POSTER ABSTRACTS / RESUMOS DE POSTERS

 

P-12

Fragile X syndrome mosaic cases presenting normal-sized alleles: how many are we missing?

 

 

Nuno Maia*^1,2; Isabel Marques*^1,2; Rosário Santos^1,2,3; Paula Jorge^1,2

*Equal contribution
¹Unidade de Genética Molecular, Centro de Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar do Porto, Porto
²Unidade Multidisciplinar de Investigação Biomédica (UMIB), Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto
³UCIBIO/REQUIMTE, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto

E-mail: isabel.marques@chporto.min-saude.pt

 

 

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. It is caused by an expansion of a CGG repeat in the 5’UTR region of the FMR1 gene that expands to over 200 triplets. In typical FXS cases, silencing of the FMR1 gene due to methylation of its promoter precludes protein expression. Loss of the FMR1 protein leads to the physical, neurocognitive and behavioural FXS features. Somatic mosaics in the FMR1 locus are uncommon and can be due either to the presence of alleles with various CGG repeat sizes or epigenetic differences in the extent of methylation. Mosaicism for more than two alleles is a particularly rare finding, although it has been previously described. These phenomena hamper prediction of the disease prognosis.

Herein, we report four cases of unrelated males with a phenotype compatible with FXS who show atypical mosaic patterns for CGG repeat number; three are mosaic for a full mutation/normal allele and the fourth for a full mutation/ premutation/normal allele. In all cases, the mothers were carriers of a premutation. A methylation-based PCR methodology enabled the characterization of these four cases and respective maternal alleles that led us to propose a hypothesis for the origin of these normal sized alleles in mosaic cases. According to our experience methylation mosaics in the FMR1 locus are not uncommon, particularly premutation/full mutation. On the other hand, normal/mutated size-mosaics are either very rare or are missed in routine PCR based methodologies. In light of the implications for FXS diagnosis, we propose that complementary technical approaches be used in cases with a highly suggestive phenotype.