title: Founder mutation for α-sarcoglycan-LGMD2D in a Magdalen Islands Acadian cluster.
abstract: BACKGROUND
  We have recruited a group of four living and reviewed the records of six deceased distantly related French-Canadians of Acadian descent affected by a childhood-onset form of recessive limb-girdle muscular dystrophy (LGMD). All cases originate from the small archipelago of the Magdalen Islands (population: 13,000) isolated in the Gulf of St-Lawrence.
  
  
  METHODS
  Based on the likely sharing of the same founder mutation we completed a 319K SNPs genome-wide scan to identify the disease locus and then screen candidate genes in this region.
  
  
  RESULTS
  All patients had normal initial motor milestones. They presented with limb girdle weakness at the average age of seven years (5-11). Progressive weakness led to loss of ambulation at a wide range of ages (10-39). Patients also developed macroglossia, large calves and mild to moderate contractures, hyperlordosis and decreased pulmonary function. Creatine kinase levels were elevated (1,800-10,000 U/L) in the first decades, but decreased with progression of disease. Homozygosity mapping uncovered a shared chromosomal region of 6.33Mb. The alpha sarcoglycan (SGCA) gene, mutated in LGMD2D, lay in this candidate interval. Sequencing of all SGCA exons uncovered a shared homozygous missense mutation (c. 229C>T, p.R77C), the most common SGCA mutation internationally reported. Using demographic data, we estimated a high carrier rate of 1/22.
  
  
  CONCLUSIONS
  The p.R77C mutation has also been observed in many populations, including in France and Spain (Basques). This corresponds to the first reported recessive founder disease for the Magdalen Islands, an archipelago settled in the XIXth century, largely by Acadian immigrants.
authors.affiliation: Laboratoire de neurogénétique de la motricité, Centre d'excellence en Neuromique de l'Université de Montréal, CRCHUM.
authors.forename: M
authors.initials: M
authors.lastname: Tétreault
authors.forename: M
authors.initials: M
authors.lastname: Srour
authors.forename: J
authors.initials: J
authors.lastname: Allyson
authors.forename: I
authors.initials: I
authors.lastname: Thiffault
authors.forename: L
authors.initials: L
authors.lastname: Loisel
authors.forename: Y
authors.initials: Y
authors.lastname: Robitaille
authors.forename: J P
authors.initials: JP
authors.lastname: Bouchard
authors.forename: B
authors.initials: B
authors.lastname: Brais
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002170:Canada / Q000453:epidemiology / Q000208:ethnology; D015331:Cohort Studies; D003402:Creatine Kinase / Q000378:metabolism; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D005602:France / Q000208:ethnology; D005787:Gene Frequency; D023281:Genomics / Q000379:methods; D005838:Genotype; D006801:Humans; D008141:Lordosis / Q000209:etiology; D008171:Lung Diseases / Q000209:etiology; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000473:pathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000150:complications / Q000208:ethnology* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D049031:Sarcoglycans / Q000235:genetics*; D013030:Spain / Q000208:ethnology
chemical_list: D049031:Sarcoglycans; D003402:Creatine Kinase