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. 2014;6(1):27.
doi: 10.1186/1866-1955-6-27. Epub 2014 Jul 30.

Genomic studies in fragile X premutation carriers

Reymundo Lozano  1 , Randi J Hagerman  1 , Michael Duyzend  2 , Dejan B Budimirovic  3 , Evan E Eichler  4 , Flora Tassone  5
Affiliations

Genomic studies in fragile X premutation carriers

Reymundo Lozano et al. J Neurodev Disord. 2014.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: ASD; Autism; FMR1 gene; Neurodevelopmental disorders; Neurological disorders; Premutation; Second hit.

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Figures

Figure 1
Figure 1
Diagram of the distribution of the CNVs among participants in the four groups. ASD, autism spectrum disorder; CNV, copy number variant.
Figure 2
Figure 2
Diagram of the clinical involvement in premutation carriers and potential players. The FMR1 premutation may represent a first hit that in addition to additional second hits may result in the variability of the phenotype. ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; FXPOI, fragile X-associated primary ovarian insufficiency; FXTAS, fragile X-associated tremor/ataxia syndrome.
See this image and copyright information in PMC

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