GREB1L – Renal Hypodysplasia/Aplasia 3

Renal hypodysplasia/aplasia 3 (RHDA3) is an autosomal dominant congenital anomaly of the kidney characterized by unilateral or bilateral renal agenesis or hypodysplasia. Loss-of-function and missense variants in GREB1L disrupt renal morphogenesis through haploinsufficiency, often with incomplete penetrance requiring careful genetic counseling.

In a Chinese family with two pregnancies affected by bilateral renal agenesis, trio-WES identified a novel nonsense variant, c.2621G>A (p.Trp874Ter), transmitted from an unaffected maternal grandfather through an asymptomatic mother to both fetuses, demonstrating incomplete dominance (PMID:38309594).

A three-generation kindred with unilateral renal aplasia harbored a novel missense mutation, c.4507C>T (p.Arg1503Trp), in all three affected individuals, segregating with disease and resulting in sharply reduced GREB1L mRNA and protein levels (PMID:36371238).

Additional case series in renal agenesis families have reported damaging missense variants (e.g., c.2333T>A (p.Val778Asp) in one family without controls) extending the variant spectrum and highlighting variable expressivity (PMID:32598191).

Functional assays demonstrate that GREB1L deficiency downregulates key nephrogenic factors PAX2 and PTH1R, aligning with human phenotypes and supporting a haploinsufficiency mechanism (PMID:36371238).

Genetic and experimental concordance across unrelated families and model systems establishes a strong autosomal dominant association between GREB1L and RHDA3. GREB1L sequencing is recommended for diagnostic evaluation of congenital renal agenesis and hypodysplasia, with attention to incomplete penetrance.

References

• Urology • 2024 • Renal Hypodysplasia/Aplasia 3 Caused by a Rare Variant of GREB1L With Incomplete Penetrance in a Chinese Family. PMID:38309594
• 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
• Genetic Testing and Molecular Biomarkers • 2020 • Clinical Exome Sequencing Identifies a Novel Mutation of the GREB1L Gene in a Chinese Family with Renal Agenesis. PMID:32598191

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