title: A unique haplotype of RCCX copy number variation: from the clinics of congenital adrenal hyperplasia to evolutionary genetics.
abstract: There 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.
authors.affiliation: Molecular Medicine Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.|William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.|3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Márton
authors.initials: M
authors.lastname: Doleschall
authors.affiliation: 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
authors.forename: Andrea
authors.initials: A
authors.lastname: Luczay
authors.affiliation: 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Klára
authors.initials: K
authors.lastname: Koncz
authors.affiliation: Department of Medical Genetics, University of Pecs, Pecs, Hungary.
authors.forename: Kinga
authors.initials: K
authors.lastname: Hadzsiev
authors.affiliation: Department of Pediatrics, University of Pecs, Pecs, Hungary.
authors.forename: Éva
authors.initials: É
authors.lastname: Erhardt
authors.affiliation: 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Ágnes
authors.initials: Á
authors.lastname: Szilágyi
authors.affiliation: Department of Pathogenetics, National Institute of Oncology, Budapest, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Doleschall
authors.affiliation: 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Németh
authors.affiliation: 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
authors.forename: Dóra
authors.initials: D
authors.lastname: Török
authors.affiliation: 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Prohászka
authors.affiliation: Department of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Gereben
authors.affiliation: 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
authors.forename: György
authors.initials: G
authors.lastname: Fekete
authors.affiliation: 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Edit
authors.initials: E
authors.lastname: Gláz
authors.affiliation: 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Igaz
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Márta
authors.initials: M
authors.lastname: Korbonits
authors.affiliation: 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Miklós
authors.initials: M
authors.lastname: Tóth
authors.affiliation: Molecular Medicine Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.|2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Károly
authors.initials: K
authors.lastname: Rácz
authors.affiliation: Molecular Medicine Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.|'Lendület' Hereditary Endocrine Tumors Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Patócs
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism; D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics* / Q000473:pathology; D056915:DNA Copy Number Variations; D019143:Evolution, Molecular; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D013255:Steroid 21-Hydroxylase / Q000235:genetics* / Q000378:metabolism
chemical_list: C531510:CYP21A2 protein, human; D013255:Steroid 21-Hydroxylase