# Genetic Contributions to Valvar Pulmonary Stenosis

> **NIH NIH R03** · CINCINNATI CHILDRENS HOSP MED CTR · 2022 · $159,000

## Abstract

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contrast, our unpublished analysis of 123 sequenced (exome or genome) probands with vPS identified a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.

## Key facts

- **NIH application ID:** 10452823
- **Project number:** 1R03HL159537-01A1
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Kathryn Nicole Weaver
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $159,000
- **Award type:** 1
- **Project period:** 2022-07-19 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10452823

## Citation

> US National Institutes of Health, RePORTER application 10452823, Genetic Contributions to Valvar Pulmonary Stenosis (1R03HL159537-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10452823. Licensed CC0.

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