The function of ARMC5 and the types of disease-causing variants in PBMAH
ARMC5 is a protein involved in fetal development, immune responses, and adrenal gland biology. Additionally, ARMC5 is thought to be a tumor suppressor gene, which means part of its function is to regulate cell growth and development. The gene is located on chromosome 16 (16p11.2).
Disease-causing variants in ARMC5 are inherited in an autosomal dominant manner, with incomplete penetrance. This means variants in ARMC5 can be passed down from parent to child, but this does not mean that the descendant will develop PBMAH. The majority of pathogenic variants lead to a loss of function of the ARMC5 protein. To develop PBMAH the carrier of an inherited pathogenic variant must present a second pathogenic variant occurring in his/her adrenal gland tissue. This second disease-causing variant is not inherited and is called a somatic variant.
Suspected Pathophysiological Mechanisms
ARMC5 may be involved in regulating the production of steroids in the adrenal gland. This may be age-dependent, which could explain the prevalence of PMAH in older adults. Ultimately, the overproduction of cortisol is believed to be due to the enlarged size of the adrenal glands.
Genetic Testing
Pathogenic variants are detected using Sanger sequencing analysis of ARMC5 gene. Targeted genetic testing is recommended in conjunction with clinical evaluation to determine if the pathogenic variant was inherited or occurred de novo.