Short tandem repeat expansions in sporadic amyotrophic lateral sclerosis and frontotemporal dementia

Pathogenic short tandem repeat (STR) expansions cause over 20 neurodegenerative diseases. To determine the contribution of STRs in sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), we used ExpansionHunter, REviewer, and polymerase chain reaction validation to assess 21 neurodegenerative disease-associated STRs in whole-genome sequencing data from 608 patients with sporadic ALS, 68 patients with sporadic FTD, and 4703 matched controls. We also propose a data-derived outlier detection method for defining allele thresholds in rare STRs. Excluding C9orf72 repeat expansions, 17.6% of clinically diagnosed ALS and FTD cases had at least one expanded STR allele reported to be pathogenic or intermediate for another neurodegenerative disease. We identified and validated 162 disease-relevant STR expansions in C9orf72 (ALS/FTD), ATXN1 [spinal cerebellar ataxia type 1 (SCA1)], ATXN2 (SCA2), ATXN8 (SCA8), TBP (SCA17), HTT (Huntington’s disease), DMPK [myotonic dystrophy type 1 (DM1)], CNBP (DM2), and FMR1 (fragile-X disorders). Our findings suggest clinical and pathological pleiotropy of neurodegenerative disease genes and highlight their importance in ALS and FTD.

[1]  Katherine R. Smith,et al.  Whole genome sequencing for the diagnosis of neurological repeat expansion disorders in the UK: a retrospective diagnostic accuracy and prospective clinical validation study , 2022, The Lancet Neurology.

[2]  Phillip A. Richmond,et al.  REViewer: haplotype-resolved visualization of read alignments in and around tandem repeats , 2021, Genome Medicine.

[3]  Ewout J. N. Groen,et al.  Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology , 2021, Nature Genetics.

[4]  Ewout J. N. Groen,et al.  Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology , 2021, Nature Genetics.

[5]  K. Marder,et al.  Amyotrophic lateral sclerosis is over-represented in two Huntington’s disease brain bank cohorts: further evidence to support genetic pleiotropy of pathogenic HTT gene expansion , 2021, Acta Neuropathologica.

[6]  Lauren A. Laboissonniere,et al.  CCG•CGG interruptions in high‐penetrance SCA8 families increase RAN translation and protein toxicity , 2021, EMBO molecular medicine.

[7]  Eric T. Wang,et al.  Molecular mechanisms underlying nucleotide repeat expansion disorders , 2021, Nature Reviews Molecular Cell Biology.

[8]  Ira W. Deveson,et al.  An update on the neurological short tandem repeat expansion disorders and the emergence of long-read sequencing diagnostics , 2021, Acta neuropathologica communications.

[9]  C. Depienne,et al.  30 years of repeat expansion disorders: What have we learned and what are the remaining challenges? , 2021, American journal of human genetics.

[10]  Lauren A. Laboissonniere,et al.  CCG•CGG interruptions in high penetrance SCA8 families increase RAN translation and protein toxicity , 2021, bioRxiv.

[11]  P. Kwan,et al.  The clinical utility of exome sequencing and extended bioinformatic analyses in adolescents and adults with a broad range of neurological phenotypes: an Australian perspective , 2020, Journal of the Neurological Sciences.

[12]  Aleksey Shatunov,et al.  The genetic architecture of ALS , 2020, Neurobiology of Disease.

[13]  Timothy A. Miller,et al.  Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis. , 2020, Neuron.

[14]  OUP accepted manuscript , 2021, Brain.

[15]  A. Al-Chalabi,et al.  Improving clinical trial outcomes in amyotrophic lateral sclerosis , 2020, Nature Reviews Neurology.

[16]  P. van Damme,et al.  TDP-43 proteinopathies: a new wave of neurodegenerative diseases , 2020, Journal of Neurology, Neurosurgery, and Psychiatry.

[17]  G. Rouleau,et al.  Expanded CAG Repeats in ATXN1, ATXN2, ATXN3, and HTT in the 1000 Genomes Project , 2020, Movement disorders : official journal of the Movement Disorder Society.

[18]  B. Tang,et al.  Identification of GGC repeat expansion in the NOTCH2NLC gene in amyotrophic lateral sclerosis , 2020, Neurology.

[19]  Denis C. Bauer,et al.  Identity by descent analysis identifies founder events and links SOD1 familial and sporadic ALS cases. , 2020, NPJ genomic medicine.

[20]  Denis C. Bauer,et al.  Identity by descent analysis identifies founder events and links SOD1 familial and sporadic ALS cases , 2020, npj Genomic Medicine.

