Advancing precision medicine in the Cardiac Intensive Care Unit using universal whole-genome sequencing

Abstract

Congenital heart defects (CHD) are a common congenital anomaly and a leading cause of neonatal mortality. Even in ostensibly isolated cases, genetic testing can reveal monogenic causes of isolated CHD or identify syndromic conditions before additional features become clinically apparent. A timely and accurate genetic diagnosis can inform medical management and surveillance, reduce the need for unnecessary investigations, and offer families valuable information about prognosis, recurrence risk, and anticipatory guidance. In September of 2023, Primary Childrens Hospital introduced a universal genetic testing protocol that implemented whole genome sequencing for all neonates admitted to the cardiac intensive care unit (CICU) undergoing cardiac surgery before 30 days of life, with the goal of increasing the number of patients who receive a timely genetic diagnosis and improving clinical care. This is a retrospective chart review of patients who underwent whole genome sequencing (WGS) under the new universal genetic testing protocol at Primary Childrens Hospital from its initiation in September 2023 to February 2026. Over the study period, 217 neonates with CHD participated in the universal WGS protocol. Of these patients, 23 (10.6%) received a genetic diagnosis that was causative of their CHD, of which 11 patients (48%) had no major extracardiac features at the time testing was ordered. Twenty patients were diagnosed with a syndromic condition, and three patients were diagnosed with a non-syndromic condition. All of these patients received additional referrals to specialists following their new diagnosis, and six families used results to inform decisions regarding continuation of care. An additional 19 patients (8.8%) received WGS results that were clinically relevant but non-diagnostic for their CHD, including partial diagnoses, secondary findings, and carrier status. In total, 19.4% of patients (n=42) had clinically relevant variants identified on their WGS.