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Introduction: Dilated cardiomyopathy (DCM) is a progressive disease of heart muscle with an incidence of approximately 0.57 per 100,000 children in the US. The spectrum and frequency of mutations in known DCM genes differ among adults, children, and infants. Aim: To evaluate the diagnostic yield of genome-wide copy number variation (CNV) analysis and trio Whole Exome Sequencing (WES) with targeted analysis of genes implicated in paediatric DCM. Methods: We identified 95 cases (from 85 families) diagnosed with DCM before 18 years of age. Thirteen families with a genetic diagnosis that was previously established by other sequencing techniques were excluded, and 41 families for other reasons. In 31 carefully phenotyped probands CNV-analysis (SNP-array) and trio-WES were performed. Human Phenotype Ontology (HPO)-terms were used for data filtering. Results: A (likely) genetic diagnosis could be made in 14/31 families (45.2%). (Likely) pathogenic heterozygous variants were identified in TNNT2, SCN5A, TTN, MYH7 (4), MYL2 (2) and TPM1, and homozygous variants in SPEG (centronuclear myopathy) and GLB1 (GM1-gangliosidosis) using WES, as well as an 1p36.33p36.32 and an 10q25.2 deletion, using SNP-array. Compound heterozygous mutations in CEP135 (primary microcephaly) were identified in a child with syndromic DCM. Five patients carried autosomal recessive disease mutations that did not explain their phenotypes. Conclusions: WES and CNV-analysis yielded diagnoses for 45% of our cohort. In 8/10 families 'solved' by WES a causal variant in a well-known DCM gene was identified. When CNV-analysis and WES would have been applied as primary tests to all patients, the potential yield could increase to approximately 51%. Combining CNV-analysis with trio-based WES, filtering for variants in a virtual, and flexible gene panel based on patient-specific HPO-terms, represent a comprehensive, personalized, cost-and time-efficient strategy to establish a diagnosis within the genetically highly heterogeneous paediatric DCM cohort. The latter technique provides the ability to stepwise analysis of a subset of genomic data, thereby minimizing the number of variants of unknown significance and preventing incidental findings in a proportion of patients.

Introduction: Dilated cardiomyopathy (DCM) is a progressive disease of heart muscle with an incidence of approximately 0.57 per 100,000 children in the US. The spectrum and frequency of mutations in known DCM genes differ among adults, children, and infants. Aim: To evaluate the diagnostic yield of genome-wide copy number variation (CNV) analysis and trio Whole Exome Sequencing (WES) with targeted analysis of genes implicated in paediatric DCM. Methods: We identified 95 cases (from 85 families) diagnosed with DCM before 18 years of age. Thirteen families with a genetic diagnosis that was previously established by other sequencing techniques were excluded, and 41 families for other reasons. In 31 carefully phenotyped probands CNV-analysis (SNP-array) and trio-WES were performed. Human Phenotype Ontology (HPO)-terms were used for data filtering. Results: A (likely) genetic diagnosis could be made in 14/31 families (45.2%). (Likely) pathogenic heterozygous variants were identified in TNNT2, SCN5A, TTN, MYH7 (4), MYL2 (2) and TPM1, and homozygous variants in SPEG (centronuclear myopathy) and GLB1 (GM1-gangliosidosis) using WES, as well as an 1p36.33p36.32 and an 10q25.2 deletion, using SNP-array. Compound heterozygous mutations in CEP135 (primary microcephaly) were identified in a child with syndromic DCM. Five patients carried autosomal recessive disease mutations that did not explain their phenotypes. Conclusions: WES and CNV-analysis yielded diagnoses for 45% of our cohort. In 8/10 families 'solved' by WES a causal variant in a well-known DCM gene was identified. When CNV-analysis and WES would have been applied as primary tests to all patients, the potential yield could increase to approximately 51%. Combining CNV-analysis with trio-based WES, filtering for variants in a virtual, and flexible gene panel based on patient-specific HPO-terms, represent a comprehensive, personalized, cost-and time-efficient strategy to establish a diagnosis within the genetically highly heterogeneous paediatric DCM cohort. The latter technique provides the ability to stepwise analysis of a subset of genomic data, thereby minimizing the number of variants of unknown significance and preventing incidental findings in a proportion of patients.

