Skip to main content
SpringerLink
Log in

Identification of genetic loci for basal cell nevus syndrome and inflammatory bowel disease in a single large pedigree

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Abecasis GR, Cherny SS, Cookson WO, Cardon LR (2002) Merlin-rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30:97–101

    Article  PubMed  CAS  Google Scholar 

  • Bale AE (1997) The nevoid basal cell carcinoma syndrome: genetics and mechanism of carcinogenesis. Cancer Invest 15:180–186

    Article  PubMed  CAS  Google Scholar 

  • Bonen DK, Cho JH (2003) The genetics of inflammatory bowel disease. Gastroenterology 124:521–536

    Article  PubMed  CAS  Google Scholar 

  • Brant SR, Shugart YY (2004) Inflammatory bowel disease gene hunting by linkage analysis: rationale, methodology, and present status of the field. Inflamm Bowel Dis 10:300–311

    Article  PubMed  Google Scholar 

  • Brant SR, Panhuysen CI, Bailey-Wilson JE, Rohal PM, Lee S, Mann J, Ravenhill G, Kirschner BS, Hanauer SB, Cho JH, Bayless TM (2000) Linkage heterogeneity for the IBD1 locus in Crohn’s disease pedigrees by disease onset and severity. Gastroenterology 119:1483–1490

    Article  PubMed  CAS  Google Scholar 

  • Brant SR, Panhuysen CI, Nicolae D, Reddy DM, Bonen DK, Karaliukas R, Zhang L, Swanson E, Datta LW, Moran T, Ravenhill G, Duerr RH, Achkar JP, Karban AS, Cho JH (2003a) MDR1 Ala893 polymorphism is associated with inflammatory bowel disease. Am J Hum Genet 73:1282–1292

    Article  PubMed  CAS  Google Scholar 

  • Brant SR, Picco MF, Achkar JP, Bayless TM, Kane SV, Brzezinski A, Nouvet FJ, Bonen D, Karban A, Dassopoulos T, Karaliukas R, Beaty TH, Hanauer SB, Duerr RH, Cho JH (2003b) Defining complex contributions of NOD2/CARD15 gene mutations, age at onset, and tobacco use on Crohn’s disease phenotypes. Inflamm Bowel Dis 9:281–289

    Article  PubMed  Google Scholar 

  • Cavanaugh J, Consortium IBDIG (2001) International collaboration provides convincing linkage replication in complex disease through analysis of a large pooled data set: Crohn disease and chromosome 16. Am J Hum Genet 68:1165–1171

    Article  PubMed  CAS  Google Scholar 

  • Cho JH, Nicolae DL, Gold LH, Fields CT, LaBuda MC, Rohal PM, Pickles MR, Qin L, Fu Y, Mann JS, Kirschner BS, Jabs EW, Weber J, Hanauer SB, Bayless TM, Brant SR (1998) Identification of novel susceptibility loci for inflammatory bowel disease on chromosomes 1p, 3q, and 4q: evidence for epistasis between 1p and IBD1. Proc Natl Acad Sci USA 95:7502–7507

    Article  PubMed  CAS  Google Scholar 

  • Cottingham RW, Idury RM, Schaffer AA (1993) Fast sequential genetic linkage computation. Am J Hum Genet 53:252–263

    PubMed  Google Scholar 

  • Curtis D, Sham PC (1995) Model-free linkage analysis using likelihoods. Am J Hum Genet 57:703–716

    PubMed  CAS  Google Scholar 

  • Curtis D, Zhao JH, Sham PC (1999) Comparison of GENEHUNTER and MFLINK for analysis of COGA linkage data. Genet Epidemiol 17(Suppl 1):S115–S120

    PubMed  Google Scholar 

  • Duerr RH, Barmada MM, Zhang L, Davis S, Preston RA, Chensny LJ, Brown JL, Ehrlich GD, Weeks DE, Aston CE (1998) Linkage and association between inflammatory bowel disease and a locus on chromosome 12. Am J Hum Genet 63:95–100

    Article  PubMed  CAS  Google Scholar 

  • Economou M, Trikalinos TA, Loizou KT, Tsianos EV, Ioannidis JP (2004) Differential effects of NOD2 variants on Crohn’s disease risk and phenotype in diverse populations: a metaanalysis. Am J Gastroenterol 99:2393–2404

    Article  PubMed  CAS  Google Scholar 

  • Farndon PA, Del Mastro RG, Evans DG, Kilpatrick MW (1992) Location of gene for Gorlin syndrome. Lancet 339:581–582

    Article  PubMed  CAS  Google Scholar 

  • Fujii K, Miyashita T, Omata T, Kobayashi K, Takanashi J, Kouchi K, Yamada M, Kohno Y (2003) Gorlin syndrome with ulcerative colitis in a Japanese girl. Am J Med Genet 121:65–68

