IllnessIntellectual deficit, cerebro-organic; differential diagnosis

NGS +

[Sanger]

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, detectable in >50% of patients. This percentage is increasing in the face of efficient NGS technologies. Brain malformations cause quite a few cases of intellectual deficits and comprise a group of genetic developmental brain disorders that present in childhood with intellectual disability (and other neurological features). In some cases, malformations of the forebrain, midbrain/hindbrain and cortex result from de novo or somatic mutation events at the gamete or postzygotic stage, but many cases of brain malformations are the result of rare, heritable causes. In particular, gene mutations for holoprosencephaly, agenesis of the corpus callosum, septo-optic dysplasia, pontocerebellar and cerebellar hypoplasia, Dandy-Walker malformation, molar tooth sign, microcephaly, megalencephaly, lissencephaly, heterotopia, polymicrogyria, schizencephaly and focal cortical dysplasias are comprised here. Autosomal dominant and recessive as well as X-linked inheritance patterns are observed. DNA diagnostic yield is increasing but is currently impossible to quantify accurately overall. Clinical diagnosis can in no way be ruled out by a negative molecular genetic result.

References: Medizinische Genetik 3/2018

• Alias: Intellectual disability, brain organic
• Alias: Psycho-motor retardation, btrain organic
• Allelic: Autism susceptibility 15 (CNTNAP2)
• Allelic: Epilepsy, familial temporal lobe, 7 (RELN)
• Allelic: Fibrosis of extraocular muscles, congenital, 3A (TUBB3)
• Allelic: Focal segmental glomerulosclerosis 9 (CRB2)
• Allelic: Hennekam lymphangiectasia-lymphedema syndrome 2 (FAT4)
• Allelic: Hydranencephaly with abnormal genitalia (ARX)
• Allelic: Leukemia, juvenile myelomonocytic (NF1)
• Allelic: Lymphangioleiomyomatosis (TSC1)
• Allelic: Lymphatic malformation 3 (GJC2)
• Allelic: Microhydranencephaly (NDE1)
• Allelic: Microphthalmia with coloboma 5 (SHH)
• Allelic: Neurofibromatosis, familial spinal (NF1)
• Allelic: Optic atrophy 9 (ACO2)
• Allelic: Parkinson disease 14, AR (PLA2G6)
• Allelic: Parkinson disease 24, AD, susceptibility to (PSAP)
• Allelic: Pitt-Hopkins like syndrome 1 (CNTNAP2)
• Allelic: Single median maxillary central incisor (SHH)
• Allelic: Sotos syndrome 3 (APC2)
• Allelic: Spastic paraplegia 44, AR (GJC2)
• Allelic: Spastic paraplegia 63 (AMPD2)
• Allelic: Subcortical laminar heterotopia (PAFAH1B1)
• Allelic: Symmetric circumferential skin creases, congenital, 1 (TUBB)
• Allelic: Vissers-Bodmer syndrome (CNOT1)
• Allelic: Watson syndrome (NF1)
• Adrenoleukodystrophy (ABCD1)
• Adrenomyeloneuropathy, adult (ABCD1)
• Agenesis of the corpus callosum with peripheral neuropathy (SLC12A6)
• Alkuraya-Kucinskas syndrome (KIAA1109))
• Band heterotopia (EML1)
• Cerebellar ataxia + mental retardation with/-out quadrupedal locomotion 3 (CA8)
• Cerebellar ataxia, nonprogressive, with mental retardation (CAMTA1)
• Cerebellar atrophy, visual impairment + psychomotor retardation (EMC1)
• Cerebellar hypoplasia + mental retardation with/-out quadrupedal locomotion 1 (VLDLR)
• Ceroid lipofuscinosis, neuronal, 1 (PPT1)
• Ceroid lipofuscinosis, neuronal, 10 (CTSD)
• Ceroid lipofuscinosis, neuronal, 2 (TPP1)
• Ceroid lipofuscinosis, neuronal, 3 (CLN3)
• Ceroid lipofuscinosis, neuronal, 4A [Kufs type], AR (CLN6)
• Ceroid lipofuscinosis, neuronal, 5 (CLN5)
• Ceroid lipofuscinosis, neuronal, 6 (CLN6)
• Ceroid lipofuscinosis, neuronal, 8 (CLN8)
• Ceroid lipofuscinosis, neuronal, 8, Northern epilepsy variant (CLN8)
• Combined SAP deficiency (PSAP)
• 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-focal epilepsy syndrome (CNTNAP2)
• Cortical malformations, occipital (LAMC3)
• Culler-Jones syndrome (GLI2)
• Developmental + epileptic encephalopathy 1 (ARX)
• Dystonia 4, torsion, AD (TUBB4A)
• Encephalopathy, progressive, early-onset, with brain atrophy + thin corpus callosum (TBCD)
• Epilepsy, progressive myoclonic 3, with/-out intracellular inclusions (KCTD7)
• FG syndrome 4 (CASK)
• Focal cortical dysplasia, type II, somatic (MTOR)
• Focal cortical dysplasia, type II, somatic (TSC1)
• Gaucher disease, atypical (PSAP)
