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Cited by 245Genetics and Neurodevelopmental DisordersAutism Spectrum Disorder ResearchGenomic variations and chromosomal abnormalities

Genome-wide detection of tandem DNA repeats that are expanded in autism

Open access
Trost, Brett, Engchuan, Worrawat, Nguyen, Charlotte M., Thiruvahindrapuram, Bhooma, Dolzhenko, Egor, Backstrom, Ian, Mirceta, Mila, Mojarad, Bahareh A. +30 more·2020·Nature
DOI 10.1038/s41586-020-2579-zPMC PMC9348607
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Abstract

Tandem DNA repeats vary in the size and sequence of each unit (motif). When expanded, these tandem DNA repeats have been associated with more than 40 monogenic disorders1. Their involvement in disorders with complex genetics is largely unknown, as is the extent of their heterogeneity. Here we investigated the genome-wide characteristics of tandem repeats that had motifs with a length of 2–20 base pairs in 17,231 genomes of families containing individuals with autism spectrum disorder (ASD)2,3 and population control individuals4. We found extensive polymorphism in the size and sequence of motifs. Many of the tandem repeat loci that we detected correlated with cytogenetic fragile sites. At 2,588 loci, gene-associated expansions of tandem repeats that were rare among population control individuals were significantly more prevalent among individuals with ASD than their siblings without ASD, particularly in exons and near splice junctions, and in genes related to the development of the nervous system and cardiovascular system or muscle. Rare tandem repeat expansions had a prevalence of 23.3% in children with ASD compared with 20.7% in children without ASD, which suggests that tandem repeat expansions make a collective contribution to the risk of ASD of 2.6%. These rare tandem repeat expansions included previously undescribed ASD-linked expansions in DMPK and FXN, which are associated with neuromuscular conditions, and in previously unknown loci such as FGF14 and CACNB1. Rare tandem repeat expansions were associated with lower IQ and adaptive ability. Our results show that tandem DNA repeat expansions contribute strongly to the genetic aetiology and phenotypic complexity of ASD. Genome-wide analysis of tandem DNA repeats in the genomes of individuals with autism spectrum disorder and control participants reveals a strong contribution of tandem repeat expansions to the genetic aetiology and phenotypic complexity of autism spectrum disorder.

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Crossref · 10.1038/s41586-020-2579-z

Cites

73 of 73 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 55 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Rare tandem repeat expansions occurred in 23.3% of autistic children and 20.7% of unaffected children.

    “Rare tandem repeat expansions had a prevalence of 23.3% in autism-affected children versus 20.7% in unaffected children”
    Quote in the paperSubstantial claim
  • Findingown data

    The study observed broad variation in tandem repeat motif size and sequence.

    “We found extensive polymorphism in motif size and sequence.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Rare gene-associated tandem repeat expansions at 2,588 loci were more common in autistic individuals than in their unaffected siblings.

    “At 2,588 loci, gene-associated tandem repeat expansions that were rare among population controls were significantly more prevalent among individuals with autism than their unaffected siblings”
    Quote in the paperSubstantial claim
  • Findingown data

    These tandem repeat expansions were associated with lower IQ and adaptive ability.

    “These were associated with lower IQ and adaptive ability.”
    Quote in the paperSubstantial claim
  • Findingown data

    These rare expansions were especially found in exons and near splice junctions.

    “particularly in exons and near splice junctions”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 40
  • May combine two claims. 21

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Many tandem repeat regions correlated with cytogenetic fragile sites.

    “Many correlated with cytogenetic fragile sites.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Tandem repeat regions were enriched in GC-rich regions and known fragile sites.

    “These tandem repeat-containing regions were more prevalent in GC-rich regions (OR=1.05; p<2.2×10−16) and all (common and rare) known fragile site regions (OR=1.12; p=1.2×10−4)”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    5.6% of motifs contained only A or T, and 0.4% only C or G.

    “Of the motifs, 5.6% were composed only of A or T nucleotides, and only 0.4% were composed of C or G only”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    2,529 regions (8%) had more than one motif, with up to 92 motifs in one region.

