Key result
CYP11B2 gene sequencing in 62 patients with aldosterone synthase deficiency identified 12 pathogenic variants, including 6 novel variants, with 96% carrying the p.T185I variant.
Why the study?
Pathogenic variants of the CYP11B2 gene cause aldosterone synthase deficiency, and the study sought to investigate their presence in patients with a suggestive profile.
Observational (n=62)
No
This study expands the known genetic spectrum of congenital hypoaldosteronism by identifying six novel pathogenic variants in the CYP11B2 gene in the largest reported cohort to date.
May support expanded genetic panels for hypoaldosteronism; leaves open clinical impact of novel CYP11B2 variants.
CONTEXT: Isolated congenital hypoaldosteronism presents in early infancy with symptoms including vomiting, severe dehydration, salt wasting, and failure to thrive. The main causes of this rare autosomal recessive disorder is pathogenic variants of the CYP11B2 gene leading to aldosterone synthase deficiency. OBJECTIVE: To investigate the presence of CYP11B2 pathogenic variants in a cohort of patients with a clinical, biochemical, and hormonal profile suggestive of aldosterone synthase deficiency. DESIGN: Clinical and molecular study. SETTING: Tertiary academic Children's Hospital, Center for Rare Pediatric Endocrine Diseases. PATIENTS AND METHODS: Sixty-two patients (56 unrelated patients and 6 siblings), with hypoaldosteronism and their parents, underwent CYP11B2 gene sequencing after its selective amplification against the highly homologous CYP11B1 gene. In silico analysis of the identified novel variants was carried out to evaluate protein stability and potential pathogenicity. RESULTS: CYP11B2 gene sequencing revealed that 62 patients carried a total of 12 different pathogenic CYP11B2 gene variants, 6 of which are novel. Importantly, 96% of the 56 patients carried the previously reported p.T185I variant either in homozygosity or in compound heterozygosity with another variant. The 6 novel variants detected were: p.M1I, p.V129M, p.R141Q, p.A165T, p.R448C, and the donor splice site variant of intron 8, c.1398 + 1G > A. CONCLUSION: Molecular diagnosis was achieved in 62 patients with aldosterone synthase deficiency, the largest cohort thus far reported. Six novel genetic variants were identified as possibly pathogenic, extending the spectrum of reported molecular defects of the CYP11B2 gene.
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Merakou et al. (2020) conducted an observational in Hypoaldosteronism due to aldosterone synthase deficiency (n=62). CYP11B2 pathogenic variants was evaluated on Presence of CYP11B2 pathogenic variants. CYP11B2 gene sequencing in 62 patients with aldosterone synthase deficiency identified 12 pathogenic variants, including 6 novel variants, with 96% carrying the p.T185I variant.
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