associated with Polymicrogyria with or without vascular-type EDS in OMIM (OMIM:618343) with a autosomal recessive mode of inheritance. Several cases reported: PMID: 19455184 Plancke et al 2009 - report an 11 year old female with consangiuneous parents, who had vascular EDS. The phenotype also included diffuse cortical dysplasia. A homozygous nucleotide duplication (c.479dupT) in COL3A1 resulting in a premature termination codon (p.Lys161GlnfsX45) was identified. Both parents were heterozygous for this variant. PMID: 25205403 Jørgensen et al 2015 - report 2 siblings who are compound heterozygous for COL3A1 sequence variants. One sibling died suddenly due to extensive aortic dissection at age 15. The younger sibling was cerebral cortical dysplasia with thickened frontoparietal cortices bilaterally, small gyri and findings consistent with pachy micropolygyria PMID:28742248 - Horn et al 2017 identified biallelic COL3A1 variants in two unrelated families. A 3-year-old female with developmental delay was compound het for a nonsense variant c.1282C>T, p.(Arg428*) and a frameshift variant c.2057delC, p.(Pro686Leufs*105). The patient phenotype at birth was bilateral clubfoot, joint laxity, and dysmorphic facial features an at age 2 years cerebral MRI showed a profound cerebral abnormalities including bilateral frontoparietal polymicrogyria of the cobblestone variant. In the second family, the two affected siblings were homozygous for the missense variant c.145C<G, p.(Pro49Ala) of COL3A1 and showed cobblestone-like cortical malformation, cerebellar cysts, and white matter abnormalities, developmental delay, and seizures. PMID: 28258187 - Vandervore et al 2017 - exome analysis of a family consisting of two affected and two non-affected siblings identified a novel homozygous variant c.145C>G (p.Pro49Ala) in exon 2 of COL3A1 in the affected siblings. Both patients had cobblestone-like malformation of the cortex and the white matter was severely abnormal. ; to: Associated with Polymicrogyria with or without vascular-type EDS in OMIM (OMIM:618343) with a autosomal recessive mode of inheritance. Several cases reported: PMID: 19455184 Plancke et al 2009 - report an 11 year old female with consangiuneous parents, who had vascular EDS. The phenotype also included diffuse cortical dysplasia. A homozygous nucleotide duplication (c.479dupT) in COL3A1 resulting in a premature termination codon (p.Lys161GlnfsX45) was identified. Both parents were heterozygous for this variant. PMID: 25205403 Jørgensen et al 2015 - report 2 siblings who are compound heterozygous for COL3A1 sequence variants. One sibling died suddenly due to extensive aortic dissection at age 15. The younger sibling was cerebral cortical dysplasia with thickened frontoparietal cortices bilaterally, small gyri and findings consistent with pachy micropolygyria PMID:28742248 - Horn et al 2017 identified biallelic COL3A1 variants in two unrelated families. A 3-year-old female with developmental delay was compound het for a nonsense variant c.1282C>T, p.(Arg428*) and a frameshift variant c.2057delC, p.(Pro686Leufs*105). The patient phenotype at birth was bilateral clubfoot, joint laxity, and dysmorphic facial features an at age 2 years cerebral MRI showed a profound cerebral abnormalities including bilateral frontoparietal polymicrogyria of the cobblestone variant. In the second family (born of unrelated parents from Chechnya and Ingushetia), the two affected siblings were homozygous for the missense variant c.145C<G, p.(Pro49Ala) of COL3A1 and showed cobblestone-like cortical malformation, cerebellar cysts, and white matter abnormalities, developmental delay, and seizures. PMID: 28258187 - Vandervore et al 2017 - exome analysis of a family with unrelated parents from the same mountain village in Chechnya, consisting of two affected and two non-affected siblings identified a novel homozygous variant c.145C>G (p.Pro49Ala) in exon 2 of COL3A1 in the affected siblings. Both patients had cobblestone-like malformation of the cortex and the white matter was severely abnormal. |
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| Malformations of cortical development v5.4 | COL3A1 |
