Genomic sequencing has a high diagnostic yield in children with congenital anomalies of the heart and urinary system

Abstract

BackgroundCongenital heart defects (CHD) and congenital anomalies of the kidney and urinary tract (CAKUT) account for significant morbidity and mortality in childhood. Dozens of monogenic causes of anomalies in each organ system have been identified. However, even though 30% of CHD patients also have a CAKUT and both organs arise from the lateral mesoderm, there is sparse overlap of the genes implicated in the congenital anomalies for these organ systems. We sought to determine whether patients with both CAKUT and CHD have a monogenic etiology, with the long-term goal of guiding future diagnostic work up and improving outcomes.MethodsRetrospective review of electronic medical records (EMR), identifying patients admitted to Rady Children's Hospital between January 2015 and July 2020 with both CAKUT and CHD who underwent either whole exome sequencing (WES) or whole genome sequencing (WGS). Data collected included demographics, presenting phenotype, genetic results, and mother's pregnancy history. WGS data was reanalyzed with a specific focus on the CAKUT and CHD phenotype. Genetic results were reviewed to identify causative, candidate, and novel genes for the CAKUT and CHD phenotype. Associated additional structural malformations were identified and categorized.ResultsThirty-two patients were identified. Eight patients had causative variants for the CAKUT/CHD phenotype, three patients had candidate variants, and three patients had potential novel variants. Five patients had variants in genes not associated with the CAKUT/CHD phenotype, and 13 patients had no variant identified. Of these, eight patients were identified as having possible alternative causes for their CHD/CAKUT phenotype. Eighty-eight percent of all CAKUT/CHD patients had at least one additional organ system with a structural malformation.ConclusionsOverall, our study demonstrated a high rate of monogenic etiologies in hospitalized patients with both CHD and CAKUT, with a diagnostic rate of 44%. Thus, physicians should have a high suspicion for genetic disease in this population. Together, these data provide valuable information on how to approach acutely ill patients with CAKUT and CHD, including guiding diagnostic work up for associated phenotypes, as well as novel insights into the genetics of CAKUT and CHD overlap syndromes in hospitalized children.

The Evolving Role of Genetic Evaluation in the Prenatal Diagnosis and Management of Congenital Heart Disease

“…For infants requiring early surgical intervention, studies have shown that positive genetic testing results have been associated with post-operative complications and survival and can impact care and resource utilization [ 16 , 41 , 42 , 43 , 44 , 45 ]. Cohort studies have demonstrated that genetic testing of newborns with CHD yields an overall diagnostic rate of ~30% with genome-wide analysis [ 46 , 47 , 48 , 49 , 50 ]. The testing yield is slightly higher in cases of CHD with extra-cardiac anomalies, but results are still robust when the CHD is isolated [ 51 , 52 ].…”