    Article  Google Scholar 

  • Gorlin RJ (1987) Nevoid basal-cell carcinoma syndrome. Medicine 66:98–113

    Article  PubMed  CAS  Google Scholar 

  • Gorlin RJ, Goltz RW (1960) Multiple nevoid basal-cell epithelioma, jaw cysts and bifid rib: a syndrome. N Engl J Med 262:908–912

    Article  PubMed  CAS  Google Scholar 

  • Hampe J, Schreiber S, Shaw SH, Lau KF, Bridger S, Macpherson AJ, Cardon LR, Sakul H, Harris TJ, Buckler A, Hall J, Stokkers P, van Deventer SJ, Nurnberg P, Mirza MM, Lee JC, Lennard-Jones JE, Mathew CG, Curran ME (1999) A genomewide analysis provides evidence for novel linkages in inflammatory bowel disease in a large European cohort. Am J Hum Genet 64:808–816

    Article  PubMed  CAS  Google Scholar 

  • van Heel DA, Fisher SA, Kirby A, Daly MJ, Rioux JD, Lewis CM (2004) Inflammatory bowel disease susceptibility loci defined by genome scan meta-analysis of 1952 affected relative pairs. Hum Mol Genet 13:763–770

    Article  PubMed  CAS  Google Scholar 

  • Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, Almer S, Tysk C, O’Morain CA, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent-Puig P, Gower-Rousseau C, Macry J, Colombel JF, Sahbatou M, Thomas G (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease [comment]. Nature 411:599–603

    Article  PubMed  CAS  Google Scholar 

  • Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas JM, Quinn AG, Myers RM, Cox DR, Epstein EH, Jr., Scott MP (1996) Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 272:1668–1671

    Article  PubMed  CAS  Google Scholar 

  • Karban A, Eliakim R, Brant SR (2002) Genetics of inflammatory bowel disease [comment]. Isr Med Assoc J 4:798–802

    PubMed  CAS  Google Scholar 

  • Katz J, Savin R, Spiro HM (1968) The basal cell nevus syndrome and inflammatory disease of the bowel. Am J Med 44:483–488

    Article  PubMed  CAS  Google Scholar 

  • Kimonis VE, Goldstein AM, Pastakia B, Yang ML, Kase R, DiGiovanna JJ, Bale AE, Bale SJ (1997) Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome. Am J Med Genet 69:299–308

    Article  PubMed  CAS  Google Scholar 

  • Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES (1996) Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet 58:1347–1363

    PubMed  CAS  Google Scholar 

  • Lander E, Kruglyak L (1995) Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 11:241–247

    Article  PubMed  CAS  Google Scholar 

  • Loftus EV Jr. (2004) Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology 126:1504–1517

    Article  PubMed  Google Scholar 

  • Markianos K, Daly MJ, Kruglyak L (2001) Efficient multipoint linkage analysis through reduction of inheritance space. Am J Hum Genet 68:963–977

    Article  PubMed  CAS  Google Scholar 

  • O’Connell JR, Weeks DE (1998) PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 63:259–66

    Article  PubMed  CAS  Google Scholar 

  • Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr RH, Achkar JP, Brant SR, Bayless TM, Kirschner BS, Hanauer SB, Nunez G, Cho JH (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease [comment]. Nature 411:603–606

    Article  PubMed  CAS  Google Scholar 

  • Orholm M, Munkholm P, Langholz E, Nielsen OH, Sorensen IA, Binder V (1991) Familial occurrence of inflammatory bowel disease. N Engl J Med 324:84–88

    Article  PubMed  CAS  Google Scholar 

  • Ott J (1989) Computer-simulation methods in human linkage analysis. Proc Natl Acad Sci USA 86:4175–4178

    Article  PubMed  CAS  Google Scholar 

  • Parkes M, Barmada MM, Satsangi J, Weeks DE, Jewell DP, Duerr RH (2000) The IBD2 locus shows linkage heterogeneity between ulcerative colitis and Crohn disease. Am J Hum Genet 67:1605–1610

    Article  PubMed  CAS  Google Scholar 

  • Podolsky DK (1991a) Inflammatory bowel disease (1). N Engl J Med 325:928–937

    Article  PubMed  CAS  Google Scholar 

  • Podolsky DK (1991b) Inflammatory bowel disease (2). N Engl J Med 325:1008–1016

    Article  PubMed  CAS  Google Scholar 

  • Risch N (1990) Linkage strategies for genetically complex traits. II. The power of affected relative pairs. Am J Hum Genet 46:229–241

    PubMed  CAS  Google Scholar 

  • Roth MP, Petersen GM, McElree C, Vadheim CM, Panish JF, Rotter JI (1989) Familial empiric risk estimates of inflammatory bowel disease in Ashkenazi Jews. Gastroenterology 96:1016–1020

    PubMed  CAS  Google Scholar 

  • Satsangi J, Parkes M, Louis E, Hashimoto L, Kato N, Welsh K, Terwilliger JD, Lathrop GM, Bell JI, Jewell DP (1996) Two stage genome-wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosome 3, 7 and 12. Nat Genet 14:199–202

