European Journal of Preventive Cardiology | 2019
Genetic counselling and testing in congenital heart defects and hereditary thoracic aortic disease: Complex but essential
Abstract
Congenital heart disease (CHD), the most common type of birth defect, has a neonatal incidence of 0.8–1%. Surgical advances have improved the pooled survival of CHD to adulthood in up to 90%. However, mortality and morbidity in adults with CHD remain high. Poor cardiac prognosis due to heart failure or life-threatening arrhythmia may be complicated further by extracardiac features, which are present in about 20% of CHD patients (syndromic CHD). Along with the prevalence of adults with CHD, the demand for cardiogenetic testing is increasing. A genetic diagnosis may serve as a marker for long-term cardiac or extracardiac outcome, or can enhance recurrence risk prediction in offspring of adults with CHD. De Backer et al. raise awareness about genetic counselling and testing for adults with CHD and hereditary thoracic aortic disease (HTAD). This European Society of Cardiology (ESC) consensus document provides guidance to healthcare providers, dealing with these diseases, about the importance, the indication and the timing of genetic counselling. In addition, the authors introduce a diagnostic algorithm with the preferred methodology of genetic testing, and give an overview of diagnoses to consider when facing syndromic or non-syndromic CHD or HTAD. As stated by the authors, the bottleneck in genetic testing is shifting from variant detection to variant interpretation. Advanced genome-wide screening technologies for chromosomal, structural or single nucleotide variants, such as chromosomal microarray or whole exome/genome sequencing, expose the patient’s genome in the blink of an eye. However, huge challenges remain in translating the abundance of genetic variants per individual into clinically relevant findings. Standardised criteria have been introduced to categorise single nucleotide variants according to their pathogenicity, based on variant type (protein truncating vs. missense variant), on frequency in a reference population, on in silico variant effect prediction and on inheritance pattern. Rare, predicted damaging variants in known disease-related genes that occur de novo in sporadic patients (i.e. not inherited from the parents) or that segregate with the disease in familial cases are typically considered pathogenic. Genomic studies report (mainly de novo) pathogenic variants in up to 35% of patients with previously unexplained syndromic CHD and inherited pathogenic variants in up to 40% of selected families with multigenerational non-syndromic CHD. The same holds true for syndromic or familial thoracic aortic disease. These syndromic and familial CHD and HTAD subgroups involve Mendelian traits with relatively high penetrance, and therefore represent obvious target populations for genetic testing and usually allow straightforward counselling. The diagnostic yield of whole exome sequencing in sporadic non-syndromic (NS)-CHD and NS-HTAD, which represents the majority of the adult CHD and HTAD cohort, is much lower. Although monogenic causes for NS-CHD and NS-HTAD have been reported in up to 4%, the majority remains gene-elusive despite chromosomal microarray and whole exome sequencing, and is considered to arise from a complex interplay between genetic and environmental factors. The diagnostic odyssey in NS-CHD is hampered by genetic heterogeneity, with more than 25 known genes, each being held responsible for less than 0.1% of the total NSCHD cohort. As a consequence, extensive NS-CHD populations should be tested genetically to reach a significant number of patients having a pathogenic variant in the same CHD gene, enabling gene-based outcome prediction. Genetic testing and counselling in NS-CHD is complicated further by reduced penetrance of