{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T13:31:31Z","timestamp":1768570291255,"version":"3.49.0"},"posted":{"date-parts":[[2025,4,22]]},"group-title":"Genetic and Genomic Medicine","reference-count":46,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,4,22]],"date-time":"2025-04-22T00:00:00Z","timestamp":1745280000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>\n                    Biallelic intronic AAGGG repeat expansions in\n                    <jats:italic>RFC1<\/jats:italic>\n                    cause Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome and may also contribute to isolated sensory neuropathy. The clinical significance of both heterozygous and biallelic\n                    <jats:italic>RFC1<\/jats:italic>\n                    expansions in more diverse patient populations remains unclear\u2014partly due to the absence of accurate, user-friendly computational pipelines specifically tailored for tandem repeat analysis.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    To discern the relationship between\n                    <jats:italic>RFC1<\/jats:italic>\n                    expansions and idiopathic peripheral neuropathy (iPN), we performed whole-genome sequencing (WGS) followed by PCR-based confirmation in a large, well-characterized U.S. cohort consisting of 788 iPN patients (369 pure small fiber neuropathy (SFN), 266 sensorimotor, 144 pure sensory, and 9 pure motor). We developed an integrative pipeline combining ExpansionHunter Denovo and ExpansionHunter coupled with unsupervised clustering to reliably detect and genotype\n                    <jats:italic>RFC1<\/jats:italic>\n                    expansions from short-read WGS data, achieving 98.2% concordance with repeat-primed PCR based validation.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Biallelic\n                    <jats:italic>RFC1<\/jats:italic>\n                    expansions were present in only one out of 854 controls but present in 2.3% of iPN patients (Fisher\u2019s exact\n                    <jats:italic>p<\/jats:italic>\n                    = 2\u00d710\n                    <jats:sup>-5<\/jats:sup>\n                    ), including 6.9% of pure sensory, 1.1% of SFN, and 1.5% of sensorimotor neuropathy, indicating that motor nerve involvement should not exclude patients from\n                    <jats:italic>RFC1<\/jats:italic>\n                    repeat screening. We also observed an increased frequency of monoallelic expansions in iPN compared to controls (9.4% versus 6.3%; Fisher\u2019s exact\n                    <jats:italic>p<\/jats:italic>\n                    = 0.02), without evidence of secondary mutations or expansions on the other allele.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Interpretation<\/jats:title>\n                  <jats:p>\n                    Our approach provides a robust, cost-effective method for detecting\n                    <jats:italic>RFC1<\/jats:italic>\n                    expansions from WGS data. Our findings indicate that both heterozygous and homozygous AAGGG repeat expansions in\n                    <jats:italic>RFC1<\/jats:italic>\n                    contribute to development of iPN.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.04.18.25325809","type":"posted-content","created":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T02:15:20Z","timestamp":1745374520000},"source":"Crossref","is-referenced-by-count":0,"title":["Heterozygous and Homozygous\n                  <i>RFC1 AAGGG<\/i>\n                  Repeat Expansions are Common in Idiopathic Peripheral Neuropathy"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5159-5695","authenticated-orcid":false,"given":"Zitian","family":"Tang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sinem S.","family":"Ovunc","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryo","family":"Iwase","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elle","family":"Mehinovic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9172-2876","authenticated-orcid":false,"given":"Simone","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jenna","family":"Ulibarri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zefan","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dustin","family":"Baldridge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0276-2899","authenticated-orcid":false,"given":"Carlos","family":"Cruchaga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matt","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5477-7689","authenticated-orcid":false,"given":"Jeffrey","family":"Milbrandt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian","family":"Callaghan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"PNRR Study