title: Mini-Exome Coupled to Read-Depth Based Copy Number Variation Analysis in Patients with Inherited Ataxias.
abstract: Next-generation sequencing (NGS) has an established diagnostic value for inherited ataxia. However, the need of a rigorous process of analysis and validation remains challenging. Moreover, copy number variations (CNV) or dynamic expansions of repeated sequence are classically considered not adequately detected by exome sequencing technique. We applied a strategy of mini-exome coupled to read-depth based CNV analysis to a series of 33 patients with probable inherited ataxia and onset <50 years. The mini-exome consisted of the capture of 4,813 genes having associated clinical phenotypes. Pathogenic variants were found in 42% and variants of uncertain significance in 24% of the patients. These results are comparable to those from whole exome sequencing and better than previous targeted NGS studies. CNV and dynamic expansions of repeated CAG sequence were identified in three patients. We identified both atypical presentation of known ataxia genes (ATM, NPC1) and mutations in genes very rarely associated with ataxia (ERCC4, HSD17B4). We show that mini-exome bioinformatics data analysis allows the identification of CNV and dynamic expansions of repeated sequence. Our study confirms the diagnostic value of the proposed genetic analysis strategy. We also provide an algorithm for the multidisciplinary process of analysis, interpretation, and validation of NGS data.
authors.affiliation: Department of Neurology, University Hospital Gui de Chauliac, Montpellier, France.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Marelli
authors.affiliation: EA7402 Institut Universitaire de Recherche Clinique, and Laboratoire de Génétique Moléculaire, University Hospital, Montpellier, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Guissart
authors.affiliation: Department of Neurology, Pitié-Salpêtrière University Hospital, Paris, France.
authors.forename: Cecile
authors.initials: C
authors.lastname: Hubsch
authors.affiliation: Department of Neurology, Strasbourg University Hospital, Strasbourg, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Renaud
authors.affiliation: EA7402 Institut Universitaire de Recherche Clinique, and Laboratoire de Génétique Moléculaire, University Hospital, Montpellier, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Villemin
authors.affiliation: EA7402 Institut Universitaire de Recherche Clinique, and Laboratoire de Génétique Moléculaire, University Hospital, Montpellier, France.
authors.forename: Lise
authors.initials: L
authors.lastname: Larrieu
authors.affiliation: Department of Genetics, Pitié-Salpêtrière University Hospital, Paris, France.
authors.forename: Perrine
authors.initials: P
authors.lastname: Charles
authors.affiliation: Department of Neurology, University Hospital Gui de Chauliac, Montpellier, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Ayrignac
authors.affiliation: Peripheral Nervous System, Muscle and ALS, Neuromuscular & ALS Specialized Center, Nice University Hospital, Pasteur 2, Nice, France.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Sacconi
authors.affiliation: Department of Medical Genetics, Sainte Musse Hospital, Toulon, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Collignon
authors.affiliation: Department of Neurology, University Hospital Gui de Chauliac, Montpellier, France.|Department of Paediatrics, University Hospital Gui de Chauliac, Montpellier, France.
authors.forename: Danielle
authors.initials: D
authors.lastname: Cuntz-Shadfar
authors.affiliation: Department of Physical Medicine and Rehabilitation and Department of Paediatric Neurology, CHU de Saint Etienne, France.
authors.forename: Laurine
authors.initials: L
authors.lastname: Perrin
authors.affiliation: Department of Neurology, Sainte Musse Hospital, Toulon, France.
authors.forename: Anelia
authors.initials: A
authors.lastname: Benarrosh
authors.affiliation: Department of Neurology, University Hospital Roger Salengro, Lille, France.
authors.forename: Adrian
authors.initials: A
authors.lastname: Degardin
authors.affiliation: Department of Neurology, Strasbourg University Hospital, Strasbourg, France.
authors.forename: Ouhaïd
authors.initials: O
authors.lastname: Lagha-Boukbiza
authors.affiliation: CHU Lille, UMR-S 1172 - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, University of Lille, Inserm, Lille, France.
authors.forename: Eugenie
authors.initials: E
authors.lastname: Mutez
authors.affiliation: Department of Neurology, University Hospital Gui de Chauliac, Montpellier, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Carlander
authors.affiliation: Department of Neurology, University Hospital Gui de Chauliac, Montpellier, France.
authors.forename: Raul Juntas
authors.initials: RJ
authors.lastname: Morales
authors.affiliation: Department of Neurology, University Hospital Gui de Chauliac, Montpellier, France.
authors.forename: Victoria
authors.initials: V
authors.lastname: Gonzalez
authors.affiliation: Department of Neurology, University Hospital Gui de Chauliac, Montpellier, France.
authors.forename: Clarisse
authors.initials: C
authors.lastname: Carra-Dalliere
authors.affiliation: Department of Neurology, University Hospital Gui de Chauliac, Montpellier, France.
authors.forename: Souhayla
authors.initials: S
authors.lastname: Azakri
authors.affiliation: Centre de Référence des Maladies Neuro-musculaires et Neurologiques Rares du CHU de la Réunion, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Mignard
authors.affiliation: Department of Medical Genetics and Reference Centre for Neurological and Neuromuscular Diseases, Croix-Rousse Hospital, Lyon, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Ollagnon
authors.affiliation: Department of Neurology, University Hospital Gui de Chauliac, Montpellier, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Pageot
authors.affiliation: INSERM UMR 1141 Robert Debré Hospital and Denis Diderot University Paris 7, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Chretien
authors.affiliation: Department of Neurology, University Hospital Gui de Chauliac, Montpellier, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Geny
authors.affiliation: Department of Neurology, La Timone University Hospital, Marseille, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Azulay
authors.affiliation: Department of Neurology, Strasbourg University Hospital, Strasbourg, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Tranchant
authors.affiliation: EA7402 Institut Universitaire de Recherche Clinique, and Laboratoire de Génétique Moléculaire, University Hospital, Montpellier, France.
authors.forename: Mireille
authors.initials: M
authors.lastname: Claustres
authors.affiliation: Department of Neurology, University Hospital Gui de Chauliac, Montpellier, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Labauge
authors.affiliation: Department of Neurology, Strasbourg University Hospital, Strasbourg, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Anheim
authors.affiliation: Department of Medical Genetics, Pellegrin University Hospital, and laboratoire Maladies Rares Génétique et Métabolisme (MRGM), INSERM U1211, Université Bordeaux, Bordeaux, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Goizet
authors.affiliation: Department of Clinical Genetics, Purpan University Hospital, Toulouse, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Calvas
authors.affiliation: EA7402 Institut Universitaire de Recherche Clinique, and Laboratoire de Génétique Moléculaire, University Hospital, Montpellier, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Koenig
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D002524:Cerebellar Ataxia / Q000209:etiology / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D004268:DNA-Binding Proteins / Q000235:genetics; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D000077296:Niemann-Pick C1 Protein; D064029:Peroxisomal Multifunctional Protein-2 / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods*; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; C095888:xeroderma pigmentosum group F protein; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D064029:Peroxisomal Multifunctional Protein-2; C104587:HSD17B4 protein, human
keywords: ataxia; copy number variations; exome sequencing; mini-exome; molecular diagnosis; trinucleotide repeat expansion