CNS malformations: gene locations of known human mutations

Abstract

aMalformationInheritanceLocusSymbol: gene or transcription productKey referencesAgenesis corpus callosum with neuropathyARSLC12A6 for transporter protein KCC35Cerebro-hepato-renal syndrome (Zellweger)aARXq22.3-q23DCX6Coffin–Lowry syndromeXRXp22.2RSK27,8Congenital muscular dystrophy with cerebral and cerebellar dysplasiaARFKRP (Fukutin)9HemimegalencephalybARXq28L1-CAM10HoloprosencephalycAD; AR7q36-qterSHH11–13HoloprosencephalyAR; sporadic13q32ZIC214HoloprosencephalyAR; sporadic2q21SIX315HoloprosencephalyAD; sporadic18p11.3TGIF16HoloprosencephalyAR; sporadic9q22.3PTCH (SHH receptor)17HoloprosencephalyAR; sporadic10q11.2DKK (head inducer)18HoloprosencephalyAR; sporadicDhcr7 (SHH related)19Kallmann syndromeaXRXp22.3KAL1; EMX220–22Lissencephaly I (isolated and Miller–Dieker syndrome)AR17p13.3LIS123–25Lissencephaly II with cerebellar hypoplasia #AR7q22RELN26Lissencephaly II, muscle–eye–brain diseaseAR1p32POMGnT127Microcephaly, primaryAR1pq25-q32MCPH54,28Midbrain agenesis and cerebellar hypoplasia?AR; sporadic7q36EN229Periventricular nodular heterotopiaXDXq28FLN-A30,31Periventricular nodular heterotopiaAD??32Periventricular nodular heterotopia and posterior pituitary ectopiaARHESX133Pituitary aplasia, ectopia (neurohypophysis)ARHESX133–35Pituitary aplasia (adenohypophysis)Pitx236Rett syndromeXDXq28MECP237Sacral agenesisdAD7q36.1-qter, 1q41-q42.1SHH, HLXB938–40SchizencephalyAR10q26.1EMX241,42Septo-optic-pituitary dysplasiaAR; sporadic3p21.1-p21.2HESX1, PAX31,2,34,35,43,44Subcortical laminar heterotopia (band heterotopia; double cortex)XDXq22.3-q23DCX3,45,46,56Tuberous sclerosisAD9q34.3, 16p13.3TSC1; hamartin, TSC2; tuberin47–52X-linked hydrocephalus (X-linked aqueductal stenosis and pachygyria)XRXq28L1-CAM53–55aThe DCX (doublecortin) mutation is primary in subcortical laminar heterotopia, but also is described in Zellweger syndrome, though it is likely only a secondary defect in this lysosomal disease associated with major neuroblast migratory defects; DCX is localized on the X-chromosome and Zellweger is an AR trait. DCX also is a secondary genetic defect in Kallmann syndrome (anosmia due to agenesis or defective migration of olfactory bulb neurons and hypogonadotropic hypogonadism, the hypothalamic secretory cells having the same origin as the olfactory neurons).bThe role of L1-CAM in hemimegalencephaly is not certain and is more likely a secondary defect and not the primary genetic mutation.cHoloprosencephaly is associated with many chromosomal defects in addition to those here listed, but the gene products associated with the others have not yet been identified. Only 20% of genetically studied cases have one of the six genetic mutations demonstrated.aThe DCX (doublecortin) mutation is primary in subcortical laminar heterotopia, but also is described in Zellweger syndrome, though it is likely only a secondary defect in this lysosomal disease associated with major neuroblast migratory defects; DCX is localized on the X-chromosome and Zellweger is an AR trait. DCX also is a secondary genetic defect in Kallmann syndrome (anosmia due to agenesis or defective migration of olfactory bulb neurons and hypogonadotropic hypogonadism, the hypothalamic secretory cells having the same origin as the olfactory neurons).dSacral agenesis (AD form) maps to the same locus at 7q36 as one form of holoprosencephaly and also is associated with defective SHH expression, the same genetic defect expressed at opposite ends of the neural tube. Both sacral agenesis and holoprosencephaly also occur with a high incidence in infants born to mothers with diabetes mellitus. Agenesis of more than two vertebral bodies is generally associated with dysplasia of the spinal cord in that region during fetal development: fusion of ventral horns; deformed central canal with heterotopic ependyma, consistent with defective neural induction. A second gene with a locus at 1q41-q42.1 is also identified as another cause of autosomal dominantly transmitted sacral agenesis.