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Cited by 39Genomics and Rare DiseasesHereditary Neurological DisordersCerebrovascular and genetic disorders

Genome sequencing in persistently unsolved white matter disorders

Open access
Helman, Guy, Lajoie, Bryan R., Crawford, Joanna, Takanohashi, Asako, Walkiewicz, Marzena, Dolzhenko, Egor, Gross, Andrew M., Gainullin, Vladimir G. +22 more·2020·Annals of Clinical and Translational Neurology
DOI 10.1002/acn3.50957PMC PMC6952322
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Abstract

Genetic white matter disorders have heterogeneous etiologies and overlapping clinical presentations. We performed a study of the diagnostic efficacy of genome sequencing in 41 unsolved cases with prior exome sequencing, resolving an additional 14 from an historical cohort (n = 191). Reanalysis in the context of novel disease‐associated genes and improved variant curation and annotation resolved 64% of cases. The remaining diagnoses were directly attributable to genome sequencing, including cases with small and large copy number variants (CNVs) and variants in deep intronic and technically difficult regions. Genome sequencing, in combination with other methodologies, achieved a diagnostic yield of 85% in this retrospective cohort.

AI snapshot

Written from the paper’s full text.

TL;DR

Genome sequencing in 41 families with persistently unsolved genetic white matter disorders after exome sequencing resolved 14 additional cases (34%). Nine of those 14 diagnoses (64%) came from reanalysis with newly described disease genes or improved variant curation, while five were directly attributable to genome sequencing findings such as CNVs, deep intronic variants, and a GC-rich region.

Key findings

  • Genome sequencing established a molecular diagnosis in 14 of 41 persistently unsolved families (34%) after prior exome sequencing.
  • Of the 14 resolved cases, 9 (64%) were resolved through reanalysis in the context of novel disease-associated genes or improved variant curation/annotation; 5 were directly attributable to genome sequencing, including 3 CNVs, 1 deep intronic variant, and 1 variant in a technically difficult region.
  • Across the original testable cohort, exome or genome sequencing solved 44/71 cases (62%), and total resolution was 145/172 (84%) in the discussion; the abstract reports an overall diagnostic yield of 85% for genome sequencing combined with other methodologies.
  • No recurring diagnoses were made in the 41-family genome sequencing cohort, and only a minority across all NGS tiers (20%) were associated with canonical leukodystrophy genes.

Methods

  • Retrospective study of 41 families from the Myelin Disorders Bioregistry Project who remained unsolved after prior exome sequencing; all had abnormal white matter on neuroimaging suggestive of leukodystrophy, with symptom onset from birth to 19 years.
  • Genome sequencing was performed at Illumina on an Illumina 2000 with 2 × 125 nucleotide paired-end reads; dual analyses used BWA/GATK/SnpEff and Illumina Secondary Analysis Software v5.11.0, with variants prioritized by allele frequency, conservation, genotype, inheritance, disease association, consequence, and predicted pathogenicity.
  • Putatively causal variants were assessed per ACMG guidelines; candidate variants in potentially novel disease genes were submitted to GeneMatcher, and candidate splice-altering variants were validated with a minigene splicing assay.

Limitations

  • The paper does not include a dedicated limitations section; it notes that some variant types detected by genome sequencing may become detectable by exome sequencing as assays and pipelines improve, while others will remain difficult due to assay limitations such as GC-rich regions or accurate detection of large genomic alterations in single cases.
  • The paper states that one case was clinically resolved but not included in the definitively resolved count because the variant remained a VUS per ACMG criteria.
  • Evident from the text: the cohort is small (n = 41), retrospective, and drawn from a single referral registry; the reported overall diagnostic yield differs between the abstract (85%) and discussion (145/172, 84%), and the genome sequencing-specific yield is partly confounded by reanalysis and newly described gene–disease relationships rather than sequencing modality alone.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1002/acn3.50957

Cites

24 of 24 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

15 of 28 cited sources checked · 6 supported · 0 flagged · accuracy not yet measured

  • Findingcitation

    The GJC2 duplication was previously undetected by exome sequencing due to a lack of coverage as it lies in the middle of a 110 nucleotide block of a ~95% GC-rich region.

    “The duplication was previously undetected by exome sequencing due to a lack of coverage as it lies in the middle of a 110 nucleotide block of a ~ 95% GC‐rich region (Fig. 1B).1”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [1] Vanderver A, Simons C, Helman G, et al. Whole exome sequencing in patients with white matter abnormalities. Ann Neurol 2016; 79: 1031– 1037. 27159321 PMC5354169 source

      The Methods (Cohort description; page unavailable) describe exome-sequencing coverage in the cohort, but not coverage at a GJC2 duplication. Searches for GJC2, the duplication, and the 110-nucleotide, approximately 95% GC-rich region found no passage addressing why this variant was missed. (LLM, conf=0.75)

      Experimental — accuracy not yet measured
  • Findingown data

    LD_0315 had biallelic variants in DARS2, associated with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL).

