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Background <p>Congenital adrenal hyperplasia (CAH) is a leading cause of ambiguous genitalia in females. Pathogenic variants in the <i>CYP21A2</i> gene cause 95% of CAH cases in Iran and other populations. Infertility, reconstructive surgery in females, and death from adrenal crises contribute significantly to the disease burden. Genetic counseling and genotype analysis in high-risk families can significantly reduce psychological and economic burdens.</p> Methods <p>This study aimed to characterize a new pathogenic variant in a girl presenting with classic salt-wasting CAH in an Iranian consanguineous family. Multiplex and long-range PCR, along with five Sanger sequencing reactions, were performed to evaluate the entire&#xa0;<i>CYP21A2</i>&#xa0;coding region and flanking intronic sequences. Co-segregation and in silico analysis were performed for candidate pathogenic variant.</p> Results <p>We detected a new pathogenic variant (NM_000500.9: c.579del) in exon five of the&#xa0;CYP21A2&#xa0;gene. This pathogenic variant gives rise to an early stop codon at residue 199. The parents were heterozygous for the allele. Based on the American College of Medical Genetics and Genomics guideline, the p. Lys193Asnfs*7 variant fulfills the criteria of being classified as pathogenic. Our results provide new insights into the pathogenicity of the c.579del variant. The genotype correlated well with the phenotype based on in silico analysis.</p> Conclusion <p>This work adds to the extent of knowledge of the molecular mechanism of 21-OHD. Genotyping is a critical tool for confirming diagnoses and carrier states, providing valuable prognostic information on disease severity, and is essential for effective genetic counseling.</p>

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A Deleterious Frameshift Deletion Variant in Exon 5 of the CYP21A2 Gene Causes Classic Salt-Wasting Congenital Adrenal Hyperplasia

  • 期刊论文

  • 发表日期：

    2025年9月9日

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  • Newsha Molavi,
  • Shahrzad Aghaei,
  • Marziyeh Hoseinzadeh,
  • Hossein KhanAhmad,
  • Mahin Hashemipour,
  • Mohammad Amin Tabatabaiefar

摘要

Background

Congenital adrenal hyperplasia (CAH) is a leading cause of ambiguous genitalia in females. Pathogenic variants in the CYP21A2 gene cause 95% of CAH cases in Iran and other populations. Infertility, reconstructive surgery in females, and death from adrenal crises contribute significantly to the disease burden. Genetic counseling and genotype analysis in high-risk families can significantly reduce psychological and economic burdens.

Methods

This study aimed to characterize a new pathogenic variant in a girl presenting with classic salt-wasting CAH in an Iranian consanguineous family. Multiplex and long-range PCR, along with five Sanger sequencing reactions, were performed to evaluate the entire CYP21A2 coding region and flanking intronic sequences. Co-segregation and in silico analysis were performed for candidate pathogenic variant.

Results

We detected a new pathogenic variant (NM_000500.9: c.579del) in exon five of the CYP21A2 gene. This pathogenic variant gives rise to an early stop codon at residue 199. The parents were heterozygous for the allele. Based on the American College of Medical Genetics and Genomics guideline, the p. Lys193Asnfs*7 variant fulfills the criteria of being classified as pathogenic. Our results provide new insights into the pathogenicity of the c.579del variant. The genotype correlated well with the phenotype based on in silico analysis.

Conclusion

This work adds to the extent of knowledge of the molecular mechanism of 21-OHD. Genotyping is a critical tool for confirming diagnoses and carrier states, providing valuable prognostic information on disease severity, and is essential for effective genetic counseling.