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Understanding and Curing RRP: a genetic undertaking Farrel J. Buchinsky, MD Pediatric Otolaryngologist Allegheny Understanding and Curing RRP: a genetic undertaking Farrel J. Buchinsky, MD Pediatric Otolaryngologist Allegheny General Hospital Center for Genomic Sciences Pittsburgh, PA Allegheny Singer Research Institute

Interest Piqued o o “Cool” Surgery Ridiculous outcome n Because kept coming back Interest Piqued o o “Cool” Surgery Ridiculous outcome n Because kept coming back

What is the cause of RRP? Necessary Is it sufficient? o o What is the cause of RRP? Necessary Is it sufficient? o o

Many exposed o Only few get the disease Many exposed o Only few get the disease

Spectrum of Understanding o Genetic s Cell Biology Understanding increases probability of developing cure Spectrum of Understanding o Genetic s Cell Biology Understanding increases probability of developing cure or eradication Disease Epidemiology

Life Life

Genetics at its simplest Genetics at its simplest

Genes Genes

Genes Genes

Center for Genomic Sciences Allegheny General Hospital, Pittsburgh Center for Genomic Sciences Allegheny General Hospital, Pittsburgh

We each have two sets of genes We each have two sets of genes

TDT Transmitted Untra nsmitt ed A A B y B x TDT Transmitted Untra nsmitt ed A A B y B x

From who? From who?

Funding Funding

Acquisition IRB IRB Acquisition IRB IRB

IRB o Approved n n n o Allegheny General Hospital, Pittsburgh Children's Hospital of IRB o Approved n n n o Allegheny General Hospital, Pittsburgh Children's Hospital of the King's Daughters, Norfolk Children's Hospital of Wisconsin, Milwaukee Children's National Medical Center, Washington Cincinnati Children's Hospital Medical Center Johns Hopkins Children's Center, Baltimore Children's Medical Center of Dallas Children's Hospital of Philadelphia SUNY Upstate Medical Center, Syracuse Hospital for Sick Children, Toronto Children's Hospital of Alabama, Birmingham Pending n n University of California - San Francisco Children's Hospital and Regional Medical Center, Seattle

Enrolment Count Institution Doctor 15 Cincinnati Children's Hospital Medical Center Charles Myer 12 Children's Enrolment Count Institution Doctor 15 Cincinnati Children's Hospital Medical Center Charles Myer 12 Children's Medical Center of Dallas John Mc. Clay 11 Children's Hospital of the King's Daughters Craig Derkay 10 The Hospital for Sick Children Paolo Campisi 9 Children's National Medical Center Sukgi Choi 7 Children's Hospital of Wisconsin Stephen Conley 3 Johns Hopkins Children's Center David Tunkel 2 Children's Hospital of Philadelphia Lisa Elden 13 from Patient Support Groups

Which gene or genes o o o 3 x 109 bases Candidate Gene Approach Which gene or genes o o o 3 x 109 bases Candidate Gene Approach Genomic Scan Approach

Epidermodysplasia Verruciformis o o Rare, autosomal recessive, skin disease Abnormal susceptibility to specific HPVs Epidermodysplasia Verruciformis o o Rare, autosomal recessive, skin disease Abnormal susceptibility to specific HPVs (5 and 8) n o persistent lesions that do not clear virus 4 specific mutations found in EVER 1 Dr. Mark Naylor, Electronic Textbook of Dermatology

EVER 1 Mutations not present in RRP First 60 Allele Specific PCR Positive control EVER 1 Mutations not present in RRP First 60 Allele Specific PCR Positive control RFLP Positive control

Maybe somewhere else in EVER 1 Looking at about 20 SNP markers in area Maybe somewhere else in EVER 1 Looking at about 20 SNP markers in area

Candidates o o MHC Innate Immunity n o Known Cell Biology Interactions n o Candidates o o MHC Innate Immunity n o Known Cell Biology Interactions n o Toll-like receptors E 5 inhibits H+ATPase from acidifying vesicles Other Diseases n n Epidermodysplasia Verruciformis Cervical Cancer

Whole Genome o A/A illumi. Code #217 #1024 //// illumi. Code #561 96 humans Whole Genome o A/A illumi. Code #217 #1024 //// illumi. Code #561 96 humans at a time 6000 SNPs, more coming T/T //// o A/T

Challenge I o Distributed, replicated with random noise n IRB Challenge I o Distributed, replicated with random noise n IRB

Challenge II o Need many more patients n n n Support Groups International www. Challenge II o Need many more patients n n n Support Groups International www. rrpgenetics. org

More Patients + Parents o o o More Data Believable Conclusions Understanding More Patients + Parents o o o More Data Believable Conclusions Understanding

Acknowledgments o CGS n n o Earliest Collaborators n o Garth Ehrlich, Chris Post Acknowledgments o CGS n n o Earliest Collaborators n o Garth Ehrlich, Chris Post Joseph Donfack, Marilyn Smith, Fen Hu Craig Derkay, Suzanne Leal Patient Support Groups n Michael Green, Bill Stern fbuchins@wpahs. org cell: (412) 779 -1073