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

BMC Medical Genetics
Khadim ShahWasim Ahmad

Abstract

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. 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. 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 an...Continue Reading

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Citations

Mar 18, 2021·American Journal of Medical Genetics. Part a·Sonja Strang-KarlssonCarina Wallgren-Pettersson

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Methods Mentioned

BETA
exome sequencing
light microscopy
genotyping
Chip
PCR
transfection

Software Mentioned

HomozygosityMapper
MERLIN
Burrows Aligner
DMLE
Ensembl
DMLE +
PolyPhen
Alamut
Genome Analysis Toolkit ( GATK )
SIFT

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