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

Louise-Laure Mariani, Christelle Tesson, Perrine Charles, Cécile Cazeneuve, Valérie Hahn, Katia Youssov, Leorah Freeman, David Grabli, Emmanuel Roze, Sandrine Noël, Jean-Noel Peuvion, Anne-Catherine Bachoud-Levi, Alexis Brice, Giovanni Stevanin, Alexandra Durr
JAMA Neurol. 2016-09-01; 73(9): 1105
DOI: 10.1001/jamaneurol.2016.2215

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1. JAMA Neurol. 2016 Sep 1;73(9):1105-14. doi: 10.1001/jamaneurol.2016.2215.

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

Mariani LL(1), Tesson C(2), Charles P(1), Cazeneuve C(3), Hahn V(4), Youssov
K(5), Freeman L(6), Grabli D(7), Roze E(8), Noël S(3), Peuvion JN(3),
Bachoud-Levi AC(5), Brice A(9), Stevanin G(10), Durr A(9).

Author information:
(1)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.
(2)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.
(3)Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital,
Department of Genetics, Paris, France.
(4)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.
(5)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.
(6)Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital,
Department of Neurology, Paris, France10Department of Neurology, McGovern Medical
School, UTHealth, Houston, Texas.
(7)Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital,
Department of Neurology, Paris, France3Institut du Cerveau et de la Moelle
Epinière, Paris, France.
(8)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.
(9)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.
(10)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.

Comment in
JAMA Neurol. 2016 Sep 1;73(9):1056-8.

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.

DOI: 10.1001/jamaneurol.2016.2215
PMID: 27400454 [Indexed for MEDLINE]

Auteurs Bordeaux Neurocampus