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ARMC5 mutations common source of primary macronodular adrenal hyperplasia
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An inherited mutation in the ARMC5 gene is a frequent cause of primary macronodular adrenal hyperplasia, a rare cause of Cushing’s syndrome.
Previous research suggested familial clustering and inheritance of this mutation.
Researchers assessed primary macronodular adrenal hyperplasia (PMAH) in 47 members of a Brazilian family, 16 of whom were diagnosed with PMAH. They conducted a single nucleotide polymorphism-based, genome-wide linkage analysis on selected members of the family. In addition, they sought to verify the genetic findings by assessing 29 other patients diagnosed with PMAH as well as 125 randomly chosen participants without PMAH. In a subsequent analysis, whole-exome sequencing, traditional sequencing and microsatellite analyses were used to evaluate extracted PMAH tissue.
The investigators identified a heterozygous mutation in the ARMC5 gene (p.Leu365Pro) by way of whole-exome sequencing in a candidate genomic area. Conventional sequencing verified the same mutation in all 16 family members diagnosed with PMAH. This mutation, which was not found in available online databases or in the 125 healthy controls, was hypothesized via computer prediction models to be damaging. In analysis, seven additional ARMC5 mutations were later seen in five of the 21 patients with seemingly intermittent PMAH, as well as two of three families affected by PMAH. In four patients whose adrenal tissue was accessible for molecular evaluation, a somatic mutational event was seen.
According to the researchers, these findings support the need to screen for ARMC5 germline mutations in patients with suspected PMAH.
“The present study demonstrates that inherited autosomal dominant mutations in ARMC5 gene are a frequent cause of PMAH,” the researchers wrote. “Therefore, all patients with PMAH or suspected of having the disease should be screened for mutations in the ARMC5 gene so that they can receive an earlier diagnosis and treatment. Once a germline mutation is confirmed, first-degree relatives should also undergo genetic screening and counseling.”
Disclosure: Please see the full study for a complete list of relevant financial disclosures.
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