IllnessIntellectual deficit + cortical dysplasia, differential diagnosis

NGS +

[Sanger]

Mental retardation (currently preferred English term, "intellectual deficit") is a lifelong debilitating condition affecting up to 2-3% of the population in Western countries. While the causal pathogenesis is extremely variable, genetic etiologies are the most common cause in >50% of patients. This percentage is increasing with expanded use of efficient NGS technologies. Brain malformations cause quite a few cases of intellectual deficits and comprise a group of genetic developmental disorders that occur in childhood alongside other neurological features. Malformations of the cortex may arise from de novo or somatic mutations in the gamete or postzygotic stage, and some brain malformations are inherited. In particular, gene mutations for mental retardation in cortical dysplasia are covered as well as the differential diagnosis. The genetics of mental retardation especially in lissencephaly is detailed separately. Autosomal dominant, rarely recessive inheritances are described. The DNA diagnostic yield cannot be stated with certainty at present. The clinical diagnosis can by no means be excluded by a negative molecular genetic result.

References: https://www.ncbi.nlm.nih.gov/books/NBK350554/

• Alias: Intellectual disability, cortical dysplasia
• Alias: Psycho-motor retardation, cortical dysplasia
• Allelic: Autism susceptibility 15 (CNTNAP2)
• Allelic: Cowden syndrome 5 (PIK3CA)
• Allelic: Deafness, AD 20 + 26 (ACTG1)
• Allelic: Deafness, AD 83 (MAP1B)
• Allelic: Dystonia 4, torsion, AD (TUBB4A)
• Allelic: Dystonia, juvenile-onset (ACTB)
• Allelic: FG syndrome 4 (CASK)
• Allelic: Fibrosis of extraocular muscles, congenital, 3A (TUBB3)
• Allelic: Heimler syndrome 1 [Peroxisome biogenesis disorder 1C] (PEX1)
• Allelic: Heimler syndrome 2 [Peroxisome biogenesis disorder 4C] (PEX6)
• Allelic: Hydranencephaly with abnormal genitalia (ARX)
• Allelic: Lymphangioleiomyomatosis (TSC1)
• Allelic: Lymphangioleiomyomatosis, somatic (TSC2)
• Allelic: Microhydranencephaly (NDE1)
• Allelic: Muscular dystrophy, limb-girdle, AR 23 (LAMA2)
• Allelic: Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 1 (POMT1)
• Allelic: Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 2 (POMT2)
• Allelic: Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 3 (POMGNT1)
• Allelic: Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 4 (FKTN)
• Allelic: Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 5 (FKRP)
• Allelic: Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 7 (CRPPA)
• Allelic: Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 8 (POMGNT2)
• Allelic: Muscular dystrophy-dystroglycanopathy, limb-girdle, type C, 9 (DAG1)
• Allelic: Pitt-Hopkins like syndrome 1 (CNTNAP2)
• Allelic: Rhizomelic chondrodysplasia punctata, type 1 (PEX7)
• Allelic: Rhizomelic chondrodysplasia punctata, type 5 (PEX5)
• Allelic: Sotos syndrome 3 (APC2)
• Allelic: Symmetric circumferential skin creases, congenital, 1 (TUBB)
• Agenesis of corpus callosum, cardiac, ocular + genital syndrome (CDH2)
• Alias: ID bei Cortex-Malformation
• Allelic: Cowden syndrome 1 (PTEN)
• Allelic: Epilepsy, familial temporal lobe, 7 (RELN)
• Allelic: Gastrointestinal defects + immunodeficiency syndrome 2 (PI4KA)
• Allelic: Mitral valve prolapse 2 (DCHS1)
• Alternating hemiplegia of childhood 2 (ATP1A3)
• Band heterotopia (EML1)
• Baraitser-Winter syndrome 1 (ACTB)
• Baraitser-Winter syndrome 2 (ACTG1)
• Bryant-Li-Bhoj neurodevelopmental syndrome 1 (H3-3A)
• CAPOS syndrome (ATP1A3)
• CEBALID [craniofacial def., dysmorphic ears, brain abnormalities, language delay, ID] syndrome (MN1)
• Cerebellar hypoplasia, impaired intellectual development + dysequilibrium syndrome 1 (VLDLR)
• Cerebral dysgenesis, neuropathy, ichthyosis, palmoplantar keratoderma syndrome (SNAP29)
• Charcot-Marie-Tooth disease, axonal, type 20 (DYNC1H1)
