Auer MK, Nordenström A, Lajic S, Reisch N. Congenital adrenal hyperplasia. Lancet (London, England). 2023;401(10372):227–44.

Article  CAS  PubMed  Google Scholar 

Speiser PW, Arlt W, Auchus RJ, Baskin LS, Conway GS, Merke DP, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2018;103(11):4043–88.

Article  PubMed  PubMed Central  Google Scholar 

Miller WL. Mechanisms in endocrinology: rare defects in adrenal steroidogenesis. Eur J Endocrinol. 2018;179(3):R125-r141.

Article  CAS  PubMed  Google Scholar 

Wilson RC, Nimkarn S, Dumic M, Obeid J, Azar MR, Najmabadi H, et al. Ethnic-specific distribution of mutations in 716 patients with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Mol Genet Metab. 2007;90(4):414–21.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Merke DP, Auchus RJ. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. N Engl J Med. 2020;383(13):1248–61.

Article  CAS  PubMed  Google Scholar 

Higashi Y, Yoshioka H, Yamane M, Gotoh O, Fujii-Kuriyama Y. Complete nucleotide sequence of two steroid 21-hydroxylase genes tandemly arranged in human chromosome: a pseudogene and a genuine gene. Proc Natl Acad Sci USA. 1986;83(9):2841–5.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Yang Z, Mendoza AR, Welch TR, Zipf WB, Yu CY. Modular variations of the human major histocompatibility complex class III genes for serine/threonine kinase RP, complement component C4, steroid 21-hydroxylase CYP21, and tenascin TNX (the RCCX module). A mechanism for gene deletions and disease associations. J Biol Chem. 1999;274(17):12147–56.

Article  CAS  PubMed  Google Scholar 

Blanchong CA, Zhou B, Rupert KL, Chung EK, Jones KN, Sotos JF, et al. Deficiencies of human complement component C4A and C4B and heterozygosity in length variants of RP-C4-CYP21-TNX (RCCX) modules in Caucasians. The load of RCCX genetic diversity on major histocompatibility complex-associated disease. J Exp Med. 2000;191(12):2183–96.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Carrozza C, Foca L, De Paolis E, Concolino P. Genes and pseudogenes: complexity of the RCCX locus and disease. Front Endocrinol. 2021;12:709758.

Article  Google Scholar 

Doleschall M, Luczay A, Koncz K, Hadzsiev K, Erhardt É, Szilágyi Á, et al. A unique haplotype of RCCX copy number variation: from the clinics of congenital adrenal hyperplasia to evolutionary genetics. Eur J Hum Genet EJHG. 2017;25(6):702–10.

Article  CAS  PubMed  Google Scholar 

Concolino P, Costella A. Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency: a comprehensive focus on 233 pathogenic variants of CYP21A2 gene. Mol Diagn Ther. 2018;22(3):261–80.

Article  CAS  PubMed  Google Scholar 

Finkielstain GP, Chen W, Mehta SP, Fujimura FK, Hanna RM, Van Ryzin C, et al. Comprehensive genetic analysis of 182 unrelated families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2011;96(1):E161-172.

Article  CAS  PubMed  Google Scholar 

Pignatelli D, Carvalho BL, Palmeiro A, Barros A, Guerreiro SG, Macut D. The complexities in genotyping of congenital adrenal hyperplasia: 21-hydroxylase deficiency. Front Endocrinol. 2019;10:432.

Article  Google Scholar 

Chen W, Xu Z, Sullivan A, Finkielstain GP, Van Ryzin C, Merke DP, et al. Junction site analysis of chimeric CYP21A1P/CYP21A2 genes in 21-hydroxylase deficiency. Clin Chem. 2012;58(2):421–30.

Article  CAS  PubMed  Google Scholar 

Merke DP, Chen W, Morissette R, Xu Z, Van Ryzin C, Sachdev V, et al. Tenascin-X haploinsufficiency associated with Ehlers–Danlos syndrome in patients with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2013;98(2):E379-387.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Paragliola RM, Perrucci A, Foca L, Urbani A, Concolino P. Prevalence of CAH-X syndrome in Italian patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. J Clin Med. 2022;11(13):3818.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Chen W, Kim MS, Shanbhag S, Arai A, VanRyzin C, McDonnell NB, et al. The phenotypic spectrum of contiguous deletion of CYP21A2 and tenascin XB: quadricuspid aortic valve and other midline defects. Am J Med Genet Part A. 2009;149a(12):2803–8.

