Work

P286: Single vs dual disease causing variant load in a pediatric cohort with congenital anomalies and cancer

Year: 2023

Type: article

Abstract: Introduction: Whole genome sequencing (WGS) presents a powerful approach to uncover genetic variants, including single nucleotide variants, deletions, and duplications, that contribute broadly to human disease.We selected 1464 molecularly undiagnosed children and 341 of their parents from our pediatric biobank and implemented WGS as a first-tier diagnostic method.Each child suffers from a major congenital malformation, including but not limited to cleft lip/palate, limb malformation, or internal organ defect, and in addition is diagnosed with childhood-onset cancer.We hypothesized that in most cases, a single diseasecausing variant would unveil their complex disease pictures constituting heterogeneous phenotypes.Methods: We used an internally newly-developed variant annotation and prioritization algorithm, driven by human phenotype ontology (HPO) terms and WGS, to provide a molecular diagnosis for children with both a congenital anomaly and a neoplasm.Four other algorithms were run for comparison.Results: The novel algorithm uncovered a single disease-causing single nucleotide variant (SNV)/insertions and deletions (indel) in over 300 cases (~30%), a double molecular diagnosis for another 20 cases, 45 aneuploidies, and 60 disease-causing copy number variation (CNVs), including haploinsufficiency, de novo variants and variable degrees of mosaic mutation patterns.Conclusion: Our findings demonstrate that structured clinical ontologies can be used to assess the degree of overlap between two Mendelian diseases in the same patient, where the conditions can exist separately or together.These results demonstrate that in children with severe and complex phenotypes, such as congenital malformation and cancer, and notably when coexisting in the same individual, WGS presents a powerful approach to unveil their molecular underpinnings and that a single genetic defect may explain phenotypes of high complexity that often appear unrelated, with double molecular finding identified in the same patient on rare occasions.

Source: Genetics in Medicine Open

DOI: 10.1016/j.gimo.2023.100314