Founder mutation for α-sarcoglycan-LGMD2D in a Magdalen Islands Acadian cluster

Area of Science:

• Genetics
• Neurology
• Rare Diseases

Background:

• Investigated a rare childhood-onset limb-girdle muscular dystrophy (LGMD) in French-Canadians from the Magdalen Islands.
• Studied a cohort of 10 patients (4 living, 6 deceased) with a shared ancestry.

Purpose of the Study:

• Identify the genetic cause of LGMD in this isolated population.
• Determine the disease locus and causative gene through genome-wide analysis.

Main Methods:

• Performed a 319K single nucleotide polymorphism (SNP) genome-wide scan to identify the disease locus.
• Screened candidate genes within the identified region, focusing on the alpha sarcoglycan (SGCA) gene.

Main Results:

• Uncovered a shared homozygous missense mutation (c. 229C>T, p.R77C) in the SGCA gene.
• Observed typical LGMD symptoms including limb girdle weakness, macroglossia, and decreased pulmonary function.
• Estimated a high carrier rate of 1/22 for this specific mutation in the population.

Conclusions:

• Identified the p.R77C mutation in SGCA as the cause of recessive LGMD in the Magdalen Islands.
• This represents the first reported recessive founder disease for the archipelago.
• The mutation is also found in other populations, including France and Spain.