Paediatric or syndromic cardiomyopathy

Gene: NPHP3

Red List (low evidence)

Comment on list classification: This gene is primarily associated with nephronophthisis in > 20 unrelated cases. There is only one patient reported with a NPHP3 synonymous variant from UK 100,000 genomes cohort and the phenotype was not explained by the variant.

Hence, this gene does not have any evidence of reliable association with cardiomyopathy and should be rated red.

Created: 1 Sep 2025, 11:42 a.m. | Last Modified: 1 Sep 2025, 11:42 a.m.

Panel Version: 7.53

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

Created: 1 Sep 2025, 11:40 a.m. | Last Modified: 1 Sep 2025, 11:40 a.m.

Panel Version: 7.52

There are >20 unrelated patients reported with biallelic variants in NPHP3 and with nephronophthisis. occasionally, patients have presented with extra-renal features, including rare congenital heart defects in a small number of cases. There are three OMIM phenotypes associated with this gene, of which Renal-hepatic-pancreatic dysplasia 1 (MIM #208540) had recorded atrial septal defect, aortic stenosis, or situs abnormalities as potential cardiovascular presentations.

The only patient that was reported with cardiomyopathy was from PMID:39472908 (2024). This publication reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one patient with hypertrophic cardiomyopathy was identified with homozygous synonymous variant in NPHP3 gene (c.2805C>T/ p.Gly935=) via reanalysis of data from duo genome sequencing. The publication states that the cardiomyopathy phenotype is not explained by the genotype.

This variant was previously reported to be responsible for hepatorenal fibrocystic disease from PMID:34212438 in five unrelated families. The two patients from the UK 100,000 genomes cohort reported in this publication also had valvular cardiopathy.
Sources: Literature

Created: 1 Sep 2025, 11:39 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Renal-hepatic-pancreatic dysplasia 1, OMIM:208540; Nephronophthisis 3, OMIM:604387; Meckel syndrome 7, OMIM:267010

Publications

• 34212438
• 39472908