Introduction: Dilated cardiomyopathy (DCM) is a progressive disease of heart muscle with an incidence of approximately 0.57 per 100,000 children in the US. The spectrum and frequency of mutations in known DCM genes differ among adults, children, and infants. Aim: To evaluate the diagnostic yield of genome-wide copy number variation (CNV) analysis and trio Whole Exome Sequencing (WES) with targeted analysis of genes implicated in paediatric DCM. Methods: We identified 95 cases (from 85 families) diagnosed with DCM before 18 years of age. Thirteen families with a genetic diagnosis that was previously established by other sequencing techniques were excluded, and 41 families for other reasons. In 31 carefully phenotyped probands CNV-analysis (SNP-array) and trio-WES were performed. Human Phenotype Ontology (HPO)-terms were used for data filtering. Results: A (likely) genetic diagnosis could be made in 14/31 families (45.2%). (Likely) pathogenic heterozygous variants were identified in TNNT2, SCN5A, TTN, MYH7 (4), MYL2 (2) and TPM1, and homozygous variants in SPEG (centronuclear myopathy) and GLB1 (GM1-gangliosidosis) using WES, as well as an 1p36.33p36.32 and an 10q25.2 deletion, using SNP-array. Compound heterozygous mutations in CEP135 (primary microcephaly) were identified in a child with syndromic DCM. Five patients carried autosomal recessive disease mutations that did not explain their phenotypes. Conclusions: WES and CNV-analysis yielded diagnoses for 45% of our cohort. In 8/10 families 'solved' by WES a causal variant in a well-known DCM gene was identified. When CNV-analysis and WES would have been applied as primary tests to all patients, the potential yield could increase to approximately 51%. Combining CNV-analysis with trio-based WES, filtering for variants in a virtual, and flexible gene panel based on patient-specific HPO-terms, represent a comprehensive, personalized, cost-and time-efficient strategy to establish a diagnosis within the genetically highly heterogeneous paediatric DCM cohort. The latter technique provides the ability to stepwise analysis of a subset of genomic data, thereby minimizing the number of variants of unknown significance and preventing incidental findings in a proportion of patients.

Objectives: The purpose of this study was to investigate the follow-up and treatment of the mutation-carrying relatives of a proband with an inherited arrhythmia syndrome. Background: The congenital long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and Brugada syndrome (BrS) are primary inherited arrhythmia syndromes that may cause syncope and sudden cardiac death in young individuals. After establishing the disease-causing deoxyribonucleic acid (DNA) mutation in probands, we actively conducted cascade screening to identify, most often asymptomatic, relatives who are also at risk of life-threatening arrhythmias. Methods: We retrospectively collected data from our cardiogenetics database and patient records and analyzed whether the identified carriers received prophylactic treatment. Results: From 1996 to 2008, 130 probands with a disease-causing mutation in one of the involved genes were identified, and 509 relatives tested positive for the disease-causing familial mutation. These subjects subsequently underwent cardiologic investigation (electrocardiography, exercise testing, Holter monitoring, ajmaline testing, echocardiography, where appropriate). After a mean follow-up of 69 ± 31 months (LQTS), 60 ± 19 months (CPVT), and 56 ± 21 months (BrS), treatment was initiated and ongoing in 65% (199 of 308), 71% (85 of 120), and 6% (5 of 81) of the relatives in the LQTS, CPVT, and BrS families, respectively. Eight carriers were lost to follow-up. Treatment included drug treatment (n = 249) or implantation of pacemakers (n = 26) or cardioverter-defibrillators (n = 14). All mutation carriers received lifestyle instructions and a list of drugs to be avoided. Conclusions: Cascade screening in families with LQTS, BrS, or CPVT, which was based on DNA mutation carrying and subsequent cardiologic investigation, resulted in immediate prophylactic treatment in a substantial proportion of carriers, although these proportions varied significantly between the different diseases. © 2010 American College of Cardiology Foundation.

