Targeted Next-Generation Sequencing Identifies Pathogenic Variants in Familial Congenital Heart Disease | Journal Scan

Study Questions:

What is the diagnostic yield using next-generation sequencing (NGS) in familial congenital heart disease (CHD)?


A NGS gene panel for 57 genes implicated in CHD was applied to probands from 16 families with strong CHD histories and in 15 controls. Variants affecting protein-coding regions were classified in silico using prediction programs and filtered according to predicted mode of inheritance, minor allele frequencies (MAF), and presence in databases such as dbSNP and Exome Sequencing Project. Disease segregation studies were conducted in variants identified in CHD cases predicted to be deleterious and with MAF <0.1%.


Thirteen potential disease-causing variants were identified in nine families. Five of these variants segregated with disease phenotype, revealing a likely molecular diagnosis in 31% of this cohort. Significant increases in the number of “indels, nonsense, and splice” variants, as well as variants classified as “probably damaging” were identified in CHD cases, but not controls. There was also a significant increase in the total number of “rare” and “low” frequency variants (MAF <0.05) in the CHD cases.


When multiple relatives are affected by CHD, a gene panel-based approach may identify its cause in up to 31% of families.


Improvements in sequencing technology may facilitate widespread application of genetic testing to many diseases where disease-causing genes have been previously identified. Although the precise contribution of the specific gene variant towards the phenotype may still need to be proven in individual patients, this study suggests that in familial CHD cases, causal variants may be identified at relatively high frequency. As the authors state, these findings have implications for clinical care and future family planning.

Keywords: Phenotype, Family Planning Services, Gene Frequency, Genetic Testing, Heart Diseases, INDEL Mutation, Open Reading Frames

< Back to Listings