Study of FRAXE-MR in intellectually disabled individuals referred for Fragile-X Syndrome testing in Portugal

Jorge, Paula; Marques, Isabel; Gonçalves, Rui; Gonçalves-Rocha, Miguel; Santos, Rosário

http://hdl.handle.net/10400.18/1199

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Authors

Jorge, Paula

Marques, Isabel

Gonçalves, Rui

Gonçalves-Rocha, Miguel

Santos, Rosário

Abstract(s)

Among the genetic causes involved in X-linked intellectual disability (XLID), pathogenic variations in FMR1 (Fragile Mental Retardation 1), AFF2 (AF4/ FMR2 family member 2) and ARX (Aristaless Related Homeobox) genes emerge as main causes. FMR1 and AFF2 genes contain (polymorphic repetitive regions) a repeat polymorphism which is susceptible to suffer dynamic mutation, a process that may induce pathogenic expansions. FRAXEassociated mental retardation (FRAXE-MR) is mainly a non-syndromic form of XLID and is due to AFF2 gene silencing as a consequence of 5’UTR-CCG expansion or gene mutations. A CCG triplet number up to 30 repeats is consider normal, while full expansion (>200 repeats) and hypermethylation of CCG cluster results in FRAXE-MR. AFF2 variants are not frequently sought. An implementation of a cost-effective strategy (co-amplification with other ID genes) represents an improvement in molecular diagnosis with consequent gains in clinical genetic diagnosis and counseling. Herein we present results of AFF2 molecular analysis in a subpopulation of 5000 intellectually-disabled individuals with primary referral for FRAXA screening, by a novel multiplex-PCR strategy. This approach accurately detected normal to pre-mutated alleles. A pre-mutated allele with 68 CCG was identified and further characterized by Southern blot analysis in order to exclude methylation and/or repeat number mosaics, as well as PCR failure. Possible phenotype-genotype correlations based on the clinical data of one previously diagnosed family with AFF2 full expansion, the newly characterized pre-mutation carrier and one case with a new variant of the AFF2 gene will be investigated and presented.

Description

Abstrat publicado em: European Journal of Human Genetics jun 2012;20(Suppl1):308 (P12.097). Disponível em: https://www.eshg.org/fileadmin/www.eshg.org/conferences/2012/ESHG2012Abstracts.pdf

Keywords

Doenças Genéticas FRAXE Mental Retardation X-linked Intellectual Disability (XLID) Dynamic Mutations AFF2 gene (AF4/FMR2 family member 2) Fragile-X Syndrome