Paediatric or syndromic cardiomyopathy

Gene: KLHL24

Green List (high evidence)

Comment on list classification: There is sufficient evidence available for the association of both monoallelic and biallelic KLHL24 variants with dilated cardiomyopathy/ hypertrophic cardiopmyopathy. Hence, this gene can be promoted to green rating in the next GMS update.

Created: 1 Sep 2025, 6:40 p.m. | Last Modified: 1 Sep 2025, 6:40 p.m.

Panel Version: 7.60

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

Created: 1 Sep 2025, 6:37 p.m. | Last Modified: 1 Sep 2025, 6:37 p.m.

Panel Version: 7.59

Monoallelic cases:
PMID:30120936 (2019) reported 20 patients from 10 families with monoallelic gain-of-function variants affecting the translation initiation codon of KLHL24 gene (c.1A>G & c.2T>C), of which ten patients have been previously reported in PMID:27889062 (2016). They all had epidermolysis bullosa (EB), which is characterised by cutaneous and mucosal fragility. 17 (85%) of these patients had evidence of cardiac involvement with either elevated cardiac biomarkers or documented dilated cardiomyopathy (DCM) (8/20 patients [40%]), leading to death at an early age in two of them.

PMID:29779254 (2018) reported a family of Dutch descent with KLHL24-EBS that was reported with the same translation initiation codon variant c.1A>G. In addition to the cutaneous phenotypes, the affected father also developed a rapidly progressive DCM of unknown aetiology at the age of 18 years for which a cardiac transplantation was necessary within a year of the first clinical signs being seen.

PMID:31649980 (2019) reported a 14-year-old female patient with EBS and severe early-onset DCM who presented with heart failure at 14, required LVAD and orthotopic heart transplant. She was also identified with the same start codon variant (c.1A>G).

PMID:35975634 (2022) reported a four‐generation Australian family where 14 members suffer(ed) from EBS and five from DCM. Next‐generation sequencing and segregation analysis identified a novel heterozygous variant in KLHL24 (c.22A>T/ p.Arg8Ter) in the proband and several other affected members.

Monoallelic variants have been associated with relevant phenotypes in OMIM (MIM #617294) and Gene2Phenotype (with 'moderate' rating on skin panel).

Biallelic cases:
PMID:30715372 (2019) reported 11 young affected adult patients from two unrelated families with hypertrophic cardiomyopathy (HCM), of which 3 died suddenly and 1 had a cardiac transplant due to heart failure. Homozygous KLHL24 variants were identified in these families using genome-wide linkage analysis and exome sequencing (c.1048G>T/ p.Glu350Ter & c.917G>A/ p.Arg306His).

PMID:32870709 (2022) reported two hundred and five unrelated families with childhood-onset cardiomyopathy from Saudi Arabia, from which one patient with HCM was identified with homozygous nonsense variant in KLHL24 gene (c.1161G>A/ p.Trp387Ter) .

PMID:36672924 (2023) reported eight unrelated probands of Middle Eastern descent presenting with HCM/DCM, of which one patient presenting with mixed HCM/DCM with LVNC was identified with homozygous p.Arg306His missense 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 hypertrophic cardiomyopathy was identified with homozygous missense variant in KLHL24 gene (c.1376T>C/ p.Ile459Thr) via reanalysis of data from trio genome sequencing. This variant was reported as hot VUS in the publication

Biallelic variants have been associated with relevant phenotypes in OMIM (MIM #620236) and ClinGen ('moderate' rating for hypertrophic cardiomyopathy (MONDO:0005045) by Hereditary Cardiovascular Disease GCEP).
Sources: Literature

Created: 1 Sep 2025, 6:33 p.m. | Last Modified: 1 Sep 2025, 6:43 p.m.

Panel Version: 7.60

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Epidermolysis bullosa simplex 6, generalized intermediate, with or without cardiomyopathy, OMIM:617294; epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, MONDO:0015006; Cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies, OMIM:620236; cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies, MONDO:0859372

Publications

• 27889062
• 29779254
• 30120936
• 31649980
• 32870709
• 35975634
• 36672924
• 39472908

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments