A whole-genome search of blood and heart muscle found no variant that can be confidently blamed for a baby's fatal heart failure
Edited by Samael A. Tejada, Founder & Editor-in-Chief
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Whole-genome sequencing of an infant who died of cardiomyopathy at eight months — blood, both parents, and heart muscle — found no variant that could be confidently blamed, a Frontiers in Genetics case study reports (November 13, 2026). A near-homoplasmic mitochondrial variant, m.4401A>G, remains of biological interest only.
This is a story about a test that worked exactly as designed and still could not deliver the answer everyone wanted — which is itself essential information about what genome testing can and cannot do.
What did the team do?
A family-based whole-genome search: sequencing of blood from the infant and both parents, plus the infant's myocardium (heart muscle) — the affected tissue itself, where a causal mitochondrial variant might be concentrated. The infant had developed rapidly progressive cardiomyopathy with severe systolic dysfunction and multiorgan failure, and died at eight months of age.
What did they find — and not find?
No nuclear or mitochondrial variant could be confidently established as causal. The standout candidate, the mitochondrial DNA variant m.4401A>G, was reproduced at near-homoplasmy — 99.8% in the infant's blood, 99.9% in myocardium, 99.9% in maternal blood — but showed no enrichment in the affected heart tissue compared with blood, and the evidence for pathogenicity is insufficient. The family lineages were also distinct: haplogroup J1d3a in infant and mother, N1b1a in the father, with the variant classified as a private mutation relative to the maternal haplogroup.
What is a reader to take from an inconclusive genome?
That 'no confident answer' is a legitimate, clinically meaningful outcome. For mitochondrial disease especially — where a variant's effect depends on how much of it each tissue carries — sequencing even the affected organ may not settle causation. Families in this position are usually offered continued research follow-up rather than closure, and any service claiming a genome scan will always find the answer is claiming more than the science supports.
Frequently asked questions
What is homoplasmy?
Mitochondrial DNA exists in many copies per cell. Homoplasmy means essentially all copies carry the same sequence — here, the variant was at 99.8–99.9%, effectively homoplasmic — while heteroplasmy means a mixture of variant and normal copies.
If the variant is in the heart too, why isn't it the cause?
Presence is not causation. The variant was equally present in the unaffected mother's blood and no more concentrated in the sick heart than elsewhere, and independent evidence that it damages function is lacking — so it cannot be confidently blamed.
Does a negative genome rule out genetic disease?
No. It rules out the variants current methods and knowledge can identify and interpret. Unexplained cases remain candidates for future reanalysis as evidence grows.
Where the evidence stands
- Established: Mitochondrial variants can cause infantile cardiomyopathy, their tissue distribution (heteroplasmy) shapes their effects, and genome sequencing is a standard tool in the search for a cause.
- Preliminary: The m.4401A>G variant itself: present at near-homoplasmy in one family, explicitly lacking sufficient evidence for pathogenicity — of biological interest only.
- Absent: An established cause for this child's disease, and any general conclusion beyond this single family.
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