    “There were 2,529 regions (8%) with more than one motif, and as many as 92 different motifs in a single region”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Tandem repeat regions co-localized with 9 of 11 molecularly mapped rare folate-sensitive fragile sites, all CG-containing.

    “tandem repeat-containing regions we identified co-localized to 9 of 11 (81.8%) of the molecularly mapped rare folate-sensitive fragile sites37, all at CG-containing tandem repeats”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Bignell, G. R. et al. Signatures of mutation and selection in the cancer genome. Nature 463, 893–898 (2010). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Motif counts per region varied across chromosomes in an apparently non-random way.

    “The number of motifs per region varied across chromosomes in an apparently non-random manner”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The most common motif size was 2 bp, found in 27.7% of repeat tracts.

    “The most common motif size was 2 bp, found in 27.7% of repeat tracts.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In genic regions, tandem repeat regions were enriched upstream and in 5' UTRs but depleted in exons and 3' UTRs.

    “In genic regions, tandem repeat-containing regions were more common than the genomic average in upstream (OR=1.33; p<2.2×10−16) (1 kb from transcription start sites) and 5’ untranslated (OR=1.2; p<2.2×10−16) regions but less common in exonic (OR=0.61; p<2.2×10−16) and 3’ untranslated (OR=0.43; p<2.2×10−16) regions”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    Tandem repeat motifs were mostly (>40%) AC- or AG-rich.

    “the motifs were predominantly (>40%) AC- (GT- on the opposite strand) or AG- (CT- on the opposite strand) rich”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Subramanian, S., Mishra, R. K. & Singh, L. Genome-wide analysis of microsatellite repeats in humans: their abundance and density in specific genomic regions. Genome Biol. 4, R13 (2003). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Among small motifs, even sizes outnumbered odd sizes, but not among larger motifs.

    “In the smallest size range, even-numbered motif sizes (2, 4 and 6 bp) notably outnumbered the odd-numbered sizes (3 and 5 bp), whereas no such trend was evident among the larger motifs”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Transmitted large repeats were enriched in unaffected SSC siblings, but were more likely further expanded in ASD-affected individuals.

    “We also detected an enrichment for transmitted large tandem repeats in SSC unaffected siblings; however, these tandem repeats were more likely to be further expanded in ASD-affected individuals”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Nervous system development and cardiovascular or muscle were among top enriched gene sets for transmitted large repeats.

    “nervous system development and cardiovascular system or muscle were also among the top enriched gene sets”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Rare expansions generally arose from further expansion of already-large parental repeats, but not in unaffected siblings.

    “These rare tandem repeat expansions generally represented further expansions from already-large tandem repeats from the previous generation (but not in the unaffected siblings)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In ASD individuals, large tandem repeats were more often transmitted and more prevalent in exons and splice sites.

    “we found that in individuals with ASD, these large tandem repeats were more likely to be transmitted and were more prevalent in exons and splice sites”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The study found 7 ASD individuals from unrelated families and 1 unaffected sibling carrying rare DMPK CTG expansions, validated experimentally.

    “We identified 7 individuals with ASD from unrelated families and 1 unaffected sibling that carry rare CTG repeat expansions in DMPK (experimentally validated with repeat-primed PCR and Southern blotting”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Subjects with rare expansions had lower IQ and Vineland Adaptive Behavioral scores.

    “subjects with rare tandem repeat expansions had lower IQ (Wilcoxon test, p=0.001) and Vineland Adaptive Behavioral standard scores (Wilcoxon test, p=0.019)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Rare expansions in 57 loci within enriched gene sets accounted for 2.2% of SSC ASD cases and 2.5% of entire cohorts.

    “Rare tandem repeat expansions in 57 loci (having a higher frequency in ASD-affected individuals than unaffected siblings) within these enriched gene sets collectively accounted for 2.2% (40 of 1,812) of the ASD cases in SSC (OR=4.76; p=2×10−5), and 2.5% in the entire cohorts (129 of 5,194)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The study revealed more extensive tandem repeat sequence variability than previously recognized, with 8% having multiple motifs.

