De novo microduplication of the FMR1 gene in a patient with developmental delay, epilepsy and hyperactivity

Abstract

Loss-of-function due to expansion of a CGG repeat located in the 5'UTR of the FMR1 gene is the most frequent cause of fragile X syndrome. Less than 1% of individuals with fragile X syndrome have been reported to have a partial or full deletion or point mutation of the FMR1 gene. However, whether a copy number gain of the FMR1 gene could result in certain clinical phenotypes has not been fully investigated. Here, we report the case of a child who presented with developmental delay starting at 9 months of age, fine motor and speech delay, progressive seizures since 18 months of age and hyperactivity. Molecular workup identified a de novo microduplication in the Xq27.3 region, including the FMR1 gene and the ASFMR1 gene. The expression level of the FMR1 gene in peripheral blood did not differ from that of the controls. In addition, an inherited 363-kb duplication on the chromosome 1q44 region and an inherited deletion of 168 kb on the chromosome 4p15.31 region were detected. It is not clear whether these inherited copy number variations (CNVs) also have a modifying role in the clinical phenotype of this patient.

Intragenic FMR1 disease-causing variants: a significant mutational mechanism leading to Fragile-X syndrome

“…Among all children with developmental delay, the actual diagnostic yield of FXS testing is only 1-2%. 4 CGG-repeat expansion in the FMR1 promoter is the most frequent cause of FXS, but deletions of the entire FMR1 gene [10][11][12] or of the 5′UTR have also been reported in FXS. 9 Rare intragenic non-synonymous variations have also been identified within the FMR1 locus [16][17][18][19][20]22,23,35,41,42 but after reanalysis in the light of new public sequencing data, prediction tools and functional evidence, we showed that only six could be reclassified as convincing.…”

“…8 Around 1-2% of all children with developmental delay are found to have FXS caused by a CGG expansion. 4 However, others disease-causing FMR1 variants have also been reported, including large gene deletions, 5′UTR or exon 1 deletions associated or not with a full FMR1 CGG expansion in the mother, [9][10][11][12][13][14][15] as well as a very small number of single-nucleotide variants (SNVs) in the FMR1 coding regions. Direct sequencing of FMR1 was not frequently carried out, and only a few groups have screened for variants in FMR1 coding regions in clinically relevant cohorts presenting 16,17 or not [18][19][20] alterations of FMRP at the protein level.…”

FMRP binding to a ranked subset of long genes is revealed by coupled CLIP and TRAP in specific neuronal cell types

“…A new mouse model, the conditionally tagged FMRP-AcGFP ("cTAG") mouse, was designed to enable cell-type-specific FMRP CLIP experiments, something not previously possible in vivo. Evidence suggests that the expression levels of FMRP are tightly controlled during development, differentiation, and in response to synaptic activity, and that overexpression in humans [56][57][58][59] and model organisms 60,61 leads to negative phenotypes. Therefore, we chose a knock-in strategy to allow cell-type-specific expression of FMRP-AcGFP without altering the normal levels, splicing or regulated expression of FMRP.…”

“…Human genomic copy number variations reveal that overexpression of FMRP results in intellectual disability [56][57][58][59] , suggesting that the properties of endogenous FMRP expression should not be altered in a model system. To this end we designed a knock-in construct to result in AcGFP tagged-FMRP expression from the endogenous Fmr1 locus in a Cre-dependent manner.…”

“…It cannot be stated enough how important it is to avoid altering the timing or levels of experimentally tagged FMRP. In addition to years of literature in the field attesting to the deleterious effects of both under-and over-expression of FMRP in many system there are multiple reports of human intellectual disability linked to overexpression of FMRP due to genomic copy number variations [56][57][58][59]112 . Moreover, the interactions of RNA binding proteins with their RNA ligands are highly dependent on the relative stoichiometry between all possible binding partners.…”