Xq27 FRAXA Locus is a Strong Candidate for Dyslexia: Evidence from a Genome-Wide Scan in French Families

Abstract

Dyslexia is a frequent neurodevelopmental learning disorder. To date, nine susceptibility loci have been identified, one of them being DYX9, located in Xq27. We performed the first French SNP linkage study followed by candidate gene investigation in dyslexia by studying 12 multiplex families (58 subjects) with at least two children affected, according to categorical restrictive criteria for phenotype definition. Significant results emerged on Xq27.3 within DYX9. The maximum multipoint LOD score reached 3,884 between rs12558359 and rs454992. Within this region, seven candidate genes were investigated for mutations in exonic sequences (CXORF1, CXORF51, SLITRK2, FMR1, FMR2, ASFMR1, FMR1NB), all having a role during brain development. We further looked for 5 0 UTR trinucleotide repeats in FMR1 and FMR2 genes. No mutation or polymorphism co-segregating with dyslexia was found. This finding in French families with Dyslexia showed significant linkage on Xq27.3 enclosing FRAXA, and consequently confirmed the DYX9 region as a robust susceptibility locus. We reduced the previously described interval from 6.8 (DXS1227-DXS8091) to 4 Mb also disclosing a higher LOD score.

Molecular Genetics of Dyslexia: An Overview

“…Xq27.3 markers showed suggestive association with dyslexia in the female sub‐sample of a study in an Afrikaner population (Platko et al ., ) and suggestive linkage to a nonsense word spelling phenotype in a general population sample (Bates et al ., ). Finally, a recent study of French dyslexic families also supported the DYX9 locus, with maximal linkage at Xq27.3 (Huc‐Chabrolle et al ., ). The authors proposed that variants affecting FMR1 , a gene implicated in fragile X syndrome (the most common genetic cause of intellectual disability), might be involved, although sequencing of this gene and six other candidates ( CXORF1 , CXORF51 , SLITRK2 , FMR2 , ASFMR1 , and FMR1NB ) failed to identify any mutation or polymorphisms co‐segregating with dyslexia.…”

A case of Bilateral Perisylvian Syndrome with reading disability

“…Variable expression of gene(s) in Xq27.3, where an X-linked pattern of BPS inheritance has been identified (Santos et al, 2008) and where a marker for dyslexia has also been identified (de Kovel et al, 2004; Huc-Chabrolle et al, 2013), appear to contribute to the expression of a dyslexia behavioral profile. Like other genetic markers for dyslexia, however (Raskind et al, 2012), DYX9 linkage to dyslexia has been inconsistent (Fisher et al, 2013).…”

TAR Cloning: Perspectives for Functional Genomics, Biomedicine, and Biotechnology

“…The subsequent analysis of these TAR-isolated fragments excluded the 750-kb genetically unstable region at Xq27 as a candidate locus for prostate malignancy 36 . The polymorphism information accumulated during analysis of this region may be useful for the analysis of other disease-associated loci that were also mapped to Xq27-q28, including the TGCT locus linked to hereditary testicular cancer and the susceptibility loci for dyslexia, autism, and migraine 54, 55. In the future, the accumulated information from individual genomes can help predict the pharmaceutical drug response for each individual and expand the therapeutic window of a treatment.…”

“…36 The polymorphism information accumulated during analysis of this region may be useful for the analysis of other disease-associated loci that were also mapped to Xq27-q28, including the TGCT locus linked to hereditary testicular cancer and the susceptibility loci for dyslexia, autism, and migraine. 54,55 In the future, the accumulated information from individual genomes can help predict the pharmaceutical drug response for each individual and expand the therapeutic window of a treatment. In addition, the uniqueness of the technology will help with the design of diagnostics for genomic disorders caused by chromosomal rearrangements.…”