Utilize este identificador para referenciar este registo: http://hdl.handle.net/10400.18/1249
Título: Fragile X syndrome: intergenerational allele instability and associated phenotypes in families
Autor: Joana, Loureiro
Marques, Isabel
Santos, Rosário
Seixas, Ana
Martins, Márcia
Vale, José
Sequeiros, Jorge
Silveira, Isabel
Palavras-chave: Doenças Genéticas
Fragile X syndrome
Data: 22-Nov-2012
Resumo: Fragile X syndrome (FXS) is the most common hereditary form of intellectual disability with an estimated frequency of 1/4000 males and 1/8000 females. This disease is caused by a (CGG)n expansion in the 5’UTR of the FMR1 gene, which as a result is methylated and gene silenced. Four classes of alleles can be found based on CGG repeat length: normal (5-44), intermediate (45-54), premutation (55-200) and full mutation (>200). In premutation carriers, both FMR1-related primary ovarian insufficiency (FXPOI) and fragile-X associated tremor/ataxia syndrome (FXTAS) have been described. To gain insights into instability of FMR1 CGG repeats and associated phenotypes, we studied 541 individuals from 128 FXS Portuguese families. DNA samples were genotyped by PCR and Southern blot analysis. Additional clinical evaluation was performed in premutation carriers. Among FXS families, 5.3% intermediate, 29.9% premutation and 26.6% full mutation alleles were found. Normal and intermediate alleles were stable upon transmission. For 115 maternal premutation transmissions, 26 (23%) with alleles ranging 60-98 CGGs remained in premutation size with an average expansion of 17 repeat units, whereas 89 (77%) with alleles ranging from 66-199 CGGs expanded to full mutation. In 44 transmissions of maternal full mutation, the offspring inherited alleles in the full mutation range. For 10 paternal transmissions of premutations, ranging 56-120 CGGs, all daughters inherited a premutation allele, with an average expansion of 7 repeat units. After clinical evaluation of 7 premutation carriers, 1 male with FXTAS and 2 females with FXPOI were identified; however the remaining premutation individuals were not yet examined. In Portuguese FXS families, allele instability upon transmission is in agreement with previous reports. The risk of premutation to full mutation expansion increases with maternal premutation size.
Peer review: yes
URI: http://hdl.handle.net/10400.18/1249
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