RESUMEN
BACKGROUND: Congenital heart disease (CHD) occurs in almost 1% of newborn children and is considered a multifactorial disorder. CHD may segregate in families due to significant contribution of genetic factors in the disease etiology. The aim of the study was to identify pathophysiological mechanisms in families segregating CHD. METHODS: We used whole exome sequencing to identify rare genetic variants in ninety consenting participants from 32 Danish families with recurrent CHD. We applied a systems biology approach to identify developmental mechanisms influenced by accumulation of rare variants. We used an independent cohort of 714 CHD cases and 4922 controls for replication and performed functional investigations using zebrafish as in vivo model. RESULTS: We identified 1785 genes, in which rare alleles were shared between affected individuals within a family. These genes were enriched for known cardiac developmental genes, and 218 of these genes were mutated in more than one family. Our analysis revealed a functional cluster, enriched for proteins with a known participation in calcium signaling. Replication in an independent cohort confirmed increased mutation burden of calcium-signaling genes in CHD patients. Functional investigation of zebrafish orthologues of ITPR1, PLCB2, and ADCY2 verified a role in cardiac development and suggests a combinatorial effect of inactivation of these genes. CONCLUSIONS: The study identifies abnormal calcium signaling as a novel pathophysiological mechanism in human CHD and confirms the complex genetic architecture underlying CHD.
Asunto(s)
Señalización del Calcio , Calcio/metabolismo , Predisposición Genética a la Enfermedad , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/metabolismo , Biología de Sistemas/métodos , Alelos , Animales , Biología Computacional/métodos , Bases de Datos Genéticas , Dinamarca , Femenino , Estudios de Asociación Genética/métodos , Variación Genética , Humanos , Masculino , Mapeo de Interacción de Proteínas , Mapas de Interacción de Proteínas , Sistema de Registros , Secuenciación del Exoma , Pez CebraRESUMEN
Aims: Congenital heart defects (CHD) affect almost 1% of all live born children and the number of adults with CHD is increasing. In families where CHD has occurred previously, estimates of recurrence risk, and the type of recurring malformation are important for counselling and clinical decision-making, but the recurrence patterns in families are poorly understood. We aimed to determine recurrence patterns, by investigating the co-occurrences of CHD in 1163 families with known malformations, comprising 3080 individuals with clinically confirmed diagnosis. Methods and results: We calculated rates of concordance and discordance for 41 specific types of malformations, observing a high variability in the rates of concordance and discordance. By calculating odds ratios for each of 1640 pairs of discordant lesions observed between affected family members, we were able to identify 178 pairs of malformations that co-occurred significantly more or less often than expected in families. The data show that distinct groups of cardiac malformations co-occur in families, suggesting influence from underlying developmental mechanisms. Analysis of human and mouse susceptibility genes showed that they were shared in 19% and 20% of pairs of co-occurring discordant malformations, respectively, but none of malformations that rarely co-occur, suggesting that a significant proportion of co-occurring lesions in families is caused by overlapping susceptibility genes. Conclusion: Familial CHD follow specific patterns of recurrence, suggesting a strong influence from genetically regulated developmental mechanisms. Co-occurrence of malformations in families is caused by shared susceptibility genes.
Asunto(s)
Anomalías Múltiples/genética , Predisposición Genética a la Enfermedad , Cardiopatías Congénitas/genética , Sistema de Registros , Anomalías Múltiples/epidemiología , Adulto , Europa (Continente)/epidemiología , Femenino , Cardiopatías Congénitas/epidemiología , Humanos , Recién Nacido , Masculino , Morbilidad/tendencias , Linaje , Factores de RiesgoRESUMEN
Development of dilated cardiomyopathy in patients with congenital complete atrioventricular block with or without pacemaker is well described. We report a case of dilated cardiomyopathy in a child with congenital complete atrioventricular block, long-QT syndrome, and VVI pacemaker. Temporary pacing in the right ventricular outflow tract demonstrated a 63% increase in cardiac output. After change to biventricular DDD pacing, left ventricular systolic function and diastolic dimensions normalised.
