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A novel de novo synonymous variant in GREB1L impacts the mRNA splicing associated with aplasia of the urogenital system. | LitMetric

AI Article Synopsis

  • The GREB1L gene is linked to autosomal dominant conditions including renal hypodysplasia/aplasia 3 (RHDA3) and deafness, with most variants being missense or frameshift, while synonyms were previously considered nonpathogenic.
  • A case study of a 7-year-old girl revealed a de novo synonymous variant in GREB1L that is likely pathogenic, alongside symptoms like clitoromegaly and absent right kidney.
  • This discovery highlights the importance of synonymous variants, as they can affect mRNA splicing and should be considered in genetic testing and counseling.

Article Abstract

GREB1-like retinoic acid receptor coactivator (GREB1L) gene is associated with autosomal dominant renal hypodysplasia/aplasia 3 (RHDA3) and deafness, autosomal dominant 80 (DFNA80). Among the GREB1L variants reported, most of them are missense or frameshift, while no pathogenic synonymous variants have been recorded. Classical theory paid little attention to synonymous variants and classified it as nonpathogenic; however, recent studies suggest that the variants might be equally important. Here, we report a 7-year-old girl with new symptoms of clitoromegaly, uterovaginal, and ovarian agenesis as well as right kidney missing. A novel de novo GREB1L synonymous variant (NM_001142966: c.4731C>T, p.G1577=) was identified via whole exome sequencing. The variant was predicted to be disease-causing through in silico analysis and was classified as likely pathogenic. Minigene splicing assays confirmed a 6 bp deletion in mutant cDNA comparing with the wild type, leading to two amino acids lost in GREB1L protein. Secondary and tertiary structure modeling showed alterations in protein structure. Our finding reveals a novel GREB1L variant with a new phenotype of urogenital system and is the first to report a pathogenic synonymous variant in GREB1L which affects mRNA splicing, suggesting synonymous variants cannot be ignored in prenatal diagnosis and genetic counseling.

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Source
http://dx.doi.org/10.1002/ajmg.a.63823DOI Listing

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