ARMC5 mutations are a frequent cause of primary macronodular adrenal Hyperplasia.

[cushing syndrome]

Primary macronodular adrenal hyperplasia (PMAH ) is a rare cause of Cushing 's syndrome , usually characterized by functioning adrenal macronodules and increased cortisol production . Familial clustering of PMAH has been described , suggesting an inherited genetic cause for this condition .The aim of the present study was to identify the gene responsible for familial PMAH .Forty -seven individuals of a Brazilian family with PMAH were evaluated . A single -nucleotide polymorphism-based genome-wide linkage analysis followed by whole-exome sequencing were then performed in selected family members . Additionally , 29 other patients with PMAH and 125 randomly selected healthy individuals were studied to validate the genetic findings . Moreover , PMAH tissue was also analyzed through whole-exome sequencing , conventional sequencing , and microsatellite analysis .A heterozygous germline variant in the ARMC 5 gene (p .Leu 365 Pro ) was identified by whole-exome sequencing in a candidate genomic region (16 p 11 .2 ). Subsequently , the same variant was confirmed by conventional sequencing in all 16 affected family members . The variant was predicted to be damaging by in silico methods and was not found in available online databases or in the 125 selected healthy individuals . Seven additional ARMC 5 variants were subsequently identified in 5 of 21 patients with apparently sporadic PMAH and in 2 of 3 families with the disease . Further molecular analysis identified a somatic mutational event in 4 patients whose adrenal tissue was available .Inherited autosomal dominant mutations in the ARMC 5 gene are a frequent cause of PMAH . Biallelic inactivation of ARMC 5 is consistent with its role as a potential tumor suppressor gene .