    “LD_0315 had biallelic variants in DARS2 (OMIM:610956), associated with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL [OMIM:611105]).”
    Quote in the paperSubstantial claim
  • Findingown data

    Of the original 191 families examined in this cohort, 101 received a definitive diagnosis using enzymatic, biochemical, or single gene molecular approaches (53%).

    “Of the original 191 families examined in this cohort, 101 received a definitive diagnosis using enzymatic, biochemical, or single gene molecular approaches (53%).”
    Quote in the paperSubstantial claim
  • Findingown data

    Genome sequencing CNV analysis provided a diagnosis in three affected individuals.

    “Genome sequencing CNV analysis provided a diagnosis in three affected individuals (Table 1).”
    Quote in the paperSubstantial claim
  • Findingown data

    Reanalysis in the context of novel disease-associated genes and improved variant curation and annotation resolved 64% of the cases.

    “Reanalysis in the context of novel disease‐associated genes and improved variant curation and annotation resolved 64% of cases.”
    Quote in the paperSubstantial claim
  • May combine two claims. 19
  • Classified as probably not a substantial claim. 7

  • May combine two claims.

    Premisecitation

    In a previously reported cohort of 191 families with suspected leukodystrophy, 71 were persistently unsolved despite targeted molecular and enzymatic testing and 19 were lost to follow-up.

    “Previously, we reported on a cohort of 191 families with a suspected leukodystrophy, of which 71 were persistently unsolved despite targeted molecular and enzymatic testing and 19 were lost to follow‐up.1”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [1] Vanderver A, Simons C, Helman G, et al. Whole exome sequencing in patients with white matter abnormalities. Ann Neurol 2016; 79: 1031– 1037. 27159321 PMC5354169 source

      The Methods (Cohort description; page not provided) report an initial 191 cases, of which 101 received diagnoses and 90 remained unsolved; 71 of the unsolved families had suitable samples for exome sequencing. The other 19 were excluded from that testing—not reported as lost to follow-up: nine obtained sequencing elsewhere, and ten lacked suitable samples despite collection attempts. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premiseown data

    Trio-or-greater exome sequencing analysis resolved 42% (30/71) of unsolved cases, which, in combination with standard of care approaches, yielded a 77% overall diagnostic rate from 172 families available for testing.

    “Trio‐or‐greater exome sequencing analysis resolved 42% (30/71) of unsolved cases, which, in combination with standard of care approaches, yielded a 77% overall diagnostic rate from 172 families available for testing.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [1] Vanderver A, Simons C, Helman G, et al. Whole exome sequencing in patients with white matter abnormalities. Ann Neurol 2016; 79: 1031– 1037. 27159321 PMC5354169 source

      The Abstract (page unavailable) reports a 42% clinical diagnostic yield in 71 trio-or-greater WES cases, comprising 25 cases with diagnostic variants and five with potentially pathogenic variants. The Methods describe 101 diagnoses by standard approaches, but the Discussion reports an overall rate of approximately 72% across the initial 191 families—not 77% across 172 families. The claim also treats all 30 WES findings as resolved without preserving the distinction between diagnostic and potentially pathogenic variants. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    LD_0587 has a clinical presentation with intellectual disability, epilepsy, aggressive behavior, and macrocephaly, all consistent features of KDM5C-related disorder, and is classified as clinically resolved but the identified variant lacks definitive proof to be classified as likely pathogenic or pathogenic.

    “LD_0587 has a clinical presentation with intellectual disability, epilepsy, aggressive behavior, and macrocephaly, all consistent features of KDM5C‐related disorder and is classified as clinically resolved but the identified variant lacks definitive proof to be classified as likely pathogenic or pathogenic.17”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [17] Vallianatos CN, Farrehi C, Friez MJ, et al. Altered gene‐regulatory function of KDM5C by a novel mutation associated with autism and intellectual disability. Front Mol Neurosci 2018; 11: 104. 29670509 PMC5893713 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    Stringent variant filtering performed during the prior exome sequencing analysis excluded this intronic variant and precluded a diagnosis.

    “Stringent variant filtering performed during the prior exome sequencing analysis excluded this intronic variant and precluded a diagnosis.1”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [1] Vanderver A, Simons C, Helman G, et al. Whole exome sequencing in patients with white matter abnormalities. Ann Neurol 2016; 79: 1031– 1037. 27159321 PMC5354169 source

      The Methods (Cohort description; page unavailable) describe variant filtering, but do not say that it excluded an intronic variant or prevented a diagnosis. A search for “intronic” found no passage in our copy establishing that event. (LLM, conf=0.73)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    Affected individuals in families LD_0579 and LD_0587 had variants in genes previously implicated in neurologic syndromes where improvements to the analysis pipeline or improved phenotypic understanding permitted a diagnosis or prioritized a high confidence candidate, in L1CAM and KDM5C, respectively.

