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Clinical Stringency Greatly Improves Mutation Detection in Rett Syndrome

Published online by Cambridge University Press:  02 December 2014

Julie Gauthier ,
Giovana de Amorim ,
Gevork N. Mnatzakanian ,
Carol Saunders ,
John B. Vincent ,
Sylvie Toupin ,
David Kauffman ,
Judith St-Onge ,
Sandra Laurent  and
Patrick M. Macleod
...Show all authors
Julie Gauthier
Affiliation:
Department of Biology, McGill University, Montreal, Quebec, Canada Centre Hospitalier de l’Université de Montréal Research Centre, Montreal, Quebec, Canada
Giovana de Amorim
Affiliation:
Department of Biology, University of Victoria, Vancouver, British Columbia, Canada
Gevork N. Mnatzakanian
Affiliation:
Program in Genetics and Genomic Biology, Hospital for Sick Children, Toronto, Ontario, Canada
Carol Saunders
Affiliation:
Clinical Molecular Genetics and Molecular Diagnostics Laboratory, Children’s Mercy Hospitals and Clinics, Kansas City, Missouri, USA
John B. Vincent
Affiliation:
Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
Sylvie Toupin
Affiliation:
Centre Hospitalier de l’Université de Montréal Research Centre, Montreal, Quebec, Canada
David Kauffman
Affiliation:
Centre Hospitalier de l’Université de Montréal Research Centre, Montreal, Quebec, Canada
Judith St-Onge
Affiliation:
Centre Hospitalier de l’Université de Montréal Research Centre, Montreal, Quebec, Canada
Sandra Laurent
Affiliation:
Centre Hospitalier de l’Université de Montréal Research Centre, Montreal, Quebec, Canada
Patrick M. Macleod
Affiliation:
Division of Medical Genetics, Victoria General Hospital, Victoria, British Columbia, Canada
Berge A. Minassian
Affiliation:
Program in Genetics and Genomic Biology, Hospital for Sick Children, Toronto, Ontario, Canada
Guy A. Rouleau*
Affiliation:
Centre Hospitalier de l’Université de Montréal Research Centre, Montreal, Quebec, Canada Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada
*
Research Centre-CHUM, 1560 Sherbrooke Street East, Room Y-3633, Montreal, Quebec, H2L 4M1, Canada
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Abstract:

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Background:

Rett syndrome (RTT) is a severe neurodevelopmental disorder of girls, caused by mutations in the X-linked MECP2 gene. Worldwide recognition of the RTT clinical phenotype in the early 1980's allowed many cases to be diagnosed, and established RTT as one of the most common mental retardation syndromes in females. The years since then led to a refinement of the phenotype and the recent elaboration of Revised Diagnostic Criteria (RDC). Here, we study the impact of the presence versus the absence of the use of diagnostic criteria from the RDC to make a diagnosis of RTT on MECP2 mutation detection in Canadian patients diagnosed and suspected of having RTT.

Methods:

Using dHPLC followed by sequencing in all exons of the MECP2 gene, we compared mutation detection in a historic cohort of 35 patients diagnosed with RTT without the use of specific diagnostic criteria to a separate more recent group of 101 patients included on the basis of strict fulfillment of the RDC.

Results:

The MECP2 mutation detection rate was much higher in subjects diagnosed using a strict adherence to the RDC (20% vs. 72%).

Conclusions:

These results suggest that clinical diagnostic procedures significantly influence the rate of mutation detection in RTT, and more generally emphasize the importance of diagnostic tools in the assessment of neurobehavioral syndromes.

Résumé:

RÉSUMÉ:Introduction:

Le syndrome de Rett (RTT) est une maladie neurodéveloppementale sévère observée chez les filles et causée par des mutations du gène MECP2 situé sur le chromosome X. L’identification à l’échelle mondiale du phénotype clinique du RTT au début des années 1980 a permis de diagnostiquer de nombreux cas et a démontré que le RTT est un des syndromes de retard mental les plus fréquents chez les filles. Depuis, la description du phénotype a été raffinée et des critères diagnostiques révisés (CDR) ont récemment été formulés. Nous avons étudié l’impact sur la détection de mutations du gène MECP2 de l’utilisation ou de la non-utilisation de ces critères diagnostiques pour poser le diagnostic de RTT chez des patientes diagnostiquées ou soupçonnées d’être porteuses du RTT.

Méthodes:

Au moyen de la chromatographie liquide à haute pression en condition dénaturante suivie du séquençage de tous les exons du gène MECP2, nous avons comparé la détection de mutations dans une cohorte historique de 35 patientes porteuses d’un diagnostic de RTT, fait sans l’aide de critères diagnostiques spécifiques, à un groupe de 101 patientes dont le diagnostic avait été posé sur la base des CDR.

Résultats:

Le taux de détection de mutations du gène MECP2 était beaucoup plus élevé chez les sujets dont le diagnostic était basé sur une utilisation rigoureuse des CDR (20% vs 72%).

Conclusions:

Ces résultats suggèrent que la démarche utilisée pour poser le diagnostic clinique influence le taux de détection de mutations dans le RTT et, de façon plus générale, souligne l’importance des outils diagnostiques dans l’évaluation des syndromes neurocomportementaux.

Type
Original Article
Information
Canadian Journal of Neurological Sciences , Volume 32 , Issue 3 , August 2005 , pp. 321 - 326
Copyright
Copyright © The Canadian Journal of Neurological 2005

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