Gene · 2025
Cardiomyopathies, heart rhythm and conduction disorders as phenotypic manifestation of genetic variants in large cohort of cardiac patients: results of whole-genome study.
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Rimskaya Elena M, Nasonova Svetlana N, Meshkov Alexey N, Daniel Veronika V, Zelenova Elena A, Dzhumaniiazova Irina H, Kumar Nayana A, Fedorov A Yu, Mitrofanov Sergey I, Ivanov Mikhail V, Kashtanova Daria A, Yudin V S, Makarov V V, Keskinov Anton A, Kozaeva Kristina N, Loginova Anastasia I, Gomyranova Nataliua V, Vorobieva Yulia S, Zhirov Igor V, Yudin Sergey M, Tereschenko Sergey N, Skvorcova Veronika I, Golitsyn Sergey P, Boytsov Sergey A
Аннотация
AIM: To analyze the genotype-phenotype associations in huge specialized cohort of inpatients with cardiac disease.
MATERIALS AND METHODS: The whole-genome sequencing data from 4,856 inpatients admitted to the hospital with various cardiovascular diseases were analyzed for pathogenic (PV), likely pathogenic (LPV), and variants of uncertain significance (VUS) in 27 genes from ACMG SF v3.1 list for reporting secondary findings associated with arrhythmias and cardiomyopathies. The carriers of detected gene variants were assessed for full, incomplete, and overlapping phenotypic expressions.
RESULTS: 267 gene variants were identified in 261 (5.37 % of the overall sample) participants: 255 were single-variant carriers and six were two-variant carriers. Among them, 20 (7.5 %) had PVs, 149 (55.8 %) had LPVs, and 98 (36.7 %) had VUSs. 18 variants (6.7 %) were detected in genes associated with arrhythmias; 73 variants (27.3 %) were detected in genes associated with cardiomyopathies. The majority of variants (n = 176; 65.9 %) were located in the genes, associated with both cardiomyopathies and arrhythmias. The most prevalent were variants in the TTN (n = 128). The full penetrance of PVs/LPVs was 37.5 % in genes associated with arrhythmias, 52.4 % in genes associated with cardiomyopathies, and 16.9 % in genes ssociated with both arrhythmias and cardiomyopathies. Overall, full phenotypic expression was observed in 36 out of 169P/LP variant carriers (0.74 % of whole sample). The analyses revealed previously unknown genotype-phenotypic associations potentially indicating an overlap syndrome, such as DCM and HCM linked to variants in TRDN.
CONCLUSION: The research conducted in cohort of inpatients with cardiac diseases provided crucial information about the prevalence and penetrance of genetic variants and allowed to describe previously unknown genotype-phenotypic associations.
MATERIALS AND METHODS: The whole-genome sequencing data from 4,856 inpatients admitted to the hospital with various cardiovascular diseases were analyzed for pathogenic (PV), likely pathogenic (LPV), and variants of uncertain significance (VUS) in 27 genes from ACMG SF v3.1 list for reporting secondary findings associated with arrhythmias and cardiomyopathies. The carriers of detected gene variants were assessed for full, incomplete, and overlapping phenotypic expressions.
RESULTS: 267 gene variants were identified in 261 (5.37 % of the overall sample) participants: 255 were single-variant carriers and six were two-variant carriers. Among them, 20 (7.5 %) had PVs, 149 (55.8 %) had LPVs, and 98 (36.7 %) had VUSs. 18 variants (6.7 %) were detected in genes associated with arrhythmias; 73 variants (27.3 %) were detected in genes associated with cardiomyopathies. The majority of variants (n = 176; 65.9 %) were located in the genes, associated with both cardiomyopathies and arrhythmias. The most prevalent were variants in the TTN (n = 128). The full penetrance of PVs/LPVs was 37.5 % in genes associated with arrhythmias, 52.4 % in genes associated with cardiomyopathies, and 16.9 % in genes ssociated with both arrhythmias and cardiomyopathies. Overall, full phenotypic expression was observed in 36 out of 169P/LP variant carriers (0.74 % of whole sample). The analyses revealed previously unknown genotype-phenotypic associations potentially indicating an overlap syndrome, such as DCM and HCM linked to variants in TRDN.
CONCLUSION: The research conducted in cohort of inpatients with cardiac diseases provided crucial information about the prevalence and penetrance of genetic variants and allowed to describe previously unknown genotype-phenotypic associations.