Abstract
The diagnosis of rare inherited diseases is becoming more and more complex as an increasing number of clinical conditions appear to be genetically heterogeneous. Multigenic inheritance also applies to the autosomal recessive progressive cerebellar ataxias (ARCAs), for which 14 genes have been identified and more are expected to be discovered. We used homozygosity mapping as a guide for identification of the defective locus in patients with ARCA born from consanguineous parents. Patients from 97 families were analyzed with GeneChip Mapping 10K or 50K SNP Affymetrix microarrays. We identified six families homozygous for regions containing the autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) gene, two families homozygous for the ataxia-telangiectasia gene (ATM), two families homozygous for the ataxia with oculomotor apraxia type 1 (AOA1) gene, and one family homozygous for the AOA type 2 (AOA2) gene. Upon direct gene testing, we were able to identify a disease-related mutation in all families but one of the two kindred homozygous at the ATM locus. Although linkage analyses pointed to a single locus on chromosome 11q22.1-q23.1 for this family, clinical features, normal levels of serum alpha-foetoprotein as well as absence of mutations in the ATM gene rather suggest the existence of an additional ARCA-related gene in that interval. While the use of homozygosity mapping was very effective at pointing to the correct gene, it also suggests that the majority of patients harbor mutations either in the genes of the rare forms of ARCA or in genes yet to be identified.
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Acknowledgments
We wish to thank Catherine Dubois d’Enghien for ATM gene sequencing and Mustafa A. Salih for sharing material and information on the families from Saudi Arabia. This study was financially supported by funds from the Institut National de la Santé et de la Recherche Scientifique (INSERM), the Centre National de la Recherche Scientifique (CNRS), and the Agence Nationale pour la Recherche-Maladies Rares (ANR-05-MRAR-013-01) to M.K., and the E-Rare EUROSPA network (to F.M.S.). D.H–B.B. was supported by the French association “Connaître les Syndromes Cérébelleux”; M.A. is supported by a BDI fellowship from CNRS; F.F. is a fellow of the Roma Tre University-IRCCS Bambino Gesù Hospital joint PhD programme.
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H’mida-Ben Brahim, D., M’zahem, A., Assoum, M. et al. Molecular diagnosis of known recessive ataxias by homozygosity mapping with SNP arrays. J Neurol 258, 56–67 (2011). https://doi.org/10.1007/s00415-010-5682-5
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DOI: https://doi.org/10.1007/s00415-010-5682-5