Whole exome sequencing identifies mutation of EDNRA involved in ACTH-independent macronodular adrenal hyperplasia.

ACTH independent macronodular adrenal hyperplasia (AIMAH) is a rare disorder characterized by bilateral macronodular hyperplasia of the adrenal glands and increased cortisol production with subclinical or overt Cushing's syndrome. Although the family clustering of AIMAH is infrequent, we have tried our best to find such a familial affected pedigree with complete clinical information and successfully collect adrenalectomy tissue samples from two members of this family. Using whole exome sequencing and several variant prioritization strategies based on disease network analysis, we identified Endothelin receptor type A (EDNRA) Ser420Thr mutation as a causative mutation of AIMAH. EDNRA is a member of G protein coupled receptor family and is involved in cardiovascular or polycystic kidney disease. Our findings indicate that the mutation of EDNRA at S420T site should be regard as a potential AIMAH causative variation in familial and sporadic affected patients.