Pavlos Fanis1, Nicos Skordis1,2,3, Leonidas A Phylactou4, Vassos Neocleous1. 1. Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus. 2. Division of Pediatric Endocrinology, Paedi Center for Specialized Pediatrics, Nicosia, Cyprus. 3. Medical School, University of Nicosia, Nicosia, Cyprus. 4. Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus. laphylac@cing.ac.cy.
Abstract
BACKGROUND: Genetic diversity of mutations in the CYP21A2 gene is the main cause of the monogenic congenital adrenal hyperplasia (CAH) disorder. On chromosome 6p21.3, the CYP21A2 gene is partially overlapped by the TNXB gene, the two residing in tandem with their highly homologous corresponding pseudogenes (CYP21A1P and TNXA), which leads to recurrent homologous recombination. METHODS AND RESULTS: In the present study, the genetic status of an ethnic Greek-Cypriot family, with a female neonate that was originally classified as male and manifested the salt-wasting (SW) form, is presented. Genetic defects in the CYP21A2 and TNXB genes were investigated by Sanger sequencing multiplex ligation-dependent probe amplification (MLPA) and a real-time PCR assay. The neonate carried in compound heterozygosity the TNXA/TNXB chimeric gene complex (termed CAH-X CH-1) that results in a contiguous CYP21A2 and TNXB deletion and in her second allele the pathogenic IVS2-13A/C > G (c.655A/C > G) in CYP21A2. CONCLUSIONS: The classic SW-CAH due to 21-hydroxylase (21-OH) deficiency may result from various complex etiological mechanisms and, as such, can involve the formation of monoallelic TNXA/TNXB chimeras found in trans with other CYP21A2 pathogenic variants. This is a rare case of CAH due to 21-hydroxylase deficiency, which elucidates the role of the complex RCCX CNV structure in the development of the disease. Identification of the correct CAH genotypes for a given phenotype is of considerable value in assisting clinicians in prenatal diagnosis, appropriate treatment, and genetic counseling.
BACKGROUND: Genetic diversity of mutations in the CYP21A2 gene is the main cause of the monogenic congenital adrenal hyperplasia (CAH) disorder. On chromosome 6p21.3, the CYP21A2 gene is partially overlapped by the TNXB gene, the two residing in tandem with their highly homologous corresponding pseudogenes (CYP21A1P and TNXA), which leads to recurrent homologous recombination. METHODS AND RESULTS: In the present study, the genetic status of an ethnic Greek-Cypriot family, with a female neonate that was originally classified as male and manifested the salt-wasting (SW) form, is presented. Genetic defects in the CYP21A2 and TNXB genes were investigated by Sanger sequencing multiplex ligation-dependent probe amplification (MLPA) and a real-time PCR assay. The neonate carried in compound heterozygosity the TNXA/TNXB chimeric gene complex (termed CAH-X CH-1) that results in a contiguous CYP21A2 and TNXB deletion and in her second allele the pathogenic IVS2-13A/C > G (c.655A/C > G) in CYP21A2. CONCLUSIONS: The classic SW-CAH due to 21-hydroxylase (21-OH) deficiency may result from various complex etiological mechanisms and, as such, can involve the formation of monoallelic TNXA/TNXB chimeras found in trans with other CYP21A2 pathogenic variants. This is a rare case of CAH due to 21-hydroxylase deficiency, which elucidates the role of the complex RCCX CNV structure in the development of the disease. Identification of the correct CAH genotypes for a given phenotype is of considerable value in assisting clinicians in prenatal diagnosis, appropriate treatment, and genetic counseling.
Authors: Hedi L Claahsen-van der Grinten; Phyllis W Speiser; S Faisal Ahmed; Wiebke Arlt; Richard J Auchus; Henrik Falhammar; Christa E Flück; Leonardo Guasti; Angela Huebner; Barbara B M Kortmann; Nils Krone; Deborah P Merke; Walter L Miller; Anna Nordenström; Nicole Reisch; David E Sandberg; Nike M M L Stikkelbroeck; Philippe Touraine; Agustini Utari; Stefan A Wudy; Perrin C White Journal: Endocr Rev Date: 2022-01-12 Impact factor: 19.871