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Titre du document / Document title

Screening and instability of FMRl alleles in a prospective sample of 24,449 mother― newborn pairs from the general population

Auteur(s) / Author(s)

LEVESQUE S. (1) ; DOMBROWSKI C. (1) ; MOREL M.-L. (1) ; REHEL R. (1) ; COTE J.-S. (1) ; BUSSIERES J. (1) ; MORGAN K. (2) ; ROUSSEAU F. (1) ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

(1) Unité de Recherche en Génétique Humaine et Moléculaire, Centre de Recherche de I'Hôpital Saint-François d'Assise du CHUQ, The CanGèneTest Research Consortium in Genetic Laboratory Services (www.cangenetest.org) and Département de Biologie, Médicale, Faculté de Médecine, Université Laval, Québec, CANADA
(2) Departments of Human Genetics and Medicine and Research Institute of the McGill, University Health Center, McGill University, Montréal, CANADA

Résumé / Abstract

To study the instability of FMR1 triplet repeats in the general population, we screened a prospective sample of 24,449 anonymized mother-offspring pairs and analyzed transmissions of intermediate-size (45-54 triplets) and premutation-size (55-200 triplets) alleles. We screened all mothers for alleles ≥45 triplets by Southern blot and studied transmission of 545 maternal alleles to their offspring using polymerase chain reaction. Out of 21,411 maternal samples with conclusive results, we identified 250 carriers of at least one intermediate-size allele and 39 carrying a premutation-size allele. Out of a subsample of 430 transmissions of normal-size alleles (< 45 triplets), we observed four (< 1%) unstable transmissions. There were 6/90 intermediate-size unstable alleles (7%) and 11/25 unstable premutation-size alleles (44%). Two mothers transmitted a typical full mutation. The incidence of fragile X syndrome was thus 1/12,225 newborns (upper limit of 95% confidence interval: 1/4638 newborns), but larger in males (1/6209) than females (none detected in over 12,000 newborn females). Intermediate-size alleles were more unstable than normal-size alleles (p = 0.0027), but more stable (about sixfold) than premutation-size alleles (p < 0.0001). Unstable premutation-size alleles harbored the major fragile X haplotype (T50-T42-T62), and this haplotype appeared to be a good predictor of instability in premutations (p = 0.02). Incidence and instability are important to determine the feasibility and cost effectiveness of putative FMR1 screening programs. Carriers of FMR1 alleles of 55+ triplets with no family history of the disease may have a significant risk of expansion to a full mutation in a single generation.

Revue / Journal Title

Clinical genetics    ISSN  0009-9163   CODEN CLGNAY 

Source / Source

2009, vol. 76, no6, pp. 511-523 [13 page(s) (article)] (44 ref.)

Langue / Language

Anglais

Editeur / Publisher

Wiley-Blackwell, Oxford, ROYAUME-UNI  (1970) (Revue)

Mots-clés anglais / English Keywords

Chromosome fragility

;

Human

;

Transmission

;

Incidence

;

Population

;

Newborn animal

;

Newborn

;

Mother

;

Sample

;

Prospective

;

Allele

;

Genetics

;

Instability

;

Screening

;

Medical screening

;

Fragile X syndrome

;

Mots-clés français / French Keywords

Fragilité chromosomique

;

Homme

;

Transmission

;

Incidence

;

Population

;

Animal nouveau né

;

Nouveau né

;

Mère

;

Echantillon

;

Prospective

;

Allèle

;

Génétique

;

Instabilité

;

Criblage

;

Dépistage

;

Syndrome du chromosome X fragile

;

Mots-clés espagnols / Spanish Keywords

Fragilidad cromosómica

;

Hombre

;

Transmisión

;

Incidencia

;

Población

;

Animal recién nacido

;

Recién nacido

;

Madre

;

Muestra

;

Prospectiva

;

Alelo

;

Genética

;

Inestabilidad

;

Cernido

;

Descubrimiento

;

X frágil síndrome

;

Mots-clés d'auteur / Author Keywords

fragile X syndrome

;

incidence

;

instability

;

population

;

screening

;

transmission

;

Localisation / Location

INIST-CNRS, Cote INIST : 15185, 35400017163776.0050

Nº notice refdoc (ud4) : 22162616



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