{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T16:34:24Z","timestamp":1791045264526,"version":"4.1.0"},"reference-count":97,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,1,4]],"date-time":"2024-01-04T00:00:00Z","timestamp":1704326400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Episodic ataxias are rare neurological disorders characterized by recurring episodes of imbalance and coordination difficulties. Obtaining definitive molecular diagnoses poses challenges, as clinical presentation is highly heterogeneous, and literature on the underlying genetics is limited. While the advent of high-throughput sequencing technologies has significantly contributed to Mendelian disorders genetics, interpretation of variants of uncertain significance and other limitations inherent to individual methods still leaves many patients undiagnosed. This study aimed to investigate the utility of multi-omics for the identification and validation of molecular candidates in a cohort of complex cases of ataxia with episodic presentation.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Eight patients lacking molecular diagnosis despite extensive clinical examination were recruited following standard genetic testing. Whole genome and RNA sequencing were performed on samples isolated from peripheral blood mononuclear cells. Integration of expression and splicing data facilitated genomic variants prioritization. Subsequently, long-read sequencing played a crucial role in the validation of those candidate variants.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Whole genome sequencing uncovered pathogenic variants in four genes (<jats:italic>SPG7<\/jats:italic>, <jats:italic>ATXN2<\/jats:italic>, <jats:italic>ELOVL4<\/jats:italic>, <jats:italic>PMPCB<\/jats:italic>). A missense and a nonsense variant, both previously reported as likely pathogenic, configured <jats:italic>in trans<\/jats:italic> in individual #1 (<jats:italic>SPG7<\/jats:italic>: c.2228T&amp;gt;C\/p.I743T, c.1861C&amp;gt;T\/p.Q621*). An <jats:italic>ATXN2<\/jats:italic> microsatellite expansion (CAG<jats:sub>32<\/jats:sub>) in another late-onset case. In two separate individuals, intronic variants near splice sites (<jats:italic>ELOVL4<\/jats:italic>: c.541 + 5G&amp;gt;A; <jats:italic>PMPCB<\/jats:italic>: c.1154 + 5G&amp;gt;C) were predicted to induce loss-of-function splicing, but had never been reported as disease-causing. Long-read sequencing confirmed the compound heterozygous variants configuration, repeat expansion length, as well as splicing landscape for those pathogenic variants. A potential genetic modifier of the <jats:italic>ATXN2<\/jats:italic> expansion was discovered in <jats:italic>ZFYVE26<\/jats:italic> (c.3022C&amp;gt;T\/p.R1008*).<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Despite failure to identify pathogenic variants through clinical genetic testing, the multi-omics approach enabled the molecular diagnosis in 50% of patients, also giving valuable insights for variant prioritization in remaining cases. The findings demonstrate the value of long-read sequencing for the validation of candidate variants in various scenarios. Our study demonstrates the effectiveness of leveraging complementary omics technologies to unravel the underlying genetics in patients with unresolved rare diseases such as ataxia. Molecular diagnoses not only hold significant promise in improving patient care management, but also alleviates the burden of diagnostic odysseys, more broadly enhancing quality of life.<\/jats:p>","DOI":"10.3389\/fgene.2023.1304711","type":"journal-article","created":{"date-parts":[[2024,1,4]],"date-time":"2024-01-04T05:02:16Z","timestamp":1704344536000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Integration of multi-omics technologies for molecular diagnosis in ataxia patients"],"prefix":"10.3389","volume":"14","author":[{"given":"Sebastien","family":"Audet","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Triassi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myriam","family":"Gelinas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nab","family":"Legault-Cadieux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Ferraro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoine","family":"Duquette","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martine","family":"Tetreault","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,1,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e0228000","DOI":"10.1371\/journal.pone.0228000","article-title":"Heterogeneity