Molecular characteristics of varicocele: integration of whole-exome and transcriptome sequencing

Objective To explore the exome and transcriptome characteristics potentially underlying the pathogenesis of varicocele (VE). Design Experimental study and cohort study. Setting Academic research laboratory and university-affiliated hospital. Patient(s) Eleven VE patients whose fathers also had VE, plus 151 additional patients and 324 healthy men for variants genotyping; for the rat model, eight Sprague–Dawley male rats. Intervention(s) Partial ligation of renal vein was conducted to establish VE rat models for whole-transcriptome RNA sequencing (RNA-seq). Main Outcome Measure(s) Genes with differential expression and/or harboring potential pathogenic variants detected via RNA-seq and whole-exome sequencing (WES) then subjected to population-based survey to define candidate genes of VE and analyzed via Gene Ontology and Kyoto Encyclopedia of Genes and Genomes to identify VE-involved pathways. Result(s) Whole-transcriptome RNA sequencing (RNA-seq) was performed using left spermatic veins of five rat VE models and three controls. We identified 9,688 genes and 18 pathways via RNA-seq, and via WES 160 genes harboring 279 potential deleterious variants and 16 pathways. Nine genes (AAMP, KMT2D, IRS2, SPINT1, IFT122, MKI67, DCHS1, LAMA2, and CBL) had variants in more than one patient who underwent WES, and six of these genes (AAMP, SPINT1, MKI67, IFT122, LAMA2, and DCHS1) showed differential expression. The population-based survey showed that AAMP, SPINT1, and MKI67 were strongly associated with VE risk. Together, two omic 67 data sets revealed four pathways potentially related to VE. Conclusion(s) For the first time, we have described the exome and transcriptome characteristics of VE. The bi-omics identified novel candidate genes and pathways involving the occurrence and development of VE.