title: Expanding the Spectrum of Genes Involved in Huntington Disease Using a Combined Clinical and Genetic Approach.
abstract: Huntington disease (HD), a prototypic monogenic disease, is caused by an expanded CAG repeat in the HTT gene exceeding 35 units. However, not all patients with an HD phenotype carry the pathological expansion in HTT, and the positive diagnosis rate is poor.
  
  
  
  To examine patients with HD phenotypes to determine the frequency of HD phenocopies with typical features of HD but without pathological CAG repeat expansions in HTT in an attempt to improve the positive diagnosis rate.
  
  
  
  Between January 1, 2004, and April 18, 2011, a total of 226 consecutive index patients with an HD phenotype were referred to specialized clinics of the French National Huntington Disease Reference Centre for Rare Diseases. They underwent detailed clinical examination and follow-up, as well as neuropsychological, biological, imaging, and genetic examinations. Nucleotide expansions in JPH3, ATN1, TBP, and C9ORF72 and mutations in PRNP, as well as acquired conditions commonly causing HD phenocopies, were first screened.
  
  
  
  The diagnostic rate of HD phenocopies and frequency of other etiologies using deep clinical phenotyping and next generation sequencing. Our goal was to improve the genetic diagnosis of HD phenocopies and to identify new HD related genes.
  
  
  
  One hundred ninety-eight patients carried a pathological CAG repeat expansion in HTT, whereas 28 patients (12 women and 16 men) did not. Huntington disease phenocopies accounted for 12.4%, and their mean (SD) age at onset was similar to those of the HD-HTT group (47.3 [12.7] years vs 50.3 [16.4] years, P = .29). We first identified 3 patients with abnormal CTG expansions in JPH3, a fourth patient with an antiphospholipid syndrome, and a fifth patient with B12 avitaminosis. A custom-made 63-gene panel was generated based on clinical evolution and exome sequencing. It contained genes responsible for HD phenocopies and other neurodegenerative conditions, as well as candidate genes from exome sequencing in 3 index cases with imaging features of brain iron accumulation. We identified mutations in genes associated with neurodegeneration, including CACNA1A (n = 2), VPS13A (n = 1), UBQLN2 (n = 1), and VCP (n = 1).
  
  
  
  Huntington disease phenocopies without CAG repeat expansions in HTT are not rare, occurring in 12.4% (28 of 226) herein, and should be considered in genetic counseling. We used next-generation sequencing combined with clinical data and disease evolution to explore multiple etiologies simultaneously. Our combined clinical and genetic exploration of 28 HD phenocopies identified the underlying cause in 35.7% (10 of 28). In conclusion, the etiologies of HD phenocopies are heterogeneous, and clinical evolution should be taken into account when searching for a genetic cause. The panel of candidate genes to be examined is larger than expected but can be guided by specific imaging and clinical features. Other neurodegenerative diseases with late onset in which variant segregation cannot be verified could be productively explored with the combined approach illustrated herein.
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Genetics, Paris, France2Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Neurology, Paris, France.
authors.forename: Louise-Laure
authors.initials: LL
authors.lastname: Mariani
authors.affiliation: Institut du Cerveau et de la Moelle Epinière, Paris, France4Institut National de la Santé et de la Récherche Médicale Unité 1127, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7225, Sorbonne Universités, Université Pierre et Marie Curie University Paris 06 Unité Mixte de Recherche S1127, Paris, France5Ecole Pratique des Hautes Etudes, Paris, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Tesson
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Genetics, Paris, France2Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Neurology, Paris, France.
authors.forename: Perrine
authors.initials: P
authors.lastname: Charles
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Genetics, Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Cazeneuve
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Neurology, Paris, France6Assistance Publique-Hôpitaux de Paris, Unité de Neurologie de la Mémoire et du Langage, Centre Hospitalier Saint-Anne, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Hahn
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Reference Centre for Huntington's Disease, Unité Fonctionnelle de Neurologie Cognitive, Henri Mondor University Hospital, Créteil, France8Institut National de la Santé et de la Récherche Médicale Unité 955 Team 1, Institut Mondor de Recherche Biomédicale, Faculté de Médecine de Créteil, Créteil, France9Institut d'Etude de la Cognition, Ecole Normale Supérieure, Paris, France.
authors.forename: Katia
authors.initials: K
authors.lastname: Youssov
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Neurology, Paris, France10Department of Neurology, McGovern Medical School, UTHealth, Houston, Texas.
authors.forename: Leorah
authors.initials: L
authors.lastname: Freeman
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Neurology, Paris, France3Institut du Cerveau et de la Moelle Epinière, Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Grabli
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Neurology, Paris, France3Institut du Cerveau et de la Moelle Epinière, Paris, France4Institut National de la Santé et de la Récherche Médicale Unité 1127, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7225, Sorbonne Universités, Université Pierre et Marie Curie University Paris 06 Unité Mixte de Recherche S1127, Paris, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Roze
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Genetics, Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Noël
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Genetics, Paris, France.
authors.forename: Jean-Noel
authors.initials: JN
authors.lastname: Peuvion
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Reference Centre for Huntington's Disease, Unité Fonctionnelle de Neurologie Cognitive, Henri Mondor University Hospital, Créteil, France8Institut National de la Santé et de la Récherche Médicale Unité 955 Team 1, Institut Mondor de Recherche Biomédicale, Faculté de Médecine de Créteil, Créteil, France9Institut d'Etude de la Cognition, Ecole Normale Supérieure, Paris, France.
authors.forename: Anne-Catherine
authors.initials: AC
authors.lastname: Bachoud-Levi
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Genetics, Paris, France3Institut du Cerveau et de la Moelle Epinière, Paris, France4Institut National de la Santé et de la Récherche Médicale Unité 1127, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7225, Sorbonne Universités, Université Pierre et Marie Curie University Paris 06 Unité Mixte de Recherche S1127, Paris, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Genetics, Paris, France3Institut du Cerveau et de la Moelle Epinière, Paris, France4Institut National de la Santé et de la Récherche Médicale Unité 1127, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7225, Sorbonne Universités, Université Pierre et Marie Curie University Paris 06 Unité Mixte de Recherche S1127, Paris, France5Ecole Pratique des Hautes Etudes, Paris, France.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stevanin
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Genetics, Paris, France3Institut du Cerveau et de la Moelle Epinière, Paris, France4Institut National de la Santé et de la Récherche Médicale Unité 1127, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7225, Sorbonne Universités, Université Pierre et Marie Curie University Paris 06 Unité Mixte de Recherche S1127, Paris, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
mesh_terms: D000328:Adult; D000368:Aged; D015220:Calcium Channels / Q000235:genetics; D005260:Female; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics*; D006816:Huntington Disease / Q000175:diagnosis* / Q000209:etiology / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D010641:Phenotype; D012189:Retrospective Studies; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*; D033921:Vesicular Transport Proteins / Q000235:genetics; D020864:Calcium Channels, N-Type
chemical_list: D015220:Calcium Channels; D000071058:Huntingtin Protein; D008565:Membrane Proteins; D033921:Vesicular Transport Proteins; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type; C086055:HTT protein, human; C429654:VPS13A protein, human; C412507:junctophilin