in the distribution of 159 drug-response related SNPs in world populations and their genetic relatedness","volume":"15","author":"Ahsan","year":"2020","journal-title":"PLoS One"},{"key":"B2","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1186\/s13059-021-02283-5","article-title":"Megabase-scale methylation phasing using nanopore long reads and NanoMethPhase","volume":"22","author":"Akbari","year":"2021","journal-title":"Genome Biol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1111\/j.1399-0004.2009.01358.x","article-title":"Estimation of the age at onset in spinocerebellar ataxia type 2 Cuban patients by survival analysis","volume":"78","author":"Almaguer-Mederos","year":"2010","journal-title":"Clin. Genet."},{"key":"B4","doi-asserted-by":"publisher","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","article-title":"Trimmomatic: a flexible trimmer for Illumina sequence data","volume":"30","author":"Bolger","year":"2014","journal-title":"Bioinformatics"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1101\/2022.03.20.485034","article-title":"A genome-wide mutational constraint map quantified from variation in 76,156 human genomes","author":"Chen","year":"2022"},{"key":"B6","doi-asserted-by":"publisher","first-page":"129","DOI":"10.14802\/jmd.16028","article-title":"Episodic ataxias: clinical and genetic features","volume":"9","author":"Choi","year":"2016","journal-title":"J. Mov. Disord."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1016","DOI":"10.1038\/ejhg.2015.240","article-title":"SPG7 mutations explain a significant proportion of French Canadian spastic ataxia cases","volume":"24","author":"Choquet","year":"","journal-title":"Eur. J. Hum. Genet."},{"key":"B8","doi-asserted-by":"publisher","first-page":"e19","DOI":"10.1093\/brain\/awv362","article-title":"Autosomal recessive cerebellar ataxia caused by a homozygous mutation in PMPCA","volume":"139","author":"Choquet","year":"","journal-title":"Brain"},{"key":"B9","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1038\/ejhg.2013.173","article-title":"A novel locus for episodic ataxia:UBR4 the likely candidate","volume":"22","author":"Conroy","year":"2014","journal-title":"Eur. J. Hum. Genet."},{"key":"B10","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1001\/archneurol.2011.111","article-title":"Association of long ATXN2 CAG repeat sizes with increased risk of amyotrophic lateral sclerosis","volume":"68","author":"Daoud","year":"2011","journal-title":"Arch. Neurol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1186\/s13059-018-1505-2","article-title":"STRetch: detecting and discovering pathogenic short tandem repeat expansions","volume":"19","author":"Dashnow","year":"2018","journal-title":"Genome Biol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"B13","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1186\/s13059-020-02017-z","article-title":"ExpansionHunter Denovo: a computational method for locating known and novel repeat expansions in short-read sequencing data","volume":"21","author":"Dolzhenko","year":"2020","journal-title":"Genome Biol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1186\/s13073-022-01073-3","article-title":"Recommendations for clinical interpretation of variants found in non-coding regions of the genome","volume":"14","author":"Ellingford","year":"2022","journal-title":"Genome Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1531","DOI":"10.1086\/302909","article-title":"Coding and noncoding variation of the human calcium-channel beta4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia","volume":"66","author":"Escayg","year":"2000","journal-title":"Am. J. Hum. Genet."},{"key":"B16","doi-asserted-by":"publisher","first-page":"3047","DOI":"10.1093\/bioinformatics\/btw354","article-title":"MultiQC: summarize analysis results for multiple tools and samples in a single report","volume":"32","author":"Ewels","year":"2016","journal-title":"Bioinformatics"},{"key":"B17","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1146\/annurev-genom-090613-094245","article-title":"Mendelian disorders of the epigenetic machinery: tipping the balance of chromatin states","volume":"15","author":"Fahrner","year":"2014","journal-title":"Annu. Rev. Genomics Hum. Genet."