O0013: Genetic Testing for Patients with Non-williams Supravalvar Aortic Stenosis: A Preliminary Guide for Clinicians

Background: Supravalvular aortic stenosis (SVAS) has been documented most commonly in patients with Williams syndrome (WS). Although other genetic conditions like elastin (ELN) arteriopathy and Noonan syndrome have been associated with SVAS, the frequency of these conditions in non-Williams SVAS is unknown. Given this knowledge gap, the yield of additional genetic testing after a negative CMA rules out Williams Syndrome is unknown. We aimed to describe the frequency and yield of genetic testing in a cohort of non-WS SVAS individuals at a tertiary children’s hospital.

Methods: A retrospective cohort study was performed including all patients with a diagnosis of SVAS cared for at our institution from May 1991 to September 2021. SVAS was defined as a peak supravalvar velocity of >2 meters/second, a sinotubular junction (STJ) or ascending aortic z-score <-2.0, or STJ z-score <-1.5 with positive family history of SVAS. Patients with WS, complex congenital heart disease, Shone complex, aortic valve disease as the primary condition, or who developed SVAS postoperatively were excluded. Descriptive statistics were employed to report the frequency of genetic testing and clinical diagnosis of genetic conditions.

Results: Of the 165 patients meeting inclusion criteria, 69 had genetic testing documented in themselves or an immediate family member with the same condition. One subject had trisomy 21 with an otherwise normal chromosomal microarray (CMA, 1.4%). Of the remaining 68, CMA was performed in 43 (63%), which was non-diagnostic in all. Thirty-six subjects (53%) received some form of ELN sequencing (ELN single gene, panel or whole exome sequencing) for themselves or had a first degree relative who received ELN sequencing. Of the 36, 20 had a pathogenic ELN variant (29% of those undergoing genetic evaluation, 56% of those with ELN sequencing). Whole exome sequencing, single gene, and panel testing for gene alterations other than ELN was documented in 23 subjects. Other diagnoses made by sequencing were Noonan syndrome (3 PTPN11, 1 RIT1, 5.8% of those receiving any testing), Alagille syndrome (3 JAG1, 4.3% of those receiving any testing), neurofibromatosis (1 NF1, 1.4% of those receiving any testing). Of note, 3 patients had familial dyslipidemia or hyperlipidemia thought to be the etiology of SVAS who did not receive testing. Overall, gene sequencing revealed a diagnosis in 28/44 (64%) of those undergoing sequencing.

Conclusion: In SVAS, once Williams syndrome was excluded, gene sequencing was high yield, with 64% of patients diagnosed using this technology. The highest yield was for the gene ELN, with positive testing in 20 of the 36 individuals tested for ELN mutation (56%). Less common genetic conditions diagnosed by sequencing included Noonan syndrome, Alagille syndrome, and neurofibromatosis. Given this, we recommend that gene sequencing using a multigene panel or exome analysis should be performed, as well as a consideration of hypercholesterolemia.