• Chudley-McCullough syndrome (GPSM2)
• Ciliary dyskinesia, primary, 47, and lissencephaly (TP73)
• Congenital heart defects, dysmorphic facial features + intellectual developmental disorder (CDK13)
• Cortical dysplasia, complex, with other brain malformations 1 (TUBB3)
• Cortical dysplasia, complex, with other brain malformations 10 (APC2)
• Cortical dysplasia, complex, with other brain malformations 2 (KIF5C)
• Cortical dysplasia, complex, with other brain malformations 3 (KIF2A)
• Cortical dysplasia, complex, with other brain malformations 4 (TUBG1)
• Cortical dysplasia, complex, with other brain malformations 5 (TUBB2A)
• Cortical dysplasia, complex, with other brain malformations 6 (TUBB)
• Cortical dysplasia, complex, with other brain malformations 7 (TUBB2B)
• Cortical dysplasia, complex, with other brain malformations 8 (TUBA8)
• Cortical dysplasia, complex, with other brain malformations 9 (CTNNA2)
• Cortical dysplasia-focal epilepsy syndrome (CNTNAP2)
• Cortical malformations, occipital (LAMC3)
• Developmental + epileptic encephalopathy 1 (ARX)
• Developmental + epileptic encephalopathy 98 (ATP1A2)
• Developmental and epileptic encephalopathy 101 (GRIN1)
• Developmental and epileptic encephalopathy 27 (GRIN2B)
• Developmental and epileptic encephalopathy 62 (SCN3A)
• Developmental and epileptic encephalopathy 99 (ATP1A3)
• Dystonia-12 (ATP1A3)
• Epilepsy, familial focal, with variable foci 1 (DEPDC5)
• Epilepsy, familial focal, with variable foci 4 (SCN3A)
• Focal cortical dysplasia, type II, somatic (MTOR)
• Focal cortical dysplasia, type II, somatic (TSC2)
• Galloway-Mowat syndrome 3 (OSGEP)
• Genitourinary and/or/brain malformation syndrome (PPP1R12A)
• Global developmental delay [panelapp] (RAB11A)
• Heterotopia, periventricular, 1 (FLNA)
• Intellectual development disorder, microcephaly +/- eye malform/hypogonadot. hypogonadism (SOX11)
• Intellectual developmental disorder + microcephaly with pontine + cereb. hypoplasia (CASK)
• Intellectual developmental disorder with autism + speech delay (TBR1)
• Intellectual developmental disorder, AD 13 (DYNC1H1)
• Intellectual developmental disorder, AD 6, +/- seizures (GRIN2B)
• Intellectual developmental disorder, AR 34, with variant lissencephaly (CRADD)
• Intellectual developmental disorder, AR 75, neuropsych. features, variant lissencephaly (PIDD1)
• Intellectual developmental disorder, XL 29 (ARX)
• Intellectual disability [panelapp] (RAB11A)
• Lhermitte-Duclos disease (PTEN)
• Lissencephaly 1 (PAFAH1B1)
• Lissencephaly 10 (CEP85L)
• Lissencephaly 2, Norman-Roberts type (RELN)
• Lissencephaly 3 (TUBA1A)
• Lissencephaly 4 {with microcephaly} (NDE1)
• Lissencephaly 5 (LAMB1)
• Lissencephaly 6, with microcephaly (KATNB1)
• Lissencephaly 9 with complex brainstem malformation (MACF1)
• Lissencephaly, XL (DCX)
• Lissencephaly, XL 2 (ARX)
• Macrocephaly/autism syndrome (PTEN)
• Martsolf syndrome 1 (RAB3GAP2)
• Martsolf syndrome 2 (RAB3GAP1)
• Megalencephalic leukoencephalopathy with subcortical cysts 2A (HEPACAM)
• Megalencephaly-capillary malformation-polymicrogyria syndrome, somatic (PIK3CA)
• Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 (PIK3R2)
• Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 (AKT3)
• Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3 (CCND2)
• Mental retardation, AD 13 (DYNC1H1)
• Mental retardation, XL 29 and others (ARX)
• Mental retardation, with/-out nystagmus (CASK)
• Microcephaly 2, primary, AR, with/-out cortical malformations (WDR62)
• Microcephaly 5, primary, AR (ASPM)
• Microcephaly, short stature + polymicrogyria with seizures (RTTN)
