Background: Although ventricular septal defects (VSD) are the most common congenital heart disease, familial clustering has been described only in rare instances. We have ascertained an extended family with VSDs and septal aneurysms requiring surgical intervention.
Methods: Detailed family history, physical exam, ECG, echocardiography and chart review was performed. Blood was sampled for genetic studies. Informed consent was obtained from all participants. Genotyping was performed using the Illumina Linkage12 panel. MERLIN was used for statistical analysis, with standard parameters for a rare autosomal dominant trait (penetrance set to 0.90, phenocopy set to 0.01 and disease allele frequency set to 0.001).
Results: 18 family members in three generations could be ascertained, out of whom 10 are affected (2 atrial septal defect, 3 septal aneurysm, 4 VSD, 1 Tetralogy of Fallot). Parametric multipoint LOD scores reach significance on chromosome 10p15.3-10p15.2 (max. 3.13). The LOD score support interval is in a gene-poor region which overlaps with numerous known cytogenetic anomalies causative in septal defects, but not the Di George syndrome 2 region on 10p.
Conclusion: The successful mapping of a rare familial form of VSDs/septal aneurysms provides evidence for further genetic heterogeneity of Mendelian cardiovascular traits. Fine-mapping, haplotype construction and resequencing will provide a unique opportunity for the pathogenesis of septal defects and shed light on candidate genes of heart development.