The genetic basis of non-syndromic, isolated, severe congenital heart defects in a population with high consanguinity rate - single center cohort 2013-2018.

Introduction: Congenital heart defects (CHD) are the most common birth defects. The underlying molecular etiology of CHD is largely unknown. Populations with relatively high rate of consanguineous marriage, such as Muslim Arabs and Ashkenazi Jews, were shown to have higher birth prevalence of conotruncal and laterality CHD.The aim of the study was to identify the genetic basis of non-syndromic, isolated, severe CHD in families suggestive of autosomal recessive (AR) inheritance pattern, in a single center pediatric cohort.

Methods: In a single center cohort, between 1/1/2013 and 31/12/2018, parents to children with non-syndromic, isolated, severe CHD coming from families suggestive to have an AR inheritance pattern were offered to participate in a genetic research aiming at elucidating the genetic basis of the CHD. We used exome analysis and filtering process, comprehensive family segregation sequencing and collaborated with international hospitals and laboratories in order to confirm pathogenicity in novel genes discovered.

Results: 49 families were offered to participate in the research, of which 36 families were recruited. A total of 42 exomes were done in those families. In 13/36 (36%) families no genetic diagnosis was done so far. In 4/36 (11%) families there is a candidate gene currently under basic science investigation. In 19/36 (53%) families a definite genetic diagnosis was determined to one of 15 genes, of whom 9/15 (60%) were novel genes proven as causing severe CHD in humans and 6/15 (40%) were already known as cardiac genes.

The cohorts` CHD phenotype was divided to 3 main subgroups: Conotruncal, laterality and valvular (mainly tricuspid or mitral atresia) - outlined in Table 1.

Conclusion: In populations with high consanguinity rate, there is high probability of identifying a monogenic cause underlying non syndromic, isolated severe CHD.