Whole-exome sequencing identifies a GREB1L variant in a three-generation family with M üllerian and renal agenesis: a novel candidate gene in Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome. A case report

AbstractThe aetiology of Mayer –Rokitansky–Küster–Hauser (MRKH) syndrome, characterized by uterovaginal agenesis in 46,XX women, remains poorly understood. Since familial occurrences are rare, genetic findings reported so far only apply to a minority of mainly sporadic cases and most studies have not included other family members enabling segregation analysis. Herein, we report on the investigation of a unique three-generation family of two female cousins with MRKH syndrome and unilateral renal agenesis (RA) and two deceased male relatives with RA. We performed whole-exome sequencing (WES) in eight family members lea ding to the identification of a novel pathogenic (CADD = 33) c.705G>T missense variant inGREB1L, a gene recently identified as a novel cause of RA. Previous reports include several cases of female fetuses with bilateral RA and uterus agenesis, which supportGREB1L as an important gene in both kidney and female genital tract development. The pedigree is compatible with autosomal dominant inheritance with incomplete penetrance following a parent-origin-specific manner, which could be due to imprinting. To our knowledge, this is the first investigation of a larger MRKH syndrome pedigree using WES, and we suggestGREB1L as a novel and promising candidate gene in the aetiology of MRKH syndrome.
Source: Human Reproduction - Category: Reproduction Medicine Source Type: research