Abstract
PURPOSE: Genome sequencing (GS) presents a powerful approach to uncover disease-causing genetic variants. We used GS to examine single vs dual molecular causes in some of the most complicated pediatric cases-those with both a neoplasm and a birth defect. METHODS: From our pediatric biobank, we selected 1463 children with a major congenital malformation, such as cleft lip/palate or internal organ defect, including 827 cases with a pediatric-onset cancer. The cohort includes nearly 40% non-White and/or multiracial individuals. We implemented GS as a first-tier diagnostic method and hypothesized that in most cases, a single disease-causing variant would explain their complex disease pictures. We developed a novel variant annotation and prioritization algorithm to provide a molecular diagnosis. RESULTS: Our algorithm uncovered 361 disease-causing single-nucleotide variants/insertion/deletions in patients with compatible phenotypes (n = 324/1373; 23.6%), including 207 known and 120 novel variants in 167 genes. In addition, we identified aneuploidies (n = 41; 3%) and disease-causing copy-number variations, including haploinsufficient regions, de novo pathogenic variants and variable degrees of mosaicism (n = 65, 4.7%). Likely deleterious variants were identified in 2 candidate genes, GNG13 and RTKN2. Most cases had a single molecular cause for the cancer and the congenital anomaly, with notable exceptions of dual molecular causes. CONCLUSION: In children with severe and complex phenotypes, our findings demonstrate that GS revealed causative molecular underpinnings, including novel causes. A single genetic defect may underlie phenotypes of high complexity that appear unrelated, with double molecular findings identified in the same patient on rare occasions.