P.5.8 Why is LGMD2G rare?

Mutations in telethonin gene cause a rare and relatively mild form of limb-girdle muscular dystrophy type 2G. Only few families were described presenting this disease, and they are mainly Brazilians. In Brazil, this form represents less than 5% of all LGMD. In other countries, only isolated sporadic cases were described in China, Moldavia, Australia and Portugal. To date, all ten families identified in Brazil present the same c.157C > T (Q53X) homozygous nonsense mutation. In five families no consanguinity was referred. All patients also share the same haplotype for microsatellite markers near the gene, suggesting a common origin of the mutation. Outside Brazil, different mutations were identified in China, Moldavia and Australian. However, the Portuguese patient described presents the same mutation found in Brazilians. As a great proportion of Brazilian people has Portuguese ancestry, and the Brazilian LGMD2G patients show a predominant European genetic background, we consider that the common mutation arose in Europe and spread through Brazilian population. However, in this case, it would still be expected to find a higher frequency of this disease in Portugal. By sequencing TCAP exon 2, we found that all the patients, including the Portuguese one, are homozygous for the allele A of rs1053651 SNP (the ancestral allele is C). This allele has a frequency of 28% in the European population. Thus, we hypothesize that the mutation may have occurred in this rarer haplotype, which could explain why this form is also rare in Portugal. Therefore, the c.157C > T mutation has a common origin, that implies the occurrence of founder effect, probably in Portugal and is in linkage disequilibrium with the rs1053651 SNP, which is compatible with its low frequency in Europe. Financial support: FAPESP-CEPID, CNPQ-INCT, FINEP, CAPES-COFECUB.