Carrier detection of CAH, in a consanguineous family with a deseased affected child

Background and Aim : Congenital adrenal hyperplasia refers to a group of inherited AR condition caused by mutations in genes that code for enzymes involved in making steroid hormones in the adrenal glands. The most common enzyme defect, 21-hydroxylase deficiency, caused by defects in the CYP21A2 gene, leads to excess amounts of male hormones being produced by the adrenal glands. Classic CAH is characterized by simple virilizing or salt wasting forms that can manifest with genital ambiguity in females and with adrenal insufficiency (in both sexes), and that presents with dehydration, hypoglycemia in the neonatal period (that can be lethal if untreated), and hyperandrogenia. An asymothomatic couple with the history of having a son who was passed away with possible diagnosis of Congenital Adrenal Hyperplasia (CAH), were referred to genetic-counseling clinic. They are second cousins once removed. They wanted to know the disease cause, recurrence risk and prevention possibility in their future pregnancies.Methods : Sequence analysis of CYP21A2 gene was performed by PCR-Sanger sequencing. Then, Long-range PCR amplification was performed, followed by RFLP. Results : There were no pathogenic variants in sequence analysis of CYP21A2 gene by sanger sequencing. We detected the 30kb deletion encompassing CYP21A2 gene in heterozygous state, in both of parents.Conclusion : Pathogenic mutations causing the disease, mostly point mutations, 70-80% are detected by the CYP21A2 gene sequencing. Approximately 20-30% of mutated alleles are the result of meiotic recombination between repeated sequences that result in a 30kb deletion that encompasses the 3/ end of the CYP21A2 pseudogene, all of the adjacent C4B complement gene, and the 5/ end of CYP21A2, thereby producing nonfunctional chimeric pseudogene.This couple are both carrier of the pathogenic 30kb deletion encompassing CYP21A2 gene. This means there is 25% risk of the couple to have an affected offspring with CAH in each of their pregnancies. Prenatal diagnosis is possible. A necessary genetic test is an important tool in confirming the diagnosis or carrier state, and is essential for genetic counseling.

کلیدواژه ها:

Congenital adrenal hyperplasia ، carrier detection ، prenatal diagnosis ، CYP21A2 gene