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Identification of a novel TBX5 c.755 + 1 G > A variant and related pathogenesis in a family with Holt-Oram syndrome. | LitMetric

AI Article Synopsis

  • A patient with congenital heart disease and an abnormal thumb was diagnosed with Holt-Oram syndrome after discovering a novel variant in the TBX5 gene through whole exome sequencing.
  • Genetic analysis showed this variant was present in multiple family members across three generations, indicating it may be inherited.
  • The variant disrupts normal splicing of the TBX5 gene, leading to abnormal protein production, impaired nuclear localization, and reduced cell activity, which may contribute to the symptoms of Holt-Oram syndrome.

Article Abstract

The proband with congenital heart disease and abnormal thumb was clinically diagnosed as Holt-Oram syndrome (HOS). A novel variant, T-box transcription factor 5 (TBX5) c.755 + 1 G > A, was identified in the proband via whole exome sequencing and validated using Sanger sequencing. Pedigree analysis and clinical examinations revealed three/seven individuals over three generations within the family, with features suggestive of HOS. Deep amplicon sequencing confirmed that the allele frequencies of the novel variant in the proband (III-1), her brother (III-2), and her mother (II-2) were 50%, 48.3%, and 38.1%, respectively, indicating that III-1 and III-2 harbored heterozygous variants, while II-2 harbored mosaic heterozygous variants. The minigene splicing assay showed that the novel variant affected the normal splicing of exon 7, resulting in the production of abnormal TBX5 transcripts. Reverse transcription-quantitative polymerase chain reaction and western blot analyses revealed that the novel variant upregulated TBX5 expression at the transcriptional and translational levels. Nuclear localization assay demonstrated impaired nuclear localization of the mutant TBX5. Cell viability assay revealed the inhibition of cell activity by the mutant TBX5. Our findings indicate that the novel variant was potentially induced HOS, probably by causing aberrant splicing, reducing the enrichment of nuclear TBX5 protein, and inhibiting cellular proliferation.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9290998PMC
http://dx.doi.org/10.1002/ajmg.a.62488DOI Listing

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