A Novel Homozygous

Context: Type 1 familial glucocorticoid deficiency (FGD) (OMIM #607397) is a rare autosomal recessive disorder due to mutations in melanocortin-2-receptor (MC2R) gene encoding the G protein-coupled adrenocorticotropic (ACTH) transmembrane receptor. Objective: The aim of the study is to describe 2 siblings born to a healthy consanguineous family presenting with clinical and biochemical features of FGD, harboring a novel homozygous MC2R variant. Methods: Both patients are siblings born at term via normal delivery with normal birth weights. The first sibling presented with symptoms of hypoglycemia, repeated episodes of infections starting from 2 days of age. At 18 months of age, low serum cortisol was found, and he was started on hydrocortisone replacement therapy. The second sibling developed hypoglycemia on day 1 after birth, investigations revealed low serum sodium and cortisol levels and was also commenced on hydrocortisone treatment. Whole exome sequencing (WES) and in vitro functional studies on cell line transfected with wild-type and mutant plasmid clones were undertaken. Results: WES revealed a novel homozygous missense mutation c.326T>A, p.Leu109Gln in the MC2R gene. In-silico prediction tools predicted the effect of this mutation to be deleterious. In vitro study using HEK293 cells transfected with MC2R wild-type and mutant clones showed a defect in protein expression and cAMP generation when stimulated with ACTH. Conclusion: Homozygous semiconserved p.Leu109Gln mutation disrupts cAMP production and MC2R protein expression leading to ACTH resistance. This study provides additional evidence that this novel pathogenic variant in MC2R results in FGD phenotypes.