Format

Send to

Choose Destination
Eur J Hum Genet. 2017 Apr;25(4):423-431. doi: 10.1038/ejhg.2016.204. Epub 2017 Feb 8.

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

Author information

1
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
2
Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.
3
Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.
4
Université de Strasbourg, Illkirch, France.
5
EA 4271 GAD « Génétique des Anomalies du Développement » and FHU TRANSLAD, CHU Dijon, Université de Bourgogne, Dijon, France.
6
Centre de Génétique et Centre de Référence Maladies Rares 'Anomalies du Développement, CHU Dijon, Dijon, France.
7
Service de Génétique et Centre de Référence Anomalies du Développement-Ouest, CHU de Poitiers; EA3808, Université de Poitiers, Poitiers, France.
8
Centre de Référence Anomalies du Développement, Service de génétique, Hospices Civils de Lyon et INSERM U1028, CNRS UMR5292, GENDEV Team, Centre de Recherche en Neurosciences de Lyon, Lyon, France.
9
Service de neuropédiatrie, CHU Angoulême, Angoulême, France.
10
Reference Center for Fragile X and Rare Intellectual Disabilities, Lyon, France.
11
Laboratoire de diagnostic génétique, Institut de Génétique Médicale d'Alsace, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
12
Laboratoire de génétique moléculaire et de Cytogénétique, Plateau Technique de Biologie, CHU Dijon, Dijon,France.
13
Laboratoire de Génétique Médicale, Institut de Génétique Médicale d'Alsace, INSERM U1112, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.
14
Service de Génétique médicale Institut de Génétique Médicale d'Alsace, Hôpitaux Universitaires de Strasbourg, France.
15
Service de Psychiatrie Générale et Addictologie, CHU, Dijon, Strasbourg,France.
16
Chaire de Génétique Humaine, Collège de France, Illkirch, France.
17
University of Strasbourg Institute for Advanced studies, Strasbourg, France.

Abstract

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.

PMID:
28176767
PMCID:
PMC5386424
DOI:
10.1038/ejhg.2016.204
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center