GREB1L – Unilateral Renal Agenesis

GREB1L has been implicated in autosomal dominant unilateral renal agenesis based on segregation analyses in two independent three-generation pedigrees. In a family with two female cousins presenting with MRKH syndrome and unilateral renal agenesis and two male relatives with renal agenesis, a heterozygous GREB1L c.705G>T (p.Trp235Cys) variant segregated in all four affected individuals, consistent with incomplete penetrance (4 affected) (PMID:31424080). Separately, a novel GREB1L c.4507C>T (p.Arg1503Trp) variant was identified in a three-generation kindred with three members exhibiting unilateral renal hypodysplasia/aplasia, with functional studies demonstrating reduced GREB1L mRNA and protein levels and downstream PAX2 and PTH1R dysregulation (3 affected) (PMID:36371238).

The pedigrees support autosomal dominant inheritance with reduced penetrance. Functional analyses of the c.4507C>T variant confirmed a loss-of-function mechanism through in vitro knockdown and mRNA downregulation. Additional animal model data in zebrafish show renal tract anomalies upon GREB1L disruption, further concordant with the human phenotype. No large-scale case-control studies or recurrent founder variants have been reported to date.

Collectively, the limited number of small pedigrees and preliminary functional data establish GREB1L as a candidate gene for unilateral renal agenesis; however, larger cohorts and mechanistic studies are required for definitive classification.

Key take-home: GREB1L heterozygous loss-of-function variants should be considered in the genetic evaluation of familial unilateral renal agenesis.

References

• Human reproduction (Oxford, England) • 2019 • Whole-exome sequencing identifies a GREB1L variant in a three-generation family with MÃŒllerian and renal agenesis: a novel candidate gene in Mayer-Rokitansky-KÃŒster-Hauser (MRKH) syndrome. A case report PMID:31424080
• Orphanet journal of rare diseases • 2022 • A novel missense mutation in GREB1L identified in a three-generation family with renal hypodysplasia/aplasia-3. PMID:36371238

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