Efficacy of Exome-Targeted Capture Sequencing to Detect Mutations in Known Cerebellar Ataxia Genes.

Marie Coutelier, Monia B. Hammer, Giovanni Stevanin, Marie-Lorraine Monin, Claire-Sophie Davoine, Fanny Mochel, Pierre Labauge, Claire Ewenczyk, Jinhui Ding, J. Raphael Gibbs, Didier Hannequin, Judith Melki, Annick Toutain, Vincent Laugel, Sylvie Forlani, Perrine Charles, Emmanuel Broussolle, Stéphane Thobois, Alexandra Afenjar, Mathieu Anheim, Patrick Calvas, Giovanni Castelnovo, Thomas de Broucker, Marie Vidailhet, Antoine Moulignier, Robert T. Ghnassia, Chantal Tallaksen, Cyril Mignot, Cyril Goizet, Isabelle Le Ber, Elisabeth Ollagnon-Roman, Jean Pouget, Alexis Brice, Andrew Singleton, Alexandra Durr,
JAMA Neurol. 2018-05-01; 75(5): 591
DOI: 10.1001/jamaneurol.2017.5121

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1. JAMA Neurol. 2018 May 1;75(5):591-599. doi: 10.1001/jamaneurol.2017.5121.

Efficacy of Exome-Targeted Capture Sequencing to Detect Mutations in Known
Cerebellar Ataxia Genes.

Coutelier M(1)(2)(3)(4)(5)(6), Hammer MB(7), Stevanin G(1)(2)(3)(4)(6)(8), Monin
ML(8), Davoine CS(1)(2)(3)(4)(6), Mochel F(1)(2)(3)(4)(8), Labauge P(9), Ewenczyk
C(8), Ding J(7), Gibbs JR(7), Hannequin D(10), Melki J(11)(12), Toutain A(13),
Laugel V(14)(15), Forlani S(1)(2)(3)(4), Charles P(8), Broussolle E(16)(17)(18),
Thobois S(16)(17)(18), Afenjar A(19), Anheim M(15)(20)(21), Calvas P(22),
Castelnovo G(23), de Broucker T(24), Vidailhet M(1)(2)(3)(4)(25), Moulignier
A(26), Ghnassia RT(27), Tallaksen C(1)(2)(3)(4)(28), Mignot C(29), Goizet
C(30)(31), Le Ber I(1)(2)(3)(4), Ollagnon-Roman E(32), Pouget J(33), Brice
A(1)(2)(3)(4)(8), Singleton A(7), Durr A(1)(2)(3)(4)(8); Spastic Paraplegia and
Ataxia Network.

Author information:
(1)Institut National de la Santé et de la Recherche Medicale (INSERM) U1127,
Paris, France.
(2)Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR)
7225, Paris, France.
(3)Unité Mixte de Recherche en Santé 1127, Université Pierre et Marie Curie
(Paris 06), Sorbonne Universités, Paris, France.
(4)Institut du Cerveau et de la Moelle Epinière, Paris, France.
(5)Laboratory of Human Molecular Genetics, de Duve Institute, Université
Catholique de Louvain, Brussels, Belgium.
(6)Ecole Pratique des Hautes Etudes, Paris Sciences et Lettres Research
University, Paris, France.
(7)Laboratory of Neurogenetics, National Institute on Aging, National Institutes
of Health, Bethesda, Maryland.
(8)Centre de Référence de Neurogénétique, Hôpital de la Pitié-Salpêtrière,
Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
(9)Service de Neurologie, Hopital Gui de Chauliac, Centre Hospitalier
Universitaire (CHU) de Montpellier, Montpellier, France.
(10)Service de Génétique, Service de Neurologie, INSERM U1079, Rouen University
Hospital, Rouen, France.
(11)UMR 1169, INSERM and University Paris Saclay, Le Kremlin Bicêtre, France.
(12)Medical Genetics Unit, Centre Hospitalier Sud-Francilien, Corbeil Essonnes,
(13)Service de Génétique, Centre Hospitalier Universitaire de Tours, INSERM U930,
Faculté de Médecine, Université François Rabelais, Tours, France.
(14)Service de Pédiatrie 1, Hôpitaux Universitaires de Strasbourg, Strasbourg,
(15)Fédération de Médecine Translationnelle de Strasbourg, Université de
Strasbourg, Strasbourg, France.
(16)Service de Neurologie C, Hôpital Neurologique Pierre-Wertheimer, Hospices
Civils de Lyon, Bron, France.
(17)Centre de Neurosciences Cognitives, Centre National de la Recherche
Scientifique (CNRS)-UMR 5229, Bron, France.
(18)Université de Lyon, Université Claude-Bernard-Lyon I, Villeurbanne, France.
(19)Service de Génétique et Centre de Référence Pour les Malformations et les
Maladies Congénitales du Cervelet, AP-HP, Paris, France.
(20)Département de Neurologie, Hôpital de Hautepierre, CHU de Strasbourg,
Strasbourg, France.
(21)Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM U964,
CNRS-UMR 7104, Université de Strasbourg, Illkirch, France.
(22)Service de Génétique Médicale, CHU de Toulouse, Hôpital Purpan, Toulouse,
(23)Service de Neurologie, CHU Caremeau, Nîmes, France.
(24)Service de Neurologie, Centre Hospitalier de Saint-Denis, Saint-Denis,
(25)Département des Maladies du Système Nerveux, Hôpital de la Pitié-Salpêtrière,
AP-HP, Paris, France.
(26)Service de Neurologie, Fondation Ophtalmologique A. de Rothschild, Paris,
(27)private practice, Chelles, France.
(28)currently affiliated with Department of Neurology, Oslo University Hospital;
and Faculty of Medicine, Oslo University, Oslo, Norway.
(29)Département de Génétique and Centre de Référence Déficiences Intellectuelles
de Causes Rares, Groupe Hospitalier Pitié Salpêtrière, AP-HP, Paris, France.
(30)Laboratoire Maladies Rares, Génétique et Métabolisme, Université de Bordeaux,
Bordeaux, France.
(31)Service de Génétique Médicale, CHU Pellegrin, Bordeaux, France.
(32)Service de Neurogénétique, Hôpital de la Croix-Rousse, Hospices Civils de
Lyon, Lyon, France.
(33)Centre de Référence des Maladies Neuromusculaires et de la Sclérose Latérale
Amyotrophique, Assistance Publique-Hôpitaux de Marseille, Aix Marseille
Université, Hôpital de La Timone, Marseille, France.