    “we have revealed far more extensive variability among tandem repeat sequences than previously recognized in the human genome, with 8% of the tandem repeats interrogated having more than one motif detected.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    The premutation CTG repeat length (42 CTGs) was close to the HiSeq X read length (150 bp).

    “Note that the length of the premutation CTG repeats (42 CTGs) was close to the read length of the HiSeq X platform (150 bp).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Slight discrepancies were observed between ExpansionHunter and PCR-based fragment analysis for premutation CTG allele size estimates.

    “While short CTG repeats were correctly sized by ExpansionHunter (the results were perfectly matched with fragment analysis), slight discrepancies were observed in the estimates for premutation alleles between ExpansionHunter and PCR-based fragment analysis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The father in those families had only the unexpanded allele.

    “The father has only the unexpanded allele.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    In both families shown, the tandem repeat expansion was transmitted from the mother to the child.

    “In both families, the expansion is transmitted from the mother to the child (samples highlighted in red).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Of the three distributions of EHdn-detected tandem repeat counts, the distribution for samples within mean ± 3 SD is closest to normal.

    “Of the 3 distributions, c is closest to the normal distribution.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Expanded tandem DNA repeats have been linked to more than 40 single-gene disorders.

    “When expanded, they have been associated with >40 monogenic disorders1.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] López Castel, A., Cleary, J. D. & Pearson, C. E. Repeat instability as the basis for human diseases and as a potential target for therapy. Nat. Rev. Mol. Cell Biol. 11, 165–170 (2010). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Genetic factors contribute to ASD etiology.

    “Genetic factors contribute to the etiology of ASD; twin studies estimate heritability in the 50–90% range, and recurrence in families is ~20%8,9.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [8] Ozonoff, S. et al. Recurrence risk for autism spectrum disorders: a Baby Siblings Research Consortium study. Pediatrics 128, e488–e495 (2011). source

      Not checked in the free run.

    • cites [9] Risch, N. et al. Familial recurrence of autism spectrum disorder: evaluating genetic and environmental contributions. Am. J. Psychiatry 171, 1206–1213 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Tandem DNA repeat expansions make a strong contribution to autism genetic etiology and phenotypic complexity.

    “Our results revealed a strong contribution of tandem DNA repeat expansions to the genetic etiology and phenotypic complexity of autism.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Known causal variants for many complex disorders, including ASD, generally confer less risk than heritability estimates suggest.

    “the causal genetic variants thus far identified generally confer less risk than expected from empirical estimates of heritability6.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Manolio, T. A. et al. Finding the missing heritability of complex diseases. Nature 461, 747–753 (2009). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Twin studies estimate ASD heritability at 50-90%.

    “twin studies estimate heritability in the 50–90% range”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [8] Ozonoff, S. et al. Recurrence risk for autism spectrum disorders: a Baby Siblings Research Consortium study. Pediatrics 128, e488–e495 (2011). source

      Not checked in the free run.

    • cites [9] Risch, N. et al. Familial recurrence of autism spectrum disorder: evaluating genetic and environmental contributions. Am. J. Psychiatry 171, 1206–1213 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Novel autism-linked tandem repeat expansions were found in DMPK and FXN, and in loci such as FGF14 and CACNB1.

    “They included novel autism-linked tandem repeat expansions in DMPK and FXN, known for neuromuscular conditions, and in novel loci such as FGF14 and CACNB1.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ASD recurrence in families is about 20%.

    “recurrence in families is ~20%8,9”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [8] Ozonoff, S. et al. Recurrence risk for autism spectrum disorders: a Baby Siblings Research Consortium study. Pediatrics 128, e488–e495 (2011). source

      Not checked in the free run.

    • cites [9] Risch, N. et al. Familial recurrence of autism spectrum disorder: evaluating genetic and environmental contributions. Am. J. Psychiatry 171, 1206–1213 (2014). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ASD individuals have two- to three-fold more rare CNVs and de novo loss-of-function variants than unaffected siblings.

