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

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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. 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.
Keywords
Autosomal recessive, Cardiomyopathy, Mitral regurgitation, MPLKIP, Nonphotosensitive, Phenotypic expansion, Splice mutation, Trichothiodystrophy, C7ORF11 TTDN1 GENE, POLO-LIKE KINASES, CELL-DIVISION, MUTATIONS, FRAMEWORK, GENOME

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Chicago
Shah, Khadim, Raja Hussain Ali, Muhammad Ansar, Kwanghyuk Lee, Muhammad Salman Chishti, Izoduwa Abbe, Biao Li, et al. 2016. “Mitral Regurgitation as a Phenotypic Manifestation of Nonphotosensitive Trichothiodystrophy Due to a Splice Variant in MPLKIP.” Bmc Medical Genetics 17.
APA
Shah, K., Ali, R. H., Ansar, M., Lee, K., Chishti, M. S., Abbe, I., Li, B., et al. (2016). Mitral regurgitation as a phenotypic manifestation of nonphotosensitive trichothiodystrophy due to a splice variant in MPLKIP. BMC MEDICAL GENETICS, 17.
Vancouver
1.
Shah K, Ali RH, Ansar M, Lee K, Chishti MS, Abbe I, et al. Mitral regurgitation as a phenotypic manifestation of nonphotosensitive trichothiodystrophy due to a splice variant in MPLKIP. BMC MEDICAL GENETICS. 2016;17.
MLA
Shah, Khadim, Raja Hussain Ali, Muhammad Ansar, et al. “Mitral Regurgitation as a Phenotypic Manifestation of Nonphotosensitive Trichothiodystrophy Due to a Splice Variant in MPLKIP.” BMC MEDICAL GENETICS 17 (2016): n. pag. Print.
@article{8051304,
  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 {\textrangle} 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.},
  articleno    = {13},
  author       = {Shah, Khadim and Ali, Raja Hussain and Ansar, Muhammad and Lee, Kwanghyuk and Chishti, Muhammad Salman and Abbe, Izoduwa and Li, Biao and Smith, Joshua D and Nickerson, Deborah A and Shendure, Jay and Coucke, Paul and Steyaert, Wouter and Bamshad, Michael J and Santos-Cortez, Regie Lyn P and Leal, Suzanne M and Ahmad, Wasim},
  issn         = {1471-2350},
  journal      = {BMC MEDICAL GENETICS},
  keyword      = {Autosomal recessive,Cardiomyopathy,Mitral regurgitation,MPLKIP,Nonphotosensitive,Phenotypic expansion,Splice mutation,Trichothiodystrophy,C7ORF11 TTDN1 GENE,POLO-LIKE KINASES,CELL-DIVISION,MUTATIONS,FRAMEWORK,GENOME},
  language     = {eng},
  pages        = {9},
  title        = {Mitral regurgitation as a phenotypic manifestation of nonphotosensitive trichothiodystrophy due to a splice variant in MPLKIP},
  url          = {http://dx.doi.org/10.1186/s12881-016-0275-5},
  volume       = {17},
  year         = {2016},
}

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