Abstract
Hereditary cerebellar ataxia (HCA) comprises a clinical and genetic heterogeneous group of neurodegenerative disorders characterized by incoordination of movement, speech, and unsteady gait. In this study, we performed whole-exome sequencing (WES) in 19 families with HCA and presumed autosomal recessive (AR) inheritance, to identify the causal genes. A phenotypic classification was performed, considering the main clinical syndromes: spastic ataxia, ataxia and neuropathy, ataxia and oculomotor apraxia (AOA), ataxia and dystonia, and ataxia with cognitive impairment. The most frequent causal genes were associated with spastic ataxia (SACS and KIF1C) and with ataxia and neuropathy or AOA (PNKP). We also identified three families with autosomal dominant (AD) forms arising from de novo variants in KIF1A, CACNA1A, or ATP1A3, reinforcing the importance of differential diagnosis (AR vs. AD forms) in families with only one affected member. Moreover, 10 novel causal-variants were identified, and the detrimental effect of two splice-site variants confirmed through functional assays. Finally, by reviewing the molecular mechanisms, we speculated that regulation of cytoskeleton function might be impaired in spastic ataxia, whereas DNA repair is clearly associated with AOA. In conclusion, our study provided a genetic diagnosis for HCA families and proposed common molecular pathways underlying cerebellar neurodegeneration.
Highlights
Hereditary cerebellar ataxias (HCA) comprise a heterogeneous group of neurological disorders
We identified 24 rare nucleotide variants in 13 genes (Table S1, supporting information): SACS, Kinesin family member 1C (KIF1C), ANO10, SPG11, synaptic nuclear envelope protein 1 (SYNE1), and CACNA1A were related to spastic ataxia (10/19 families, 52.6%); KIF1A, POLG, SETX, and PNKP to ataxia and neuropathy
Our study provided the molecular diagnosis of 19 families with various types of HCA through whole-exome sequencing (WES), expanding the genetic and phenotypic spectrum of HCA
Summary
Hereditary cerebellar ataxias (HCA) comprise a heterogeneous group of neurological disorders. All modes of inheritance have been recognized, with the autosomal recessive (AR) forms being the most complex, both from a clinical and genetic point of view [1]. AD-HCA are generally caused by repeat expansions, with Machado-Joseph Disease/Spinocerebellar ataxia type 3 (MJD/SCA3). Being, overall, the most frequent form and SCA2 the second on a global basis, but first in countries such as Cuba or India [2,3]. The genetic diversity of HCA has greatly increased over the past years, due to the contribution of generation sequencing (NGS) techniques. With a diagnostic yield of 20–25%, NGS has allowed for the identification of new ataxia-causing genes and redefining genotype–phenotype correlations; it has uncovered a large number of variants of unknown clinical significance [4,5]
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