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dc.contributor.authorDoleschall, Men_US
dc.contributor.authorLuczay, Aen_US
dc.contributor.authorKoncz, Ken_US
dc.contributor.authorHadzsiev, Ken_US
dc.contributor.authorErhardt, Éen_US
dc.contributor.authorSzilágyi, Áen_US
dc.contributor.authorDoleschall, Zen_US
dc.contributor.authorNémeth, Ken_US
dc.contributor.authorTörök, Den_US
dc.contributor.authorProhászka, Zen_US
dc.contributor.authorGereben, Ben_US
dc.contributor.authorFekete, Gen_US
dc.contributor.authorGláz, Een_US
dc.contributor.authorIgaz, Pen_US
dc.contributor.authorKorbonits, Men_US
dc.contributor.authorTóth, Men_US
dc.contributor.authorRácz, Ken_US
dc.contributor.authorPatócs, Aen_US
dc.date.accessioned2017-06-22T09:31:02Z
dc.date.available2017-02-14en_US
dc.date.issued2017-06en_US
dc.date.submitted2017-06-22T10:24:15.964Z
dc.identifier.urihttp://qmro.qmul.ac.uk/xmlui/handle/123456789/24509
dc.description.abstractThere is a difficulty in the molecular diagnosis of congenital adrenal hyperplasia (CAH) due to the c.955C>T (p.(Q319*), formerly Q318X, rs7755898) variant of the CYP21A2 gene. Therefore, a systematic assessment of the genetic and evolutionary relationships between c.955C>T, CYP21A2 haplotypes and the RCCX copy number variation (CNV) structures, which harbor CYP21A2, was performed. In total, 389 unrelated Hungarian individuals with European ancestry (164 healthy subjects, 125 patients with non-functioning adrenal incidentaloma and 100 patients with classical CAH) as well as 34 adrenocortical tumor specimens were studied using a set of experimental and bioinformatic methods. A unique, moderately frequent (2%) haplotypic RCCX CNV structure with three repeated segments, abbreviated to LBSASB, harboring a CYP21A2 with a c.955C>T variant in the 3'-segment, and a second CYP21A2 with a specific c.*12C>T (rs150697472) variant in the middle segment occurred in all c.955C>T carriers with normal steroid levels. The second CYP21A2 was free of CAH-causing mutations and produced mRNA in the adrenal gland, confirming its functionality and ability to rescue the carriers from CAH. Neither LBSASB nor c.*12C>T occurred in classical CAH patients. However, CAH-causing CYP21A2 haplotypes with c.955C>T could be derived from the 3'-segment of LBSASB after the loss of functional CYP21A2 from the middle segment. The c.*12C>T indicated a functional CYP21A2 and could distinguish between non-pathogenic and pathogenic genomic contexts of the c.955C>T variant in the studied European population. Therefore, c.*12C>T may be suitable as a marker to avoid this genetic confound and improve the diagnosis of CAH.en_US
dc.format.extent702 - 710en_US
dc.languageengen_US
dc.relation.ispartofEur J Hum Geneten_US
dc.subjectAdrenal Glandsen_US
dc.subjectAdrenal Hyperplasia, Congenitalen_US
dc.subjectDNA Copy Number Variationsen_US
dc.subjectEvolution, Molecularen_US
dc.subjectFemaleen_US
dc.subjectHaplotypesen_US
dc.subjectHumansen_US
dc.subjectMaleen_US
dc.subjectSteroid 21-Hydroxylaseen_US
dc.titleA unique haplotype of RCCX copy number variation: from the clinics of congenital adrenal hyperplasia to evolutionary genetics.en_US
dc.typeArticle
dc.rights.holder© 2017 European Society of Human Genetics
dc.identifier.doi10.1038/ejhg.2017.38en_US
pubs.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/28401898en_US
pubs.issue6en_US
pubs.notesNot knownen_US
pubs.publication-statusPublisheden_US
pubs.volume25en_US
dcterms.dateAccepted2017-02-14en_US


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