Abstract: PD31-12
Sources of Funding: AWP is a K12 scholar supported by a Male Reproductive Health Research (MRHR) Career Development Physician-Scientist Award (Grant # HD073917-01) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Program. This work is also supported in part by the Burnett Research Fund.

Introduction

Peyronie&[prime]s disease (PD) is inherited in a subset of men and has a co-prevalence of ≈20% in men with Dupuytren&[prime]s disease (DD), a related fibrotic diathesis. Recent forward-genetic screening for genetic factors with potential involvement in PD and DD identified several candidate genes involved in fibrosis and inflammation. Here, we examine nucleotide-level genetic alterations with potential involvement in pathogenesis of PD and DD in a father-son duo using whole-exome sequencing.

Methods

Whole-exome genomic data was generated at the RNA and Genomic Profiling Sequencing Core (https://www.bcm.edu/garp/), and mapped using BOWTIE2 to the human genome build UCSC hg19; single nucleotide variants (SNVs) were inferred using the GATK platform and annotated using the annovar software, and then filtered for novel, non-synonymous SNVs. Enriched pathways were determined using the Gene Set Enrichment (GSEA) method, and the gene set collection from the Molecular Signature Database (MSigDB).

Results

Whole-exome sequencing identified 95/117 unique SNVs in each sample, with 150 SNVs shared between the two samples. Further analysis identified 150 nonsynonymous SNVs shared between the samples. Pathway analysis revealed enrichment of genes in known PD and DD pathogenic pathways including collagen formation / extracellular matrix organization (COL1A2, CRTAP), regulation of cell proliferation (SPEG, QSOX1, FGR1OP, LRP5), and the inflammatory response (HLA-DRB5, KDM6B). Several pathways not previously implicated in PD and DD were identified, including chromosomal rearrangement (FGFR1OP, COL1A2, AUTS2, AFF1, SHANK3), EGF-like domain-containing genes (MUC3A, SNED1, CD93, FAT2, SSPO, LRP5, MUC4), and maintenance of gastrointestinal epithelium (MUC2, MUC6, MUC4). SNVs in disease-associated genes, including osteoporosis and Parkinson&[prime]s disease, as well as SNVs in genes involved in head and neck, genitourinary, gastrointestinal, neurologic, and lung malignancies, were also identified. Neither of the two family members have reported any of the listed conditions to date.

Conclusions

In addition to pathways that can affect fibrosis, men with a genetic predisposition to PD and DD exhibit genetic alterations in cellular functions and disease-related pathways, including malignancies. This is the first study to genetically link fibrotic diatheses to other health conditions, and future work should focus on confirming these relationships. Moreover, men with PD or DD may warrant additional follow-up after diagnosis and treatment of these conditions.

Funding

AWP is a K12 scholar supported by a Male Reproductive Health Research (MRHR) Career Development Physician-Scientist Award (Grant # HD073917-01) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Program. This work is also supported in part by the Burnett Research Fund.