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ARMC5 mutations are common in familial bilateral macronodular adrenal hyperplasia

Gagliardi, Lucia, Schreiber, Andreas W., Hahn, Christopher N., Feng, Jinghua, Cranston, Treena, Boon, Hannah, Hotu, Cheri, Oftedal, Bergithe E., Cutfield, Richard, Adelson, David L., Braund, Wilton J., Gordon, Richard D., Rees, Dafydd Aled ORCID:, Grossman, Ashley B., Torpy, David J. and Scott, Hamish S. 2014. ARMC5 mutations are common in familial bilateral macronodular adrenal hyperplasia. Journal of Clinical Endocrinology & Metabolism 99 (9) , E1784. 10.1210/jc.2014-1265

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Context: Bilateral macronodular adrenal hyperplasia (BMAH) is a rare form of adrenal Cushing's syndrome. Familial cases have been reported, but at the time we conducted this study, the genetic basis of BMAH was 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. 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. 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Publisher: The Endocrine Society
ISSN: 0021-972X
Date of Acceptance: 29 May 2014
Last Modified: 28 Oct 2022 10:39

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