Genetic Testing for Supravalvar Aortic Stenosis: What to Do When It Is Not Williams Syndrome

Abstract

Background: We aimed to describe the frequency and yield of genetic testing in supravalvar aortic stenosis (SVAS) following negative evaluation for Williams-Beuren syndrome (WS).

Methods and results: This retrospective cohort study included patients with SVAS at our institution who had a negative evaluation for WS from May 1991 to September 2021. SVAS was defined as (1) peak supravalvar velocity of ≥2 meters/second, (2) sinotubular junction or ascending aortic Z score <-2.0, or (3) sinotubular junction Z score <-1.5 with family history of SVAS. Patients with complex congenital heart disease, aortic valve disease as the primary condition, or only postoperative SVAS were excluded. Genetic testing and diagnoses were reported. Of 162 patients who were WS negative meeting inclusion criteria, 61 had genetic testing results available (38%). Chromosomal microarray had been performed in 44 of 61 and was nondiagnostic for non-WS causes of SVAS. Sequencing of 1 or more genes was performed in 47 of 61. Of these, 39 of 47 underwent ELN sequencing, 20 of 39 (51%) of whom had a diagnostic variant. Other diagnoses made by gene sequencing were Noonan syndrome (3 PTPN11, 1 RIT1), Alagille syndrome (3 JAG1), neurofibromatosis (1 NF1), and homozygous familial hypercholesterolemia (1 LDLR1). Overall, sequencing was diagnostic in 29 of 47 (62%).

Conclusions: When WS is excluded, gene sequencing for SVAS is high yield, with the highest yield for the ELN gene. Therefore, we recommend gene sequencing using a multigene panel or exome analysis. Hypercholesterolemia can also be considered in individuals bearing the stigmata of this disease.

Keywords: SVAS; Williams syndrome; cardiovascular; genetics.

Figure 1. Diagnostic genetic yield among patients with non‐WS SVAS.

Patients include both probands and related family members. *Of these 100 patients with no additional genetic testing, 2 (2%) were found to have a phenotype consistent with familial hypercholesterolemia, which was considered to be the cause of SVAS. CMA indicates chromosomal microarray analysis; SVAS, supravalvar aortic stenosis; and WS, Williams syndrome.

Figure 2. Frequency of genetic diagnoses by affected gene (A) among all patients, including family members and (B) exclusively among probands.

“N sequencing for testing” corresponds to the number of patients with sequencing including each respective gene. “N diagnostic testing” corresponds to the subset of patients with sequencing who returned with diagnostic results for the gene. Each frequency is computed by dividing the number of patients with diagnostic testing by the number of patients with sequencing for the gene.

Figure 3. Diagnostic genetic yield by testing modality among 52 probands.

CMA indicates chromosomal microarray analysis.

Figure 4. Proposed clinical algorithm for genetic testing in SVAS.

*Often SVAS develops following detection of severe hypercholesterolemia. In the case of a patient with severe hypercholesterolemia, consider ordering a hyperlipidemia‐focused genetic panel or single testing for LDLR. ^†As genome sequencing becomes more widely accessible in the future, these options may progress to include genome sequencing as a possible testing method. ^‡Including duplication and deletion analysis. For patients with a family history of SVAS who underwent ELN gene sequencing before CMA, ELN testing may not need to be repeated. Instead, the clinician should consider more expansive testing such as panel or exome sequencing if not already performed. CMA indicates chromosomal microarray analysis; and SVAS, supravalvar aortic stenosis.