Introduction: Peyronie’s Disease (PD) is a superficial fibrosing disorder characterized by inelastic fibrous plaques within the tunica albuginea. Dupuytren’s and Ledderhose disease (DD and LD respectively) are related diseases that affect tissues in the palmar and plantar fascia, respectively. Using a large population database, we previously reported an increased relative risk of disease to relatives of PD probands. We also observed that 75% of PD cases existed within high-risk pedigrees. Both of these findings suggest a genetic component to this disease. Here, we describe the identification of a single high-risk pedigree from which we are identifying genetic variants that may predispose to these disorders.
Methods: The Utah Population Database (UPDB), a resource that includes genealogy information linked to electronic medical records (available since 1995), was used to identify men and their relatives with PD, as well as high risk PD pedigrees. Pedigrees with a significant excess (p < 0.05) of observed PD cases among descendants were termed high-risk. For genetic sequencing, individuals from a pedigree demonstrating a high degree of prevalence of PD, DD, and LD were recruited to provide samples from which genomic DNA (gDNA) was extracted. Whole genome sequencing is being conducted on these samples and variants will be evaluated based on variant type, population frequency, role in signaling pathways/gene ontology, co-segregation within the family, and potential impact on protein function.
Results: Previous analyses found that 75% of individuals with PD were part of high-risk PD pedigrees. One such high-risk pedigree containing a founder and 19 descendants was identified from our clinic. The founder and two descendants in the pedigree are deceased. Of the living descendants, 9 are male and 8 are female. Twelve of the descendants have responded to survey requests. Of these, 2/6 males report symptoms of PD (33%), 4/12 of the respondents report symptoms of Dupuytren’s Disease (33%), and 3/12 report symptoms of Ledderhose Disease (25%). Saliva samples from respondent individuals have been collected for whole-genome sequencing, which is being initiated.
Conclusions: Most PD cases identified in the UPDB were part of high-risk PD pedigrees, suggesting a familial component to PD, which may extend to other fibrosing disorders. Next-generation sequencing of gDNA from individuals within a high-risk pedigree will determine if genetic variants that may predispose to superficial fibrosing disorders exist within such a pedigree.
Source of Funding: Mentored Career Development Award (K08DK115835-01) from the National Institute of Diabetes and Digestive and Kidney Diseases (A.P.) & Sexual Medicine Society of North America Pfizer Research Fellowship in Men’s Health (M.B.C.)
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