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We are excited to announce Laura’s first research manuscript is online today in the American Journal of Human Genetics (AJHG)! In this genome-wide study of rare germline copy number variations (CNVs), we found that chromosome 16p11.2 microdeletion predisposes to neuroblastoma, with a much larger effect size than seen for common variants identified by GWAS.  This represents the culmination of nearly a decade of work to establish the numbers needed to definitively reach this conclusion in a relatively rare childhood cancer. The 16p11.2 deletion corresponds to a rare genetic syndrome associated with autism and other neurodevelopmental disorders. When parental DNA was available, the 550-kb deletion arose de novo in children diagnosed with neuroblastoma. It will be of interest to consider implications for genetic counseling for those diagnosed with 16p11.2 deletion syndrome, particularly given the diversity of phenotypes associated with the chromosomal deletion.   To view the full report, please visit  https://doi.org/10.1016/j.ajhg.2019.07.020 .

Full pdf is available at the following Share Link: https://authors.elsevier.com/a/1ZgzkgeWuDj-

Germline 16p11.2 Microdeletion Predisposes to Neuroblastoma

Neuroblastoma is a cancer of the developing sympathetic nervous system. It is diagnosed in 600–700 children per year in the United States and accounts for 12% of pediatric cancer deaths. Despite recent advances in our understanding of this malignancy’s complex genetic architecture, the contribution of rare germline variants remains undefined. Here, we conducted a genome-wide analysis of large (>500 kb), rare (<1%) germline copy number variants (CNVs) in two independent, multi-ethnic cohorts totaling 5,585 children with neuroblastoma and 23,505 cancer-free control children. We identified a 550-kb deletion on chromosome 16p11.2 significantly enriched in neuroblastoma cases (0.39% of cases and 0.03% of controls; p = 3.34 × 10⁻⁹). Notably, this CNV corresponds to a known microdeletion syndrome that affects approximately one in 3,000 children and confers risk for diverse developmental phenotypes including autism spectrum disorder and other neurodevelopmental disorders. The CNV had a substantial impact on neuroblastoma risk, with an odds ratio of 13.9 (95% confidence interval = 5.8–33.4). The association remained significant when we restricted our analysis to individuals of European ancestry in order to mitigate potential confounding by population stratification (0.42% of cases and 0.03% of controls; p = 4.10 × 10⁻⁸). We used whole-genome sequencing (WGS) to validate the deletion in paired germline and tumor DNA from 12 cases. Finally, WGS of four parent-child trios revealed that the deletion primarily arose de novo without maternal or paternal bias. This finding expands the clinical phenotypes associated with 16p11.2 microdeletion syndrome to include cancer, and it suggests that disruption of the 16p11.2 region may dysregulate neurodevelopmental pathways that influence both neurological phenotypes and neuroblastoma.