# A Case of Salt-Wasting Congenital Adrenal Hyperplasia Caused by a Rare Intronic Variant in the CYP21A2 Gene

## TL;DR

A rare intronic mutation in the CYP21A2 gene is identified in a child with congenital adrenal insufficiency, expanding the known genetic causes of this condition.

## Contribution

The study reports a novel intronic variant in CYP21A2 and demonstrates the utility of amplicon sequencing in diagnosing rare genetic mutations.

## Key findings

- Compound heterozygosity involving a gene deletion and a novel intronic mutation in CYP21A2 was identified.
- Amplicon sequencing proved effective in detecting rare intronic variants in early-onset adrenal failure.
- Whole genome sequencing ruled out other genetic causes, confirming the role of CYP21A2 in the patient's condition.

## Abstract

This case report describes a novel intronic mutation, CYP21A2:c.738+75C>T (rs1463196531), identified in a 4-year-old male with congenital adrenal insufficiency, and expands the known mutation spectrum associated with this condition. The patient, born full-term to unrelated parents, presented with adrenal failure within the first month of life, characterized by acute adrenal crisis symptoms such as vomiting, dehydration, weight loss, hypotension, and electrolyte imbalances. Hormonal evaluations confirmed primary adrenocortical insufficiency, necessitating ongoing hydrocortisone and fludrocortisone therapy. Using family trio-based amplicon sequencing of the CYP21A2 gene, we identified compound heterozygosity consisting of a full gene deletion and a novel pathogenic intronic mutation. Additionally, analysis of WGS data was performed to rule out pathogenic variants in genes that might lead to a similar phenotype, thereby eliminating the possibility of other genes contributing to the proband’s disease. This case demonstrates the potential of using amplicon sequencing in molecular genetic diagnostic testing to detect rare intronic variants in the CYP21A2 gene in cases of early-onset adrenal failure. It also contributes to a better understanding of the genetic basis of congenital adrenal hyperplasia (CAH), which remains a significant autosomal recessive disorder affecting cortisol and aldosterone production, with an incidence of 1 in 10,000 to 1 in 15,000 globally.