Multiple sclerosis is a common disease with proven heritability, but, despite large-scale attempts, no underlying risk genes have been identified. Traditional linkage scans have so far identified only one risk haplotype for multiple sclerosis (at HLA on chromosome 6), which explains only a fraction of the increased risk to siblings. Association scans such as admixture mapping have much more power, in principle, to find the weak factors that must explain most of the disease risk. We describe here the first high-powered admixture scan, focusing on 605 African American cases and 1,043 African American controls, and report a locus on chromosome 1 that is significantly associated with multiple sclerosis.

To optimize the molecular diagnosis of hereditary breast and ovarian cancer (HBOC), we developed a next-generation sequencing (NGS)-based screening based on the capture of a panel of genes involved, or suspected to be involved in HBOC, on pooling of indexed DNA and on paired-end sequencing in an Illumina GAIIx platform, followed by confirmation by Sanger sequencing or MLPA/QMPSF. The bioinformatic pipeline included CASAVA, NextGENe, CNVseq and Alamut-HT. We validated this procedure by the analysis of 59 patients' DNAs harbouring SNVs, indels or large genomic rearrangements of BRCA1 or BRCA2. We also conducted a blind study in 168 patients comparing NGS versus Sanger sequencing or MLPA analyses of BRCA1 and BRCA2. All mutations detected by conventional procedures were detected by NGS. We then screened, using three different versions of the capture set, a large series of 708 consecutive patients. We detected in these patients 69 germline deleterious alterations within BRCA1 and BRCA2, and 4 TP53 mutations in 468 patients also tested for this gene. We also found 36 variations inducing either a premature codon stop or a splicing defect among other genes: 5/708 in CHEK2, 3/708 in RAD51C, 1/708 in RAD50, 7/708 in PALB2, 3/708 in MRE11A, 5/708 in ATM, 3/708 in NBS1, 1/708 in CDH1, 3/468 in MSH2, 2/468 in PMS2, 1/708 in BARD1, 1/468 in PMS1 and 1/468 in MLH3. These results demonstrate the efficiency of NGS in performing molecular diagnosis of HBOC. Detection of mutations within other genes than BRCA1 and BRCA2 highlights the genetic heterogeneity of HBOC. In BRCA1 and BRCA2 mutation carriers, the cumulative risk of breast cancer at 70 years has been estimated to 65 and 45%, respectively, and the risk of ovarian cancer to 39 and 10%, respectively. 3 The identification of a deleterious BRCA1/BRCA2 mutation within a family is crucial for the medical follow-up, as mutation carriers should be offered annual MRI or, alternatively, prophylactic mastectomy and prophylactic salpingooophorectomy. Furthermore, in a breast cancer patient, the detection of a germline BRCA1 or BRCA2 mutation may have important therapeutic consequences: complete mastectomy instead of partial mastectomy and, in the future, the prescription of specific targeted therapies, such as PARP inhibitors. 4,5 Considering the medical consequences of the identification of a germline BRCA1 or BRCA2 mutation and the frequency of mutation carriers, which has

The island of Martinique appears to have a low to medium prevalence of MS. MS was almost unknown in FAC in Martinique until the late 1970s. The apparent recent increase may be explained by improved recognition of patients, increased availability of MRI for diagnosis, increased disease awareness among physicians, increased survival of MS patients, or an actual increase in disease frequency.

No abstract

The emergence of multiple sclerosis in island societies has been investigated only in a few Caucasian populations living in temperate regions. The effect of human migration on the risk of developing this disease is still an open question because of possible genetic selection. We conducted an epidemiological study of the multiple sclerosis population in the French West Indies (Martinique and Guadeloupe), a population which includes large numbers of West Indians who have returned after emigrating to metropolitan France. Standardized incidence ratios (SIRs) for multiple sclerosis among migrants were calculated and their genetic characteristics were compared to those of non-migrants. The crude prevalence of multiple sclerosis was 14.8/10(5) on December 31, 1999 (95% CI: 11.9-17.7); and its crude mean annual incidence for the period July 1, 1999 to June 30, 2002 was 1.4/10(5) (95% CI: 1.0-1.8), confirming its emergence in the French West Indies. Recurrent neuromyelitis optica, which is virtually the only form of multiple sclerosis in black African populations in tropical regions, represented not >17.8% of these cases. During the 1,440,000 person-years of follow-up, 33 incidence cases were identified in migrants. Since the number of expected cases was 19.3, the overall SIR was 1.71 (95% CI: 1.19-2.38; P < 0.01) among migrants. The increase in the SIR was more marked if the stay was made before the age of 15 years (4.05, 95% CI: 2.17-6.83; P < 0.0001). European ancestry in the two migrating and non-migrating populations was similar. Martinique, which has a higher rate of return migration, has a higher prevalence of multiple sclerosis (21.0/10(5) versus 8.5/10(5)) and a higher incidence (2.0/10(5) versus 0.7/10(5)) than Guadeloupe. The emergence of the disease in the French West Indies is of environmental rather than genetic origin. It may be explained either through the introduction by migrants of precipitating environmental factors that operate in a critical way before the age of 15 years, and/or by the recent disappearance from the French West Indies of protective environmental factors acting before this age.