Severe early-onset cardiomyopathy and poor prognosis observed in 73 patients with pathogenic KLHL24 variants

Abstract

Abstract Background/Introduction Pathogenic variants in KLHL24 might cause skin fragility or cardiomyopathy. KLHL24 controls desmin turnover and patients with heterozygous gain-of-function variants (HET-GOF; i.e. overactivity), typically born with epidermolysis bullosa simplex (EBS), can develop dilated cardiomyopathy (DCM), whereas patients with homozygous loss-of-function variants (HOM-LOF) can develop hypertrophic cardiomyopathy (HCM). Purpose This study aims to characterize the cardiac phenotype and prognosis of patients with pathogenic KLHL24 variants. Methods Observational studies on KLHL24 found in PUBMED were included in this analysis. Patients were stratified according to their genotype and the study outcomes were cardiomyopathy diagnosis and cardiovascular (CV) events. CV events were defined as sudden cardiac death (SCD), death from heart failure (HF) or heart transplantation (HTx). Kaplan-Meier (KM) curves were constructed to visualize the age at diagnosis and CV event free-survival. For the HET-GOF group, this analysis was stratified by sex and log-rank testing was used to test for significant differences in the distribution. To achieve between group balance, the sex-stratified KM curves were weighted for age and cohort. Results In total, 73 patients from 14 studies were included in this analysis and Figure 1A shows their geographic distribution. In general, patients have a median age [IQR] of 18 [7–33]), 53% were men, 38% were diagnosed with cardiomyopathy, and 84% were patients with HET-GOF variants. Patients with HOM-LOF variants have a median age of 27 [26–31] and 55% is male (Figure 1B). HOM-LOF variants c.917G>A [p.(Arg306His)] and c.1048G>T [p.(Glu350*)] segregated in 2 Middle Eastern families, reporting 11 patients born from seemingly unaffected consanguineous heterozygous parents. All HOM-LOF patients were diagnosed with HCM before the age of 32 (27, [26–31]; Figure 1C), resulting in 4 CV events (SCD n=3; HTx n=1; Figure 1D). Patients with HET-GOF variants have a median age of 14 [6–33] and 53% were men (Figure 1B). HET-GOF variants c.1A>G, c.1A>T, c.2T>C, c.3G>T, c.3G>A and c.22A>T [p.(Val2_Met29)] segregated with disease in 34 families, reporting 62 patients in 14 countries. All patients with HET-GOF had EBS at birth and 27% was diagnosed with DCM. The probability of diagnosis during lifetime was significantly different (p<0.001, weighted p<0.001) between men (25 [16–34], n=9) and women (45 [31–47], n=8; Figure 1E). In total, 7 CV events (SCD n=1; HF n=4; HTx n=2) were reported for patients with HET-GOF variants. Figure 1F shows the general differences in CV events between sexes (p=0.026, weighted p=0.073). The median age of CV events for men was 20 (n=4) and 54 for women (n=3). Conclusions Patients with HOM-LOF variants were diagnosed at an early age with a severe form of HCM. Men with HET-GOF variants were diagnosed with DCM earlier than women. Men also have a higher probability for CV events at a younger age than women. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Research Counsel (ERC-2016-STG)