Conclusions: Our studies have detected ARMC5 mutations in 4 of 5 BMAH families tested, confirming that these mutations are a frequent cause of BMAH. Two of the 4 families had novel mutations, indicating allelic heterogeneity. Preclinical evaluation did not predict mutation status. The ARMC5-negative family had unusual prominent hyperaldosteronism. Further studies are needed to determine the penetrance of BMAH in ARMC5 mutation-positive relatives of affected patients, the practical utility of genetic screening and genotype-phenotype correlations.
Context: Bilateralmacronodularadrenalhyperplasia(BMAH)isarareformofadrenalCushing'ssyndrome. Familial cases have been reported, but at the timeweconducted this study, the genetic basis ofBMAHwas unknown. Recently, germline variants of armadillo repeat containing 5 (ARMC5) in patients with isolated BMAH and somatic, second-hit mutations in tumor nodules, were identified. Copyright
Objective: Our objective was to identify the genetic basis of familial BMAH.
Design: We performed whole exome capture and sequencing of 2 affected individuals from each of 4 BMAH families (BMAH-01, BMAH-02, BMAH-03, and BMAH-05). Based on clinical evaluation, there were 7, 3, 3, and 4 affected individuals in these families, respectively. Sanger sequencing of ARMC5 was performed in 1 other BMAH kindred, BMAH-06.
Results: Exome sequencing identified novel variants Chr16:g.31477540, c.2139delT, p.(Thr715Leufs∗1) (BMAH-02) and Chr16:g.31473811, c.943C→T, p.(Arg315Trp) (BMAH-03) in ARMC5 (GRch37/hg19), validated by Sanger sequencing. BMAH-01 had a recently reported mutation Chr16:g.31476121, c.1777C→T, p.(Arg593Trp). Sanger sequencing of ARMC5 in BMAH-06 identified a previously reported mutation, Chr16:g. 31473688; c.799C→T, p.(Arg267∗). The genetic basis of BMAH in BMAH-05 was not identified.