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

Abstract

The 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 leading to the identification of a novel pathogenic (CADD = 33) c.705G>T missense variant in GREB1L, 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 support GREB1L 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 suggest GREB1L as a novel and promising candidate gene in the aetiology of MRKH syndrome.

Autosomal Dominantly Inherited GREB1L Variants in Individuals with Profound Sensorineural Hearing Impairment

“…We also detected a maternal bias in the inheritance of GREB1L variants ( Table 2 ). This maternal bias has previously observed and two mechanisms have been suggested: (1) imprinting [ 8 , 36 ] (2) or GREB1L variants could affect male fertility resulting in a low rate of paternal inheritance [ 8 ]. Genital issues, including uterus aplasia, are common and have been reported in many females ( Table 2 ), but the presence in males may be underestimated as the defect might not be a gross morphological abnormality that causes infertility.…”

“…Previous reports on disease-related GREB1L variants showed that a variable phenotype is present, including within families segregating the same variant (e.g., left vs. right ear) [ 36 , 37 ]. In addition, a high level of reduced penetrance has been reported, including in family 2 of this study.…”

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: a comprehensive update

“…Recently, Pan et al performed whole-genome sequencing (WGS) analysis of nine MRKH syndrome trios (patient and both parents) demonstrating the capacity of WGS in unbiased detection of de novo genomic variation [77]. Other recent studies also used NGS technology in genomic searches for genetic variation [24,64,78,79]. However, it remains a challenge to interpret the pathogenicity of these findings and investigations of larger cohorts will likely be needed in order to identify recurrent genetic variation.…”

“…In 2019, Herlin et al described whole-exome sequencing (WES) in a three-generation family with two female cousins having type II MRKH syndrome and unilateral renal agenesis, and two male relatives with renal agenesis. The study reported a co-segregating missense variant in GREB1L (Table 1) [24], a gene identified in 2017 to cause bilateral renal agenesis in fetuses of which several female fetuses also had uterus agenesis [73,74]. Just recently, Jacquinet et al reported four additional multiplex families with either type II MRKH syndrome or uterovaginal aplasia (fetuses) associated with renal malformations (agenesis in particular) in which pathogenic GREB1L variants were identified from WES data [72].…”

“…Increasing reports of familial occurrence of MRKH syndrome and its associated anomalies support a monogenic genetic etiology [ 19 , 20 ]. Most pedigrees suggest autosomal dominant inheritance with incomplete penetrance and this especially seems to include families with aggregation of both MRKH syndrome and renal abnormalities which in previous literature has been referred to as hereditary urogenital adysplasia [ 19 , 21 – 24 ]. In contrast, most cases occurring sporadically, lacking recurrence in outcomes of surrogate pregnancies [ 25 , 26 ] and several reports of discordant twin pairs [ 3 , 27 – 30 ] support either polygenic/multifactorial or non-genetic etiologies (e.g.…”