Paediatric or syndromic cardiomyopathy

Gene: FGFR3

Red List (low evidence)

Comment on list classification: There is no evidence directly linking FGFR3 variants to any cardiac phenotype except one patient reported from the reanalysis of the UK 100,000 genomes cohort. The phenotype was not fully explained by the genotype in this patient.

Hence, there is no reliable evidence for this association and the gene should be rated red.

Created: 2 Sep 2025, 8:37 a.m. | Last Modified: 2 Sep 2025, 8:37 a.m.

Panel Version: 7.67

All reported FGFR3 variants cause skeletal or craniofacial syndromes (e.g. achondroplasia, thanatophoric dysplasia) and there are no reports of FGFR3 variants causing cardiomyopathy as a direct phenotype.

It is reported in Rare disease advisor (https://www.rarediseaseadvisor.com/disease-info-pages/achondroplasia-comorbidities/) that some children with achondroplasia (MIM #100800) develop hypertrophic cardiomyopathy or heart failure secondary to severe obstructive sleep apnea and obesity – but the FGFR3 variant itself only indirectly contributes via these complications . Lethal de novo FGFR3 variants cause perinatal dwarfism syndromes; affected infants die from respiratory insufficiency before cardiomyopathy could manifest, and no survivors with these variants have been reported to develop cardiomyopathy.

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 dilated cardiomyopathy was identified with heterozygous missense variant in FGFR3 gene (c.667C>T/ p.Arg223Cys) via reanalysis of data from trio genome sequencing. This variant was reported as hot VUS and the publication states that the cardiomyopathy phenotype was not fully explained by the genotype.
Sources: Literature

Created: 2 Sep 2025, 8:35 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

• 39472908