期刊
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
卷 99, 期 9, 页码 E1784-E1792出版社
ENDOCRINE SOC
DOI: 10.1210/jc.2014-1265
关键词
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资金
- Royal Adelaide Hospital/Institute of Medical and Veterinary Science Research Committee
- Royal Australasian College of Physicians Novartis Oncology Endocrinology Fellowship Award
- Endocrine Society of Australia Higher Research Degree Scholarship
- National Health and Medical Research Council (NHMRC) [1023059]
- Gum Bequest, Royal Adelaide Hospital
- Medvet Pty Ltd
- University of Adelaide
- Australian Cancer Research Foundation
- University of Queensland Irene Patricia Hunt Memorial
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.
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