},{"key":"B18","doi-asserted-by":"publisher","first-page":"e155","DOI":"10.1212\/NXG.0000000000000155","article-title":"Genetic analysis of age at onset variation in spinocerebellar ataxia type 2","volume":"3","author":"Figueroa","year":"2017","journal-title":"Neurol. Genet."},{"key":"B19","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1186\/s40478-018-0547-8","article-title":"Interrupted CAG expansions in ATXN2 gene expand the genetic spectrum of frontotemporal dementias","volume":"6","author":"Fournier","year":"2018","journal-title":"Acta Neuropathol. Commun."},{"key":"B20","doi-asserted-by":"publisher","first-page":"D916","DOI":"10.1093\/nar\/gkaa1087","article-title":"Gencode 2021","volume":"49","author":"Frankish","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"B21","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1016\/j.tig.2021.08.010","article-title":"Uncovering the impact of noncoding variants in neurodegenerative brain diseases","volume":"38","author":"Frydas","year":"2022","journal-title":"Trends Genet."},{"key":"B22","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1159\/000515974","article-title":"Episodic vestibulocerebellar ataxia associated with a CACNA1G missense variant","volume":"13","author":"Gazulla","year":"2021","journal-title":"Case Rep. Neurol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"6472","DOI":"10.3390\/ijms21186472","article-title":"Episodic ataxias: faux or real?","volume":"21","author":"Giunti","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B24","doi-asserted-by":"publisher","first-page":"2671","DOI":"10.1093\/brain\/awac167","article-title":"ATXN2 intermediate expansions in amyotrophic lateral sclerosis","volume":"145","author":"Glass","year":"2022","journal-title":"Brain"},{"key":"B25","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1038\/s12276-018-0087-0","article-title":"Realizing the significance of noncoding functionality in clinical genomics","volume":"50","author":"Gloss","year":"2018","journal-title":"Exp. Mol. Med."},{"key":"B26","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1038\/embor.2012.14","article-title":"Mitochondrial processing peptidase regulates PINK1 processing, import and Parkin recruitment","volume":"13","author":"Greene","year":"2012","journal-title":"EMBO Rep."},{"key":"B27","doi-asserted-by":"publisher","first-page":"100317","DOI":"10.1016\/j.jlr.2022.100317","article-title":"ELOVL4 mutations that cause spinocerebellar ataxia-34 differentially alter very long chain fatty acid biosynthesis","volume":"64","author":"Gyening","year":"2023","journal-title":"J. Lipid Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"D514","DOI":"10.1093\/nar\/gki033","article-title":"Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders","volume":"33","author":"Hamosh","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"B29","doi-asserted-by":"publisher","first-page":"103208","DOI":"10.1016\/j.jbi.2019.103208","article-title":"The REDCap consortium: building an international community of software platform partners","volume":"95","author":"Harris","year":"2019","journal-title":"J. Biomed. Inf."},{"key":"B30","doi-asserted-by":"publisher","first-page":"9","DOI":"10.5334\/tohm.747","article-title":"Episodic ataxias: primary and secondary etiologies, treatment, and classification approaches","volume":"13","author":"Hassan","year":"2023","journal-title":"Tremor Other Hyperkinet Mov. (N Y)"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1324","DOI":"10.1002\/humu.22132","article-title":"The inherited ataxias: genetic heterogeneity, mutation databases, and future directions in research and clinical diagnostics","volume":"33","author":"Hersheson","year":"2012","journal-title":"Hum. Mutat."