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

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

doi:10.1186/s12881-017-0394-7

Abstract

BackgroundLoss-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.MethodsWe 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.ResultsThe 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.ConclusionsMECP2/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.

Highlights

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
Clinical manifestations are male-specific with symptoms such as recurrent infections that may lead to premature death, infantile hypotonia, mild dysmorphic features, progressive spasticity of the lower limbs observed after 3 years of age, autistic features, and generalized epilepsy [8]
These clinical features were first described as Lubs-type X-linked mental retardation syndrome (MIM #300260) [18], and current understanding of the genetic basis was recognized as chromosomal duplication of the MECP2 region [19]

Summary

Introduction

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. X-linked intellectual disability (XLID) is found in approximately 5–10% of the intellectually disabled men [1]. XLID is divided into syndromic forms in which intellectual disability is one of many symptoms, and non-syndromic forms, in which intellectual disability is the only symptom. 102 genes were shown to be associated with 81 out of 160 cases of XLID syndromes in over 50 families with non-syndromic XLID [1]. Most of the genetic defects leading to XLID are loss-of-function mutations, including point mutations Additional symptoms of Rett syndrome include acquired microcephaly, profound intellectual disability, epilepsy, ataxia, and autistic behaviors. There is a wide spectrum of disease severity for Rett syndrome as determined by molecular diagnostics [5]

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Discussion

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