Title: An extended Flemish pedigree affected by multiple sclerosis: genome-wide linkage analysis and study of clinical features
Authors: Breban, Tine ×
Goris, An
Van Wijmeersch, Bart
D'hooghe, Marie-Beatrice
Dubois, Bénédicte #
Issue Date: Sep-2008
Publisher: Sage publications ltd
Host Document: Multiple sclerosis vol:14 pages:S59-S59
Conference: World Congress of Treatment and Research in Multiple Sclerosis edition:24th ECTRIMS location:Montreal date:17-20 September 2008
Abstract: Introduction
Multiple Sclerosis (MS) is generally considered to be a multifactorial polygenetic disorder. A marked familial clustering is observed, with 20% of MS patients having another relative with MS. Families with seven or more affected individuals are extremely rare, but it is hoped that such pedigrees may facilitate the identification of genetic susceptibility genes. We have identified and clinically characterized an extended and unique Flemish pedigree affected by MS and have performed a genome-wide linkage analysis.

All affected individuals were clinically characterized. Blood samples were obtained from six persons with MS, and twelve connecting non-affected family members. HLA-DRB1 typing was done with SSP-based methods. Samples were genotyped with an Affymetrix 10K micro-array. Non-parametric linkage analysis (according to the Kong and Cox exponential model) was performed with the Merlin package. Linkage disequilibrium was accounted for by removing SNPs until no pair of SNPs had an r² ≥ 0.16. Microsatellite genotyping was performed using fluorescent dye-labeled primers on a MegaBACE System.

The pedigree now counts eleven individuals affected by MS, amongst them four individuals out of a sibship of nine (Fig. 1). The ancestors of the affected individuals could be traced back for at least four generations to two founding couples, originating from a rural village in Flanders, consisting out of approximately 850 inhabitants at that time. The prevalence in this family is approximately 1%, at least a magnitude higher than that of the Flemish population in general (88/100,000). Clinical data were available for nine affected family members. They were all diagnosed with definite MS according to the revised Mc Donald criteria, except for one person who was classified as possible MS (Table 1). Average age at onset was 36. Five affected individuals suffered from RRMS, three persons from PPMS.
Three of the affected individuals from whom a sample was obtained (50%) and three of the asymptomatic individuals (25%) carried the HLA-DRB1*15 allele (Fig. 1). Two regions reached non-parametric LOD-scores of ≥ 2, an observation that remained unchanged after accounting for linkage disequilibrium. A 3 Mb haplotype on chromosome 5 (Fig. 2A) and a 2,5 Mb haplotype on chromosome 9 (Fig. 2B) were shared by all individuals with definite MS, from whom a blood sample was available, and the individual with possible MS.

We identified and characterized an extended Flemish pedigree with eleven affected individuals and with a prevalence that is at least a magnitude higher than that of the Flemish population in general. We aimed at identifying genomic regions possibly harbouring MS susceptibility loci acting within this family. HLA does not appear to account for the increased prevalence in this family. Two regions on chromosome 5 and 9 were shared amongst all affected individuals from whom blood samples were available.
ISSN: 1352-4585
Publication status: published
KU Leuven publication type: IMa
Appears in Collections:Research Group Experimental Neurology
Functional and Cognitive Linguistics: Grammar and Typology (FunC), Leuven
Laboratory for Neuroimmunology
× corresponding author
# (joint) last author

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