Eleanor Williams changed review comment from: Associated with Polymicrogyria with or without vascular-type EDS in OMIM (OMIM:618343) with a autosomal recessive mode of inheritance. Several cases reported: PMID: 19455184 Plancke et al 2009 - report an 11 year old female with consangiuneous parents, who had vascular EDS. The phenotype also included diffuse cortical dysplasia. A homozygous nucleotide duplication (c.479dupT) in COL3A1 resulting in a premature termination codon (p.Lys161GlnfsX45) was identified. Both parents were heterozygous for this variant. PMID: 25205403 Jørgensen et al 2015 - report 2 siblings who are compound heterozygous for COL3A1 sequence variants. One sibling died suddenly due to extensive aortic dissection at age 15. The younger sibling was cerebral cortical dysplasia with thickened frontoparietal cortices bilaterally, small gyri and findings consistent with pachy micropolygyria Sources: Literature; to: Associated with Polymicrogyria with or without vascular-type EDS in OMIM (OMIM:618343) with a autosomal recessive mode of inheritance. Several cases reported: PMID: 19455184 Plancke et al 2009 - report an 11 year old female with consangiuneous parents, who had vascular EDS. The phenotype also included diffuse cortical dysplasia. A homozygous nucleotide duplication (c.479dupT) in COL3A1 resulting in a premature termination codon (p.Lys161GlnfsX45) was identified. Both parents were heterozygous for this variant. PMID: 25205403 Jørgensen et al 2015 - report 2 siblings who are compound heterozygous for COL3A1 sequence variants. One sibling died suddenly due to extensive aortic dissection at age 15. The younger sibling was cerebral cortical dysplasia with thickened frontoparietal cortices bilaterally, small gyri and findings consistent with pachy micropolygyria PMID:28742248 - Horn et al 2017 identified biallelic COL3A1 variants in two unrelated families. A 3-year-old female with developmental delay was compound het for a nonsense variant c.1282C>T, p.(Arg428*) and a frameshift variant c.2057delC, p.(Pro686Leufs*105). The patient phenotype at birth was bilateral clubfoot, joint laxity, and dysmorphic facial features an at age 2 years cerebral MRI showed a profound cerebral abnormalities including bilateral frontoparietal polymicrogyria of the cobblestone variant. In the second family, the two affected siblings were homozygous for the missense variant c.145C<G, p.(Pro49Ala) of COL3A1 and showed cobblestone-like cortical malformation, cerebellar cysts, and white matter abnormalities, developmental delay, and seizures. PMID: 28258187 - Vandervore et al 2017 - exome analysis of a family consisting of two affected and two non-affected siblings identified a novel homozygous variant c.145C>G (p.Pro49Ala) in exon 2 of COL3A1 in the affected siblings. Both patients had cobblestone-like malformation of the cortex and the white matter was severely abnormal. |
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| Malformations of cortical development v4.2 | RAC3 |
Arina Puzriakova gene: RAC3 was added gene: RAC3 was added to Malformations of cortical development. Sources: Literature,Expert Review Green Mode of inheritance for gene: RAC3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: RAC3 were set to 29276006; 30293988; 35851598; 35595279 Phenotypes for gene: RAC3 were set to Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies, OMIM:618577 Penetrance for gene: RAC3 were set to unknown Mode of pathogenicity for gene: RAC3 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments |
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| Malformations of cortical development v2.143 | SOX11 | Sarah Leigh Phenotypes for gene: SOX11 were changed from intellectual disability; facial dysmorphism; microcephaly; digit anomalies; central nervous system malformations to Coffin-Siris syndrome 9, OMIM:615866 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Malformations of cortical development v2.141 | SOX11 |
Tracy Lester gene: SOX11 was added gene: SOX11 was added to Malformations of cortical development. Sources: NHS GMS Mode of inheritance for gene: SOX11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SOX11 were set to 24886874; 26543203; 23556151 Phenotypes for gene: SOX11 were set to intellectual disability; facial dysmorphism; microcephaly; digit anomalies; central nervous system malformations Penetrance for gene: SOX11 were set to unknown Review for gene: SOX11 was set to GREEN Added comment: Coffin-Siris syndrome is associated with brain malformations and variable ID. A pathogenic variant in this gene was identified in a case with brain malformations who had R87 panel applied but not R29 or R27. The gene is already green on these other panels. Sources: NHS GMS |
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| Malformations of cortical development v2.133 | TUBGCP2 | Eleanor Williams Phenotypes for gene: TUBGCP2 were changed from Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures, 618737 to Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures, OMIM:618737 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Malformations of cortical development v2.76 | DCHS1 |