• Hiatt-Neu-Cooper neurodevelopmental syndrome (RALA)
• Holoprosencephaly 11 (CDON)
• Holoprosencephaly 12, with/-out pancreatic agenesis (CNOT1)
• Holoprosencephaly 2 (SIX3)
• Holoprosencephaly 3 (SHH)
• Holoprosencephaly 4 (TGIF1)
• Holoprosencephaly 5 (ZIC2)
• Holoprosencephaly 9 (GLI2)
• Hypomyelination with brainstem + spinal cord involvement + leg spasticity (DARS1)
• Infantile cerebellar-retinal degeneration (ACO2)
• Infantile neuroaxonal dystrophy 1 (PLA2G6)
• Krabbe disease, atypical (PSAP)
• Leukodystrophy, hypomyelinating, 10 (PYCR2)
• Leukodystrophy, hypomyelinating, 14 (UFM1)
• Leukodystrophy, hypomyelinating, 18 (DEGS1)
• Leukodystrophy, hypomyelinating, 2 (GJC2)
• Leukodystrophy, hypomyelinating, 3 (AIMP)
• Leukodystrophy, hypomyelinating, 5 (FAM126A)
• Leukodystrophy, hypomyelinating, 6 (TUBB4A)
• Leukodystrophy, hypomyelinating, 7, with/-out oligodontia +/- hypogonadotr. hypogonadism (POLR3A)
• Leukodystrophy, hypomyelinating, 8, with/-out oligodontia +/- hypogonadotr. hypogonadism (POLR3B)
• Leukoencephalopathy with brain stem + spinal cord involvement + lactate elevation (DARS2)
• Leukoencephalopathy with vanishing white matter (EIF2B5)
• Leukoencephalopathy, cystic, without megalencephaly (RNASET2)
• Lissencephaly 1 (PAFAH1B1)
• Lissencephaly 2 [Norman-Roberts type] (RELN)
• Lissencephaly 3 (TUBA1A)
• Lissencephaly 4 [with microcephaly] (NDE1) Lissencephaly 8 (TMTC3)
• Lissencephaly 5 (LAMB1)
• Lissencephaly 9 with complex brainstem malformation (MACF1)
• Lissencephaly, XL (DCX)
• Lissencephaly, XL 2 (ARX)
• Megalencephalic leukoencephalopathy with subcortical cysts (MLC1)
• Megalencephalic leukoencephalopathy with subcortical cysts 2A (HEPACAM)
• Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitt., +/- ment. retard. (HEPACAM)
• Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3 (CCND2)
• Mental retardation, AR 34, with variant lissencephaly (CRADD)
• Mental retardation, XL 29 + others (ARX)
• Mental retardation, XL, with cerebellar hypoplasia + distinctive facial appearance (OPHN1)
• Mental retardation, microcephaly with pontine + cerebellar hypoplasia (CASK)
• Mental retardation, with or without nystagmus (CASK)
• Metachromatic leukodystrophy due to SAP-b deficiency (PSAP)
• Muscular dystrophy-dystroglycanopathy (cong. with brain + eye anomalies), type A, 10 (RXYLT1)
• Neurodegeneration with brain iron accumulation 2B (PLA2G6)
• Neurodegeneration with brain iron accumulation 5 (WDR45)
• Neurodegeneration, childhood-onset, with brain atrophy (UBTF)
• Neurodevelopmental disorder with microcephaly, cortical malformations + spasticity (TMX2)
• Neurodevelopmental disorder with structural brain anomalies + dysmorphic facies (RAC3)
• Neurofibromatosis, type 1 (NF1)
• Neurofibromatosis-Noonan syndrome (NF1)
• Ovarioleukodystrophy (EIF2B5)
• Partington syndrome (ARX)
• Pelizaeus-Merzbacher disease (PLP1)
• Periventricular heterotopia with microcephaly (ARFGEF2)
• Polymicrogyria, bilateral frontoparietal (ADGRG1)
• Polymicrogyria, bilateral perisylvian (ADGRG1)
• Pontocerebellar hypoplasia type 10 (CLP1)
• Pontocerebellar hypoplasia type 11 (TBC1D23)
• Pontocerebellar hypoplasia type 1A (VRK1)
• Pontocerebellar hypoplasia type 1B (EXOC3)
• Pontocerebellar hypoplasia type 2A (TSEN54)
• Pontocerebellar hypoplasia type 2B (TSEN2)
• Pontocerebellar hypoplasia type 2C (TSEN34)
• Pontocerebellar hypoplasia type 2D (SEPSECS)
• Pontocerebellar hypoplasia type 2E (VPS53)
• Pontocerebellar hypoplasia type 4 (TSEN54)
• Pontocerebellar hypoplasia type 5 (TSEN54)
• Pontocerebellar hypoplasia type 6 (RARS2)
• Pontocerebellar hypoplasia type 8 (CHMP1A)
• Pontocerebellar hypoplasia type 9 (AMPD2)
• Pontocerebellar hypoplasia, type 7 (TOE1)
• Proud syndrome (ARX)
• Pseudo-TORCH syndrome 1 (OCLN)
• Schizencephaly (EMX2)
• Schizencephaly (SHH)
• Schizencephaly (SIX3)
• Smith-Kingsmore syndrome (MTOR)
• Spastic paraplegia 2, XL (PLP1)
• Speech-language disorder-1 (FOXP2)
• Spinocerebellar ataxia, AR 20 (SNX14)
• Spinocerebellar ataxia, AR 7 (TPP1)
• Subcortical laminal heterotopia, XL (DCX)
• Tuberous sclerosis-1 (TSC1)
• Van Maldergem syndrome 2 (FAT4)
• Ventriculomegaly with cystic kidney disease (CRB2)
• Wiedemann-Rautenstrauch syndrome (POLR3A)