TINAG – pectus excavatum

This report describes a potential association between TINAG and pectus excavatum, supported by evidence from a four‑generation pedigree (PMID:31981812). In this pedigree, four affected individuals harbored a novel heterozygous stop‑gain variant in TINAG, indicating an autosomal dominant mode of inheritance. Sanger sequencing confirmed the presence of the variant and segregation analysis within the family provided additional supportive genetic evidence.

The variant identified is a complete coding change, noted as c.6G>A (p.Trp2Ter). This stop‑gain alteration is consistent with a loss‑of‑function mechanism, and functional assays in hFOB1.19 cells demonstrated that knockdown of TINAG reduced cell proliferation, which aligns with the hypothesized pathogenic process in pectus excavatum (PMID:31981812).

Genetic evidence is further supported by segregation data across the pedigree where all affected individuals carry the variant, although the association is currently derived from a single extended family. The detection of this variant by whole‑exome sequencing and subsequent validation by Sanger sequencing enhances the credibility of the genetic findings.

Functional studies underscore that the TINAG c.6G>A (p.Trp2Ter) variant likely disrupts the normal function of the protein by causing premature truncation, leading to reduced TINAG expression. This loss‑of‑function model is in line with the observed phenotype and supports a potential pathogenic role in pectus excavatum.

There is, however, a need for additional replication in unrelated families and further functional analyses to fully delineate the mechanistic details of TINAG in skeletal development associated with pectus excavatum. Despite these limitations, the current findings offer valuable insights into a novel genetic cause for the condition.

Key take‑home message: The identification of the TINAG c.6G>A (p.Trp2Ter) variant in a multi‑generation pedigree, coupled with supportive in vitro functional data, offers a biologically plausible candidate for the genetic etiology of pectus excavatum that may guide future diagnostic and therapeutic strategies.

References

• Medical hypotheses • 2020 • TINAG mutation as a genetic cause of pectus excavatum PMID:31981812

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