Recent Advances in the Genetics of Ataxias: An Update on Novel Autosomal Dominant Repeat Expansions

Klockgether T, Mariotti C, Paulson HL. Spinocerebellar ataxia. Nat Rev Dis Primers. 2019;5(1):24.

Article  PubMed  Google Scholar 

Sullivan R, Yau WY, O’Connor E, Houlden H. Spinocerebellar ataxia: an update. J Neurol. 2019;266(2):533–44.

Article  PubMed  Google Scholar 

Coarelli G, Coutelier M, Durr A. Autosomal dominant cerebellar ataxias: new genes and progress towards treatments. Lancet Neurol. 2023;22(8):735–49.

Article  CAS  PubMed  Google Scholar 

Ruano L, Melo C, Silva MC, Coutinho P. The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies. Neuroepidemiology. 2014;42(3):174–83.

Article  PubMed  Google Scholar 

Rudaks LI, Yeow D, Ng K, Deveson IW, Kennerson ML, Kumar KR. An Update on the Adult-Onset Hereditary Cerebellar Ataxias: Novel Genetic Causes and New Diagnostic Approaches. Cerebellum. 2024;23(5):2152–68.

Article  PubMed  PubMed Central  Google Scholar 

Hengel H, Pellerin D, Wilke C, Fleszar Z, Brais B, Haack T, et al. As Frequent as Polyglutamine Spinocerebellar Ataxias: SCA27B in a Large German Autosomal Dominant Ataxia Cohort. Mov Disord. 2023;38(8):1557–8.

Article  CAS  PubMed  Google Scholar 

Durr A. Autosomal dominant cerebellar ataxias: polyglutamine expansions and beyond. Lancet Neurol. 2010;9(9):885–94.

Article  CAS  PubMed  Google Scholar 

Chen Z, Wang P, Wang C, Peng Y, Hou X, Zhou X, et al. Updated frequency analysis of spinocerebellar ataxia in China. Brain. 2018;141(4):e22.

Article  PubMed  Google Scholar 

Alshimemeri S, Abo Alsamh D, Zhou L, Furtado S, Kraft S, Bruno V, et al. Demographics and Clinical Characteristics of Autosomal Dominant Spinocerebellar Ataxia in Canada. Mov Disord Clin Pract. 2023;10(3):440–51.

Article  PubMed  PubMed Central  Google Scholar 

Perlman S. Hereditary Ataxia Overview. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews(®). Seattle (WA): University of Washington, Seattle Copyright © 1993–2024, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved 1993

Coutinho P, Ruano L, Loureiro JL, Cruz VT, Barros J, Tuna A, et al. Hereditary ataxia and spastic paraplegia in Portugal: a population-based prevalence study. JAMA Neurol. 2013;70(6):746–55.

Article  PubMed  Google Scholar 

Barbier M, Bahlo M, Pennisi A, Jacoupy M, Tankard RM, Ewenczyk C, et al. Heterozygous PNPT1 Variants Cause Spinocerebellar Ataxia Type 25. Ann Neurol. 2022;92(1):122–37.

Article  CAS  PubMed  Google Scholar 

Coutelier M, Jacoupy M, Janer A, Renaud F, Auger N, Saripella GV, et al. NPTX1 mutations trigger endoplasmic reticulum stress and cause autosomal dominant cerebellar ataxia. Brain. 2022;145(4):1519–34.

Article  PubMed  Google Scholar 

Corral-Juan M, Casquero P, Giraldo-Restrepo N, Laurie S, Martinez-Piñeiro A, Mateo-Montero RC, et al. New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49). Brain Commun. 2022;4(2):fcac030.

Article  PubMed  PubMed Central  Google Scholar 

Mantere T, Kersten S, Hoischen A. Long-Read Sequencing Emerging in Medical Genetics. Front Genet. 2019;10:426.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kernohan KD, Boycott KM. The expanding diagnostic toolbox for rare genetic diseases. Nat Rev Genet. 2024;25(6):401–15.

Article  CAS  PubMed  Google Scholar 

Tanudisastro HA, Deveson IW, Dashnow H, MacArthur DG. Sequencing and characterizing short tandem repeats in the human genome. Nat Rev Genet. 2024;25(7):460–75.

