344: Homozygous TNNI3 p.Arg136* and severe pediatric restrictive cardiomyopathy

Kühnisch J et al., Human Genetics and Genomics Advances 7, 100598 (2026) - Case report and tissue analysis linking a homozygous TNNI3 nonsense variant (c.406C>T; p.Arg136*) to early-onset, treatment-refractory restrictive cardiomyopathy in a young child who required heart transplantation. Key terms: TNNI3, restrictive cardiomyopathy, pediatric cardiomyopathy, troponin I, protein truncation.

Study Highlights:
A 2-year-old female with severe pediatric restrictive cardiomyopathy carried a homozygous TNNI3 c.406C>T (p.Arg136*) nonsense variant. Myocardial immunostaining showed approximately 50% reduced TNNI3 protein abundance though truncated protein remained detectable. Electron microscopy revealed myofibrillar disarray, irregular Z bands, indistinct M lines, and mitochondrial hyperplasia. The clinical course was treatment refractory and led to heart transplant at 28 months, implicating variant zygosity and truncation position in phenotype determination.

Conclusion:
Biallelic truncation of TNNI3 (p.Arg136*) can cause severe early-onset pediatric restrictive cardiomyopathy, with reduced but partially stable truncated protein and severe sarcomeric pathology prompting early transplantation.

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Article title:
A homozygous variant in cardiac troponin I3, TNNI3, causes severe pediatric restrictive cardiomyopathy

First author:
Kühnisch J

Journal:
Human Genetics and Genomics Advances 7, 100598 (2026)

DOI:
10.1016/j.xhgg.2026.100598

Reference:
Kühnisch J, Barnett CL, Brendel J, et al. A homozygous variant in cardiac troponin I3, TNNI3, causes severe pediatric restrictive cardiomyopathy. Human Genetics and Genomics Advances. 7:100598. https://doi.org/10.1016/j.xhgg.2026.100598

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-04-17.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript's representation of the genetic case, protein expression, tissue analyses, mechanistic interpretation, and genotype–phenotype implications as described in the article.
- transcript topics: RCM vs DCM distinctions; TNNI3 function in the troponin complex; Case presentation and homozygous TNNI3 variant; DNA sequencing and parental segregation; Protein expression by immunostaining; Ultrastructural TEM findings

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 6
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Homozygous TNNI3 nonsense variant c.406C>T (p.Arg136*) identified in the proband.
- Proband presented with severe restrictive cardiomyopathy (RCM) requiring heart transplantation at 28 months.
- TNNI3 protein abundance was reduced by approximately 50%, with detectable truncated protein remaining.
- TEM showed sarcomeric disarray and mitochondrial hyperplasia in explanted heart tissue.
- NMD failed to completely eliminate the truncated transcript due to exon 7 being near the end of the gene.
- Heterozygous parents were clinically healthy carriers, supporting non-penetrance of haploinsufficiency in this context.

QC result: Pass.