Exploring Familial Hypospadias: Genetic Insights from Copy Number Variants in a Quad Family

Abstract The genetic aetiology of hypospadias is likely to be oligogenic with possible interactions between multiple genetic variants and contributory environmental factors. A pathogenic copy number variant (CNV) is usually harboured by 3–14% of patients with rare developmental disorders. With this background, a landscape of CNVs in a family with multiple affected and unaffected progeny is presented with an investigation into the potentially responsible, molecular pathways underlying the etiopathogenesis of hypospadias. The family consists of both parents, two sons with hypospadias, and two unaffected sons (whole exome data unavailable for one unaffected son). CNVkit pipeline was executed and the structural variant files were annotated. The identified CNVs were studied for distribution within the family, inheritance, gene-composition and correlated with available information for potential relevance to the phenotype. Cumulative analysis (F:father, M:mother, P1-P2:affected progeny, U:unaffected progeny) identified 152 unique CNVs[size:1.49 kb–6.53 Mb) comprising 139 deletions and 13 duplications. P1 & P2 have been represented by 29(of 52) & 22(of 50) de novo CNVs respectively. P1 & P2 have 16 common deletion CNVs:8/16 CNVs are absent in U (inherited:6, de novo:2); de novo CNVs: chr6:29100942:29306930:DEL & chr16:11379821:11441076:D. de novo CNVs encompass OR2J1 and OR14J1 genes expressed in testis and spermatozoa as major histocompatibility complex (MHC)-linked olfactory receptors. CNVs encompassing GREM1, RRN3, KIAA0753 and HNF1B genes relevant to hypospadias were identified. The landscape of CNVs in familial hypospadias has been presented to enhance the understanding of their distribution, frequency and impact on the development of hypospadias and a database has been generated for future research.