A sibship with duplication of Xq28 inherited from the mother; genomic characterization and clinical outcomes

Dong Keon Yon, Ji Eun Park, Seung Jun Kim, Sung Han Shim, Kyu Young Chae

Loss-of-function mutations in methyl-CpG-binding protein 2 (MECP2; MIM *300005) results in the Rett syndrome, whereas gain-of-function mutations are associated with the MECP2 duplication syndrome. We did research on a family with two brothers showing Xq28 duplication syndrome using various molecular cytogenetic techniques such as multiplex ligation-dependent probe amplification and array-based genomic hybridization. The duplicated region had several genes including MECP2 and interleukin-1 receptor associated kinase 1 (IRAK1; MIM *300283). MECP2 and IRAK1 were associated with the neurological phenotypes in dose-sensitive and dose-critical manner. The brothers demonstrated severe intellectual disability, autistic features, generalized hypotonia, recurrent infections, epilepsy, choreiform movements such as hand-wringing movement, and moderate increased spasticity with the lower limbs. The X-inactivation test showed a complete skewed X inactivation pattern of mother. In this reason, the mother had the same loci duplication but showed significantly little neurological manifestation compared to the two sons. MECP2/IRAK1 duplication at Xq28 is inherited as an X-linked recessive trait and male-specific disorder associated with severe intellectual disability. We tried to analyze the information of the relationship between neuropsychiatric phenotype and the extent of duplication at Xq28 by comparing with previous reports.