},{"key":"B32","doi-asserted-by":"publisher","first-page":"764","DOI":"10.1093\/occmed\/kqv078","article-title":"The Montreal Cognitive assessment (MoCA)","volume":"65","author":"Hobson","year":"2015","journal-title":"Occup. Med. (Lond)"},{"key":"B33","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1007\/s12311-012-0421-3","article-title":"Inventory of Non-Ataxia Signs (INAS): validation of a new clinical assessment instrument","volume":"12","author":"Jacobi","year":"2013","journal-title":"Cerebellum"},{"key":"B34","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/j.cell.2018.12.015","article-title":"Predicting splicing from primary sequence with deep learning","volume":"176","author":"Jaganathan","year":"2019","journal-title":"Cell"},{"key":"B35","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1212\/01.wnl.0000172638.58172.5a","article-title":"Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures","volume":"65","author":"Jen","year":"2005","journal-title":"Neurology"},{"key":"B36","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1186\/s13073-020-00791-w","article-title":"Best practices for variant calling in clinical sequencing","volume":"12","author":"Koboldt","year":"2020","journal-title":"Genome Med."},{"key":"B37","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1186\/s13059-019-1720-5","article-title":"Comprehensive evaluation of structural variation detection algorithms for whole genome sequencing","volume":"20","author":"Kosugi","year":"2019","journal-title":"Genome Biol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1038\/s41565-021-00898-0","article-title":"The current landscape of nucleic acid therapeutics","volume":"16","author":"Kulkarni","year":"2021","journal-title":"Nat. Nanotechnol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.3390\/ijms23031297","article-title":"Mitochondrial processing peptidases-structure, function and the role in human diseases","volume":"23","author":"Kunova","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B40","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/ejhg.2011.154","article-title":"Unexpanded and intermediate CAG polymorphisms at the SCA2 locus (ATXN2) in the Cuban population: evidence about the origin of expanded SCA2 alleles","volume":"20","author":"Laffita-Mesa","year":"2012","journal-title":"Eur. J. Hum. Genet."},{"key":"B41","doi-asserted-by":"publisher","first-page":"D1062","DOI":"10.1093\/nar\/gkx1153","article-title":"ClinVar: improving access to variant interpretations and supporting evidence","volume":"46","author":"Landrum","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"B42","doi-asserted-by":"publisher","first-page":"R84","DOI":"10.1186\/gb-2014-15-6-r84","article-title":"LUMPY: a probabilistic framework for structural variant discovery","volume":"15","author":"Layer","year":"2014","journal-title":"Genome Biol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1164","DOI":"10.1172\/JCI97103","article-title":"TIA1 variant drives myodegeneration in multisystem proteinopathy with SQSTM1 mutations","volume":"128","author":"Lee","year":"2018","journal-title":"J. Clin. Invest."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1236","DOI":"10.21105\/joss.01236","article-title":"pycoQC, interactive quality control for Oxford Nanopore Sequencing","volume":"4","author":"Leger","year":"2019","journal-title":"J. Open Source Softw."},{"key":"B45","doi-asserted-by":"publisher","first-page":"2077","DOI":"10.1002\/mds.28621","article-title":"Genetic modifiers of age at onset for Parkinson's disease in asians: a genome-wide association study","volume":"36","author":"Li","year":"2021","journal-title":"Mov. Disord."},{"key":"B46","doi-asserted-by":"publisher","first-page":"3094","DOI":"10.1093\/bioinformatics\/bty191","article-title":"Minimap2: pairwise alignment for nucleotide sequences","volume":"34","author":"Li","year":"2018","journal-title":"Bioinformatics"},{"key":"B47","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and accurate short read alignment with Burrows-Wheeler transform","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"B48","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1093\/bioinformatics\/btt656","article-title":"featureCounts: an efficient general purpose program for assigning sequence reads to genomic features","volume":"30","author":"Liao","year":"2014","journal-title":"Bioinformatics"},{"key":"B49","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1681","DOI":"10.1038\/s41591-023-02401-9","article-title":"Integrated multi-omics for rapid rare disease diagnosis on a national scale","volume":"29","author":"Lunke","year":"2023","journal-title":"Nat. Med."