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Targeted Next-Generation Sequencing of a 12.5 Mb Homozygous Region Reveals ANO10 Mutations in Patients with Autosomal-Recessive Cerebellar Ataxia

Lookup NU author(s): Professor Hanns Lochmuller, Professor Joris VeltmanORCiD


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Autosomal-recessive cerebellar ataxias comprise a clinically and genetically heterogeneous group of neurodegenerative disorders. In contrast to their dominant counterparts, unraveling the molecular background of these ataxias has proven to be more complicated and the currently known mutations provide incomplete coverage for genotyping of patients. By combining SNP array-based linkage analysis and targeted resequencing of relevant sequences in the linkage interval with the use of next-generation sequencing technology, we identified a mutation in a gene and have shown its association with autosomal-recessive cerebellar ataxia. In a Dutch consanguineous family with three affected siblings a homozygous 12.5 Mb region on chromosome 3 was targeted by array-based sequence capture. Prioritization of all detected sequence variants led to four candidate genes, one of which contained a variant with a high base pair conservation score (phyloP score: 5.26). This variant was a leucine-to-arginine substitution in the DUF 590 domain of a 16K transmembrane protein, a putative calcium-activated chloride channel encoded by anoctamin 10 (ANO10). The analysis of ANO10 by Sanger sequencing revealed three additional mutations: a homozygous mutation (c.1150_1151del [p.Leu384fs]) in a Serbian family and a compound-heterozygous splice-site mutation (c.1476+1G>T) and a frameshift mutation (c.1604del [p.Leu535X]) in a French family. This illustrates the power of using initial homozygosity mapping with next-generation sequencing technology to identify genes involved in autosomal-recessive diseases. Moreover, identifying a putative calcium-dependent chloride channel involved in cerebellar ataxia adds another pathway to the list of pathophysiological mechanisms that may cause cerebellar ataxia.

Publication metadata

Author(s): Vermeer S, Hoischen A, Meijer RPP, Gilissen C, Neveling K, Wieskamp N, de Brouwer A, Koenig M, Anheim M, Assoum M, Drouot N, Todorovic S, Milic-Rasic V, Lochmuller H, Stevanin G, Goizet C, David A, Durr A, Brice A, Kremer B, van de Warrenburg BPC, Schijvenaars MMVAP, Heister A, Kwint M, Arts P, van der Wijst J, Veltman J, Kamsteeg EJ, Scheffer H, Knoers N

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 2010

Volume: 87

Issue: 6

Pages: 813-819

Print publication date: 18/11/2010

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press


DOI: 10.1016/j.ajhg.2010.10.015


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Funder referenceFunder name
Verum Foundation
French National Agency for Research
223143European Community
917-66-36Netherlands Organization of Health Research and Development
ANR-09-MNPS-001-01Agence Nationale pour la Recherche-Maladies Neurologiques et Psychiatriques
911-08-025Netherlands Organization of Health Research and Development
FP7/2007-2013European Community
ZonMW RM000085Netherlands Organization of Health Research and Development