The online version of this article (doi:10.1186/1866-1955-6-27) contains supplementary material, which is available to authorized users.
RH has received funding for treatment trials in fragile X syndrome or autism from Novartis (Basel, Switzerland), Roche (Basel, Switzerland), Seaside Therapeutics (Cambridge, MA, USA), Curemark (Rye, NY, USA), Forest Pharmaceuticals (New York City, NY, USA) and the National Fragile X Foundation (Walnut Creek, CA, USA). RH is also on the fragile X advisory boards for Novartis and Genentech/Roche. DH received support from Novartis, Roche and Seaside Therapeutics for clinical trials in fragile X syndrome. FT received research support from Roche. The Kennedy Krieger Institute (Baltimore, MD, USA) has received funding for treatment trials in fragile X syndrome from Novartis. EEE is on the scientific advisory boards for Pacific Biosciences, Inc (Menlo Park, CA, USA), SynapDx Corporation (Southborough, MA, USA) and DNAnexus, Inc (Mountain View, CA, USA). RL and MD have no conflicts of interest to disclose.
RL carried out the analysis of all the clinical and molecular data and participated to the writing of the manuscript. He also participated in obtaining clinical data. RH collected all clinical data and participated in the interpretation of all results and the analysis as well as participated to the writing of the manuscript. MD carried out the molecular CNVs studies and their analysis and participated to the writing of the manuscript. DB provided clinical data and and participated to the writing of the manuscript. EE designed the study, carried out the molecular CNVs studies and their analysis and participated to the writing of the manuscript. FT designed the study, carried out the molecular studies and their analysis. She overlook all the data analysis and interpretation as well as participated to the writing of the manuscript. All authors read and approved the final manuscript.
The FMR1 premutation is defined as having 55 to 200 CGG repeats in the 5′ untranslated region of the fragile X mental retardation 1 gene (FMR1). The clinical involvement has been well characterized for fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI). The behavior/psychiatric and other neurological manifestations remain to be specified as well as the molecular mechanisms that will explain the phenotypic variability observed in individuals with the FMR1 premutation.
Here we describe a small pilot study of copy number variants (CNVs) in 56 participants with a premutation ranging from 55 to 192 repeats. The participants were divided into four different clinical groups for the analysis: those with behavioral problems but no autism spectrum disorder (ASD); those with ASD but without neurological problems; those with ASD and neurological problems including seizures; and those with neurological problems without ASD.
We found 12 rare CNVs (eight duplications and four deletions) in 11 cases (19.6%) that were not found in approximately 8,000 controls. Three of them were at 10q26 and two at Xp22.3, with small areas of overlap. The CNVs were more commonly identified in individuals with neurological involvement and ASD.
The frequencies were not statistically significant across the groups. There were no significant differences in the psychometric and behavior scores among all groups. Further studies are necessary to determine the frequency of second genetic hits in individuals with the FMR1 premutation; however, these preliminary results suggest that genomic studies can be useful in understanding the molecular etiology of clinical involvement in premutation carriers with ASD and neurological involvement.
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- Genomic studies in fragile X premutation carriers
Randi J Hagerman
Dejan B Budimirovic
Evan E Eichler
- BioMed Central
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