IllnessIntellectual deficit + lissencephaly, differential diagnosis

NGS +

Mental retardation (currently accepted English term, "intellectual deficits") 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 due to 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 symptoms. In some cases, malformations of the cortex arise from de novo or somatic mutational events in the gamete or postzygotic stages, but brain malformations can also be inherited as in lissencephaly, for example, through mutated PAFAH1B1, DCX, ARX and RELN genes. Mutations in PAFAH1B1 and DCX account for some 85% of classic lissencephaly cases, mostly via de novo mutations in the PAFAH1B1 gene, less commonly in other genes. Autosomal dominant or recessive, rarely X-linked inheritance patterns are observed. The DNA diagnostic yield cannot be stated with certainty at present. Clinical diagnosis can by no means be excluded by a negative molecular genetic result.

References: https://www.ncbi.nlm.nih.gov/books/NBK1185/

https://www.ncbi.nlm.nih.gov/books/NBK5189/

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

• Alias: Intellectual disability, metabolic disorder
• Alias: Psycho-motor retardation, metabolic disorder
• Allelic: Cardiomyopathy, dilated, 1X (FKTN)
• Allelic: Charcot-Marie-Tooth disease, axonal, type 20 (DYNC1H1)
• Allelic: Deafness, AD 20/26 (ACGT1)
• Allelic: Dystonia, juvenile-onset (ACTB)
• Allelic: Epilepsy, familial temporal lobe, 7 (RELN)
• Allelic: Epileptic encephalopathy, early infantile, 1 (ARX)
• Allelic: Fibrosis of extraocular muscles, congenital, 3A (TUBB3)
• Allelic: Hydranencephaly with abnormal genitalia (ARX)
• Allelic: Mental retardation, XL 29, 32, 33, 38, 43, 52, 54, 76, 87 (ARX)
• Allelic: Microhydranencephaly (NDE1)
• Allelic: Muscular dystrophy-dystroglycanopathy (cong. without mental retardation), type B, 4 (FKTN)
• Allelic: Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 1 (POMT1)
• Allelic: Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 (GMPPB)
• 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: Partington syndrome (ARX)
• Allelic: Proud syndrome (ARX)
• Allelic: Retinitis pigmentosa 76 (POMGNT1)
• Allelic: Roifman syndrome (RNU4ATAC)
• Allelic: Sotos syndrome 3 (APC2)
• Allelic: Spinal muscular atrophy, lower extremity-predominant 1, AD (DYNC1H1)
• Allelic: Subcortical laminal heterotopia, XL (DCX)
• Allelic: Subcortical laminar heterotopia (PAFAH1B1)
• Allelic: Symmetric circumferential skin creases, congenital, 1 (TUBB)
• Band heterotopia (EML1)
• Baraitser-Winter syndrome 1 (ACTB)
• Baraitser-Winter syndrome 2 (ACTG1)
• Cerebellar hypoplasia + mental retardation with/-out quadrupedal locomotion 1 (VLDLR)
• Ciliary dyskinesia, primary, 47, + lissencephaly (TP73)
• 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)
• Developmental + epileptic encephalopathy 1 (ARX)
• Intellectual developmental disorder, AR 74 (APC2)
• 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 7 with cerebellar hypoplasia (CDK5)
• Lissencephaly 8 (TMTC3)
• Lissencephaly 9 with complex brainstem malformation (MACF1)
• Lissencephaly [panelapp] (PIDD1)
• Lissencephaly most severe grade (YWHAE deletion)
• Lissencephaly, XL (DCX)
• Lissencephaly, XL 2 (ARX)
• Lowry-Wood syndrome (RNU4ATAC)
• Mega-corpus-callosum syndrome with cerebellar hypoplasia + cortical malformations (MAST1)
• Mental retardation, AD 13 (DYNC1H1)
• Mental retardation, AR 34, with variant lissencephaly (CRADD)
• Mental retardation, XL 29 + others (ARX)
• Microcephalic osteodysplastic primordial dwarfism, type I (RNU4ATAC)
• Microcephaly 17, primary, AR (CIT)
• Microcephaly 2, primary, autosomal recessive, with/-out cortical malformations (WDR62)
• Muscular dystrophy-dystroglycanopathy (cong. with mental retardation), type B, 1 (POMT1)
• Muscular dystrophy-dystroglycanopathy (cong. with mental retardation), type B, 14 (GMPPB)
• 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 retardation), type B, 5 (FKRP)
• Muscular dystrophy-dystroglycanopathy, congenital with brain + eye anomalies, type A, 1 (POMT1)
• Muscular dystrophy-dystroglycanopathy, congenital with brain + eye anomalies, type A, 10 (RXYLT1)
• Muscular dystrophy-dystroglycanopathy, congenital with brain + eye anomalies, type A, 14 (GMPPB)
• Muscular dystrophy-dystroglycanopathy, congenital with brain + eye anomalies, type A, 2 (POMT2)
• Muscular dystrophy-dystroglycanopathy, congenital with brain + eye anomalies, type A, 3 (POMGNT1)
• Muscular dystrophy-dystroglycanopathy, congenital with brain + eye anomalies, type A, 4 (FKTN)
• Muscular dystrophy-dystroglycanopathy, congenital with brain + eye anomalies, type A, 5 (FKRP)
• Muscular dystrophy-dystroglycanopathy, congenital with brain + eye anomalies, type A, 6 (LARGE1)
• Muscular dystrophy-dystroglycanopathy, congenital with brain + eye anomalies, type A, 7 (CRPPA)
• Muscular dystrophy-dystroglycanopathy, congenital with brain + eye anomalies, type A, 8 (POMGNT2)
• Pachygyria, microcephaly, developmental delay, dysmorphic facies, with/-out seizures (TUBGCP2)
• Partington syndrome (ARX)
• Polymicrogyria, bilateral frontoparietal (ADGRG1)
• Polymicrogyria, bilateral perisylvian (ADGRG1)
• Proud syndrome (ARX)
• Subcortical laminal heterotopia, XL (DCX)