Genome-wide investigation of rare germline copy-number variants in retinoblastoma

Abstract

Approximately 8,000 children are diagnosed with retinoblastoma (Rb) globally each year, and the rate of survival as well as prognosis can differ greatly based on access to quality screening and treatment. Over 90% of patients with the inherited bilateral form of Rb have germline variants RB1, whereas approximately 20-30% of the unilateral form of Rb harbor germline variants in RB1. In the following study, rare germline copy-number variants (CNVs) within and outside of the RB1 gene were evaluated. Germline whole-genome sequencing (WGS) data from 134 Rb samples and 313 non-cancer controls of European ancestry were analyzed from the St. Jude Cloud. In an analysis of 1514 rare germline CNVs, non-negative matrix factorization (NMF) and Bayesian logistic regression identified 18 CNVs associated with Rb status. NMF analysis was used to reduce the high-dimensional feature space and resulted in 412 rare germline CNVs, one of which was found in RB1. A rare intronic germline CNV within the ACDY9 gene (OR= 3.29, 95% CI = 0.56 to 6.63) as well as an event within the intronic region of the PLXNC1 gene (OR= 2.24, 95% CI = 0.87 to 3.67) were found. In an evaluation of gene function within the UCSC hg38 Fetal Gene Atlas, ACDY9 has a role in eye photoreceptor cell development, and PLXNC1 has a role in eye horizontal cell development; both cell types have a functional role in Rb development. These findings suggest novel rare germline CNVs outside of the RB1 gene could be associated with Rb risk.