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NEUROLOGY 2005;64:1762-1767
© 2005 American Academy of Neurology

Two mutations in the HSN2 gene explain the high prevalence of HSAN2 in French Canadians

K. Roddier, BSc^*, T. Thomas, MD^*, G. Marleau, BSc, A. M. Gagnon, BSc, M. J. Dicaire, BSc, A. St-Denis, MSc, I. Gosselin, BSc, A. M. Sarrazin, MD, A. Larbrisseau, MD, M. Lambert, MD, M. Vanasse, MD, D. Gaudet, MD, PhD, G. A. Rouleau, MD, PhD and B. Brais, MD, PhD

From the Laboratoire de neurogénétique (Drs. Thomas and Brais, K. Roddier, G. Marleau, A.M. Gagnon, M.J. Dicaire, A. St-Denis, and I. Gosselin), Centre de recherche du CHUM, Université de Montréal, Centre Hospitalier Régional de Lanaudière (Dr. Sarrazin), Saint-Charles-Borromée, Département de pédiatrie (Drs. Larbrisseau, Lambert, and Vanasse), Hôpital Sainte-Justine et Université de Montréal, Centre de médecine génique communautaire de l’Université de Montréal (Dr. Gaudet), Centre Hospitalier de la Saguamie, Saguenay, and McGill Health Centre (Dr. Rouleau), McGill University, Montréal, Québec, Canada.

Address correspondence and reprint requests to Dr. B. Brais, Centre de recherche du CHUM, Hôpital Notre-Dame-CHUM, M4211-L3, 1560, rue Sherbrooke est, Montréal, Québec, Canada H2L 4M1; e-mail: Bernard.Brais{at}umontreal.ca

Background: Hereditary sensory and autonomic neuropathy type 2 (HSAN2; MIM 201300) is a rare recessive neuropathy typically diagnosed in the first decade. The 1973 study of a French Canadian family led to the definition of HSAN2.

Objectives: To demonstrate that the apparent higher prevalence of HSAN2 in Quebec is due to the presence of two HSN2 mutations and that carriers of different mutations appear to have a similar phenotype.

Methods: Through attending physicians, the authors recruited French Canadian patients with HSAN2. Exclusion of linkage to the known HSAN loci and linkage to the HSAN2 was performed using standard methods. Sequencing of the HSN2 gene was used to uncover the causal mutations.

Results: A large cluster of HSAN2 patients comprising 16 affected individuals belonging to 13 families was identified. The mode of inheritance is clearly autosomal recessive. All patients originated from southern Quebec, and 75% are from the Lanaudière region. Whereas linkage to the HSAN1, 3, and 4 loci was excluded, linkage to the 12p13.33 HSAN2 locus was confirmed. Sequencing of the HSN2 gene uncovered two French Canadian mutations and a novel nonsense mutation in a patient of Lebanese origin, all predicted to lead to truncations of the HSN2 protein. The comparison of clinical variables between patients with different genotypes does not suggest any difference in phenotype.

Conclusions: Two founder mutations are responsible for the apparently higher prevalence of HSAN2 in French Canadians. Genotype-phenotype correlation does not suggest any significant clinical variability.

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Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the May 24 issue to find the title link for this article.

*These authors have contributed equally to this work.

Supported by the ECOGENE-21 Interdisciplinary CIHR team grant of the Centre de médecine génique communautaire de l’Université de Montréal, the Démogénique and Génétique communautaire axes of the Réseau de médecine génétique appliquée (RMGA) du Fonds de recherche en santé du Québec (FRSQ), and the Association de la Neuropathie sensorielle et autonomique héréditaire de type 2.

Dr. Brais is a chercheur-boursier of the FRSQ.

Received September 3, 2004. Accepted in final form January 25, 2005.

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