Dataset Information

Inherited 2q23.1 microdeletions involving the MBD5 locus.

ABSTRACT: BACKGROUND:Microdeletions of 2q23.1 disrupting MBD5 and loss of function mutations of MBD5 cause MBD5-Associated Neurodevelopmental disorders (MAND). Nearly all reported patients have been isolated cases of de novo origin. METHODS:This study investigates three families with inherited MBD5 mutations from three different Regional Genetics Centres in the UK. RESULTS:Two of the parents in the study had MBD5 deletions in a mosaic form. The parent with an MBD5 deletion in an apparently nonmosaic form has a psychiatric disorder in the absence of developmental delay or dysmorphism. CONCLUSIONS:Inherited forms of MBD5 deletions are rare, but do occur, especially in a mosaic form. The phenotypic spectrum of MAND may be wider than previously thought.

SUBMITTER: Tadros S

PROVIDER: S-EPMC5606852 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Inherited 2q23.1 microdeletions involving the <i>MBD5</i> locus.

Tadros Shereen S Wang Rubin R Waters Jonathan J JJ Waterman Christine C Collins Amanda L AL Collinson Morag N MN Ahn Joo W JW Josifova Dragana D Chetan Ravi R Kumar Ajith A

Molecular genetics & genomic medicine 20170808 5

<h4>Background</h4>Microdeletions of 2q23.1 disrupting <i>MBD5</i> and loss of function mutations of <i>MBD5</i> cause <i>MBD5-</i>Associated Neurodevelopmental disorders (MAND). Nearly all reported patients have been isolated cases of de novo origin.<h4>Methods</h4>This study investigates three families with inherited <i>MBD5</i> mutations from three different Regional Genetics Centres in the UK.<h4>Results</h4>Two of the parents in the study had <i>MBD5</i> deletions in a mosaic form. The pare ...[more]

PMID: 28944244

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Project description:BACKGROUND:Infantile spasms (IS) is a specific type of epileptic encephalopathy associated with severe developmental disabilities. Genetic factors are strongly implicated in IS, however, the exact genetic defects remain unknown in the majority of cases. Rare mutations in a single gene or in copy number variants (CNVs) have been implicated in IS of children in Western countries. The objective of this study was to dissect the role of copy number variations in Chinese children with infantile spasms. METHODS:We used the Agilent Human Genome CGH microarray 180 K for genome-wide detection of CNVs. Real-time qPCR was used to validate the CNVs. We performed genomic and medical annotations for individual CNVs to determine the pathogenicity of CNVs related to IS. RESULTS:We report herein the first genome-wide CNV analysis in children with IS, detecting a total of 14 CNVs in a cohort of 47 Chinese children with IS. Four CNVs (4/47?=?8.5%) (1q21.1 gain; 1q44, 2q31.1, and 17p13 loss) are considered to be pathogenic. The CNV loss at 17p13.3 contains PAFAH1B1 (LIS1), a causative gene for lissencephaly. Although the CNVs at 1q21.1, 1q44, and 2q23.1 have been previously implicated in a wide spectrum of clinical features including autism spectrum disorders (ASD) and generalized seizure, our study is the first report identifying them in individuals with a primary diagnosis of IS. The CNV loss in the 1q44 region contains HNRNPU, a strong candidate gene recently suggested in IS by the whole exome sequencing of children with IS. The CNV loss at 2q23.1 includes MBD5, a methyl-DNA binding protein that is a causative gene of ASD and a candidate gene for epileptic encephalopathy. We also report a distinct clinical presentation of IS, microcephaly, intellectual disability, and absent hallux in a case with the 2q23.1 deletion. CONCLUSION:Our findings strongly support the role of CNVs in infantile spasms and expand the clinical spectrum associate with 2q23.1 deletion. In particular, our study implicates the HNRNPU and MBD5 genes in Chinese children with IS. Our study also supports that the molecular mechanisms of infantile spasms appear conserved among different ethnic backgrounds.

Dataset Information

Inherited 2q23.1 microdeletions involving the MBD5 locus.

Publications

Inherited 2q23.1 microdeletions involving the <i>MBD5</i> locus.

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