A unique haplotype of RCCX copy number variation

From the clinics of congenital adrenal hyperplasia to evolutionary genetics

Márton Doleschall, Andrea Luczay, Klára Koncz, Kinga Hadzsiev, Éva Erhardt, Ágnes Szilágyi, Zoltán Doleschall, Krisztina Németh, Dóra Török, Z. Prohászka, B. Gereben, G. Fekete, E. Gláz, P. Igaz, Márta Korbonits, Miklós Tóth, K. Rácz, A. Patócs

Research output: Contribution to journalArticle

1 Citation (Scopus)

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. ∗12C4T 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.

Original languageEnglish
Pages (from-to)702-710
Number of pages9
JournalEuropean Journal of Human Genetics
Volume25
Issue number6
DOIs
Publication statusPublished - Apr 12 2017

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Congenital Adrenal Hyperplasia
Haplotypes
Adrenal Glands
Computational Biology
Healthy Volunteers
Steroids
Messenger RNA
Mutation
Population
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

A unique haplotype of RCCX copy number variation : From the clinics of congenital adrenal hyperplasia to evolutionary genetics. / Doleschall, Márton; Luczay, Andrea; Koncz, Klára; Hadzsiev, Kinga; Erhardt, Éva; Szilágyi, Ágnes; Doleschall, Zoltán; Németh, Krisztina; Török, Dóra; Prohászka, Z.; Gereben, B.; Fekete, G.; Gláz, E.; Igaz, P.; Korbonits, Márta; Tóth, Miklós; Rácz, K.; Patócs, A.

In: European Journal of Human Genetics, Vol. 25, No. 6, 12.04.2017, p. 702-710.

Research output: Contribution to journalArticle

Doleschall, Márton ; Luczay, Andrea ; Koncz, Klára ; Hadzsiev, Kinga ; Erhardt, Éva ; Szilágyi, Ágnes ; Doleschall, Zoltán ; Németh, Krisztina ; Török, Dóra ; Prohászka, Z. ; Gereben, B. ; Fekete, G. ; Gláz, E. ; Igaz, P. ; Korbonits, Márta ; Tóth, Miklós ; Rácz, K. ; Patócs, A. / A unique haplotype of RCCX copy number variation : From the clinics of congenital adrenal hyperplasia to evolutionary genetics. In: European Journal of Human Genetics. 2017 ; Vol. 25, No. 6. pp. 702-710.
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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. ∗12C4T 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.",
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AU - Hadzsiev, Kinga

AU - Erhardt, Éva

AU - Szilágyi, Ágnes

AU - Doleschall, Zoltán

AU - Németh, Krisztina

AU - Török, Dóra

AU - Prohászka, Z.

AU - Gereben, B.

AU - Fekete, G.

AU - Gláz, E.

AU - Igaz, P.

AU - Korbonits, Márta

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AU - Patócs, A.

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