Genetic Contributions to Valvar Pulmonary Stenosis

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ABSTRACT Congenital heart disease (CHD) is the most common class of birth defects, occurring in 1 in 100 live births, and is known to have both Mendelian and complex genetic etiologies. There are multiple studies investigating genetic contributions to specific types of CHD, but right ventricular outflow tract lesions are missing or underrepresented in such studies. Valvar pulmonary stenosis (vPS), a type of right ventricular outflow tract obstruction, accounts for ~10% of CHD. One quarter of individuals with vPS require invasive treatment with balloon valvuloplasty and/or open heart surgical repair, and a subset of these will require repeat intervention for recurrent valve stenosis, or to repair valve insufficiency/regurgitation. Thus, a diagnosis of vPS represents a significant lifetime healthcare burden. Our single-center retrospective study demonstrated that 10% of 204 probands with vPS carried a genetic diagnosis, but only 18% of the cohort had received genetic evaluation and/or testing (Anderson et al 2019). In contrast, our unpublished analysis of 123 sequenced (exome or genome) probands with vPS identified a Mendelian diagnosis in 17%. Noonan syndrome, an autosomal dominant condition with variable expression, was the most common diagnosis identified in both cohorts. In both groups, there was a high frequency of coexisting extracardiac and/or neurodevelopmental anomalies among children without a genetic diagnosis. In sum, this is highly suggestive that Mendelian diagnoses are under-recognized among individuals with vPS, and that there are novel causative genes yet to be identified. Further, studies of familial recurrence of right ventricular outflow tract obstructive CHD identified a relative recurrence risk of 48, one of the highest among all types of CHD. This suggests that common and rare variants may contribute to risk of non-Mendelian vPS. To address these important gaps in knowledge about Mendelian and complex genetic (non-Mendelian) etiologies of vPS, we will analyze genome sequencing from our own Gabriella Miller Kids First cohort, which includes over 500 individuals with vPS. Our analysis of this data set will 1) Identify rare and novel Mendelian etiologies of vPS and 2) Define the genetic etiology of non-Mendelian vPS. Results of our study will inform genetic testing recommendations for infants and children with vPS. Earlier diagnosis of genetic disorders and understanding how genetic variants contribute to pathogenesis and ultimately outcomes of vPS can improve health and developmental outcomes by allowing anticipatory rather than reactionary guidance and management. Ultimately, the goal of this study is to advance the use of genomic information as part of routine care for individuals with vPS in order to provide early and accurate anticipatory guidance to families and healthcare teams.