Journal of Neurology

, Volume 258, Issue 1, pp 56–67

Molecular diagnosis of known recessive ataxias by homozygosity mapping with SNP arrays

  • D. H’mida-Ben Brahim
  • A. M’zahem
  • M. Assoum
  • Y. Bouhlal
  • F. Fattori
  • M. Anheim
  • L. Ali-Pacha
  • F. Ferrat
  • M. Chaouch
  • C. Lagier-Tourenne
  • N. Drouot
  • C. Thibaut
  • T. Benhassine
  • Y. Sifi
  • D. Stoppa-Lyonnet
  • K. N’Guyen
  • J. Poujet
  • A. Hamri
  • F. Hentati
  • R. Amouri
  • F. M. Santorelli
  • M. Tazir
  • M. Koenig
Original Communication

DOI: 10.1007/s00415-010-5682-5

Cite this article as:
H’mida-Ben Brahim, D., M’zahem, A., Assoum, M. et al. J Neurol (2011) 258: 56. doi:10.1007/s00415-010-5682-5
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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.

Keywords

Recessive ataxiaHomozygosity mappingSNP microarrays

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • D. H’mida-Ben Brahim
    • 1
    • 2
    • 3
  • A. M’zahem
    • 4
  • M. Assoum
    • 1
    • 2
  • Y. Bouhlal
    • 5
  • F. Fattori
    • 6
  • M. Anheim
    • 1
    • 2
    • 7
  • L. Ali-Pacha
    • 8
  • F. Ferrat
    • 9
  • M. Chaouch
    • 9
  • C. Lagier-Tourenne
    • 1
    • 2
  • N. Drouot
    • 1
    • 2
  • C. Thibaut
    • 1
    • 2
  • T. Benhassine
    • 10
  • Y. Sifi
    • 4
  • D. Stoppa-Lyonnet
    • 11
    • 12
  • K. N’Guyen
    • 13
  • J. Poujet
    • 13
  • A. Hamri
    • 4
  • F. Hentati
    • 5
  • R. Amouri
    • 5
  • F. M. Santorelli
    • 6
  • M. Tazir
    • 8
  • M. Koenig
    • 1
    • 2
  1. 1.Institut de Génétique et de Biologie Moléculaire et CellulaireCNRS/INSERM/Université de StrasbourgIllkirchFrance
  2. 2.Hôpitaux Universitaires de StrasbourgStrasbourgFrance
  3. 3.Laboratoire de Cytogénétique, Génétique Moléculaire et Biologie de la Reproduction HumainesCHU Farhat HACHEDSousseTunisia
  4. 4.Centre Hospitalo-Universitaire Ben BadisConstantineAlgeria
  5. 5.Institut de NeurologieTunisTunisia
  6. 6.Molecular Medicine and Neurosciences IRCCS Bambino Gesù HospitalRomeItaly
  7. 7.Service de NeurologieHôpitaux Universitaires de StrasbourgStrasbourgFrance
  8. 8.Service de NeurologieCentre Hospitalo-Universitaire MustaphaAlgerAlgeria
  9. 9.Service de NeurologieEtablissement Hospitalier Spécialisé de Ben AknounAlgerAlgeria
  10. 10.Institut PasteurAlgerAlgeria
  11. 11.Institut CurieService de GénétiqueParisFrance
  12. 12.Université Paris DescartesParisFrance
  13. 13.Hôpitaux Universitaires de MarseilleMarseilleFrance