Arina Puzriakova changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). DCHS1 is associated with a relevant phenotype in OMIM (MIM# 601390) and G2P ('confirmed' disease confidence rating). Sufficient number of unrelated cases with relevant phenotype and variants in this gene to rate as Green. Brain MRI typically shows periventricular nodular heterotopia, often with a dysmorphic corpus callosum or simplified gyral pattern, consistent with a neuronal migration defect.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). DCHS1 is associated with a relevant phenotype in OMIM (MIM# 601390) and G2P ('confirmed' disease confidence rating). Sufficient number of unrelated cases (4 patients from 3 families) with relevant phenotype and confirmed variants in this gene to rate as Green. Brain MRI typically shows periventricular nodular heterotopia, often with a dysmorphic corpus callosum or simplified gyral pattern, consistent with a neuronal migration defect. |
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| Malformations of cortical development v2.75 | DCHS1 |
Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). DCHS1 is associated with a relevant phenotype in OMIM (MIM# 601390) and G2P ('confirmed' disease confidence rating). Sufficient number of unrelated cases with relevant phenotype and variants in this gene to rate as Green. Brain MRI typically shows periventricular nodular heterotopia, often with a dysmorphic corpus callosum or simplified gyral pattern, consistent with a neuronal migration defect. |
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| Malformations of cortical development v2.62 | CDK13 | Arina Puzriakova reviewed gene: CDK13: Rating: GREEN; Mode of pathogenicity: None; Publications: 27479907, 29021403; Phenotypes: Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder, OMIM:617360; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Malformations of cortical development v2.21 | H3F3A |
Arina Puzriakova gene: H3F3A was added gene: H3F3A was added to Malformations of cortical development. Sources: Literature new-gene-name, for-review tags were added to gene: H3F3A. Mode of inheritance for gene: H3F3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: H3F3A were set to 31942419; 33268356 Phenotypes for gene: H3F3A were set to Developmental delay; Intellectual disability; Neurodegeneration; Epilepsy; Facial dysmorphism; Congenital anomalies Review for gene: H3F3A was set to GREEN Added comment: Currently not associated with any phenotype in OMIM, but is listed in Gene2Phenotype with a 'confirmed' disease confidence rating for 'Craniofacial with neurodevelopment disorders'. - PMID: 31942419 (2019) - De novo missense variant identified by trio exome sequencing in a girl with secondary microcephaly, severe DD and ID, growth retardation and dysmorphic features. Brain MRI demonstrated hypoplasia of corpus callosum and cerebellum as well as thin layer of frontal and parietal periventricular gliosis. No functional analyses of the variant or patient cells were performed. - PMID: 33268356 (2020) - De novo missense variants identified in 33 unrelated individuals with a shared phenotype of GDD/ID, usually severe and often progressive, with mostly minor congenital anomalies. 23/28 patients showed abnormalities on brain MRI including hypoplasia/agenesis of the corpus collosum (9), cortical atrophy (6) and impaired myelination (5). Variable seizure phenotypes were reported in 17/33 cases, all early-onset where specified, mostly during infancy (latest onset at 14 years of age). Sources: Literature |
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| Malformations of cortical development v2.13 | GRIN2B |
Zornitza Stark gene: GRIN2B was added gene: GRIN2B was added to Malformations of cortical development. Sources: Expert list Mode of inheritance for gene: GRIN2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: GRIN2B were set to 28377535 Phenotypes for gene: GRIN2B were set to Mental retardation, autosomal dominant 6, MIM# 613970 Review for gene: GRIN2B was set to GREEN Added comment: PMID: 28377535 - Neuroimaging was performed in 44 of 58 individuals: six unrelated individuals (6/44, 14%) showed a consistent MCD intermediate between typical polymicrogyria (PMG) and the cortical appearance of tubulinopathies, consisting of mixed large and small gyri separated by shallow sulci, a smooth grey-white border and little infolding. These individuals also had hypoplastic corpus callosum of varying degrees, enlarged and mildly dysplastic basal ganglia, hippocampal dysplasia with thick leaves and open hilus as well as enlarged tecta. One had no septum pellucidum. Generalised cerebral volume loss, compatible with cerebral atrophy, was described in four additional patients (4/44; 9%). Sources: Expert list |
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| Malformations of cortical development v2.12 | TUBGCP2 |
