Key result
Rare XIRP1/2 variants linked to sarcomere-negative HCM, occurring in ~9% of patients versus controls.
Why the study?
The molecular mechanisms underlying hypertrophic cardiomyopathy (HCM) phenotypes are incompletely understood, and the specific contribution of mutations in the intercalated disc adhesion protein genes XIRP1 and XIRP2 to HCM phenotypes was unclear.
Are rare genetic variants in XIRP1 and XIRP2 associated with disease susceptibility and adverse clinical phenotypes in patients with sarcomere-negative hypertrophic cardiomyopathy?
Case-Control (n=926)
No
Are rare genetic variants in XIRP1 and XIRP2 associated with disease susceptibility and adverse clinical phenotypes in patients with sarcomere-negative hypertrophic cardiomyopathy?
Answers are grounded in this paper and cite their sources.
Identifies XIRP2 as a novel non-sarcomeric susceptibility and modifier gene in hypertrophic cardiomyopathy whose rare variants correlate with increased LV outflow tract obstruction, myocardial fibrosis, and syncope.
Objective The molecular mechanisms underlying hypertrophic cardiomyopathy (HCM) phenotypes remain incompletely understood. Xin actin‐binding repeat containing 1 and 2 (XIRP1 and XIRP2) are adhesion proteins localized to the adherens junctions of intercalated discs (ICDs). While mutations in these genes are known to cause cardiomyopathy, their specific contribution to HCM phenotypes is unclear. Methods The study was conducted on heart tissue samples from 36 patients diagnosed with HCM and 8 healthy donors. The upregulation of XIRP2 has been observed, which was confirmed by Quantitative RT‐PCR analysis. We further evaluated the association between genetic variants of XIRP1 and XIRP2 genes and HCM phenotype by targeted resequencing in 619 unrelated HCM patients and 307 healthy controls who did not carry any mutation in eight genes commonly mutated in myofilament disease. Using capillary Sanger sequencing, which excludes polymorphisms and probably neutral variants, the number of rare variants was verified in HCM patients. Results mRNAs demonstrating a statistically significant difference in expression levels of at least twofold ( p < 0.01) between experimental groups were chosen for subsequent analysis. The prevalence of rare variants in XIRP1 and XIRP2 genes was higher in HCM patients compared to controls [9.0% (56/619) vs. 3.9% (12/307), χ 2 = 7.96, p = 0.005], particularly XIRP2 (6.0% vs. 2.0%, p = 0.006). In HCM tissues, the expression of XIRP2 had increased dramatically by more than nine times ( p < 0.001). The rates of inexplicable syncope ( p = 0.036) and LV outflow obstruction ( p = 0.012) and myocardial fibrosis ( p = 0.010) were higher in the carriers. Conclusions Rare variants in XIRP1 and XIRP2 correlate with adverse HCM phenotypes, implicating ICD dysfunction in disease progression. Thereby giving more in‐depth information about the relationship between the prognosis of HCM and XIRP1 and that of XIRP2.
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Wang et al. (2026) conducted a case-control in Hypertrophic cardiomyopathy (HCM) (n=926). Rare variants in XIRP1 and XIRP2 genes vs. Healthy controls without HCM / HCM patients without pathogenic rare XIRP1/XIRP2 variants was evaluated on Prevalence of rare variants in XIRP1 and XIRP2 genes (p=0.005). Rare variants in XIRP1 and XIRP2 were more prevalent in sarcomere-negative HCM patients than in healthy controls, particularly XIRP2.
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