    “individuals with ASD have a two- to three-fold increase in the number of rare copy number variations (CNVs) and de novo loss-of-function (nonsense, frameshift, and splice site) variants compared to their unaffected siblings11–14.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [11] De Rubeis, S. et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515, 209–215 (2014). source

      Not checked in the free run.

    • cites [12] Iossifov, I. et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature 515, 216–221 (2014). source

      Not checked in the free run.

    • cites [13] Sanders, S. J. et al. Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci. Neuron 87, 1215–1233 (2015). source

      Not checked in the free run.

    • cites [14] Yuen, R. K. C. et al. Genome-wide characteristics of de novo mutations in autism. NPJ Genom. Med. 1, 16027 (2016). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Over 100 genes and loci are known to increase ASD likelihood.

    “more than 100 genes and loci are known to be associated with increased likelihood of ASD2,13.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] Yuen, R. K. C. et al. Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. Nat. Neurosci. 20, 602–611 (2017). source

      Not checked in the free run.

    • cites [13] Sanders, S. J. et al. Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci. Neuron 87, 1215–1233 (2015). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The FMR1 CGG tract has been linked to fragile X syndrome, fragile X premature ovarian insufficiency, fragile X associated ataxia, endocrine, autoimmune, metabolic disease, and ASD.

    “the unstable CGG tract of FMR1 has been linked to intellectual delay in fragile X syndrome, fragile X premature ovarian insufficiency, fragile X associated ataxia, endocrine, autoimmune, metabolic disease, and ASD29.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Hagerman, R. J. et al. Fragile X-associated neuropsychiatric disorders (FXAND). Front. Psychiatry 9, 564 (2018). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Sex and intergenic expansion count were used as covariates in statistical tests.

    “We used sex and number of intergenic tandem repeat expansions as covariates in the statistical tests”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    About 5% of DM1 individuals also have ASD.

    “Approximately 5% of individuals with DM1 also have ASD45,46.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [45] Shoubridge, C. et al. Is there a Mendelian transmission ratio distortion of the c.429_452dup(24bp) polyalanine tract ARX mutation? Eur. J. Hum. Genet. 20, 1311–1314 (2012). source

      Not checked in the free run.

    • cites [46] Ekström, A.-B., Hakenäs-Plate, L., Samuelsson, L., Tulinius, M. & Wentz, E. Autism spectrum conditions in myotonic dystrophy type 1: a study on 57 individuals with congenital and childhood forms. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 147B, 918–926 (2008). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Preferential transmission of premutated or expanded repeats to unaffected, subclinical, and affected individuals occurs in many repeat diseases.

    “Preferential transmission of premutated or expanded repeats to unaffected, subclinical, and affected individuals has been observed in many different repeat-related diseases42–44.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [42] Trost, B. et al. A comprehensive workflow for read depth-based identification of copy-number variation from whole-genome sequence data. Am. J. Hum. Genet. 102, 142–155 (2018). source

      Not checked in the free run.

    • cites [43] Takiyama, Y. et al. Single sperm analysis of the CAG repeats in the gene for Machado–Joseph disease (MJD1): evidence for non-Mendelian transmission of the MJD1 gene and for the effect of the intragenic CGG/GGG polymorphism on the intergenerational instability. Hum. Mol. Genet. 6, 1063–1068 (1997). source

      Not checked in the free run.

    • cites [44] Dean, N. L. et al. Transmission ratio distortion in the myotonic dystrophy locus in human preimplantation embryos. Eur. J. Hum. Genet. 14, 299–306 (2006). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    DMPK CTG expansion above 50 units causes myotonic dystrophy type 1.

    “whose expansion to greater than 50 repeat units causes myotonic dystrophy type 1 (DM1) (OMIM ID: 160900)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites OMIM ID: 160900

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationnone given

    The strategy provides a model to search for missing heritability in other complex disorders.