},{"key":"B51","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1111\/bpa.12427","article-title":"RNA toxicity induced by expanded CAG repeats in Huntington's disease","volume":"26","author":"Marti","year":"2016","journal-title":"Brain Pathol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.1101\/gr.107524.110","article-title":"The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data","volume":"20","author":"McKenna","year":"2010","journal-title":"Genome Res."},{"key":"B53","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1038\/s41525-022-00307-y","article-title":"Novel homozygous nonsense mutation of MLIP and compensatory alternative splicing","volume":"7","author":"Mezreani","year":"2022","journal-title":"NPJ Genom Med."},{"key":"B54","doi-asserted-by":"publisher","first-page":"1087","DOI":"10.1136\/jmedgenet-2022-108485","article-title":"Targeted long-read sequencing identifies missing pathogenic variants in unsolved Werner syndrome cases","volume":"59","author":"Miller","year":"2022","journal-title":"J. Med. Genet."},{"key":"B55","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1186\/s13059-019-1667-6","article-title":"Tandem-genotypes: robust detection of tandem repeat expansions from long DNA reads","volume":"20","author":"Mitsuhashi","year":"2019","journal-title":"Genome Biol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1186\/s13073-022-01062-6","article-title":"Addressing the routine failure to clinically identify monogenic cases of common disease","volume":"14","author":"Murray","year":"2022","journal-title":"Genome Med."},{"key":"B57","doi-asserted-by":"publisher","first-page":"1385","DOI":"10.1007\/s00415-015-7685-8","article-title":"Acquired ataxias: the clinical spectrum, diagnosis and management","volume":"262","author":"Nachbauer","year":"2015","journal-title":"J. Neurol."},{"key":"B58","doi-asserted-by":"publisher","first-page":"1529","DOI":"10.1001\/jamaneurol.2014.2082","article-title":"Amyotrophic lateral sclerosis risk for spinocerebellar ataxia type 2 ATXN2 CAG repeat alleles: a meta-analysis","volume":"71","author":"Neuenschwander","year":"2014","journal-title":"JAMA Neurol."},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1007\/s12311-023-01522-8","article-title":"Two new families and a literature review of ELOVL4-associated spinocerebellar ataxia type 34","volume":"23","author":"Nishide","year":"2023","journal-title":"Cerebellum"},{"key":"B60","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1038\/nmeth.4197","article-title":"Salmon provides fast and bias-aware quantification of transcript expression","volume":"14","author":"Patro","year":"2017","journal-title":"Nat. Methods"},{"key":"B61","doi-asserted-by":"publisher","first-page":"2802","DOI":"10.3390\/ijms21082802","article-title":"Clinical spectrum of KCNA1 mutations: new insights into episodic ataxia and epilepsy comorbidity","volume":"21","author":"Paulhus","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B62","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1056\/NEJMoa2207406","article-title":"Deep intronic FGF14 GAA repeat expansion in late-onset cerebellar ataxia","volume":"388","author":"Pellerin","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"B63","doi-asserted-by":"publisher","first-page":"13509","DOI":"10.1038\/s41598-017-13841-y","article-title":"Evaluating phenotype-driven approaches for genetic diagnoses from exomes in a clinical setting","volume":"7","author":"Pengelly","year":"2017","journal-title":"Sci. Rep."},{"key":"B64","article-title":"Hereditary ataxia overview","volume-title":"GeneReviews","author":"Perlman","year":"1993"},{"key":"B65","doi-asserted-by":"publisher","first-page":"1174","DOI":"10.1212\/WNL.0000000000001369","article-title":"SPG7 mutations are a common cause of undiagnosed ataxia","volume":"84","author":"Pfeffer","year":"2015","journal-title":"Neurology"},{"key":"B66","doi-asserted-by":"publisher","first-page":"239","DOI":"10.3390\/genes11030239","article-title":"Genetic modifiers and rare mendelian disease","volume":"11","author":"Rahit","year":"2020","journal-title":"Genes (Basel)"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1101\/2023.05.15.540865","article-title":"The ENCODE4 long-read RNA-seq collection reveals distinct classes of transcript structure diversity","author":"Reese","year":"2023"},{"key":"B68","doi-asserted-by":"publisher","first-page":"100947","DOI":"10.1016\/j.gim.2023.100947","article-title":"The landscape of reported VUS in multi-gene panel and genomic testing: time for a change","volume":"25","author":"Rehm","year":"2023","journal-title":"Genet. Med."