Single vs dual genetic disease in children with congenital anomalies and solid tumors

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.

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.

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.

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.