Identifying the disease gene for a new locus of congenital myasthenic syndrome

Abstract

AIMS OF STUDY: Currently, 17 disease genes of congenital myasthenic syndromes (CMS) have been identified. Here, we aim to determine the molecular basis of CMS in a consanguineous family with limb girdle type of CMS by microarray analysis. METHODS: DNA samples from two affected siblings (P1, P2) and unaffected father, mother and sisters (S1 and S2) will be analyzed using high-density single-nucleotide polymorphism (SNP) microarray (Affymetrix SNP 6.0). RESULTS: We determined a 21 MB absence of heterozygosity (AOH) region on chromosome 6q15-21 with high degree of allele sharing between P1 and P2. Intriguingly, another AOH region was found on chromosome 11p in all children (P1, P2, S1 and S2). DISCUSSIONS: RAPSN is the only disease gene of CMS located in the AOH region on chromosome 11p. We hypothesized all P1, P2, S1 and S2 may harbor the same homozygous disease-causing mutation in RAPSN gene. This mutation will be confirmed by Sanger sequencing. Furthermore, the disease phenotype in our patients may be determined by a novel disease-modifying gene located in the AOH region on chromosome 6q15-21. Thus, RAPSN-associated CMS is only manifested in P1 and P2 but not in S1 and S2. We will identify this novel gene by using whole exome sequencing.