Arina Puzriakova gene: TUBGCP2 was added gene: TUBGCP2 was added to Malformations of cortical development. Sources: Literature Mode of inheritance for gene: TUBGCP2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TUBGCP2 were set to 31630790 Phenotypes for gene: TUBGCP2 were set to Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures, 618737 Review for gene: TUBGCP2 was set to GREEN Added comment: Associated with phenotype in OMIM, and a probable gene for Microcephaly and Lissencephaly Spectrum Disorders in G2P. PMID: 31630790 (2019) - Five patients from four families with biallelic variants in the TUBGCP2 gene. Affected individuals shared phenotypic features that included progressive microcephaly (4/4), developmental delay (5/5, mild-severe), seizures (4/5). All patients exhibited lissencephaly-spectrum phenotypes with varying degrees of cortical malformations on brain imaging including pachygyria and subcortical band heterotopia. All variants segregated with disease in each family. Analysis of fibroblasts derived from one patient with a splice site variant revealed several abnormal transcripts, predicted to result in LoF. No further functional studies of other variants or patient cells were performed. Sources: Literature |
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| Malformations of cortical development v2.9 | MN1 |
Arina Puzriakova changed review comment from: Over 20 unrelated probands reported with heterozygous MN1 truncating variants, associated with a distinct phenotype which includes DD, craniofacial abnormalities, hearing loss, and structural abnormalities in the brain (e.g. polymicrogyria, dysmorphic corpus callosum and anomalies of the cerebellum). Most variants cluster in the C-terminal, and all were predicted to escape NMD. Authors postulated that the resulting truncated protein may have a dominant-negative or gain-of-function effect. Also phenotypically supportive knockout mouse model. Sources: Literature; to: Associated with phenotype in OMIM, and a probable gene for MN1 C-terminal truncation syndrome in G2P. Over 20 unrelated probands reported with heterozygous MN1 truncating variants, associated with a distinct phenotype which includes DD, craniofacial abnormalities, hearing loss, and structural abnormalities in the brain (e.g. polymicrogyria, dysmorphic corpus callosum and anomalies of the cerebellum). Most variants cluster in the C-terminal, and all were predicted to escape NMD. Authors postulated that the resulting truncated protein may have a dominant-negative or gain-of-function effect. Also phenotypically supportive knockout mouse model. Sources: Literature |
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| Malformations of cortical development v2.8 | MN1 |
Arina Puzriakova gene: MN1 was added gene: MN1 was added to Malformations of cortical development. Sources: Literature for-review tags were added to gene: MN1. 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 CEBALID syndrome, 618774 Review for gene: MN1 was set to GREEN Added comment: Over 20 unrelated probands reported with heterozygous MN1 truncating variants, associated with a distinct phenotype which includes DD, craniofacial abnormalities, hearing loss, and structural abnormalities in the brain (e.g. polymicrogyria, dysmorphic corpus callosum and anomalies of the cerebellum). Most variants cluster in the C-terminal, and all were predicted to escape NMD. Authors postulated that the resulting truncated protein may have a dominant-negative or gain-of-function effect. Also phenotypically supportive knockout mouse model. Sources: Literature |
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| Malformations of cortical development v2.7 | CDK13 | Zornitza Stark reviewed gene: CDK13: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder, MIM# 617360; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Malformations of cortical development v1.158 | SMO | Rebecca Foulger Added comment: Comment on mode of inheritance: Changed MOI from 'Other' in order to capture variants within this gene in our current tiering pipeline. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Malformations of cortical development v1.158 | SMO | Rebecca Foulger Mode of inheritance for gene: SMO was changed from Other - please specifiy in evaluation comments to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Malformations of cortical development v1.152 | ISCA-37430-Loss |
Louise Daugherty Region: ISCA-37430-Loss was added Region: ISCA-37430-Loss was added to Malformations of cortical development. 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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| Malformations of cortical development | SMO | Louise Daugherty classified SMO as green | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Malformations of cortical development | SMO | Louise Daugherty commented on SMO | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Malformations of cortical development | SMO | Louise Daugherty commented on SMO | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Malformations of cortical development | SMO | Louise Daugherty added SMO to panel | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Malformations of cortical development | SMO | Louise Daugherty reviewed SMO | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||