title: Identification of genetic loci for basal cell nevus syndrome and inflammatory bowel disease in a single large pedigree.
abstract: Basal Cell Nevus Syndrome (BCNS) is an autosomal dominant disease. PTCH1 gene mutations have been found responsible in many but not all pedigrees. Inflammatory Bowel Disease (IBD) is a complex genetic disorder, disproportionate in Ashkenazim, and characterized by chronic intestinal inflammation. We revisited a large Ashkenazim pedigree, first reported in 1968, with multiple diagnoses of BCNS and IBD, and with a common genetic cause for both disorders proposed. We expanded the pedigree to four generations and performed a genome-wide linkage study for BCNS and IBD traits. Twelve members with BCNS, seven with IBD, five with both diagnoses and eight unaffected were genotyped. Both non-parametric (GENEHUNTER 2.1) and parametric (FASTLINK) linkage analyses were performed and a validation through simulation was performed. BCNS linked to chromosome 9q22 (D9S1120) just proximal to the PTCH1 gene (NPL=3.26, P=0.003; parametric two-point LOD=2.4, parametric multipoint LOD=3.7). Novel IBD linkage evidence was observed at chromosome 1p13 (D1S420, NPL 3.92, P=0.0047; parametric two-point LOD=1.9). Linkage evidence was also observed to previously reported IBD loci on 4q, (D4S2623, NPL 3.02, P=0.012; parametric two-point LOD=2.15), 10q23 (D10S1225 near DLG5, NPL 3.33, P=0.0085; parametric two-point LOD=1.3), 12 overlapping the IBD2 locus (D12S313, NPL 2.6, P=0.018; parametric two-point LOD=1.52), and 7q (D7S510 and D7S3046, NPL 4.06, P=0.0035; parametric two-point LOD=2.18). In this pedigree affected by both BCNS and IBD, the two traits and their respective candidate genetic loci segregate independently; BCNS maps to the PTCH1 gene and IBD maps to several candidate regions, mostly overlapping previously observed IBD loci.
authors.affiliation: Genetics Program, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Carolien I
authors.initials: CI
authors.lastname: Panhuysen
authors.forename: Amir
authors.initials: A
authors.lastname: Karban
authors.forename: Alisa
authors.initials: A
authors.lastname: Knodle Manning
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Bayless
authors.forename: Richard H
authors.initials: RH
authors.lastname: Duerr
authors.forename: Joan E
authors.initials: JE
authors.lastname: Bailey-Wilson
authors.forename: Ervin H
authors.initials: EH
authors.lastname: Epstein
authors.forename: Steven R
authors.initials: SR
authors.lastname: Brant
mesh_terms: D001478:Basal Cell Nevus Syndrome / Q000235:genetics*; D002874:Chromosome Mapping; D003198:Computer Simulation; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics*; D007585:Jews / Q000235:genetics; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats; D008957:Models, Genetic; D010375:Pedigree; D012878:Skin Neoplasms / Q000235:genetics*