},{"key":"B69","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/s13073-021-00835-9","article-title":"CADD-Splice-improving genome-wide variant effect prediction using deep learning-derived splice scores","volume":"13","author":"Rentzsch","year":"2021","journal-title":"Genome Med."},{"key":"B70","doi-asserted-by":"publisher","first-page":"D886","DOI":"10.1093\/nar\/gky1016","article-title":"CADD: predicting the deleteriousness of variants throughout the human genome","volume":"47","author":"Rentzsch","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"B71","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"B72","doi-asserted-by":"publisher","first-page":"e200021","DOI":"10.1212\/NXG.0000000000200021","article-title":"Overview of the clinical approach to individuals with cerebellar ataxia and neuropathy","volume":"8","author":"Roberts","year":"2022","journal-title":"Neurol. Genet."},{"key":"B73","doi-asserted-by":"publisher","first-page":"2648","DOI":"10.1093\/hmg\/ddz081","article-title":"Pathogenic effects of agrin V1727F mutation are isoform specific and decrease its expression and affinity for HSPGs and LRP4","volume":"28","author":"Rudell","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"B74","doi-asserted-by":"publisher","first-page":"2003","DOI":"10.1093\/brain\/awac391","article-title":"The clinical and molecular spectrum of ZFYVE26-associated hereditary spastic paraplegia: SPG15","volume":"146","author":"Saffari","year":"2023","journal-title":"Brain"},{"key":"B75","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1097\/MOP.0000000000000283","article-title":"Mutations in the noncoding genome","volume":"27","author":"Scacheri","year":"2015","journal-title":"Curr. Opin. Pediatr."},{"key":"B76","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1007\/s12311-018-0997-3","article-title":"Acetazolamide-responsive episodic ataxia linked to novel splice site variant in FGF14 gene","volume":"18","author":"Schesny","year":"2019","journal-title":"Cerebellum"},{"key":"B77","doi-asserted-by":"publisher","first-page":"1717","DOI":"10.1212\/01.wnl.0000219042.60538.92","article-title":"Scale for the assessment and rating of ataxia: development of a new clinical scale","volume":"66","author":"Schmitz-Hubsch","year":"2006","journal-title":"Neurology"},{"key":"B78","doi-asserted-by":"publisher","first-page":"3521","DOI":"10.1093\/hmg\/ddn244","article-title":"The in vivo mitochondrial two-step maturation of human frataxin","volume":"17","author":"Schmucker","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"B79","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1007\/s00415-015-7984-0","article-title":"Mutations in the sodium channel gene SCN2A cause neonatal epilepsy with late-onset episodic ataxia","volume":"263","author":"Schwarz","year":"2016","journal-title":"J. Neurol."},{"key":"B80","doi-asserted-by":"publisher","first-page":"E5593","DOI":"10.1073\/pnas.1419161111","article-title":"rMATS: robust and flexible detection of differential alternative splicing from replicate RNA-Seq data","volume":"111","author":"Shen","year":"2014","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B81","doi-asserted-by":"publisher","first-page":"2514","DOI":"10.1038\/s41598-017-02554-x","article-title":"Mutation spectrum in the CACNA1A gene in 49 patients with episodic ataxia","volume":"7","author":"Sintas","year":"2017","journal-title":"Sci. Rep."},{"key":"B82","doi-asserted-by":"publisher","first-page":"W446","DOI":"10.1093\/nar\/gkab266","article-title":"MutationTaster2021","volume":"49","author":"Steinhaus","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"B83","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/cpbi.5","article-title":"The GeneCards suite: from gene data mining to disease genome sequence analyses","volume":"54","author":"Stelzer","year":"2016","journal-title":"Curr. Protoc. Bioinforma."