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Objectives <p>Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder, with a wide range of clinical manifestations. It is caused by pathogenic variants in the <i>CYP21A2</i> gene causing deficiency of steroid 21-hydroxylase enzyme. Knowledge of the variant spectrum, which varies significantly across populations and ethnic groups, is essential for developing effective screening strategies to improve the diagnosis of 21-hydroxylase deficiency, provide accurate prognosis and reproductive options.</p> Methods <p><i>CYP21A2</i> gene was amplified by highly specific primer pairs. Sequencing, multiplex ligation dependent probe amplification (MLPA) and fragment analysis were employed to determine pathogenic variants (including point variants and large deletion duplications) in 315 unrelated Asian Indian patients with CAH.</p> Results <p>Variants were detected in 94.3% (297/315) of cases, with the most common being deletions (36.2%), i2g (29.6%) and p.Gln319* (11.3%), comprising 77.1% of the total pathogenic variants. The variant p.Ile173Asn and p.Arg357Trp were observed in 7% and 4%, respectively. Cluster E6 and p.Leu308Phefs*6 were uncommon and found in 1.2% and 1.6% respectively. Only one pathogenic variant was identified in 7 (2.3%) patients, most of whom had a mild phenotype. There were 16 (2.7%) alleles carrying more than one variant on one allele, indicating large gene conversion events in the <i>CYP21A2</i> gene. The authors report 14 rare (3.7%) and 5 novel (0.9%) variants.</p> Conclusions <p>This study provides a comprehensive compilation of the largest number of Indian CAH patients with complete genotype. Deletions, i2g and p.Gln319* were the most prevalent variants in this study.</p>

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Molecular Landscape of Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency in India

  • 期刊论文

  • 发表日期：

    2026年1月28日

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  • Sudhisha Dubey,
  • Renu Saxena,
  • Sudha Kohli,
  • Hansraj Jaswal,
  • Asha Rawat,
  • Kuldeep Singh,
  • Sunita Bijarnia-Mahay,
  • Veronica Arora,
  • Anurupa Maitra,
  • Chinnaraj Saravana,
  • Sudha Rao Chandrashekhar,
  • Madhumita Roy Chowdhury,
  • Neerja Gupta,
  • Vandana Jain,
  • Madhulika Kabra,
  • Ratna Dua Puri

摘要

Objectives

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder, with a wide range of clinical manifestations. It is caused by pathogenic variants in the CYP21A2 gene causing deficiency of steroid 21-hydroxylase enzyme. Knowledge of the variant spectrum, which varies significantly across populations and ethnic groups, is essential for developing effective screening strategies to improve the diagnosis of 21-hydroxylase deficiency, provide accurate prognosis and reproductive options.

Methods

CYP21A2 gene was amplified by highly specific primer pairs. Sequencing, multiplex ligation dependent probe amplification (MLPA) and fragment analysis were employed to determine pathogenic variants (including point variants and large deletion duplications) in 315 unrelated Asian Indian patients with CAH.

Results

Variants were detected in 94.3% (297/315) of cases, with the most common being deletions (36.2%), i2g (29.6%) and p.Gln319* (11.3%), comprising 77.1% of the total pathogenic variants. The variant p.Ile173Asn and p.Arg357Trp were observed in 7% and 4%, respectively. Cluster E6 and p.Leu308Phefs*6 were uncommon and found in 1.2% and 1.6% respectively. Only one pathogenic variant was identified in 7 (2.3%) patients, most of whom had a mild phenotype. There were 16 (2.7%) alleles carrying more than one variant on one allele, indicating large gene conversion events in the CYP21A2 gene. The authors report 14 rare (3.7%) and 5 novel (0.9%) variants.

Conclusions

This study provides a comprehensive compilation of the largest number of Indian CAH patients with complete genotype. Deletions, i2g and p.Gln319* were the most prevalent variants in this study.