Paediatric or syndromic cardiomyopathy

Gene: TREX1

I don't know

Comment on list classification: There are two unrelated cases reported with cardiomyopathy (one with fetal CM abdominal other being paediatric). The paediatric case was from the UK 100,000 genomes cohort and with a missense hot VUS variant. In addition, there is functional evidence from knockout mouse model.

This gene should be rated amber with the current evidence. However, the 'watchlist' tag has been added to review this gene in the future in light of new evidence.

Created: 1 Sep 2025, 7:26 p.m. | Last Modified: 1 Sep 2025, 7:28 p.m.

Panel Version: 7.63

Comment on phenotypes: OMIM phenotype accessed on 01 September 2025.

Created: 1 Sep 2025, 7:23 p.m. | Last Modified: 1 Sep 2025, 7:23 p.m.

Panel Version: 7.62

PMID:36581356 (2022) reported a case of fetal cardiomyopathy whose postnatal symptoms resembled TORCH (toxoplasmosis, other agents, rubella, cytomegalovirus, herpes and syphilis) infection. The mother had a history of two lost pregnancies due to fetal cardiomyopathy and the same was identified in the current pregnancy. A homozygous single base pair insertion in exon 2 of the TREX1 gene (chr3:g.48466711_48466712insG/ p.Glu20GlyfsTer82) was identified in the neonate and the parents were positive for the same heterozygous pathological variant.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one paediatric patient with unspecified cardiomyopathy was identified with homozygous missense variant in TREX1 gene (c.45C>G/ p.Ile15Met) via reanalysis of data from trio genome sequencing. This variant is reported to be a hot VUS in the publication, which also stated that the phenotype was explained by the genotype.

PMID:15254239 (2004) reported the generation of Trex1(-/-) null mice, which exhibited a dramatically reduced survival, and developed inflammatory myocarditis leading to progressive, often dilated cardiomyopathy and circulatory failure.
Sources: Literature

Created: 1 Sep 2025, 7:21 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Aicardi-Goutieres syndrome 1, dominant and recessive, OMIM:225750; Aicardi-Goutieres syndrome 1, MONDO:0009165; cardiomyopathy, MONDO:0004994

Publications

• 15254239
• 36581356
• 39472908