Variant Synonymizer: Platform to identify mutations defined in different ways is available now!

VarSy

Over 2,000 gene–disease validation summaries are now available—no login required!

Browse Summaries

CACNA1H – Familial Hyperaldosteronism Type IV

Familial hyperaldosteronism type IV (FH4) is a rare autosomal dominant form of primary aldosteronism characterized by inappropriate aldosterone production, hypokalemia, and metabolic alkalosis. A single 27-year-old female presenting with persistent hypokalemia and metabolic alkalosis despite normotension was reported; clinical exome sequencing identified a heterozygous CACNA1H variant in the T-type calcium channel gene, implicating FH4 in her phenotype (1 proband) (PMID:39803142).

Whole-exome sequencing in patients with various forms of primary aldosteronism identified four unrelated individuals with heterozygous germline CACNA1H variants, including a recurrent de novo c.4647G>T (p.Met1549Ile), plus c.587C>T (p.Ser196Leu), c.5852T>A (p.Val1951Glu), and p.Pro2083Leu, segregating in FH pedigrees (4 probands) (PMID:27729216).

Functional assays in human adrenocortical H295R-S2 cells and zona glomerulosa preparations demonstrated that these Cav3.2 channel mutants exhibit slowed inactivation, enhanced recovery, and increased window currents, resulting in elevated CYP11B2 expression and aldosterone production consistent with a gain-of-function mechanism (PMID:31706065; PMID:27729216).

Collectively, the presence of de novo and familial heterozygous CACNA1H variants in independent probands, along with concordant gain-of-function data, supports a Moderate clinical validity for the gene–disease association. Genetic testing of CACNA1H should be incorporated into the diagnostic workup of early-onset primary aldosteronism, with functional studies guiding targeted therapeutic strategies.

References

  • Cureus • 2024 • A Case of Primary Aldosteronism Masquerading as Bartter and Gitelman Syndromes. PMID:39803142
  • EBioMedicine • 2016 • CACNA1H Mutations Are Associated With Different Forms of Primary Aldosteronism. PMID:27729216
  • Cell Calcium • 2019 • Splice-variant-specific effects of primary aldosteronism point mutations on human CaV3.2 calcium channels. PMID:31706065
  • BMJ Case Reports • 2019 • Primary aldosteronism associated with a germline variant in CACNA1H. PMID:31126930

Evidence Based Scoring (AI generated)

Gene–Disease Association

Moderate

5 probands with heterozygous CACNA1H variants in FH4 and related PA cases; functional concordance

Genetic Evidence

Moderate

Four unrelated germline variants including de novo events in FH4 probands (PMID:27729216)

Functional Evidence

Strong

Multiple in vitro assays in H295R-S2 and ZG cells demonstrate gain-of-function effects increasing aldosterone synthesis (PMID:31706065; PMID:27729216)