Intragenic FMR1 disease-causing variants: a significant mutational mechanism leading to Fragile-X syndrome.
Angélique QuartierHélène PoquetBrigitte Gilbert-DussardierMassimiliano RossiAnne-Sophie CasteleynVincent des PortesClaire FegerElsa NourissonPaul KuentzClaire RedinJulien ThevenonAnne-Laure Mosca-BoidronPatrick CallierJean MullerGaetan LescaFrédéric HuetVéronique GeoffroySalima El ChehadehMatthieu JungBenoit TrojakStéphanie Le GrasDaphné LehalleBernard JostStéphanie MauryAlice MasurelPatrick EderyChristel Thauvin-RobinetBénédicte GérardJean-Louis MandelLaurence FaivreAmélie PitonPublished in: European journal of human genetics : EJHG (2017)
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.
Keyphrases
- patient reported outcomes
- copy number
- intellectual disability
- poor prognosis
- autism spectrum disorder
- newly diagnosed
- healthcare
- genome wide
- end stage renal disease
- ejection fraction
- high resolution
- gene expression
- long non coding rna
- mass spectrometry
- early onset
- high throughput
- binding protein
- amyotrophic lateral sclerosis
- prognostic factors
- high density