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

TitleMitral regurgitation as a phenotypic manifestation of nonphotosensitive trichothiodystrophy due to a splice variant in MPLKIP.
Publication TypeJournal Article
Year of Publication2016
AuthorsShah, K, Ali, RHussain, Ansar, M, Lee, K, Chishti, MSalman, Abbe, I, Li, B, Smith, JD, Nickerson, DA, Shendure, J, Coucke, PJ, Steyaert, W, Bamshad, MJ, Santos-Cortez, RLyn P, Leal, SM, Ahmad, W
Corporate AuthorsUniversity of Washington Center for Mendelian Genomics
JournalBMC Med Genet
Date Published2016 Feb 16
KeywordsAdaptor Proteins, Signal Transducing, Adolescent, Adult, Alleles, Asian Continental Ancestry Group, Child, Cloning, Molecular, Exome, Female, Genetic Linkage, Haplotypes, HEK293 Cells, Homozygote, Humans, Introns, Male, Mitral Valve Insufficiency, Pakistan, Pedigree, Phenotype, Polymorphism, Single Nucleotide, RNA Splicing, Sequence Analysis, DNA, Trichothiodystrophy Syndromes, Young Adult

BACKGROUND: Nonphotosensitive 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.

METHODS: We 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.

RESULTS: Affected 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.

CONCLUSION: This 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.

Alternate JournalBMC Med. Genet.
PubMed ID26880286
PubMed Central IDPMC4754937
Grant ListU54 HG006493 / HG / NHGRI NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States