Targeted massively parallel sequencing of a representative cohort of Czech patients with various rare aortopathies demonstrates the clinical utility of genetic testing and the need for a multidisciplinary approach to at risk families
Abstrakt
Introduction: Aortopathies represent heterogeneous group of rare inherited disorders with a variable phenotype ranging form of aortic aneurysm/dissection with/without associated cardiac valvular disease. We studied the distribution of variants within selected candidate genes in a representative cohort of Czech paediatric-/adult patients.
Materials and Methods: Massively parallel sequencing was performed in 120 unrelated individuals (average age 42,5 years) using a custom-made panel comprising either 136 or 229 cardiac/aortic conditions-related genes (NimbleGen/Illumina). Detected variants were validated by Sanger DNA sequencing and segregation analysis.
In 40 "sequencing-negative" cases CNVs in the FBN1, TGFBR1 and TGFBR2 genes were examined by MLPA (MRC-Holland). Results: Pathogenic/likely pathogenic DNA variant (Class >= 4) were found in 10/120 (8.3 %) cases, while VUS (Class 3) were detected in 40/120 (33.3%) patients comprising genes FBN1, NOTCH1, FBN2, MYH11 and others.
Majority of pathogenic variants were observed in FBN1 (20.0%), while CNVs were not identified. Interestingly, pathogenic variants were also observed in 7/120 (5,8%) patients within aortopathy-unrelated genes conferring other cardiovascular risks.
Conclusions: As expected majority of variants were identified in connective tissue-related genes. The overall lower variant detection rate corresponds to published data.
The detection of pathogenic or potentially pathogenic variants for other cardiac conditions (e.g. arrhythmias) demonstrates the diagnostic usefulness of broader gene panels. Segregation analysis together with clinical examination of positive cases increases the utility of DNA sequencing, thereby underscores the multidisciplinary character of our approach and usefulness of cooperating with compliant at risk families.