[21]  S. Scherer,et al.  Genome-wide detection of tandem DNA repeats that are expanded in autism , 2020, Nature.

[22]  J. Kirby,et al.  Multifaceted Genes in Amyotrophic Lateral Sclerosis-Frontotemporal Dementia , 2020, Frontiers in Neuroscience.

[23]  Annelot M. Dekker,et al.  ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization , 2020, Brain communications.

[24]  Denis C. Bauer,et al.  Evidence for polygenic and oligogenic basis of Australian sporadic amyotrophic lateral sclerosis , 2020, Journal of Medical Genetics.

[25]  D. Burke,et al.  A proposal for new diagnostic criteria for ALS , 2020, Clinical Neurophysiology.

[26]  J. Hodges,et al.  Phenotypic variability in ALS-FTD and effect on survival , 2020, Neurology.

[27]  B. Traynor,et al.  The Overlapping Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia , 2020, Frontiers in Neuroscience.

[28]  C. van Broeckhoven,et al.  author-version of: Role for ATXN1, ATXN2, and HTT intermediate repeats in frontotemporal dementia and Alzheimer's disease , 2022 .

[29]  Ryan L. Collins,et al.  The mutational constraint spectrum quantified from variation in 141,456 humans , 2020, Nature.

[30]  O. Hardiman,et al.  Lifetime Risk and Heritability of Amyotrophic Lateral Sclerosis. , 2019, JAMA neurology.

[31]  T. Matsukawa,et al.  Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease , 2019, Nature Genetics.

[32]  Melanie Bahlo,et al.  Bioinformatics-Based Identification of Expanded Repeats: A Non-reference Intronic Pentamer Expansion in RFC1 Causes CANVAS , 2019, American journal of human genetics.

[33]  R. Roos,et al.  Prevalence of Carriers of Intermediate and Pathological Polyglutamine Disease-Associated Alleles Among Large Population-Based Cohorts. , 2019, JAMA neurology.

[34]  Konrad Scheffler,et al.  ExpansionHunter: a sequence-graph-based tool to analyze variation in short tandem repeat regions , 2019, Bioinformatics.

[35]  J. Rohrer,et al.  An update on genetic frontotemporal dementia , 2019, Journal of Neurology.

[36]  T. Lynch,et al.  Autosomal Dominant Gene Negative Frontotemporal Dementia-Think of SCA17 , 2019, The Cerebellum.

[37]  Melanie Bahlo,et al.  Recent advances in the detection of repeat expansions with short-read next-generation sequencing , 2018, F1000Research.

[38]  Yeting Zhang,et al.  Functional equivalence of genome sequencing analysis pipelines enables harmonized variant calling across human genetics projects , 2018, Nature Communications.

[39]  M. Bee,et al.  ATXN1 intermediate-length polyglutamine expansions are associated with amyotrophic lateral sclerosis , 2017, Neurobiology of Aging.

[40]  N. Pearce,et al.  The multistep hypothesis of ALS revisited , 2018, Neurology.

[41]  P. Giunti,et al.  Friedreich’s ataxia: clinical features, pathogenesis and management , 2017, British medical bulletin.

[42]  D. Rowe,et al.  The genotype–phenotype landscape of familial amyotrophic lateral sclerosis in Australia , 2017, Clinical genetics.

[43]  Patrizia Rizzu,et al.  A Pentanucleotide ATTTC Repeat Insertion in the Non-coding Region of DAB1, Mapping to SCA37, Causes Spinocerebellar Ataxia. , 2017, American journal of human genetics.

[44]  J. Rowe,et al.  Genetic screening in sporadic ALS and FTD , 2017, Journal of Neurology, Neurosurgery, and Psychiatry.

[45]  Ashley R. Jones,et al.  ATXN2 trinucleotide repeat length correlates with risk of ALS , 2017, Neurobiology of Aging.

[46]  Chris Shaw,et al.  Detection of long repeat expansions from PCR-free whole-genome sequence data , 2016, bioRxiv.

[47]  J. Hodges,et al.  The frontotemporal dementia-motor neuron disease continuum , 2016, The Lancet.

[48]  Annelot M. Dekker,et al.  Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis , 2016, Nature Genetics.

[49]  Daniela C. Zarnescu,et al.  Fragile X protein mitigates TDP-43 toxicity by remodeling RNA granules and restoring translation. , 2015, Human molecular genetics.