    Article  PubMed  CAS  Google Scholar 

  • Sawyer CS, Braverman IM (1969) Basal cell nevus syndrome with inflammatory disease of the bowel. Arch Dermatol 99:131–132

    Article  PubMed  CAS  Google Scholar 

  • Stoll M, Corneliussen B, Costello CM, Waetzig GH, Mellgard B, Koch WA, Rosenstiel P, Albrecht M, Croucher PJ, Seegert D, Nikolaus S, Hampe J, Lengauer T, Pierrou S, Foelsch UR, Mathew CG, Lagerstrom-Fermer M, Schreiber S (2004) Genetic variation in DLG5 is associated with inflammatory bowel disease. Nat Genet 36:476–480

    Article  PubMed  CAS  Google Scholar 

  • Tukel T, Shalata A, Present D, Rachmilewitz D, Mayer L, Grant D, Risch N, Desnick RJ (2004) Crohn disease: frequency and nature of CARD15 mutations in Ashkenazi and Sephardi/Oriental Jewish families. Am J Hum Genet 74:623–636

    Article  PubMed  CAS  Google Scholar 

  • Vermeire S, Rutgeerts P (2005) Current status of genetics research in inflammatory bowel disease. Genes Immun 6:637–645

    PubMed  CAS  Google Scholar 

  • Weber JL, May PE (1989) Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction. Am J Hum Genet 44:388–396

    PubMed  CAS  Google Scholar 

  • Weeks DE, Ott J, Lathrop GM (1990) SLINK: a general simulation program for linkage analysis. Am J Hum Genet 47:A204

    Google Scholar 

  • Wicking C, Bale AE (1997) Molecular basis of the nevoid basal cell carcinoma syndrome. Curr Opin Pediatr 9:630–635

    Article  PubMed  CAS  Google Scholar 

  • Wicking C, Gillies S, Smyth I, Shanley S, Fowles L, Ratcliffe J, Wainwright B, Chenevix-Trench G (1997) De novo mutations of the Patched gene in nevoid basal cell carcinoma syndrome help to define the clinical phenotype. Am J Med Genet 73:304–307

    Article  PubMed  CAS  Google Scholar 

  • Yuan B, Vaske D, Weber JL, Beck J, Sheffield VC (1997) Improved set of short-tandem-repeat polymorphisms for screening the human genome. Am J Hum Genet 60:459–460

    PubMed  CAS  Google Scholar 

  • Zlotogora J, Zimmerman J, Rachmilewitz D (1991) Prevalence of inflammatory bowel disease in family members of Jewish Crohn’s disease patients in Israel. Dig Dis Sci 36:471–475

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank all the participating family members for their time and engagement to enhance our understanding of the etiology of IBD and BCNS. We thank Dr. Patrick Rohal and Mr. Franklin Nouvet for technical and recruitment assistance. We thank Dr Ethylin Wang Jabs for her critical review of the manuscript. This study was funded in part by National Institutes of Health Grants R01DK58189 (C.I.P, S.R.B.) and RR00052 (S.R.B.), The Harvey M. and Lyn P. Meyerhoff IBD Center (A.S.K., T.M.B., and S.R.B.); Israeli Society of Gastroenterology (A.S.K.), the Mammalian Genotyping Service (National Heart, Lung, and Blood Institute) (RHD), and the Stewart W. Bainum family (S.R.B.).

Author information

Authors and Affiliations

  1. Genetics Program, Department of Medicine, Boston University School of Medicine, Boston, MA, USA

    Carolien I. Panhuysen & Alisa Knodle Manning

  2. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA

    Carolien I. Panhuysen & Alisa Knodle Manning

  3. Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, The School of Medicine, Johns Hopkins University, Baltimore, MD, USA

    Amir Karban, Theodore M. Bayless & Steven R. Brant

  4. Department of Gastroenterology, Rambam Medical Center, Haifa, Israel

    Amir Karban

  5. Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Richard H. Duerr

  6. National Human Genome Research Institute, National Institutes of Health, Baltimore, MD, USA

    Joan E. Bailey-Wilson

  7. Department of Dermatology, University of California San Francisco, San Francisco, CA, USA

    Ervin H. Epstein Jr.

  8. Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA

    Steven R. Brant

  9. JHUSOM, 1503, E. Jefferson Street, Baltimore, MD, 21231, USA

    Steven R. Brant

Authors
  1. Carolien I. Panhuysen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amir Karban
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alisa Knodle Manning
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Theodore M. Bayless
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Richard H. Duerr
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Joan E. Bailey-Wilson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ervin H. Epstein Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Steven R. Brant
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Steven R. Brant.

Additional information

Carolien I. Panhuysen and Amir Karban contributed equally to this work

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Panhuysen, C.I., Karban, A., Knodle Manning, A. et al. Identification of genetic loci for basal cell nevus syndrome and inflammatory bowel disease in a single large pedigree. Hum Genet 120, 31–41 (2006). https://doi.org/10.1007/s00439-006-0163-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-006-0163-8

Keywords

Search

Navigation