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Original Investigation
September 2016

Expanding the Spectrum of Genes Involved in Huntington Disease Using a Combined Clinical and Genetic Approach

Author Affiliations
  • 1Assistance Publique–Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Genetics, Paris, France
  • 2Assistance Publique–Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Neurology, Paris, France
  • 3Institut du Cerveau et de la Moelle Epinière, Paris, France
  • 4Institut 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
  • 5Ecole Pratique des Hautes Etudes, Paris, France
  • 6Assistance Publique–Hôpitaux de Paris, Unité de Neurologie de la Mémoire et du Langage, Centre Hospitalier Saint-Anne, Paris, France
  • 7Assistance Publique–Hôpitaux de Paris, Reference Centre for Huntington’s Disease, Unité Fonctionnelle de Neurologie Cognitive, Henri Mondor University Hospital, Créteil, France
  • 8Institut National de la Santé et de la Récherche Médicale Unité 955 Team 1, Institut Mondor de Recherche Biomédicale, Faculté de Médecine de Créteil, Créteil, France
  • 9Institut d’Etude de la Cognition, Ecole Normale Supérieure, Paris, France
  • 10Department of Neurology, McGovern Medical School, UTHealth, Houston, Texas
JAMA Neurol. 2016;73(9):1105-1114. doi:10.1001/jamaneurol.2016.2215

Importance  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.

Objectives  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.

Design, Setting, and Participants  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.

Main Outcomes and Measures  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.

Results  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).

Conclusions and Relevance  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.