• Muscular dystrophy, congenital, merosin deficient or partially deficient (LAMA2)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies), type A, 1 (POMT1)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies), type A, 11 (B3GALNT2)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies), type A, 2 (POMT2)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies), type A, 3 (POMGNT1)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies), type A, 4 (FKTN)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies), type A, 5 (FKRP)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies), type A, 6 (LARGE1)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies), type A, 7 (CRPPA)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies), type A, 8 (POMGNT2)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies), type A, 9 (DAG1)
• Muscular dystrophy-dystroglycanopathy (cong. with mental retardation), type B, 1 (POMT1)
• Muscular dystrophy-dystroglycanopathy (cong. with mental retardation), type B, 2 (POMT2)
• Muscular dystrophy-dystroglycanopathy (cong. with mental retardation), type B, 3 (POMGNT1)
• Muscular dystrophy-dystroglycanopathy (cong. with mental retardation), type B, 6 (LARGE1)
• Muscular dystrophy-dystroglycanopathy (cong. with/-out mental retard.), type B, 5 (FKRP)
• Neurodevelopmental disorder +/- variable brain abnormalities (MAPK8IP3)
• Neurodevelopmental disorder with microcephaly, cortical malformations + spasticity (TMX2)
• Neurodevelopmental disorder with microcephaly, seizures + cortical atrophy (VARS1)
• Neurodevelopmental disorder with or without hyperkinetic movements and seizures, AD (GRIN1)
• Neurodevelopmental disorder with or without hyperkinetic movements and seizures, AR (GRIN1)
• Neurodevelopmental disorder with spasticity, seizures + brain abnormalities (NSRP1)
• Okur-Chung neurodevelopmental syndrome (CSNK2A1)
• Orofaciodigital syndrome [panelapp, MONDO:0015375] (TBC1D32)
• Pachygyria, microcephaly, developmental delay, dysmorphic facies, with/-out seizures (TUBGCP2)
• Pallister-Hall-like syndrome (SMO)
• Partington syndrome (ARX)
• Periventricular heterotopia with microcephaly (ARFGEF2)
• Periventricular nodular heterotopia 7 (NEDD4L)
• Periventricular nodular heterotopia 8 (ARF1)
• Periventricular nodular heterotopia 9 (MAP1B)
• Peroxisome biogenesis disorder 10A [Zellweger] (PEX3)
• Peroxisome biogenesis disorder 10B (PEX3)
• Peroxisome biogenesis disorder 11A [Zellweger] (PEX13)
• Peroxisome biogenesis disorder 11B (PEX13)
• Peroxisome biogenesis disorder 12A [Zellweger] (PEX19)
• Peroxisome biogenesis disorder 13A [Zellweger] (PEX14)
• Peroxisome biogenesis disorder 14B (PEX11B)
• Peroxisome biogenesis disorder 1A [Zellweger] (PEX1)
• Peroxisome biogenesis disorder 1B [NALD/IRD] (PEX1)
• Peroxisome biogenesis disorder 2A [Zellweger] (PEX5)
• Peroxisome biogenesis disorder 2B (PEX5)
• Peroxisome biogenesis disorder 3A [Zellweger] (PEX12)
• Peroxisome biogenesis disorder 3B (PEX12)
• Peroxisome biogenesis disorder 4A [Zellweger] (PEX6)
• Peroxisome biogenesis disorder 4B (PEX6)
• Peroxisome biogenesis disorder 5A [Zellweger] (PEX2)
• Peroxisome biogenesis disorder 5B (PEX2)
• Peroxisome biogenesis disorder 6A [Zellweger] (PEX10)
• Peroxisome biogenesis disorder 6B (PEX10)
• Peroxisome biogenesis disorder 7A [Zellweger] (PEX26)
• Peroxisome biogenesis disorder 7B (PEX26)
• Peroxisome biogenesis disorder 8A [Zellweger] (PEX16)
• Peroxisome biogenesis disorder 8B (PEX16)
• Peroxisome biogenesis disorder 9B (PEX7)
• Polymicrogyria, bilateral frontoparietal (ADGRG1)
• Polymicrogyria, bilateral perisylvian (ADGRG1)
• Polymicrogyria, perisylvian, cerebellar hypoplasia + arthrogryposis (PI4KA)
• Proud syndrome (ARX)
• Pseudo-TORCH syndrome 1 (OCLN)
• Ritscher-Schinzel syndrome 4 (DPYSL5)
• Schizencephaly (EMX2)
• Smith-Kingsmore syndrome (MTOR)
• Spastic paraplegia 84, AR (PI4KA)
• Subcortical laminal heterotopia, XL (DCX)
• Subcortical laminar heterotopia (PAFAH1B1)
• Tuberous sclerosis-1 (TSC1)
• Tuberous sclerosis-2 (TSC2)
• Van Maldergem syndrome 1 (DCHS1)
• Warburg micro syndrome 1 (RAB3GAP1)
• Warburg micro syndrome 2 (RAB3GAP2)
• Warburg micro syndrome 3 (RAB18)