Paediatric or syndromic cardiomyopathy

Gene: XPNPEP3

I don't know

Comment on list classification: There are now 3 unrelated families reported in literature with biallelic XPNPEP3 variants and paediatric cardiomyopathy (1 from a pre-print article). Hence, this gene should remain Amber on Paediatric or syndromic cardiomyopathy until more evidence emerges.

Created: 17 Aug 2026, 10:34 a.m. | Last Modified: 17 Aug 2026, 10:34 a.m.

Panel Version: 8.7

PMID: 20179356 O'Toole et al., 2010
2 affected individuals of kindred F543 (Turkish decent) had a homozygous 4-base deletion in XPNPEP3 c.931_934 delAACA, (p.N311LfsX5). Patient phenotype: Cardiomyopathy, seizure, mental/developmental delay, chronic pancreatitis with pancreatic cysts, mitochondrial disorder.

Kindred A131 - 3 affected individuals (North Finnish) harboured a homozygous splice-site mutation (1357G>T) in XPNPEP3. Patient phenotype: mild form of an NPHP-like kidney disease, with residual kidney function beyond the age of 20 years; hypertension, essential tremor, hearing loss.

PMID: 39363162 Zhen et al., 2024
13-year-old Chinese female patient with intellectual disability presented with a 2-year history of convulsions and fatigue, with a recent episode of swelling, breathlessness, and nocturnal dyspnea. The patient was diagnosed with cardiomyopathy, ventricular tachycardia, heart failure, and kidney failure. WES revealed a homozygous c.970–2A > G mutation in XPNPEP3.

doi:https://doi.org/10.1101/2025.01.11.25320052 Ruijmbeek et al., 2025 - PRE-PRINT
Report of two siblings with renal insufficiency and rapidly progressive cardiomyopathy revealed a novel homozygous variant (NM_022098.4 c.1357G>A) in the XPNPEP3 gene, showed to cause abnormal splicing, leading to an abnormal transcript and loss of XPNPEP3 protein function.

PMID: 35328774 Wachoski-Dark et al., 2022 - review article
XPNPEP3 is a mitochondrial protease that is responsible for the secondary cleavage of proteins localized to the matrix. XPNPEP3-related disease is caused by mitochondrial dysfunction rather than ciliary dysfunction (hypothesised previously).
Sources: Literature

Created: 17 Aug 2026, 10:32 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
cardiomyopathy, MONDO:0004994

Publications

• 20179356
• 35328774
• 39363162
• doi:https://doi.org/10.1101/2025.01.11.25320052