Primary Aldosteronism via CACNA1D Gene

Primary aldosteronism is characterized by a constitutive overproduction of aldosterone (Dutta et al. 2016; Mulatero et al. 2013). It is the most common form of secondary hypertension and affects 8–13% of patients with hypertension. The two most common causes of primary aldosteronism are aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH).

In addition to familial hyperaldosteronism types I, II and III, germline pathogenic variants in genes encoding voltage-gated calcium channels (CACNA1D and CACNA1H) can cause primary aldosteronism with or without neuromuscular abnormalities. In particular, patients with CACNA1D-causative primary aldosteronism present early onset (at birth) hypertension followed by seizures and neurologic abnormalities (global developmental delay and severe generalized intellectual disability) (Scholl et al. 2013).

Germline pathogenic variants causing primary aldosteronism with autosomal dominant inheritance have been found in the CYP11B2, KCNJ5, CACNA1D and CACNA1H genes (Dutta et al. 2016; Mulatero et al. 2013).

To date, only a very limited number of germline missense changes have been found in CACNA1D in patients with primary aldosteronism (Scholl et al. 2013). CACNA1D encodes the α1 subunit of L-type voltage calcium channel.

Scholl et al. sequenced the CACNA1D gene in 100 unrelated individuals with unexplained early-onset primary aldosteronism and identified two girls with de novo heterozygous gain-of-function missense pathogenic variants (Scholl et al. 2013).

This test provides full coverage of all coding exons of the CACNA1D gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).