Article  CAS  PubMed  Google Scholar 

Dolzhenko E, English A, Dashnow H, De Sena Brandine G, Mokveld T, Rowell WJ, Karniski C, Kronenberg Z, Danzi MC, Cheung WA, Bi C, Farrow E, Wenger A, Chua KP, Martínez-Cerdeño V, Bartley TD, Jin P, Nelson DL, Zuchner S, Pastinen T, ... Eberle MA. Characterization and visualization of tandem repeats at genome scale. Nat Biotechnol. 2024;42(10):1606–14. https://doi.org/10.1038/s41587-023-02057-3.

Article  CAS  PubMed  Google Scholar 

Dolzhenko E, Bennett MF, Richmond PA, Trost B, Chen S, van Vugt J, et al. ExpansionHunter Denovo: a computational method for locating known and novel repeat expansions in short-read sequencing data. Genome Biol. 2020;21(1):102.

Article  PubMed  PubMed Central  Google Scholar 

Danzi MC, Dohrn MF, Fazal S, Beijer D, Rebelo AP, Cintra V, et al. Deep structured learning for variant prioritization in Mendelian diseases. Nat Commun. 2023;14(1):4167.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Fazal S, Danzi MC, Xu I, Kobren SN, Sunyaev S, Reuter C, et al. RExPRT: a machine learning tool to predict pathogenicity of tandem repeat loci. Genome Biol. 2024;25(1):39.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Vegezzi E, Ishiura H, Bragg DC, Pellerin D, Magrinelli F, Currò R, et al. Neurological disorders caused by novel non-coding repeat expansions: clinical features and differential diagnosis. Lancet Neurol. 2024;23(7):725–39.

Article  CAS  PubMed  Google Scholar 

Cortese A, Simone R, Sullivan R, Vandrovcova J, Tariq H, Yau WY, et al. Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia. Nat Genet. 2019;51(4):649–58.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Rafehi H, Szmulewicz DJ, Bennett MF, Sobreira NLM, Pope K, Smith KR, et al. Bioinformatics-Based Identification of Expanded Repeats: A Non-reference Intronic Pentamer Expansion in RFC1 Causes CANVAS. Am J Hum Genet. 2019;105(1):151–65.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Jadhav B, Garg P, van Vugt J, Ibanez K, Gagliardi D, Lee W, et al. A phenome-wide association study of methylated GC-rich repeats identifies a GCC repeat expansion in AFF3 associated with intellectual disability. Nat Genet. 2024;56(11):2322–32.

Article  CAS  PubMed  Google Scholar 

Pellerin D, Danzi MC, Wilke C, Renaud M, Fazal S, Dicaire MJ, et al. Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia. N Engl J Med. 2023;388(2):128–41.

Article  CAS  PubMed  Google Scholar 

Rafehi H, Read J, Szmulewicz DJ, Davies KC, Snell P, Fearnley LG, et al. An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA27B/ATX-FGF14. Am J Hum Genet. 2023;110(6):1018.

Article  PubMed  PubMed Central  Google Scholar 

Chen Z, Gustavsson EK, Macpherson H, Anderson C, Clarkson C, Rocca C, et al. Adaptive Long-Read Sequencing Reveals GGC Repeat Expansion in ZFHX3 Associated with Spinocerebellar Ataxia Type 4. Mov Disord. 2024;39(3):486–97.

Article  CAS  PubMed  Google Scholar 

Figueroa KP, Gross C, Buena-Atienza E, Paul S, Gandelman M, Kakar N, et al. A GGC-repeat expansion in ZFHX3 encoding polyglycine causes spinocerebellar ataxia type 4 and impairs autophagy. Nat Genet. 2024;56(6):1080–9.

Article  CAS  PubMed  Google Scholar 

Wallenius J, Kafantari E, Jhaveri E, Gorcenco S, Ameur A, Karremo C, et al. Exonic trinucleotide repeat expansions in ZFHX3 cause spinocerebellar ataxia type 4: A poly-glycine disease. Am J Hum Genet. 2024;111(1):82–95.

Article  CAS  PubMed  Google Scholar 

Paucar M, Nilsson D, Engvall M, Laffita-Mesa J, Söderhäll C, Skorpil M, Halldin C, Fazio P, Lagerstedt-Robinson K, Solders G, Angeria M, Varrone A, Risling M, Jiao H, Nennesmo I, Wedell A, Svenningsson P. Spinocerebellar ataxia type 4 is caused by a GGC expansion in the ZFHX3 gene and is associated with prominent dysautonomia and motor neuron signs. J Intern Med. 2024;296(3):234–48. https://doi.org/10.1111/joim.13815.

Article  CAS  PubMed 

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