Objectives: The purpose of this study was to investigate the follow-up and treatment of the mutation-carrying relatives of a proband with an inherited arrhythmia syndrome. Background: The congenital long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and Brugada syndrome (BrS) are primary inherited arrhythmia syndromes that may cause syncope and sudden cardiac death in young individuals. After establishing the disease-causing deoxyribonucleic acid (DNA) mutation in probands, we actively conducted cascade screening to identify, most often asymptomatic, relatives who are also at risk of life-threatening arrhythmias. Methods: We retrospectively collected data from our cardiogenetics database and patient records and analyzed whether the identified carriers received prophylactic treatment. Results: From 1996 to 2008, 130 probands with a disease-causing mutation in one of the involved genes were identified, and 509 relatives tested positive for the disease-causing familial mutation. These subjects subsequently underwent cardiologic investigation (electrocardiography, exercise testing, Holter monitoring, ajmaline testing, echocardiography, where appropriate). After a mean follow-up of 69 ± 31 months (LQTS), 60 ± 19 months (CPVT), and 56 ± 21 months (BrS), treatment was initiated and ongoing in 65% (199 of 308), 71% (85 of 120), and 6% (5 of 81) of the relatives in the LQTS, CPVT, and BrS families, respectively. Eight carriers were lost to follow-up. Treatment included drug treatment (n = 249) or implantation of pacemakers (n = 26) or cardioverter-defibrillators (n = 14). All mutation carriers received lifestyle instructions and a list of drugs to be avoided. Conclusions: Cascade screening in families with LQTS, BrS, or CPVT, which was based on DNA mutation carrying and subsequent cardiologic investigation, resulted in immediate prophylactic treatment in a substantial proportion of carriers, although these proportions varied significantly between the different diseases. © 2010 American College of Cardiology Foundation.

Objectives: The purpose of this study was to investigate the follow-up and treatment of the mutation-carrying relatives of a proband with an inherited arrhythmia syndrome. Background: The congenital long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and Brugada syndrome (BrS) are primary inherited arrhythmia syndromes that may cause syncope and sudden cardiac death in young individuals. After establishing the disease-causing deoxyribonucleic acid (DNA) mutation in probands, we actively conducted cascade screening to identify, most often asymptomatic, relatives who are also at risk of life-threatening arrhythmias. Methods: We retrospectively collected data from our cardiogenetics database and patient records and analyzed whether the identified carriers received prophylactic treatment. Results: From 1996 to 2008, 130 probands with a disease-causing mutation in one of the involved genes were identified, and 509 relatives tested positive for the disease-causing familial mutation. These subjects subsequently underwent cardiologic investigation (electrocardiography, exercise testing, Holter monitoring, ajmaline testing, echocardiography, where appropriate). After a mean follow-up of 69 ± 31 months (LQTS), 60 ± 19 months (CPVT), and 56 ± 21 months (BrS), treatment was initiated and ongoing in 65% (199 of 308), 71% (85 of 120), and 6% (5 of 81) of the relatives in the LQTS, CPVT, and BrS families, respectively. Eight carriers were lost to follow-up. Treatment included drug treatment (n = 249) or implantation of pacemakers (n = 26) or cardioverter-defibrillators (n = 14). All mutation carriers received lifestyle instructions and a list of drugs to be avoided. Conclusions: Cascade screening in families with LQTS, BrS, or CPVT, which was based on DNA mutation carrying and subsequent cardiologic investigation, resulted in immediate prophylactic treatment in a substantial proportion of carriers, although these proportions varied significantly between the different diseases. © 2010 American College of Cardiology Foundation.