COUTELIER M et al. Genetic landscape remodelling in spinocerebellar ataxias: the influence of next-generation sequencing [REVIEW]. J Neurol 2015


Genetic landscape remodelling in spinocerebellar ataxias: the influence of next-generation sequencing [REVIEW].

J Neurol 2015 (online April 11)

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.


Schematic representation of the phenotypic spectrum linked to newly described genes involved in ataxia plus hypogonadism. RNF216 mutations are responsible for a uniform phenotype (dark red) with constant clinical signs. Apart from severe D-bifunctional protein deficiency, the ataxia plus hypogonadism phenotype caused by HSD17B4 mutations is also rather homogeneous (dark blue). In contrast, PNPLA6 (orange) and STUB1 (light blue) have been shown to induce variable phenotypes, with no or few mandatory signs. This illustrates the complexity of genotype-phenotype correlations, accentuated with the next generation sequencing era.