title: Molecular diagnosis of known recessive ataxias by homozygosity mapping with SNP arrays.
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.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université de Strasbourg, 67404, Illkirch, France. dorrahmida@yahoo.fr
authors.forename: D
authors.initials: D
authors.lastname: H'mida-Ben Brahim
authors.forename: A
authors.initials: A
authors.lastname: M'zahem
authors.forename: M
authors.initials: M
authors.lastname: Assoum
authors.forename: Y
authors.initials: Y
authors.lastname: Bouhlal
authors.forename: F
authors.initials: F
authors.lastname: Fattori
authors.forename: M
authors.initials: M
authors.lastname: Anheim
authors.forename: L
authors.initials: L
authors.lastname: Ali-Pacha
authors.forename: F
authors.initials: F
authors.lastname: Ferrat
authors.forename: M
authors.initials: M
authors.lastname: Chaouch
authors.forename: C
authors.initials: C
authors.lastname: Lagier-Tourenne
authors.forename: N
authors.initials: N
authors.lastname: Drouot
authors.forename: C
authors.initials: C
authors.lastname: Thibaut
authors.forename: T
authors.initials: T
authors.lastname: Benhassine
authors.forename: Y
authors.initials: Y
authors.lastname: Sifi
authors.forename: D
authors.initials: D
authors.lastname: Stoppa-Lyonnet
authors.forename: K
authors.initials: K
authors.lastname: N'Guyen
authors.forename: J
authors.initials: J
authors.lastname: Poujet
authors.forename: A
authors.initials: A
authors.lastname: Hamri
authors.forename: F
authors.initials: F
authors.lastname: Hentati
authors.forename: R
authors.initials: R
authors.lastname: Amouri
authors.forename: F M
authors.initials: FM
authors.lastname: Santorelli
authors.forename: M
authors.initials: M
authors.lastname: Tazir
authors.forename: M
authors.initials: M
authors.lastname: Koenig
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001260:Ataxia Telangiectasia / Q000235:genetics; D002524:Cerebellar Ataxia / Q000175:diagnosis* / Q000235:genetics*; D002648:Child; D002874:Chromosome Mapping; D003241:Consanguinity; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D006360:Heat-Shock Proteins / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D018895:Microsatellite Repeats; D009154:Mutation / Q000235:genetics; D015840:Oculomotor Nerve Diseases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D013132:Spinocerebellar Degenerations / Q000235:genetics; D055815:Young Adult
chemical_list: D006360:Heat-Shock Proteins; C404403:SACS protein, human; D004247:DNA
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