Oral Presentation Annual Meetings of the Endocrine Society of Australia and Society for Reproductive Biology and Australia and New Zealand Bone and Mineral Society 2016

Sequence variants in ARMC5 are not implicated in familial hyperaldosteronism type II (#83)

Sunita MC De Sousa 1 2 3 , Michael Stowasser 4 , Jinghua Feng 5 6 , Andreas W Schreiber 5 6 , Chris N Hahn 7 8 , David J Torpy 2 8 , Lucia Gagliardi 2 7 8 , Hamish S Scott 5 6 7 8 9
  1. Hormones and Cancer Group, Cancer Division, Garvan Institute of Medical Research, Sydney, NSW, Australia
  2. Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, SA, Australia
  3. Adult Genetics Unit, SA Clinical Genetics Service, Adelaide, SA, Australia
  4. Endocrine Hypertension Research Centre, University of Queensland School of Medicine, Greenslopes and Princess Alexandria Hospitals, Brisbane, Qld, Australia
  5. ACRF Cancer Genomics Facility, SA Pathology, Adelaide, SA, Australia
  6. School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA, Australia
  7. Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia
  8. School of Medicine, University of Adelaide, Adelaide, SA, Australia
  9. Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia

Background: Germline variants in the armadillo-repeat-containing 5 (ARMC5) gene were recently identified in sporadic and familial bilateral macronodular adrenal hyperplasia (BMAH) resulting in Cushing’s syndrome (1, 2). Following evidence of biallelic inactivation of ARMC5 in a meningioma from a patient with BMAH (3), there is ongoing investigation into the complete adrenal and extra-adrenal phenotype.

Pathogenic ARMC5 variants have been reported in African-American patients with primary aldosteronism (PA) (4), however a subsequent study of 39 PA patients found no pathogenic variants in ARMC5 (5). Familial hyperaldosteronism type II (FH-II) is clinically indistinguishable from sporadic PA (6). The genetic basis of FH-II has not yet been elucidated; but ARMC5 has not been systematically evaluated (6-9). We hypothesised that germline variants in ARMC5 may underlie FH-II.

Methods: Clinical and genetic evaluation was undertaken in 13 affected and 3 unaffected individuals from four Australian FH-II families. Clinical and biochemical screening for primary aldosteronism was undertaken according to the Endocrine Society Guidelines (10). Whole exome sequencing was performed at the Australian Genome Research Facility. Heterozygous variants in affected individuals were considered in line with the two-hit model of tumour development, and the status of unaffected individuals was ignored because of the possibility of non-penetrance.

Results: Pedigrees are shown in Figure 1. Both adrenal adenomas and hyperplasia were observed, with heterogeneity even within families. Despite analysis of all sequence variant types at allele frequencies below 1% in population databases, we found no ARMC5 variants which segregated in affected individuals.

Conclusions: FH-II does not appear to be caused by germline sequence variants in ARMC5, at least in the four families studied herein. The genetic basis to FH-II remains to be elucidated.

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