[Genetic analysis of a fetus with renal dysplasia/hypoplasia due to a variant of GREB1L gene and literature review].

OBJECTIVE

To carry out clinical and genetic analysis for a fetus with absent kidneys and bladder.

METHODS

Clinical data of the fetus were collected. Whole exome sequencing (WES) and Sanger sequencing were carried out on fetal tissue and peripheral blood samples from its family members. A RDDC online tool was used to predict the impact of the variant on the GREB1L gene splicing, which was further validated by in vitro minigene assays. Long-range PCR was employed to verify the exonic deletional variant. An I-TASSER server was used to predict the three-dimensional structure of the mutant protein. A systematic search of Chinese and English databases was conducted using "GREB1L gene" as the keyword to summarize the clinical phenotypic spectrum associated with GREB1L gene mutations. This study was approved by the Medical Ethics Committee of the Pearl River Hospital of South Medical University (Ethics No.: 2023-KY-016).

RESULTS

The fetus was confirmed to have bilateral renal agenesis by autopsy. WES and Sanger sequencing revealed that the fetus, its father and grandfather have all carried a heterozygous c.4369-3_4375del variant of the GREB1L gene (NM_001142966.3), whilst its mother and grandmother did not carry the same variant. Based on the guidelines from American College of Medical Genetics and Genomics (ACMG), the variant was rated as "pathogenic". As predicted by bioinformatics analysis and confirmed by the minigene assay, this deletional variant may lead to aberrant splicing of exon 26 and result in alteration in the protein's three-dimensional structure. Literature review indicated that GREB1L gene mutations mainly cause renal dysplasia with significant clinical heterogeneity.

CONCLUSION

The heterozygous c.4369-3_4375del variant of the GREB1L gene probably underlay the pathogenesis of renal dysplasia/hypoplasia in this fetus. Discovery of this novel splicing site variant has enriched the mutational spectrum of the GREB1L gene and provided a basis for clinical diagnosis and genetic counseling.