title: Mitral regurgitation as a phenotypic manifestation of nonphotosensitive trichothiodystrophy due to a splice variant in MPLKIP.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, 45320, Pakistan.
authors.forename: Khadim
authors.initials: K
authors.lastname: Shah
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, 45320, Pakistan.|Center for Medical Genetics, Ghent University Hospital, 9000, Ghent, Belgium.
authors.forename: Raja Hussain
authors.initials: RH
authors.lastname: Ali
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, 45320, Pakistan.|Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ansar
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Kwanghyuk
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, Hazara University, Mansehra, Khyber Pakhtunkhwa, 21300, Pakistan.
authors.forename: Muhammad Salman
authors.initials: MS
authors.lastname: Chishti
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Izoduwa
authors.initials: I
authors.lastname: Abbe
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Biao
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, 98195, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Smith
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, 98195, USA.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, 98195, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, 9000, Ghent, Belgium.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coucke
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, 9000, Ghent, Belgium.
authors.forename: Wouter
authors.initials: W
authors.lastname: Steyaert
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, 98195, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bamshad
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Regie Lyn P
authors.initials: RLP
authors.lastname: Santos-Cortez
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA. sleal@bcm.edu.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Leal
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, 45320, Pakistan. wahmadqau@gmail.com.
authors.forename: Wasim
authors.initials: W
authors.lastname: Ahmad
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000483:Alleles; D044466:Asian People / Q000235:genetics; D002648:Child; D003001:Cloning, Molecular; D059472:Exome; D005260:Female; D008040:Genetic Linkage; D057809:HEK293 Cells; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D007438:Introns; D008297:Male; D008944:Mitral Valve Insufficiency / Q000235:genetics*; D010154:Pakistan; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012326:RNA Splicing; D017422:Sequence Analysis, DNA; D054463:Trichothiodystrophy Syndromes / Q000235:genetics*; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C519267:MPLKIP protein, human