SAT-276 - Functional Dominance of Mutant ATP2B3 Expression in Primary Aldosteronism Across the Sexes

Background: ATP2B3 is an X-chromosome gene infrequently implicated in primary aldosteronism (PA) – accounting for approximately 6% of cases in our institutional database – but which demonstrates a strong male predilection (male-to-female ratio = 5:1). Despite this intriguing observation, how ATP2B3 mutant and wild-type alleles are expressed in human PA adrenal tissue and whether this differs by sex remains incompletely defined. Thus, in this study, we sought to examine ATP2B3 allelic expression in ATP2B3-mutant PA adrenal lesions.

Methods: We evaluated formalin-fixed paraffin-embedded (FFPE) PA adrenal tissue from 17 patients harboring adrenal lesions with somatic ATP2B3 mutations. Histopathology was classified according to HISTALDO as aldosterone-producing adenoma (APA) or aldosterone-producing nodule (APN). Genomic variant allele fraction (VAF) was obtained from targeted DNA sequencing via the Ion Torrent Next-Generation Sequencing (NGS) System. Allelic expression was quantified in a manner similar to genomic VAF using a novel targeted RNA sequencing approach for the Ion Torrent NGS System.

Results: The cohort included 12 men and 5 women (mean age = 55.7 years). 14 patients were Caucasian, and two were African American; the race/ethnicity of one patient was unknown. The studied adrenal lesions included 9 APA and 8 APN. ATP2B3 genomic VAF ranges were 26.4%-32.3% for women and 55.2%-74% for men, whereas ATP2B3-mutant allelic expression was uniformly high at approximately 91.1–99.5%. This marked discordance between ATP2B3 genomic VAF and allelic expression was observed regardless of sex, consistent with functional dominance of the ATP2B3 mutant allele and/or suppression of the ATP2B3 wild-type allele rather than a simple reflection of X-chromosome copy number.

Conclusions: Using a newly developed Ion Torrent–based targeted RNA sequencing panel, we demonstrate a strong expression bias for the ATP2B3 mutant allele in ATP2B3-mutant PA lesions across the sexes. These findings support the functional dominance of the ATP2B3 mutant allele in ATP2B3-driven aldosterone excess, nominate epigenomic and/or post-genomic mechanisms that may contribute to allelic imbalance in these cases, and have implications for interpreting genomic variant data when transcript-level data are also available.

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