Genetic landscape remodelling in spinocerebellar ataxias: the influence of next-generation sequencing.
J Neurol. 2015-04-11; 262(10): 2382-2395
DOI: 10.1007/s00415-015-7725-4
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1. J Neurol. 2015 Oct;262(10):2382-95. doi: 10.1007/s00415-015-7725-4. Epub 2015 Apr
11.
Genetic landscape remodelling in spinocerebellar ataxias: the influence of
next-generation sequencing.
Coutelier M(1)(2)(3)(4)(5)(6), Stevanin G(7)(8)(9)(10)(11)(12), Brice
A(13)(14)(15)(16)(17).
Author information:
(1)INSERM, U 1127, 75013, Paris, France. .
(2)CNRS, UMR 7225, 75013, Paris, France. .
(3)Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1127, 75013, Paris, France.
.
(4)Institut du Cerveau et de la Moelle épinière, ICM, 75013, Paris, France.
.
(5)Ecole Pratique des Hautes Etudes, 75014, Paris, France.
.
(6)Laboratory of Human Molecular Genetics, de Duve Institute, Université
catholique de Louvain, 1200, Brussels, Belgium.
.
(7)INSERM, U 1127, 75013, Paris, France.
(8)CNRS, UMR 7225, 75013, Paris, France.
(9)Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1127, 75013, Paris, France.
(10)Institut du Cerveau et de la Moelle épinière, ICM, 75013, Paris, France.
(11)Ecole Pratique des Hautes Etudes, 75014, Paris, France.
(12)APHP, Department of Genetics and Cytogenetics, Groupe Hospitalier Pitié-
Salpêtrière, 75013, Paris, France.
(13)INSERM, U 1127, 75013, Paris, France. .
(14)CNRS, UMR 7225, 75013, Paris, France. .
(15)Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1127, 75013, Paris, France.
.
(16)Institut du Cerveau et de la Moelle épinière, ICM, 75013, Paris, France.
.
(17)APHP, Department of Genetics and Cytogenetics, Groupe Hospitalier Pitié-
Salpêtrière, 75013, Paris, France. .
Hereditary cerebellar ataxias (HCAs) are clinically and genetically heterogeneous
neurodegenerative disorders, characterised by a cerebellar syndrome and other
neurological or non-neurological signs. So far, more than 20 genes have been
described in autosomal dominant HCA; in autosomal recessive HCA, even more genes
are involved, in often more complex phenotypes. Because of that complexity, the
genetic diagnosis of these diseases is often based on the next-generation
sequencing techniques. In this review paper, we discuss the major contributions
that they have made to the genetic landscape of HCAs. Numerous novel genes have
been identified; still more have recently been implicated in HCAs in addition to
being responsible for other diseases. The phenotypic spectrum associated with a
single gene constantly gains in complexity. Novel types of mutations or
transmissions in known genes are regularly being identified. All these factors
make genotype-phenotype correlations particularly difficult. Some but not all of
this variability can be explained by different pathophysiological consequences
(loss of function, gain of function, variable levels of haploinsufficiency). This
also raises the question of modifier genes. Finally, we highlight some functional
pathways that increasingly appear important in HCAs.
DOI: 10.1007/s00415-015-7725-4
PMID: 25862482 [Indexed for MEDLINE]