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Exclusion of an extracolonic disease modifier locus on chromosome 1p33-36 in a large Swiss familial adenomatous polyposis kindred.
Eur J Hum Genet. 2004 May; 12(5):365-71.EJ

Abstract

Familial adenomatous polyposis (FAP), an autosomal dominantly inherited colorectal cancer predisposition syndrome, displays considerable inter- and intrafamilial phenotypic heterogeneity, which represents a major problem in genetic counselling of APC mutation carriers. The Min mouse model indicated a putative disease modifier locus on chromosome 4, which is syntenic to human chromosome 1p35-36. This finding was subsequently supported by parametric and nonparametric linkage analyses in FAP families, however, without identifying functional variants in candidate genes. Recently, germline mutations in the base-excision repair gene MYH (1p33-34) have been described in patients with multiple adenomas, pointing to a possible role as disease modifier in FAP. Here, we present critical reassessment of one of the largest FAP kindreds published, which was previously used in linkage mapping of 1p35-36. In this family, all affected members harbour the same APC germline mutation (5945delA), but display marked phenotypic variability, in particular regarding the occurrence of extracolonic disease that segregates in several branches of the family tree. Using updated clinical information, additional mutation carriers and polymorphic markers, fine mapping of the critical region as well as mutation analysis of the MYH gene were performed. These investigations allowed us to significantly exclude (i) the 1p33-36 region as a modifier locus and (ii) MYH as a modifier gene for extracolonic disease in this FAP kindred. Our results do not eliminate 1p33-36 from suspicion in other families, but clearly indicate that in our family linkage analysis of further putative candidate regions is necessary to identify a disease modifier locus in FAP.

Authors+Show Affiliations

Research Group Human Genetics, Division of Medical Genetics, University Children's Hospital, Department of Research and Clinico-Biological Sciences, Vesalgasse1, 4031 Basel, Switzerland. martina.plasilova@unibas.chNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

14735163

Citation

Plasilova, M, et al. "Exclusion of an Extracolonic Disease Modifier Locus On Chromosome 1p33-36 in a Large Swiss Familial Adenomatous Polyposis Kindred." European Journal of Human Genetics : EJHG, vol. 12, no. 5, 2004, pp. 365-71.
Plasilova M, Russell AM, Wanner A, et al. Exclusion of an extracolonic disease modifier locus on chromosome 1p33-36 in a large Swiss familial adenomatous polyposis kindred. Eur J Hum Genet. 2004;12(5):365-71.
Plasilova, M., Russell, A. M., Wanner, A., Wolf, A., Dobbie, Z., Müller, H. J., & Heinimann, K. (2004). Exclusion of an extracolonic disease modifier locus on chromosome 1p33-36 in a large Swiss familial adenomatous polyposis kindred. European Journal of Human Genetics : EJHG, 12(5), 365-71.
Plasilova M, et al. Exclusion of an Extracolonic Disease Modifier Locus On Chromosome 1p33-36 in a Large Swiss Familial Adenomatous Polyposis Kindred. Eur J Hum Genet. 2004;12(5):365-71. PubMed PMID: 14735163.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Exclusion of an extracolonic disease modifier locus on chromosome 1p33-36 in a large Swiss familial adenomatous polyposis kindred. AU - Plasilova,M, AU - Russell,A M, AU - Wanner,A, AU - Wolf,A, AU - Dobbie,Z, AU - Müller,H J, AU - Heinimann,K, PY - 2004/1/22/pubmed PY - 2004/11/4/medline PY - 2004/1/22/entrez SP - 365 EP - 71 JF - European journal of human genetics : EJHG JO - Eur. J. Hum. Genet. VL - 12 IS - 5 N2 - Familial adenomatous polyposis (FAP), an autosomal dominantly inherited colorectal cancer predisposition syndrome, displays considerable inter- and intrafamilial phenotypic heterogeneity, which represents a major problem in genetic counselling of APC mutation carriers. The Min mouse model indicated a putative disease modifier locus on chromosome 4, which is syntenic to human chromosome 1p35-36. This finding was subsequently supported by parametric and nonparametric linkage analyses in FAP families, however, without identifying functional variants in candidate genes. Recently, germline mutations in the base-excision repair gene MYH (1p33-34) have been described in patients with multiple adenomas, pointing to a possible role as disease modifier in FAP. Here, we present critical reassessment of one of the largest FAP kindreds published, which was previously used in linkage mapping of 1p35-36. In this family, all affected members harbour the same APC germline mutation (5945delA), but display marked phenotypic variability, in particular regarding the occurrence of extracolonic disease that segregates in several branches of the family tree. Using updated clinical information, additional mutation carriers and polymorphic markers, fine mapping of the critical region as well as mutation analysis of the MYH gene were performed. These investigations allowed us to significantly exclude (i) the 1p33-36 region as a modifier locus and (ii) MYH as a modifier gene for extracolonic disease in this FAP kindred. Our results do not eliminate 1p33-36 from suspicion in other families, but clearly indicate that in our family linkage analysis of further putative candidate regions is necessary to identify a disease modifier locus in FAP. SN - 1018-4813 UR - https://www.unboundmedicine.com/medline/citation/14735163/Exclusion_of_an_extracolonic_disease_modifier_locus_on_chromosome_1p33_36_in_a_large_Swiss_familial_adenomatous_polyposis_kindred_ L2 - http://dx.doi.org/10.1038/sj.ejhg.5201157 DB - PRIME DP - Unbound Medicine ER -