TNNI3 – Autosomal recessive Dilated Cardiomyopathy 2A

A 1-year-old girl presented with severe left ventricular enlargement (HP:0001715), markedly reduced systolic function (HP:0001659), and rapidly progressive heart failure leading to death soon after diagnosis. Trio–whole-exome sequencing in this Chinese family revealed compound heterozygosity for a novel synonymous TNNI3 variant, c.24G>A (p.Ala8=) and a complete gene deletion ([PMID:36565796]). Sanger sequencing confirmed segregation, and minigene splicing assays demonstrated intron 2 retention (c.24+1_24+45ins), establishing a loss-of-function mechanism for the synonymous allele ([PMID:36565796]).

The evidence is currently limited to a single unrelated proband with recessive inheritance and functional splicing validation. Additional unrelated cases and segregation data are required to strengthen the association. Nevertheless, this report underscores the necessity of functional assays for interpreting synonymous TNNI3 variants in DCM2A.

Key take-home: TNNI3 loss-of-function variants can cause autosomal recessive DCM2A; functional splicing assays are essential for evaluating synonymous alleles.

References

• Gene • 2023 • Identification of a novel TNNI3 synonymous variant causing intron retention in autosomal recessive dilated cardiomyopathy. PMID:36565796

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