},{"key":"B84","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/B978-0-12-821751-1.00009-9","article-title":"Ataxia and spastic paraplegia in mitochondrial disease","volume":"194","author":"Synofzik","year":"2023","journal-title":"Handb. Clin. Neurol."},{"key":"B85","doi-asserted-by":"publisher","first-page":"e1004873","DOI":"10.1371\/journal.pcbi.1004873","article-title":"CNVkit: genome-wide copy number detection and visualization from targeted DNA sequencing","volume":"12","author":"Talevich","year":"2016","journal-title":"PLoS Comput. Biol."},{"key":"B86","doi-asserted-by":"publisher","first-page":"1438","DOI":"10.1038\/s41467-020-15171-6","article-title":"Full-length transcript characterization of SF3B1 mutation in chronic lymphocytic leukemia reveals downregulation of retained introns","volume":"11","author":"Tang","year":"2020","journal-title":"Nat. Commun."},{"key":"B87","doi-asserted-by":"publisher","first-page":"1477","DOI":"10.1093\/brain\/awv074","article-title":"Adult-onset painful axonal polyneuropathy caused by a dominant NAGLU mutation","volume":"138","author":"Tetreault","year":"2015","journal-title":"Brain"},{"key":"B88","doi-asserted-by":"publisher","first-page":"e1369","DOI":"10.1212\/WNL.0000000000011528","article-title":"Natural history, phenotypic spectrum, and discriminative features of multisystemic RFC1 disease","volume":"96","author":"Traschutz","year":"2021","journal-title":"Neurology"},{"key":"B89","doi-asserted-by":"publisher","first-page":"eaax9198","DOI":"10.1126\/science.aax9198","article-title":"A genome-wide transcriptomic analysis of protein-coding genes in human blood cells","volume":"366","author":"Uhlen","year":"2019","journal-title":"Science"},{"key":"B90","doi-asserted-by":"publisher","first-page":"D523","DOI":"10.1093\/nar\/gkac1052","article-title":"UniProt: the universal protein knowledgebase in 2023","volume":"51","author":"UniProt","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"B91","doi-asserted-by":"publisher","first-page":"e115","DOI":"10.1093\/nar\/gks596","article-title":"Primer3--new capabilities and interfaces","volume":"40","author":"Untergasser","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"B92","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1016\/j.ajhg.2018.02.014","article-title":"Mutations in PMPCB encoding the catalytic subunit of the mitochondrial presequence protease cause neurodegeneration in early childhood","volume":"102","author":"Vogtle","year":"2018","journal-title":"Am. J. Hum. Genet."},{"key":"B93","doi-asserted-by":"publisher","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"B94","doi-asserted-by":"publisher","first-page":"1130","DOI":"10.1111\/ene.13954","article-title":"(CAG)(n) loci as genetic modifiers of age at onset in patients with spinocerebellar ataxia type 1 from mainland China","volume":"26","author":"Wang","year":"2019","journal-title":"Eur. J. Neurol."},{"key":"B95","doi-asserted-by":"publisher","first-page":"1131","DOI":"10.1002\/mds.29005","article-title":"The movement disorder society criteria for the diagnosis of multiple system atrophy","volume":"37","author":"Wenning","year":"2022","journal-title":"Mov. Disord."},{"key":"B96","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1186\/s13059-019-1727-y","article-title":"Performance of neural network basecalling tools for Oxford Nanopore sequencing","volume":"20","author":"Wick","year":"2019","journal-title":"Genome Biol."},{"key":"B97","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1186\/s13073-022-01019-9","article-title":"Clinical implementation of RNA sequencing for Mendelian disease diagnostics","volume":"14","author":"Yepez","year":"2022","journal-title":"Genome Med."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2023.1304711\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,4]],"date-time":"2024-01-04T05:02:22Z","timestamp":1704344542000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2023.1304711\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,4]]},"references-count":97,"alternative-id":["10.3389\/fgene.2023.1304711"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2023.1304711","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,4]]},"article-number":"1304711"}}