ClinVar Genomic variation as it relates to human health

In a boy with Lubs-type X-linked intellectual developmental disorder (MRXSL; 300260), Meins et al. (2005) found a submicroscopic duplication of Xq28, including the MECP2 gene. Dosage analysis of family members showed 2 gene copies in the boy and 3 copies in his healthy mother, who had severely skewed X inactivation. Quantification of transcript levels suggested a double dose of MECP2 in the boy, but not in his mother. Further analysis showed that the duplication included 12 genes, from AVPR2 (300538) to TKTL1 (300044); the L1CAM (308840) gene was excluded. By array comparative genomic hybridization (CGH) analysis, Van Esch et al. (2005) identified a small duplication at Xq28 in affected males from 4 families with a severe form of mental retardation associated with progressive spasticity and respiratory infections. The duplications in the 4 patients varied in size from 0.4 to 0.8 Mb and comprised the MECP2 and L1CAM genes in each case. Increased dosage of MECP2 appeared to be responsible for the mental retardation phenotype. The main features present in the affected males were severe to profound mental retardation with onset at birth, axial and facial hypotonia, progressive spasticity predominantly at the lower limbs, seizures, and recurrent infections leading to early death in 4 of the affected members of 1 family. The affected males also shared some mild dysmorphic features, including large ears and flat nasal bridge. Del Gaudio et al. (2006) reported 6 males with duplication and 1 male with triplication of MECP2. All had developmental delay and infantile hypotonia. All but 1 had absent speech. The spasticity reported by Van Esch et al. (2005) was not seen in the patients reported by del Gaudio et al. (2006). Belligni et al. (2010) reported a 5-year-old boy who demonstrated severe central hypotonia and central hypoventilation at birth, necessitating a tracheostomy. He showed severe developmental delay with poor head control. He also had a persistent ductus arteriosus and chronic constipation, without evidence of Hirschsprung disease. Brain MRI showed decreased white matter bulk and bilateral optic nerve hypoplasia. Genetic analysis identified a 0.5- to 0.8-Mb interstitial duplication of chromosome Xq28 including the MECP2 and L1CAM genes, which was inherited from his asymptomatic mother. Belligni et al. (2010) suggested that MECP2 be evaluated in patients with features of the congenital hypoventilation syndrome (209880). (less)