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


Fragile-X syndrome (FXS) is a frequent genetic form of intellectual disability (ID). The main recurrent mutagenic mechanism causing FXS is the expansion of a CGG repeat sequence in the 5'-UTR of the FMR1 gene, therefore, routinely tested in ID patients. We report here three FMR1 intragenic pathogenic variants not affecting this sequence, identified using high-throughput sequencing (HTS): a previously reported hemizygous deletion encompassing the last exon of FMR1, too small to be detected by array-CGH and inducing decreased expression of a truncated form of FMRP protein, in three brothers with ID (family 1) and two splice variants in boys with sporadic ID: a de novo variant c.990+1G>A (family 2) and a maternally inherited c.420-8A>G variant (family 3). After clinical reevaluation, the five patients presented features consistent with FXS (mean Hagerman's scores=15). We conducted a systematic review of all rare non-synonymous variants previously reported in FMR1 in ID patients and showed that six of them are convincing pathogenic variants. This study suggests that intragenic FMR1 variants, although much less frequent than CGG expansions, are a significant mutational mechanism leading to FXS and demonstrates the interest of HTS approaches to detect them in ID patients with a negative standard work-up.

DOI: 10.1038/ejhg.2016.204


Citations per Year

332 Citations

Semantic Scholar estimates that this publication has 332 citations based on the available data.

See our FAQ for additional information.

Cite this paper

@article{Quartier2017IntragenicFD, title={Intragenic FMR1 disease-causing variants: a significant mutational mechanism leading to Fragile-X syndrome.}, author={Ang{\'e}lique Quartier and H{\'e}l{\`e}ne Poquet and Brigitte Gilbert-Dussardier and Massimiliano Rossi and Anne-Sophie Casteleyn and V. des Portes and Claire Feger and Elsa Nourisson and Paul Kuentz and Claire E. Redin and Julien Thevenon and Anne-Laure Mosca-Boidron and Patrick Callier and Jean Muller and G. Lesca and Fr{\'e}d{\'e}ric Huet and V{\'e}ronique de Geoffroy and Salima El Chehadeh and Matthieu Jung and Beno{\^i}t Trojak and St{\'e}phanie Le Gras and Daphn{\'e} Lehalle and Bernard Jost and St{\'e}phanie Maury and Alice Masurel and Patrick Edery and Christel Thauvin-Robinet and B{\'e}n{\'e}dicte G{\'e}rard and Jean-Louis Mandel and Laurence Olivier Faivre and Am{\'e}lie Piton}, journal={European journal of human genetics : EJHG}, year={2017}, volume={25 4}, pages={423-431} }