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

Q: What are the key findings of this study?

Homozygous TNNI3 c.406C>T (p.Arg136) reduced myocardial TNNI3 protein staining by ~50% (p<0.05) and caused treatment-refractory pediatric restrictive cardiomyopathy requiring heart transplant.

Q: What is the clinical evidence from this study?

Study design: Case Report. Population: Severe pediatric restrictive cardiomyopathy and alpha-1-antitrypsin deficiency (n=1). Intervention: Homozygous TNNI3 nonsense variant c.406C>T, p.Arg136 vs. Age-matched pediatric control subjects without myocardial disease (n=3 heart biopsy controls). Primary outcome: Myocardial TNNI3 protein abundance and clinical cardiomyopathy phenotype (50% reduction in TNNI3 staining intensity, p=<0.05).

Q: What does this research mean for the field?

A homozygous truncating variant in TNNI3 (c.406C>T, p.Arg136*) reduces myocardial TNNI3 protein abundance and causes severe, treatment-refractory pediatric restrictive cardiomyopathy. Novelty: ClaimNovelty.CONFIRMATORY. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

To investigate the genetic and molecular basis of severe, early-onset restrictive cardiomyopathy in a pediatric patient carrying a homozygous TNNI3 nonsense variant.

Jirko Kühnisch; Cara L Barnett; Josephine Brendel; Lara Berklite; Chet S Villa; Wenke Seifert; Sabine Klaassen; Karin Klingel; K. Nicole Weaver

doi:10.1016/j.xhgg.2026.100598

March 1, 2026Human Genetics and Genomics AdvancesOpen Access

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

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Key result

Homozygous TNNI3 nonsense mutation reduces myocardial protein by ~50%, causing severe pediatric restrictive cardiomyopathy.

50% reduction in TNNI3 staining intensity
P<0.05
n=1

Figures

Why the study?

In children, biallelic truncating TNNI3 variants typically associate with DCM and heterozygous missense variants with RCM, leaving the phenotypic impact of specific distal truncations unclear.

Key Points

To investigate the genetic and molecular basis of severe, early-onset restrictive cardiomyopathy in a pediatric patient carrying a homozygous TNNI3 nonsense variant.
Clinical exome sequencing and segregation analysis were performed in a 26-month-old female proband presenting with restrictive cardiomyopathy and ischemic stroke.
Quantitative immunostaining and confocal imaging for TNNI3 protein abundance were evaluated in myocardial biopsies from the explanted heart (n=3) and age-matched controls (n=3).
Ultrastructural assessment of immersion-fixed myocardium from the explanted heart was conducted using transmission electron microscopy.
Exome sequencing identified a homozygous nonsense variant in TNNI3 (c.406C>T, p.Arg136) in exon 7 that deletes the C-terminal actin-tropomyosin binding domain, reclassified as likely pathogenic (class 4).
Immunostaining of myocardial tissue showed approximately 50% reduction of TNNI3 staining intensity compared with control subjects (p < 0.05), with transmission electron microscopy revealing myofibrillar disarray, indistinct M-lines, irregular Z-bands, and mitochondrial hyperplasia.
The patient had severe treatment-refractory restrictive cardiomyopathy with elevated left ventricular end diastolic pressure (29 mmHg by wedge pressure) and underwent heart transplantation at 28 months of age (2 years 4 months).

Study Design

Type

Case Report (n=1)

Multicenter

No

Structured PICO

P

Population

A 2-year-old female proband with severe restrictive cardiomyopathy and alpha-1-antitrypsin deficiency, undergoing heart transplant at 28 months and followed until 53 months of age.

E

Exposure

Homozygous TNNI3 nonsense variant c.406C>T (p.Arg136) in exon 7 causing C-terminal protein truncation.

C

Comparator

Three independent heart biopsies from age-matched pediatric patients without myocardial disease (for immunofluorescence analysis), and heterozygous family members (mother age 20, maternal half-brother age 21 months).

O

Outcome

Clinical cardiomyopathy phenotype progression (treatment-refractory RCM leading to heart transplantation at 28 months) and myocardial TNNI3 protein expression via quantitative immunofluorescence and transmission electron microscopy.hard clinical

Main Result

Effect estimate: 50% reduction in TNNI3 staining intensity

p-value: p=<0.05

Demonstrates that distal homozygous truncating variants in TNNI3 (p.Arg136) retain partial protein stability (~50% abundance) and can cause severe early-onset pediatric restrictive cardiomyopathy rather than the dilated cardiomyopathy typically seen with complete TNNI3 loss.

Limitations

Only one patient with RCM due to the homozygous TNNI3 p.Arg136 variant is presented.
Could not monitor the cardiac TNNI1-to-TNNI3 isoform switch in fresh frozen tissue by measuring transcript levels.
Infrequent reporting of outcomes and clinical assessment among parental TNNI3 variant carriers in the literature.
Inability to monitor the cardiac TNNI1-to-TNNI3 isoform switch in fresh frozen tissue by measuring transcript levels.
Infrequent reporting of outcomes and clinical assessment in parental TNNI3 variant carriers in the reviewed literature.

Implication

Supports TNNI3 evaluation in refractory pediatric restrictive cardiomyopathy; extends biallelic truncating variant phenotypes but leaves broader applicability open.

Abstract

Dilated cardiomyopathy (DCM) results from systolic dysfunction, while restrictive cardiomyopathy (RCM) is due to diastolic dysfunction. The diverse pathophysiology of primary DCM and RCM suggest distinct underlying genetic mechanisms. A well-established disease gene for DCM and RCM is cardiac troponin I3 (TNNI3) causing dominant and recessively inherited forms. In children, biallelic truncating TNNI3 variants have typically been associated with DCM and heterozygous missense TNNI3 variants are associated with RCM. We report a two-year-old female with severe RCM that is genetically caused by a homozygous TNNI3 nonsense variant c.406C>T, p.Arg136* which results in a more distal (C-terminus) truncation than most previously reported disease-associated nonsense variants. In myocardial biopsies of the patient, TNNI3 protein abundance was diminished suggesting that residual TNNI3 function may underlie RCM, while TNNI3 absence causes DCM. The RCM in this patient was treatment refractory and resulted in heart transplant at the age of 28 months. Overall, recessive TNNI3 protein truncation causes severe pediatric RCM suggesting that the allelic status, type of genetic alteration, and length of TNNI3 protein truncation determines cardiomyopathy onset and subtype manifestation.

Discussion

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Cite This Study

Kühnisch et al. (2026) conducted a case report in Severe pediatric restrictive cardiomyopathy and alpha-1-antitrypsin deficiency (n=1). Homozygous TNNI3 nonsense variant c.406C>T, p.Arg136 vs. Age-matched pediatric control subjects without myocardial disease (n=3 heart biopsy controls) was evaluated on Myocardial TNNI3 protein abundance and clinical cardiomyopathy phenotype (50% reduction in TNNI3 staining intensity, p=<0.05). Homozygous TNNI3 c.406C>T (p.Arg136) reduced myocardial TNNI3 protein staining by ~50% (p<0.05) and caused treatment-refractory pediatric restrictive cardiomyopathy requiring heart transplant.

synapsesocial.com/papers/69cf588f5a333a82146097b5 https://doi.org/10.1016/j.xhgg.2026.100598

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

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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