Article  CAS  PubMed  Google Scholar 

Ezquieta B, Beneyto M, Muñoz-Pacheco R, Barrio R, Oyarzabal M, Lechuga JL, et al. Gene duplications in 21-hydroxylase deficiency: the importance of accurate molecular diagnosis in carrier detection and prenatal diagnosis. Prenat Diagn. 2006;26(12):1172–8.

Article  CAS  PubMed  Google Scholar 

Kleinle S, Lang R, Fischer GF, Vierhapper H, Waldhauser F, Födinger M, et al. Duplications of the functional CYP21A2 gene are primarily restricted to Q318X alleles: evidence for a founder effect. J Clin Endocrinol Metab. 2009;94(10):3954–8.

Article  CAS  PubMed  Google Scholar 

White PC, Curnow KM, Pascoe L. Disorders of steroid 11 beta-hydroxylase isozymes. Endocr Rev. 1994;15(4):421–38.

CAS  PubMed  Google Scholar 

Xie H, Yin H, Ye X, Liu Y, Liu N, Zhang Y, et al. Detection of small CYP11B1 deletions and one founder chimeric CYP11B2/CYP11B1 gene in 11β-hydroxylase deficiency. Front Endocrinol. 2022;13:882863.

Article  Google Scholar 

Xu Z, Chen W, Merke DP, McDonnell NB. Comprehensive mutation analysis of the CYP21A2 gene: an efficient multistep approach to the molecular diagnosis of congenital adrenal hyperplasia. J Mol Diagn JMD. 2013;15(6):745–53.

Article  CAS  PubMed  Google Scholar 

Gao Y, Lu L, Yu B, Mao J, Wang X, Nie M, et al. The prevalence of the chimeric TNXA/TNXB gene and clinical symptoms of Ehlers–Danlos syndrome with 21-hydroxylase deficiency. J Clin Endocrinol Metabol. 2020;105(7):2288–99.

Article  Google Scholar 

Ewans LJ, Schofield D, Shrestha R, Zhu Y, Gayevskiy V, Ying K, et al. Whole-exome sequencing reanalysis at 12 months boosts diagnosis and is cost-effective when applied early in Mendelian disorders. Genet Med Off J Am Coll Med Genet. 2018;20(12):1564–74.

Google Scholar 

Ewans LJ, Minoche AE, Schofield D, Shrestha R, Puttick C, Zhu Y, et al. Whole exome and genome sequencing in mendelian disorders: a diagnostic and health economic analysis. Eur J Hum Genet EJHG. 2022;30(10):1121–31.

Article  CAS  PubMed  Google Scholar 

Hiz Kurul S, Oktay Y, Töpf A, Szabó NZ, Güngör S, Yaramis A, et al. High diagnostic rate of trio exome sequencing in consanguineous families with neurogenetic diseases. Brain J Neurol. 2022;145(4):1507–18.

Article  Google Scholar 

Gangodkar P, Khadilkar V, Raghupathy P, Kumar R, Dayal AA, Dayal D, et al. Clinical application of a novel next generation sequencing assay for CYP21A2 gene in 310 cases of 21- hydroxylase congenital adrenal hyperplasia from India. Endocrine. 2021;71(1):189–98.

Article  CAS  PubMed  Google Scholar 

Turan I, Tastan M, Boga DD, Gurbuz F, Kotan LD, Tuli A, et al. 21-Hydroxylase deficiency: mutational spectrum and genotype–phenotype relations analyses by next-generation sequencing and multiplex ligation-dependent probe amplification. Eur J Med Genet. 2020;63(4):103782.

Article  PubMed  Google Scholar 

Wang W, Han R, Yang Z, Zheng S, Li H, Wan Z, et al. Targeted gene panel sequencing for molecular diagnosis of congenital adrenal hyperplasia. J Steroid Biochem Mol Biol. 2021;211:105899.

Article  CAS  PubMed  Google Scholar 

Wenger AM, Peluso P, Rowell WJ, Chang PC, Hall RJ, Concepcion GT, et al. Accurate circular consensus long-read sequencing improves variant detection and assembly of a human genome. Nat Biotechnol. 2019;37(10):1155–62.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Mastrorosa FK, Miller DE, Eichler EE. Applications of long-read sequencing to Mendelian genetics. Genome Med. 2023;15(1):42.

Article  PubMed  PubMed Central