Abstract 4369256: Patterns of genetic testing in fetuses and neonates with hypoplastic left heart syndrome are highly variable among centers in North America: A Fetal Heart Society collaborative study

Background: In research cohorts, pathologic genetic variants have been reported in nearly 30% of children with hypoplastic left heart syndrome (HLHS). However, reports of real-world genetic testing practices and findings are limited. Research Questions We aimed to describe the variation in rates and type of genetic testing performed among academic centers in North America caring for newborns with HLHS. We also aimed to describe the real-world diagnostic yield in this population. Methods: We performed an ancillary study to a multicenter retrospective cohort study of fetuses and infants <2 months of age with HLHS admitted 1/2012-12/2016 to participating Fetal Heart Society institutions in North America. Prenatal and postnatal genetic testing and extracardiac anomalies (EA) were collected from participating centers. Results: Among 11 centers, 521 fetuses and infants were included. Rates of any form of diagnostic genetic testing varied between centers (24% to 96%). Overall, 109 (20%) had prenatal testing (excluding non-invasive prenatal testing, NIPT), and 302 (58%) eventually had some form of diagnostic testing (other than FISH for 22q11.2 deletion). Aneuploidy was evaluated for in 290 (56%); 16 were diagnostic (5.5%, Table), predominantly for Turner syndrome (TS). Comprehensive evaluation for copy number variation by chromosomal microarray (CMA) occurred in 216 patients (41.5%), with 16 positive findings, for a 7.4% yield. Of these, 6 were detected prenatally (of 59 with prenatal CMA, 10.2%). Only 19 patients (3.6%) underwent whole exome sequencing (WES) of which 6 had sequence variants, for a solve rate of 31.6%. Of the 494 in whom presence of EA was characterized, 86 had EA (17.4%). Among those with both genetic testing and information on EA (n=292), the yield of genetic testing was higher in those with EA but still ranged from 3.8-18.2% in those without (Table). Conclusions: Patterns of genetic testing in fetuses and neonates with HLHS vary significantly among academic centers in North America. Only 20% of the cohort had prenatal genetic testing beyond NIPT, and just over half had any testing. During the study period, WES was rarely performed but had the highest yield. Offering consistent genetic testing, including appropriate testing for sequence variants, will likely result in more frequent diagnosis of genetic disorders. In turn, this may improve our understanding of neurodevelopmental variability and inform personalized counseling and medical care in HLHS.