[50]  G. Meola,et al.  Myotonic Dystrophy Type 2: An Update on Clinical Aspects, Genetic and Pathomolecular Mechanism , 2015, Journal of neuromuscular diseases.

[51]  Dalyir I. Pretto,et al.  Clinical and molecular implications of mosaicism in FMR1 full mutations , 2014, Front. Genet..

[52]  Anna T. Thomas,et al.  Evaluating noncoding nucleotide repeat expansions in amyotrophic lateral sclerosis , 2014, Neurobiology of Aging.

[53]  Dalyir I. Pretto,et al.  CGG allele size somatic mosaicism and methylation in FMR1 premutation alleles , 2014, Journal of Medical Genetics.

[54]  C. Ki,et al.  Non-Ataxic Phenotypes of SCA8 Mimicking Amyotrophic Lateral Sclerosis and Parkinson Disease , 2013, Journal of clinical neurology.

[55]  Ewout J. N. Groen,et al.  CGG-repeat expansion in FMR1 is not associated with amyotrophic lateral sclerosis , 2012, Neurobiology of Aging.

[56]  H. Paulson,et al.  Coexistence of Huntington’s disease and amyotrophic lateral sclerosis: a clinicopathologic study , 2012, Acta Neuropathologica.

[57]  N. Wood,et al.  Genetic screening of Greek patients with Huntington's disease phenocopies identifies an SCA8 expansion , 2012, Journal of Neurology.

[58]  D. Cutler,et al.  The Heritability of Amyotrophic Lateral Sclerosis in a Clinically Ascertained United States Research Registry , 2011, PloS one.

[59]  Bruce L. Miller,et al.  Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS , 2011, Neuron.

[60]  David Heckerman,et al.  A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD , 2011, Neuron.

[61]  J. Hodges,et al.  Motor neuron dysfunction in frontotemporal dementia. , 2011, Brain : a journal of neurology.

[62]  M. Lima,et al.  Machado-Joseph Disease: from first descriptions to new perspectives , 2011, Orphanet journal of rare diseases.

[63]  R. Myers.  Huntington’s disease genetics , 2004, NeuroRx.

[64]  Josyf Mychaleckyj,et al.  Robust relationship inference in genome-wide association studies , 2010, Bioinform..

[65]  A. Al-Chalabi,et al.  An estimate of amyotrophic lateral sclerosis heritability using twin data , 2010, Journal of Neurology, Neurosurgery & Psychiatry.

[66]  John Q. Trojanowski,et al.  Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS , 2010, Nature.

[67]  D. Hilton‐Jones,et al.  The myotonic dystrophies: diagnosis and management , 2010, Journal of Neurology, Neurosurgery & Psychiatry.

[68]  Peter K. Todd,et al.  RNA‐mediated neurodegeneration in repeat expansion disorders , 2009, Annals of neurology.

[69]  Yuko Saito,et al.  Spinocerebellar ataxia type 31 is associated with "inserted" penta-nucleotide repeats containing (TGGAA)n. , 2009, American journal of human genetics.

[70]  Nick C Fox,et al.  The heritability and genetics of frontotemporal lobar degeneration , 2009, Neurology.

[71]  C. Gellera,et al.  Rare association of motor neuron disease and spinocerebellar ataxia type 2 (SCA2): a new case and review of the literature , 2009, Journal of Neurology.

[72]  Radim Mazanec,et al.  Highly unstable sequence interruptions of the CTG repeat in the myotonic dystrophy gene , 2009, American journal of medical genetics. Part A.

[73]  M. Shriver,et al.  Premutation allele pool in myotonic dystrophy type 2 , 2009, Neurology.

[74]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[75]  S H Appel,et al.  Prevalence and patterns of cognitive impairment in sporadic ALS , 2005, Neurology.

[76]  Toshihiro Tanaka.  The International HapMap Project , 2003, Nature.

[77]  P. Tam.  The International HapMap Consortium. The International HapMap Project (Co-PI of Hong Kong Centre which responsible for 2.5% of genome) , 2003 .

[78]  I. Kanazawa,et al.  SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein. , 2001, Human molecular genetics.

[79]  P. Andersen,et al.  Multiple founder effects in spinal and bulbar muscular atrophy (SBMA, Kennedy disease) around the world , 2001, European Journal of Human Genetics.

[80]  M. Swash,et al.  El Escorial revisited: Revised criteria for the diagnosis of amyotrophic lateral sclerosis , 2000, Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases.

[81]  M. Ruberg,et al.  De novo expansion of intermediate alleles in spinocerebellar ataxia 7. , 1998, Human molecular genetics.