Mitral regurgitation as a phenotypic manifestation of nonphotosensitive trichothiodystrophy due to a splice variant in MPLKIP

BMC Medical Genetics

Research Article

Wouter Steyaert¹  Paul J. Coucke¹  Biao Li²  Izoduwa Abbe²  Regie Lyn P. Santos-Cortez²  Kwanghyuk Lee²  Suzanne M. Leal²  Khadim Shah³  Wasim Ahmad³  Raja Hussain Ali⁴  Muhammad Ansar⁵  Muhammad Salman Chishti⁶  Jay Shendure⁷  Michael J. Bamshad⁷  Joshua D. Smith⁷  Deborah A. Nickerson⁷ 

[1] Center for Medical Genetics, Ghent University Hospital, 9000, Ghent, Belgium;Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, 77030, Houston, TX, USA;Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, 45320, Islamabad, Pakistan;Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, 45320, Islamabad, Pakistan;Center for Medical Genetics, Ghent University Hospital, 9000, Ghent, Belgium;Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, 45320, Islamabad, Pakistan;Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, 77030, Houston, TX, USA;Department of Biochemistry, Hazara University, 21300, Mansehra, Khyber Pakhtunkhwa, Pakistan;Department of Genome Sciences, University of Washington, 98195, Seattle, Washington, USA;

关键词: Autosomal recessive;    Cardiomyopathy;    Mitral regurgitation;    MPLKIP;    Nonphotosensitive;    Phenotypic expansion;    Splice mutation;    Trichothiodystrophy;   

DOI  :  10.1186/s12881-016-0275-5

 received in 2015-04-28, accepted in 2016-02-03,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundNonphotosensitive trichothiodystrophy (TTDN) is a rare autosomal recessive disorder of neuroectodermal origin. The condition is marked by hair abnormalities, intellectual impairment, nail dystrophies and susceptibility to infections but with no UV sensitivity.MethodsWe identified three consanguineous Pakistani families with varied TTDN features and used homozygosity mapping, linkage analysis, and Sanger and exome sequencing in order to identify pathogenic variants. Haplotype analysis was performed and haplotype age estimated. A splicing assay was used to validate the effect of the MPLKIP splice variant on expression.ResultsAffected individuals from all families exhibit several TTDN features along with a heart-specific feature, i.e. mitral regurgitation. Exome sequencing in the probands from families ED168 and ED241 identified a homozygous splice mutation c.339 + 1G > A within MPLKIP. The same splice variant co-segregates with TTDN in a third family ED210. The MPLKIP splice variant was not found in public databases, e.g. the Exome Aggregation Consortium, and in unrelated Pakistani controls. Functional analysis of the splice variant confirmed intron retention, which leads to protein truncation and loss of a phosphorylation site. Haplotype analysis identified a 585.1-kb haplotype which includes the MPLKIP variant, supporting the existence of a founder haplotype that is estimated to be 25,900 years old.ConclusionThis study extends the allelic and phenotypic spectra of MPLKIP-related TTDN, to include a splice variant that causes cardiomyopathy as part of the TTDN phenotype.

【 授权许可】

CC BY   
© Shah et al. 2016