Abstract
The autosomal recessive spinocerebellar ataxias are an exciting field of study, with a growing number of causal genes and an expanding phenotypic spectrum. SYNE1 was originally discovered in 2007 as the causal gene underlying autosomal recessive spinocerebellar ataxia 1, a disease clinically thought to manifest with mainly pure cerebellar ataxia. Since the original report SYNE1 mutations have also been identified in families with motor neuronopathy and arthrogryposis but few families have been screened as the gene is very large at 146 exons in length. We screened 196 recessive and sporadic ataxia patients for mutations in SYNE1 using next generation sequencing in order to assess its frequency and extend the clinicogenetic spectrum. We identified four novel truncating mutations spread throughout the SYNE1 gene from three families living in London that originated from England, Turkey and Sri Lanka. The phenotype was mainly pure cerebellar ataxia in two families, cognitive decline was present in all three families, axonal neuropathy in one family and marked spasticity in the Turkish family, with a range of disease severities. Searching for genotype–phenotype correlations in the SYNE1 gene, defects located near the 3′ prime end of the gene are more frequently associated with motor neuron or neuromuscular involvement so far. Our data indicate SYNE1 mutations are not an uncommon cause of recessive ataxia with or without additional clinical features in patients from various ethnicities. The use of next generation sequencing allows the rapid analysis of large genes and will likely reveal more SYNE1 associated cases and further expand genotype–phenotype correlations.Electronic supplementary materialThe online version of this article (doi:10.1007/s00415-016-8148-6) contains supplementary material, which is available to authorized users.
Highlights
The recessive spinocerebellar ataxias (ARCAs or SCARs) are a complex group of neurodegenerative conditions with significant genetic and clinical heterogeneity [1]
SYNE1 was originally discovered in 2007 as the causal gene underlying autosomal recessive spinocerebellar ataxia 1, a disease clinically thought to manifest with mainly pure cerebellar ataxia
Since the original report SYNE1 mutations have been identified in families with motor neuronopathy and arthrogryposis but few families have been screened as the gene is very large at 146 exons in length
Summary
The recessive spinocerebellar ataxias (ARCAs or SCARs) are a complex group of neurodegenerative conditions with significant genetic and clinical heterogeneity [1]. In 2007, SYNE1 was identified as a cause of pure cerebellar phenotypes It was termed recessive ataxia of Beauce (SCAR8 or ARCA1, MIM# 610743), since it was originally identified in a number of French-Canadian families originating from the Beauce and Bas-St-Laurent regions of Quebec [5]. More recently families from Japan and Turkey with homozygous truncating SYNE1 mutations have been associated with a motor neuron phenotype in addition to cerebellar ataxia [7, 10]. We examined an ethnically diverse UK cohort of autosomal recessive families and sporadic cerebellar ataxia patients through a combination of targeted generation sequencing and exome sequencing, identifying biallelic SYNE1 mutations in three families from England, Turkey and Sri Lanka with the phenotypes and severities described here. Identified variants were confirmed using Sanger sequencing (see Supplementary Table 1 for primers employed) in affected cases and in parents or unaffected siblings where available to confirm segregation or mutation phase for compound heterozygous mutations
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