TY - JOUR
T1 - New insights on genetic diagnostics in cardiomyopathy and arrhythmia patients gained by stepwise exome data analysis
AU - Kolokotronis, Konstantinos
AU - Pluta, Natalie
AU - Klopocki, Eva
AU - Kunstmann, Erdmute
AU - Messroghli, Daniel
AU - Maack, Christoph
AU - Tejman-Yarden, Shai
AU - Arad, Michael
AU - Rost, Simone
AU - Gerull, Brenda
N1 - Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/7
Y1 - 2020/7
N2 - Inherited cardiomyopathies are characterized by clinical and genetic heterogeneity that challenge genetic diagnostics. In this study, we examined the diagnostic benefit of exome data compared to targeted gene panel analyses, and we propose new candidate genes. We performed exome sequencing in a cohort of 61 consecutive patients with a diagnosis of cardiomyopathy or primary arrhythmia, and we analyzed the data following a stepwise approach. Overall, in 64% of patients, a variant of interest (VOI) was detected. The detection rate in the main sub-cohort consisting of patients with dilated cardiomyopathy (DCM) was much higher than previously reported (25/36; 69%). The majority of VOIs were found in disease-specific panels, while a further analysis of an extended panel and exome data led to an additional diagnostic yield of 13% and 5%, respectively. Exome data analysis also detected variants in candidate genes whose functional profile suggested a probable pathogenetic role, the strongest candidate being a truncating variant in STK38. In conclusion, although the diagnostic yield of gene panels is acceptable for routine diagnostics, the genetic heterogeneity of cardiomyopathies and the presence of still-unknown causes favor exome sequencing, which enables the detection of interesting phenotype–genotype correlations, as well as the identification of novel candidate genes.
AB - Inherited cardiomyopathies are characterized by clinical and genetic heterogeneity that challenge genetic diagnostics. In this study, we examined the diagnostic benefit of exome data compared to targeted gene panel analyses, and we propose new candidate genes. We performed exome sequencing in a cohort of 61 consecutive patients with a diagnosis of cardiomyopathy or primary arrhythmia, and we analyzed the data following a stepwise approach. Overall, in 64% of patients, a variant of interest (VOI) was detected. The detection rate in the main sub-cohort consisting of patients with dilated cardiomyopathy (DCM) was much higher than previously reported (25/36; 69%). The majority of VOIs were found in disease-specific panels, while a further analysis of an extended panel and exome data led to an additional diagnostic yield of 13% and 5%, respectively. Exome data analysis also detected variants in candidate genes whose functional profile suggested a probable pathogenetic role, the strongest candidate being a truncating variant in STK38. In conclusion, although the diagnostic yield of gene panels is acceptable for routine diagnostics, the genetic heterogeneity of cardiomyopathies and the presence of still-unknown causes favor exome sequencing, which enables the detection of interesting phenotype–genotype correlations, as well as the identification of novel candidate genes.
KW - Candidate genes
KW - Cardiogenetics
KW - Cardiomyopathy
KW - Targeted gene panel
KW - Whole exome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85099409661&partnerID=8YFLogxK
U2 - 10.3390/jcm9072168
DO - 10.3390/jcm9072168
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AN - SCOPUS:85099409661
SN - 2077-0383
VL - 9
SP - 1
EP - 15
JO - Journal of Clinical Medicine
JF - Journal of Clinical Medicine
IS - 7
M1 - 2168
ER -