Linked homozygous BMPR1B and PDHA2 variants in a consanguineous family with complex digit malformation and male infertility

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dc.contributor.authorYildirim, Yeserin
dc.contributor.authorOuriachi, Toufik
dc.contributor.authorWoehlbier, Ute
dc.contributor.authorOuahioune, Wahiba
dc.contributor.authorBalkan, Mahmut
dc.contributor.authorMalik, Sajid
dc.contributor.authorTolun, Aslihan
dc.date.accessioned2024-04-24T16:24:03Z
dc.date.available2024-04-24T16:24:03Z
dc.date.issued2018
dc.departmentDicle Üniversitesien_US
dc.description.abstractIn affected members of a consanguineous family, a syndrome, which is concurrence of set of medical signs, is often observed and commonly assumed to have arisen from pleiotropy, i.e., the phenomenon of a single gene variant affecting multiple traits. We detected six sibs afflicted with a unique combination of digit malformation that includes brachydactyly, symphalangism and zygodactyly plus infertility in males owing to azoospermia, sperm immotility or necrospermia, which we hypothesised to have arisen from a defect in a single gene. We mapped the disease locus and by exome sequencing identified in patients homozygous missense variants bone morphogenetic protein receptor type IB (BMPR1B) c.640C>T (p.(Arg214Cys)) and alpha-2 pyruvate dehydrogenase (PDHA2) c.679A>G (p.(Met227Val)). Structural protein modelling, protein sequence conservation and in silico analysis indicate that both variants affect protein function. BMPR1B is known to be responsible for autosomal dominant brachydactyly and autosomal recessive acromesomelic chondrodysplasia. Our findings show that also recessive complex digit malformation can be caused by BMPR1B variant and not all biallelic BMPR1B variants cause acromesomelic dysplasia. PDHA2 is a novel candidate gene for male infertility; the protein product is a mitochondrial enzyme with highest expression in ejaculated sperm. Our findings are a unique example of two linked variants, similar to 711 Kb apart, in different genes that together manifest as a novel syndrome. They demonstrate that exome sequencing and not candidate gene approach should be employed in disease gene hunt, defining new diseases and genetic testing, to rule out the coincidental presence of two variants contributing together to the phenotype, which may be discerned as a novel disease.en_US
dc.description.sponsorshipScientific and Technologic Research Council of Turkey (TUBITAK) [114Z829]; Bogazici University [10860]; FONDECYT [1150743]en_US
dc.description.sponsorshipWe thank the family members for their cooperation. This study was supported by Scientific and Technologic Research Council of Turkey (TUBITAK) grant 114Z829 and Bogazici University Research Fund grant 10860. UW is supported by FONDECYT no. 1150743.en_US
dc.identifier.doi10.1038/s41431-018-0121-7
dc.identifier.endpage885en_US
dc.identifier.issn1018-4813
dc.identifier.issn1476-5438
dc.identifier.issue6en_US
dc.identifier.pmid29581481
dc.identifier.scopus2-s2.0-85044456322
dc.identifier.scopusqualityQ1
dc.identifier.startpage876en_US
dc.identifier.urihttps://doi.org/10.1038/s41431-018-0121-7
dc.identifier.urihttps://hdl.handle.net/11468/16442
dc.identifier.volume26en_US
dc.identifier.wosWOS:000433424200012
dc.identifier.wosqualityQ2
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoenen_US
dc.publisherNature Publishing Groupen_US
dc.relation.ispartofEuropean Journal of Human Genetics
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subject[No Keyword]en_US
dc.titleLinked homozygous BMPR1B and PDHA2 variants in a consanguineous family with complex digit malformation and male infertilityen_US
dc.titleLinked homozygous BMPR1B and PDHA2 variants in a consanguineous family with complex digit malformation and male infertility
dc.typeArticleen_US

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