Targeted next-generation sequencing of a 12.5 Mb homozygous region reveals ANO10 mutations in patients with autosomal-recessive cerebellar ataxia.

Sascha Vermeer, Alexander Hoischen, Rowdy P.P. Meijer, Christian Gilissen, Kornelia Neveling, Nienke Wieskamp, Arjan de Brouwer, Michel Koenig, Mathieu Anheim, Mirna Assoum, Nathalie Drouot, Slobodanka Todorovic, Vedrana Milic-Rasic, Hanns Lochmüller, Giovanni Stevanin, Cyril Goizet, Albert David, Alexandra Durr, Alexis Brice, Berry Kremer, Bart P.C. van de Warrenburg, Mascha M.V.A.P. Schijvenaars, Angelien Heister, Michael Kwint, Peer Arts, Jenny van der Wijst, Joris Veltman, Erik-Jan Kamsteeg, Hans Scheffer, Nine Knoers
The American Journal of Human Genetics. 2010-12-01; 87(6): 813-819
DOI: 10.1016/j.ajhg.2010.10.015

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1. Am J Hum Genet. 2010 Dec 10;87(6):813-9. doi: 10.1016/j.ajhg.2010.10.015. Epub
2010 Nov 18.

Targeted next-generation sequencing of a 12.5 Mb homozygous region reveals ANO10
mutations in patients with autosomal-recessive cerebellar ataxia.

Vermeer S(1), Hoischen A, Meijer RP, Gilissen C, Neveling K, Wieskamp N, de
Brouwer A, Koenig M, Anheim M, Assoum M, Drouot N, Todorovic S, Milic-Rasic V,
Lochmüller H, Stevanin G, Goizet C, David A, Durr A, Brice A, Kremer B, van de
Warrenburg BP, Schijvenaars MM, Heister A, Kwint M, Arts P, van der Wijst J,
Veltman J, Kamsteeg EJ, Scheffer H, Knoers N.

Author information:
(1)Department of Human Genetics, Radboud University Nijmegen Medical Centre, The

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.

Copyright © 2010 The American Society of Human Genetics. Published by Elsevier
Inc. All rights reserved.

DOI: 10.1016/j.ajhg.2010.10.015
PMCID: PMC2997370
PMID: 21092923 [Indexed for MEDLINE]

Auteurs Bordeaux Neurocampus