A unique haplotype of RCCX copy number variation: from the clinics of congenital adrenal hyperplasia to evolutionary genetics

作者：Doleschall Marton; Luczay Andrea; Koncz Klara; Hadzsiev Kinga; Erhardt Eva; Szilagyi Agnes; Doleschall Zoltan; Nemeth Krisztina; Torok Dora; Prohaszka Zoltan; Gereben Balazs; Fekete Gyorgy; Glaz Edit; Igaz Peter; Korbonits Marta; Toth Miklos; Racz Karoly; Patocs Attila

来源：European Journal of Human Genetics, 2017, 25(6): 702-710.

DOI：10.1038/ejhg.2017.38

There is a difficulty in the molecular diagnosis of congenital adrenal hyperplasia (CAH) due to the c. 955C4>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. 955C4T 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. 955C4T 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. 955C4T 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. 955C4T 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.

• 出版日期2017-6