    “Our strategy of genome-wide detection of expanded tandem repeats in ASD also provides a model to search for missing heritability in other complex disorders.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductnone given

    The method provides only estimated relative aggregated tandem repeat length and does not resolve zygosity or orientation.

    “the method we developed here only provides an estimated relative aggregated length of the tandem repeat tracts and does not resolve zygosity or orientation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    For tandem repeats detected with multiple motifs at the same region, Sanger sequencing of PCR-amplified alleles after gel extraction confirmed the reported motifs.

    “For tandem repeats that were detected with multiple different motifs at the same repeat-containing regions (e.g., CACNB1 and FXN) (Extended Data Fig. 9), we performed Sanger sequencing on the PCR-amplified alleles after gel extraction to confirm the presence of the reported motifs.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    The DBSCAN ε value was chosen because it gave reasonable outlier numbers and good agreement between EHdn and ExpansionHunter outliers.

    “This value was selected because it resulted in both a reasonable number of outliers and good agreement between outliers detected from EHdn and outliers detected in corresponding loci from ExpansionHunter”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Some tandem repeat diseases are caused by one or two additional repeat units, which EHdn would miss.

    “there are tandem repeat-associated diseases for which one or two additional repeat units leads to disease. Such changes will be missed by EHdn.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    No subject showed an unusually large count of rare tandem repeat expansions.

    “No individual had an extreme number of rare tandem repeat expansions (Supplementary Fig. 4).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    Samples that did not meet the size minimum for a region had no EHdn size estimate.

    “As a result, samples that did not meet this size minimum for a given region were left without EHdn’s size estimation.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: For EHdn to detect a tandem repeat, the repeat must be longer than the sequence read length (e.g., >150 bp).

  • Classified as probably not a substantial claim.

    Study design and conductown data

    PCR and gel electrophoresis results for CACNB1 and FXN loci were consistently reproduced at least twice.

    “Results from PCR and gel electrophoresis were consistently reproduced at least twice for CACNB1 and FXN loci (see Supplementary Figures).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Repeat-primed PCR experiments for large expansions were consistently reproduced at least three times.

    “Repeat-primed PCR experiments were consistently reproduced at least three times for the large expansions.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Informed consent was obtained from all participants.

    “Informed consent was obtained from all participants through the recruitment sites.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Multiple comparisons were adjusted using family-wise error rate.

    “We estimated family-wise error rate (FWER) to adjust for multiple comparisons.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    Sex bias was avoided in burden analysis by restricting to autosomal regions and including sex as a covariate.

    “We avoided sex bias by performing the test only on autosomal regions, as well as using sex as a covariate for correction of the regression model.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Bias in the number of rare tandem repeat expansions per subject in genic, functional, and gene set burden tests was accounted for by covarying the number of such expansions in intergenic regions.

    “We further accounted for the bias in number of rare tandem repeat expansions per subject in genic, functional, and gene set burden tests by covarying the number of rare tandem repeat expansions found in intergenic regions.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    When a sample looked homozygous by length, expanded repeats were confirmed using repeat-primed PCR and/or Southern blot.

    “For samples that appeared to be homozygous for the tandem repeat length, we validated the presence of expanded tandem repeats by repeat-primed PCR (RP-PCR) and/or Southern blot.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Sizing experiments on PCR-amplifiable samples were repeated consistently at least twice.

    “Repeat sizing experiments of PCR-amplifiable samples were consistently reproduced at least twice.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    In the phenotype comparison, samples with and without rare tandem repeat expansions were mutually exclusive and there were no replicates.

    “Samples included were mutually exclusive to each other and there were no replicates (randomization not applicable).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The study protocol was approved by The Hospital for Sick Children's Research Ethics Board.

    “The study protocol was approved by The Hospital for Sick Children’s Research Ethics Board (REB).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The lengths of tandem repeats called by ExpansionHunter or EHdn were checked using fragment analysis and capillary electrophoresis with fluorescently labelled primers.

