Identification of novel senataxin mutations in Chinese patients with autosomal recessive cerebellar ataxias by targeted next-generation sequencing

Abstract

BackgroundAutosomal recessive cerebellar ataxias (ARCA) are a group of neurodegenerative disorders characterized by early onset of gait impairment, disturbed limb coordination, dysarthria, and eye movement abnormalities, most likely due to the degeneration of cerebellum, brainstem, and spinal cord. Despite of the rarity, ARCA are both clinically and genetically heterogeneous. To date, more than 30 culprit genes have been identified in ARCA. Unraveling the specific causative mutation in cases with ARCA remains challenging so far.MethodsThree ARCA pedigrees of Chinese ancestry were recruited. Clinical features were evaluated and peripheral blood was collected after obtaining the written inform. Laboratory examinations, brain MRI, and EMG were performed for all the affected individuals. Genomic DNA was extracted, followed by the screening of GAA repeat expansion in FXN gene to exclude Friedreich’s ataxia. Targeted next-generation sequencing combining Sanger sequencing was performed in each proband of these families.ResultsCompound heterozygous mutations, c.3190G > T (p.E1064X) and c.4883C > G (p.S1628X) of senataxin (SETX) gene were identified in one family with two affected cases. Both of the patients presented with early onset of unsteady walk, dysarthria, and diplopia. EMG test revealed decreased conduction velocity and evoked potential of both motor and sensory nerve. Moreover, elevated serum alpha-fetoprotein (AFP) and apparent cerebellar atrophy were observed. These features were typical features of ataxia with oculomotor apraxia type 2 (AOA2) and in line with the genetic results. However, no specific mutation was identified in the other two pedigrees.ConclusionsWe identified novel compound heterozygous mutations of SETX in Chinese AOA2 pedigree, which broaden the mutation spectrum of SETX. To our knowledge, this is the first report concerning Chinese AOA2 cases with SETX mutations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12883-016-0696-y) contains supplementary material, which is available to authorized users.

Clinical features and genetic spectrum in Chinese patients with recessive hereditary spastic paraplegia

“…Deep sequencing was executed on the Illumuna HiSeq2000 platform (Genergy Biotechnology, Shanghai, China). The annotations and analyses of sequenced reads were carried out as described in our previous publications [16, 17]. After annotation, data on the detected variants were extracted from publicly available databases including the 1000 Genomes Project, the Exome Aggregation Consortium (ExAC) Browser, and the Single Nucleotide Polymorphism (dbSNP) Database.…”

Genetic spectrum and clinical profiles in a southeast Chinese cohort of Charcot‐Marie‐Tooth disease

“…Owing to CMT's clinical and genetic heterogeneity, it is expensive and time‐consuming to screen all the possible causative genes using conventional Sanger sequencing. However, highthroughput targeted next‐generation sequencing (NGS) has been employed successfully in CMT and other neurogenetic diseases such as amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegia (HSP), and hereditary ataxia (HA) . Consequently, nearly 90 genes associated with CMT and other inherited peripheral neuropathies have been assembled in a gene panel, and parallel sequencing can be performed to interrogate these genes.…”

“…However, highthroughput targeted next-generation sequencing (NGS) has been employed successfully in CMT 9,10 and other neurogenetic diseases such as amyotrophic lateral sclerosis (ALS), [11][12][13] hereditary spastic paraplegia (HSP), 14,15 and hereditary ataxia (HA). 16,17 Consequently, nearly 90 genes associated with CMT and other inherited peripheral neuropathies have been assembled in a gene panel, and parallel sequencing can be performed to interrogate these genes. Patients were evaluated and diagnosed by at least two senior neurologists according to the strategy described in our previous reports.…”

Genetic Spectrum and Clinical Features in a Cohort of Chinese Patients with Autosomal Recessive Cerebellar Ataxias

“…Therefore, 25 out of 54 (46.3%) patients were genetically diagnosed with ARCA. Previously, we reported an index patient with AOA2 [19] and an index patient with SCAR27 [20]. Taken together, genetic diagnoses were made for a total of 27 out of 56 (48.2%) ARCA index patients in our center.…”