Importance: Molecular diagnosis is difficult to achieve in disease groups with a
highly heterogeneous genetic background, such as cerebellar ataxia (CA). In many
patients, candidate gene sequencing or focused resequencing arrays do not allow
investigators to reach a genetic conclusion.
Objectives: To assess the efficacy of exome-targeted capture sequencing to detect
mutations in genes broadly linked to CA in a large cohort of undiagnosed patients
and to investigate their prevalence.
Design, Setting, and Participants: Three hundred nineteen index patients with CA
and without a history of dominant transmission were included in the this cohort
study by the Spastic Paraplegia and Ataxia Network. Centralized storage was in
the DNA and cell bank of the Brain and Spine Institute, Salpetriere Hospital,
Paris, France. Patients were classified into 6 clinical groups, with the largest
being those with spastic ataxia (ie, CA with pyramidal signs [n = 100]).
Sequencing was performed from January 1, 2014, through December 31, 2016.
Detected variants were classified as very probably or definitely causative,
possibly causative, or of unknown significance based on genetic evidence and
genotype-phenotype considerations.
Main Outcomes and Measures: Identification of variants in genes broadly linked to
CA, classified in pathogenicity groups.
Results: The 319 included patients had equal sex distribution (160 female [50.2%]
and 159 male patients [49.8%]; mean [SD] age at onset, 27.9 [18.6] years). The
age at onset was younger than 25 years for 131 of 298 patients (44.0%) with
complete clinical information. Consanguinity was present in 101 of 298 (33.9%).
Very probable or definite diagnoses were achieved for 72 patients (22.6%), with
an additional 19 (6.0%) harboring possibly pathogenic variants. The most
frequently mutated genes were SPG7 (n = 14), SACS (n = 8), SETX (n = 7), SYNE1
(n = 6), and CACNA1A (n = 6). The highest diagnostic rate was obtained for
patients with an autosomal recessive CA with oculomotor apraxia-like phenotype (6
of 17 [35.3%]) or spastic ataxia (35 of 100 [35.0%]) and patients with onset
before 25 years of age (41 of 131 [31.3%]). Peculiar phenotypes were reported for
patients carrying KCND3 or ERCC5 variants.
Conclusions and Relevance: Exome capture followed by targeted analysis allows the
molecular diagnosis in patients with highly heterogeneous mendelian disorders,
such as CA, without prior assumption of the inheritance mode or causative gene.
Being commonly available without specific design need, this procedure allows
testing of a broader range of genes, consequently describing less classic
phenotype-genotype correlations, and post hoc reanalysis of data as new genes are
implicated in the disease.

DOI: 10.1001/jamaneurol.2017.5121
PMCID: PMC5885259
PMID: 29482223 [Indexed for MEDLINE]

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