    “The validation of the tandem repeat length estimated by ExpansionHunter or EHdn was done by fragment analysis with FAM-labelled primers and capillary electrophoresis.”
    Quote in the paperSubstantial claim
55 of 55

  • The paper relies on this without support.

    The involvement of tandem DNA repeats in complex disorders and the extent of their heterogeneity are largely unknown.

    “Their involvement in complex disorders is largely unknown, as is the extent of their heterogeneity.”

  • The paper relies on this without support.

    The population control cohorts used are representative of the general population for estimating the rarity of tandem repeat expansions.

    “we used 1,612 genomic samples from GTEx32 and the Mayo Clinic33”

  • The paper relies on this without support.

    For EHdn to detect a tandem repeat, the repeat must be longer than the sequence read length (e.g., >150 bp).

    “For a tandem repeat to be detected by EHdn, it must be larger than the sequence read length (e.g., > 150 bp).”

  • The paper relies on this without support.

    DBSCAN may fail to detect outliers when only a few samples have genotype data.

    “Similarly, DBSCAN might fail to detect outliers when only a few samples have genotype data.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Emerging evidence suggests a role for other classes of genetic variants (e.g., rare inherited and de novo tandem repeats) in autism.

    “yet emerging evidence suggests a role for other classes (for example, rare inherited and de novo tandem repeats) of genetic variants as well17,19,60,61.”

    From Genetic correlates of phenotypic heterogeneity in autism (2022) · cites this paper as [60]

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Authors
Trost, B., Engchuan, W., Nguyen, C. M., Thiruvahindrapuram, B., Dolzhenko, E., Backstrom, I., Mirceta, M., Mojarad, B. A., Yin, Y., Dov, A., Chandrakumar, I., Prasolava, T., Shum, N., Hamdan, O., Pellecchia, G., Howe, J. L., Whitney, J., Klee, E. W., Baheti, S., Amaral, D. G., Anagnostou, E., Elsabbagh, M., Fernandez, B. A., Hoang, N., Lewis, M. E. S., Liu, X., Sjaarda, C., Smith, I. M., Szatmari, P., Zwaigenbaum, L., Glazer, D., Hartley, D., Stewart, A. K., Eberle, M. A., Sato, N., Pearson, C. E., Scherer, S. W., & Yuen, R. K. C.
Affiliations
  • Hospital for Sick Children (CA)
  • University of Toronto (CA)
  • Illumina (United States) (US)
  • Mayo Clinic (US)
  • University of California Davis Medical Center (US)
  • Centre Azrieli de recherche sur l'autisme (CA)
  • Memorial University of Newfoundland (CA)
  • University of British Columbia (CA)
  • Queen's University (CA)
  • Dalhousie University (CA)
  • University of Alberta (CA)
  • Verily Life Sciences LLC (United States) (US)
  • Autism Speaks (US)
Corresponding author
Yuen, Ryan K. C.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2020-07-27
Volume
586
Issue
7827
Pages
80-86
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-020-2579-z
PMC
PMC9348607
OpenAlex
W3044594590
Semantic Scholar
24871e7070485b8f5dc5da18e1a1f12aa9f1a514
Cited by
238
References
73
Citations by year
2026: 24 · 2025: 36 · 2024: 39 · 2023: 36 · 2022: 47 · 2021: 44 · 2020: 10 · 2012: 1
FWCI
20.05
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
National Institute of Mental Health (R01MH103371)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
Keywords
tandem repeat expansion, autism spectrum disorder, genetic aetiology, fragile sites, DMPK, frataxin, FGF14, neuromuscular disorders, intellectual disability, phenotypic complexity, splice junctions
MeSH terms
Autism Spectrum Disorder, Frataxin, Female, Fibroblast Growth Factors, Humans, Intelligence, Male, Polymorphism, Genetic, Genome, Human, Genetic Predisposition to Disease, Tandem Repeat Sequences, Genomics, Iron-Binding Proteins, DNA Repeat Expansion, Nucleotide Motifs, Myotonin-Protein Kinase

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-05.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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