Group","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1215-3373","authenticated-orcid":false,"given":"Ahmet","family":"H\u00f6ke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4781-6376","authenticated-orcid":false,"given":"Peter K.","family":"Todd","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5777-7262","authenticated-orcid":false,"given":"Sheng Chih","family":"Jin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"issue":"1","key":"2025101005100467000_2025.04.18.25325809v3.1","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s42466-020-00064-2","article-title":"Diagnosis of peripheral neuropathy","volume":"2","year":"2020","journal-title":"Neurol. Res. Pract"},{"issue":"1","key":"2025101005100467000_2025.04.18.25325809v3.2","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1212\/WNL.0000000000001714","article-title":"Longitudinal patient-oriented outcomes in neuropathy","volume":"85","year":"2015","journal-title":"Neurology"},{"key":"2025101005100467000_2025.04.18.25325809v3.3","doi-asserted-by":"publisher","DOI":"10.1111\/j.1529-8027.2012.00395.x"},{"key":"2025101005100467000_2025.04.18.25325809v3.4","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000011132"},{"key":"2025101005100467000_2025.04.18.25325809v3.5","unstructured":"PEPAN - Overview: Comprehensive Peripheral Neuropathy Gene Panel, Varies [Internet]. [date unknown];[cited 2023 Dec 4] Available from: https:\/\/www.mayocliniclabs.com\/test-catalog\/Overview\/617688"},{"key":"2025101005100467000_2025.04.18.25325809v3.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2017.01.012"},{"key":"2025101005100467000_2025.04.18.25325809v3.7","doi-asserted-by":"publisher","DOI":"10.1101\/gr.269530.120"},{"key":"2025101005100467000_2025.04.18.25325809v3.8","unstructured":"Deynze KV , Mumm C , Maltby CJ , et al. Enhanced Detection and Genotyping of Disease-Associated Tandem Repeats Using HMMSTR and Targeted Long-Read Sequencing [Internet]. 2024;2024.05.01.24306681.[cited 2024 Sep 9] Available from: https:\/\/www.medrxiv.org\/content\/10.1101\/2024.05.01.24306681v1"},{"key":"2025101005100467000_2025.04.18.25325809v3.9","doi-asserted-by":"publisher","DOI":"10.1016\/S1672-0229(07)60009-6"},{"issue":"6","key":"2025101005100467000_2025.04.18.25325809v3.10","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1086\/430427","article-title":"Human Evolutionary Genetics: Origins, Peoples and Disease","volume":"76","year":"2005","journal-title":"Am J Hum Genet"},{"key":"2025101005100467000_2025.04.18.25325809v3.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-021-00382-6"},{"key":"2025101005100467000_2025.04.18.25325809v3.12","doi-asserted-by":"publisher","DOI":"10.1101\/gr.177774.114"},{"key":"2025101005100467000_2025.04.18.25325809v3.13","doi-asserted-by":"publisher","DOI":"10.1038\/nature18964"},{"key":"2025101005100467000_2025.04.18.25325809v3.14","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-020-02017-z"},{"key":"2025101005100467000_2025.04.18.25325809v3.15","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btz431"},{"key":"2025101005100467000_2025.04.18.25325809v3.16","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz501"},{"key":"2025101005100467000_2025.04.18.25325809v3.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.10.015"},{"key":"2025101005100467000_2025.04.18.25325809v3.18","doi-asserted-by":"crossref","unstructured":"Sullivan R , Chen S , Saunders CT , et al. RFC1 repeat expansion analysis from whole genome sequencing data simplifies screening and increases diagnostic rates [Internet]. 2024;2024.02.28.24303510.[cited 2025 Oct 3] Available from: https:\/\/www.medrxiv.org\/content\/10.1101\/2024.02.28.24303510v1","DOI":"10.1101\/2024.02.28.24303510"},{"key":"2025101005100467000_2025.04.18.25325809v3.19","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awz418"},{"key":"2025101005100467000_2025.04.18.25325809v3.20","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0372-4"},{"key":"2025101005100467000_2025.04.18.25325809v3.21","doi-asserted-by":"publisher","DOI":"10.1093\/BRAIN\/AWAB072"},{"key":"2025101005100467000_2025.04.18.25325809v3.22","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000200016"},{"key":"2025101005100467000_2025.04.18.25325809v3.23","doi-asserted-by":"publisher","DOI":"10.1126\/science.aax9198"},{"issue":"5","key":"2025101005100467000_2025.04.18.25325809v3.24","doi-asserted-by":"crossref","first-page":"1887","DOI":"10.1093\/brain\/awad436","article-title":"Role of the repeat expansion size in predicting age of onset and severity in RFC1 disease","volume":"147","year":"2024","journal-title":"Brain"},{"key":"2025101005100467000_2025.04.18.25325809v3.25","doi-asserted-by":"publisher","DOI":"10.1093\/BRAIN\/AWAA263"},{"issue":"12","key":"2025101005100467000_2025.04.18.25325809v3.26","doi-asserted-by":"crossref","first-page":"5060","DOI":"10.1093\/brain\/awad240","article-title":"Normal and