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

Project Description

Explored the genetic cause of Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome, a rare disorder characterized by uterovaginal agenesis in 46,XX women.
Investigated a unique three-generation family with two female members affected by MRKH and unilateral renal agenesis (RA), along with two deceased male relatives with RA.
Applied whole-exome sequencing (WES) on eight family members to identify a novel pathogenic variant (c.705G>T) in the GREB1L gene.
Provided strong evidence supporting GREB1L as a key gene in kidney and female reproductive tract development.
The family’s genetic pattern suggests autosomal dominant inheritance with incomplete penetrance, possibly influenced by genomic imprinting.
This is the first WES-based study on a large MRKH family pedigree, highlighting GREB1L as a promising candidate gene in understanding MRKH syndrome.

Identified over 131,000 unique variants through whole-exome sequencing (WES) across eight family members.
Narrowed down to three shared variants, with one novel heterozygous missense variant in the GREB1L gene (c.705G>T) identified as the strongest candidate.
This variant:
- Alters a highly conserved amino acid (tryptophan to cysteine).
- Predicted to disrupt protein structure and splicing signals.
- Scored 33 on the CADD scale (top ~0.05% of pathogenic potential genome-wide).
- Rated as deleterious by SIFT, PolyPhen, and PROVEAN tools.
GREB1L is known to play a critical role in kidney and reproductive tract development, aligning with the family’s clinical features.
Sanger sequencing confirmed the variant in additional family members, supporting its segregation with the phenotype.
Inheritance pattern shows incomplete penetrance and possible parent-origin-specific expression (imprinting).
Two other variants (in DSG3 and PGK2) were deemed not biologically relevant to MRKH syndrome.
No large deletions or duplications detected in key chromosomal regions (17q12, 22q11, 16p11.2).
Additional analysis found no genetic cause for renal cysts in one affected uncle, suggesting a distinct etiology for his case.

Identified a novel disease-associated variant: Discovered a previously unreported missense variant (c.705G>T) in the GREB1L gene, which is strongly associated with MRKH syndrome type II and renal agenesis.
Strengthened genetic understanding of MRKH syndrome: Provided compelling evidence that GREB1L is a strong candidate gene contributing to the genetic basis of MRKH type II, especially in familial cases.
Revealed a potential parent-origin effect: Uncovered a parent-origin-specific pattern of inheritance, suggesting genomic imprinting may influence GREB1L variant penetrance—an insight not previously well-documented in MRKH research.
Validated through extended family analysis: Used whole-exome sequencing (WES) and segregation analysis across three generations, supporting a pattern of autosomal dominant inheritance with incomplete penetrance.
Contributed to future diagnostic pathways: Positioned GREB1L as a potential biomarker for genetic testing in suspected familial MRKH syndrome cases, especially those with co-occurring renal anomalies.

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