DGH - Dissertações de mestrado
Permanent URI for this collection
Browse
Browsing DGH - Dissertações de mestrado by Subject "[AGG] Interruptions"
Now showing 1 - 1 of 1
Results Per Page
Sort Options
- Molecular Assessment of X-Linked Intellectual Disability: A Gene Cluster Based ApproachPublication . Oliveira, Bárbara; Jorge, Paula; Criado, Maria BegoñaIntellectual disability (ID) is a common form of cognitive impairment, responsible by a significant number of limitations in intellectual function and adaptive behavior. X-linked intellectual disability represents a common cause of monogenic mental retardation affecting mostly males. Among the genetic causes involved, mutations in FMR1, AFF2 and ARX genes emerge as the major causes. FMR1 and AFF2 genes contain polymorphic repetitive regions susceptible to suffer dynamic mutations, a process that may give rise to pathogenic expansions. In ARX gene, the second exon represents a mutational hot spot as holds repetitive regions that codify to alanines. Among the mutations described, variations in polyalanine tracts, namely the c.429_452dup24, are among the most frequent. Aiming the characterization of a population at risk for ID, a multiplex molecular screening was performed regarding mutational hotspots in FMR1, AFF2 and ARX genes in intellectually-disabled individuals and in a control population. A Triplet-primed PCR technique was optimized to evaluate [AGG] interspersion pattern in FMR1 repetitive regions to assess allele stability. Furthermore, ARX exon 2 size variations were characterized by sequencing analysis. Allelic frequencies of FMR1 and AFF2 genes in the Portuguese population are similar to other Caucasian populations. The present work shows that the increase of triplet content in FMR1 gene is independent of variations in AFF2 triplet content (Pearson’s R: ρ >0,05), although, the occurrence of 30 repeat-sized alleles (for FMR1) and 14 repeat-sized alleles (for AFF2) is the most frequent combination (13,4%) (X2: ρ<0,05). FMR1 alleles with the first interruption after nine or ten [CGG] triplets demonstrated to have different origins (X2: ρ <0,05; Pearson’s R: ρ <0,05). A strong correlation among the 29 repeat-sized alleles and the CTC SNP haplotype and between the 30 repeat-sized alleles and the TTT lineage (X2: ρ <0,05) was observed. In ARX analysis the c.429_452dup24 mutation was identified in three individuals from two different families and the polymorphic variant c.441_464del24 in other three patients. Small insertions codifying for alanines were also detected (c.304GCG[11] and c.304GCG[13]) with a pathogenic effect yet to be determined. The importance of studying FMR1 alleles in terms of [AGG] interruption and genetic background is evident for an accurate clinical diagnosis. ARX mutations of known pathogenicity, although few frequent, are a strong indication that this genes should be included in routine screening of ID.