pathogenic variation of RFC1 repeat expansions: implications for clinical diagnosis","volume":"146","year":"2023","journal-title":"Brain"},{"key":"2025101005100467000_2025.04.18.25325809v3.27","doi-asserted-by":"crossref","unstructured":"Ronco R , Perini C , Curr\u00f2 R , et al. Truncating Variants in RFC1 in Cerebellar Ataxia, Neuropathy, and Vestibular Areflexia Syndrome [Internet]. Neurology 2023;100(5)[cited 2025 Apr 1] Available from: https:\/\/www.neurology.org\/doi\/10.1212\/WNL.0000000000201486","DOI":"10.1212\/WNL.0000000000201486"},{"issue":"3","key":"2025101005100467000_2025.04.18.25325809v3.28","doi-asserted-by":"crossref","first-page":"e14","DOI":"10.1093\/brain\/awac466","article-title":"Two RFC1 splicing variants in CANVAS","volume":"146","year":"2023","journal-title":"Brain"},{"issue":"36","key":"2025101005100467000_2025.04.18.25325809v3.29","doi-asserted-by":"crossref","first-page":"eadn2321","DOI":"10.1126\/sciadv.adn2321","article-title":"AAGGG repeat expansions trigger RFC1-independent synaptic dysregulation in human CANVAS neurons","volume":"10","year":"2024","journal-title":"Science Advances"},{"key":"2025101005100467000_2025.04.18.25325809v3.30","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.008706"},{"key":"2025101005100467000_2025.04.18.25325809v3.31","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp352"},{"key":"2025101005100467000_2025.04.18.25325809v3.32","unstructured":"NVIDIA. Clara Parabricks [Internet]. 2025;Available from: https:\/\/www.nvidia.com\/en-us\/clara\/genomics\/"},{"key":"2025101005100467000_2025.04.18.25325809v3.33","unstructured":"Li H. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM [Internet]. 2013;[cited 2025 Feb 27] Available from: http:\/\/arxiv.org\/abs\/1303.3997"},{"key":"2025101005100467000_2025.04.18.25325809v3.34","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"2025101005100467000_2025.04.18.25325809v3.35","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq603"},{"key":"2025101005100467000_2025.04.18.25325809v3.36","unstructured":"Smit A , Hubley R , Green P. RepeatMasker Open-4.0 [Internet]. 2013;Available from: http:\/\/www.repeatmasker.org"},{"key":"2025101005100467000_2025.04.18.25325809v3.37","doi-asserted-by":"crossref","unstructured":"Poplin R , Ruano-Rubio V , DePristo MA , et al. Scaling accurate genetic variant discovery to tens of thousands of samples [Internet]. 2018;201178.[cited 2025 Apr 4] Available from: https:\/\/www.biorxiv.org\/content\/10.1101\/201178v3","DOI":"10.1101\/201178"},{"issue":"2","key":"2025101005100467000_2025.04.18.25325809v3.38","first-page":"80","article-title":"A program for annotating and predicting the effects of single nucleotide polymorphisms","volume":"6","year":"2012","journal-title":"SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118L"},{"key":"2025101005100467000_2025.04.18.25325809v3.39","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad1049"},{"key":"2025101005100467000_2025.04.18.25325809v3.40","doi-asserted-by":"crossref","unstructured":"Cingolani P , Patel VM , Coon M , et al. Using Drosophila melanogaster as a Model for Genotoxic Chemical Mutational Studies with a New Program, SnpSift [Internet]. Front. Gene. 2012;3[cited 2025 Apr 4] Available from: http:\/\/journal.frontiersin.org\/article\/10.3389\/fgene.2012.00035\/abstract","DOI":"10.3389\/fgene.2012.00035"},{"key":"2025101005100467000_2025.04.18.25325809v3.41","doi-asserted-by":"publisher","DOI":"10.1111\/jns.12301"},{"key":"2025101005100467000_2025.04.18.25325809v3.42","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000336370.51010.a1"},{"key":"2025101005100467000_2025.04.18.25325809v3.43","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-021-10552-3"},{"key":"2025101005100467000_2025.04.18.25325809v3.44","doi-asserted-by":"crossref","unstructured":"Danzi MC , Xu IRL , Fazal S , et al. Detailed tandem repeat allele profiling in 1,027 long-read genomes reveals genome-wide patterns of pathogenicity [Internet]. 2025;2025.01.06.631535.[cited 2025 Sep 22] Available from: https:\/\/www.biorxiv.org\/content\/10.1101\/2025.01.06.631535v2","DOI":"10.1101\/2025.01.06.631535"},{"key":"2025101005100467000_2025.04.18.25325809v3.45","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-03190-5"},{"key":"2025101005100467000_2025.04.18.25325809v3.46","doi-asserted-by":"publisher","DOI":"10.1038\/nature15393"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.04.18.25325809","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:34:15Z","timestamp":1768509255000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2025.04.18.25325809"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,22]]},"references-count":46,"URL":"https:\/\/doi.org\/10.1101\/2025.04.18.25325809","relation":{},"subject":[],"published":{"date-parts":[[2025,4,22]]},"subtype":"preprint"}}