    “Affected individuals in families LD_0579 and LD_0587 had variants in genes previously implicated in neurologic syndromes where improvements to our analysis pipeline or improved phenotypic understand permitted a diagnosis or prioritized a high confidence candidate, in L1CAM (OMIM:308840)16 and KDM5C (OMIM:314690),17 respectively.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [16] Tsurusaki Y, Okamoto N, Suzuki Y, et al. Exome sequencing of two patients in a family with atypical X‐linked leukodystrophy. Clin Genet 2011; 80: 161– 166. 21644943 source
    • cites [17] Vallianatos CN, Farrehi C, Friez MJ, et al. Altered gene‐regulatory function of KDM5C by a novel mutation associated with autism and intellectual disability. Front Mol Neurosci 2018; 11: 104. 29670509 PMC5893713 source

      Split into 2 atoms — 1 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    Reanalysis by genome sequencing also led to the identification of variants in recently described disease genes AIFM1, HIKESHI, H3F3B, NKX6-2, and SPATA5, and genes missed in the previous analysis (L1CAM).

    “Reanalysis by genome sequencing also led to the identification of variants in recently described disease genes AIFM1,12 HIKESHI, 13 H3F3B, 11 NKX6‐2, 14 and SPATA5, 15 and genes missed in the previous analysis (L1CAM).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [12] Miyake N, Wolf NI, Cayami FK, et al. X‐linked hypomyelination with spondylometaphyseal dysplasia (H‐SMD) associated with mutations in AIFM1. Neurogenetics 2017; 18: 185– 194. 28842795 PMC5705759 source
    • cites [13] Edvardson S, Kose S, Jalas C, et al. Leukoencephalopathy and early death associated with an Ashkenazi‐Jewish founder mutation in the Hikeshi gene. J Med Genet 2016; 53: 132– 137. 26545878 source
    • cites [11] Farwell Hagman KD, Shinde DN, Mroske C, et al. Candidate‐gene criteria for clinical reporting: diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnosed diseases. Genet Med 2017; 19: 224– 235. 27513193 PMC5303763 source

      The Materials and Methods section describes whole-exome sequencing, not the claimed genome-sequencing reanalysis. Searches for AIFM1, HIKESHI, H3F3B, NKX6-2, SPATA5, L1CAM, and the reanalysis wording found no passage in our copy reporting those findings. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Genome sequencing has the potential to detect a wide variety of variant types, including single-nucleotide variants and indels, copy number variants, repeat expansions, and pathogenic nonprotein-coding variation that is missed by other NGS approaches.

    “Genome sequencing has the potential to detect a wide variety of variant types, including single‐nucleotide variants and indels (out‐performing exome sequencing in protein‐coding regions), copy number variants (CNV),4 repeat expansions,5 and detection of pathogenic nonprotein‐coding variation that is missed by other NGS approaches.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [4] Roller E, Ivakhno S, Lee S, et al. Canvas: versatile and scalable detection of copy number variants. Bioinformatics 2016; 32: 2375– 2377. 27153601 source
    • cites [5] Dolzhenko E, van Vugt J, Shaw RJ, et al. Detection of long repeat expansions from PCR‐free whole‐genome sequence data. Genome Res 2017; 27: 1895– 1903. 28887402 PMC5668946 source

  • May combine two claims.

    Findingown data

    Thirty cases were solved by exome sequencing, and in this study, genome sequencing established a diagnosis in an additional 14 families yielding a 20% improvement, and an overall diagnostic efficacy of NGS of genome or exome sequencing increased to 44/71 (62%) and in total resolution of 145/172 (84%) of the original testable cohort.

    “Thirty cases were solved by exome sequencing,1 and in this study, genome sequencing established a diagnosis in an additional 14 families yielding a 20% improvement, and an overall diagnostic efficacy of NGS of genome or exome sequencing increased to 44/71 (62%) and in total resolution of 145/172 (84%) of the original testable cohort.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [1] Vanderver A, Simons C, Helman G, et al. Whole exome sequencing in patients with white matter abnormalities. Ann Neurol 2016; 79: 1031– 1037. 27159321 PMC5354169 source
    • Rests on an assumption: The 19 families lost to follow-up do not differ systematically in diagnostic outcome from the 172 families available for testing.

  • May combine two claims.

    Findingcitation

    Causal nonprotein-coding variants were identified in SNORD118, confirming a clinical diagnosis of leukoencephalopathy with calcifications and cysts in LD_0807.

    “Finally, causal nonprotein‐coding variants were identified in SNORD118 (OMIM:616663), confirming a clinical diagnosis of leukoencephalopathy with calcifications and cysts (OMIM:614561) in LD_0807.18”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [18] Jenkinson EM, Rodero MP, Kasher PR, et al. Mutations in SNORD118 cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts. Nat Genet 2016; 48: 1185– 1192. 27571260 PMC5045717 source

      The Results (page unavailable) identify rare SNORD118 variants in patients with leukoencephalopathy with calcifications and cysts, and the Discussion (page unavailable) concludes that these variants cause the disease. Our copy does not identify LD_0807 or report variants confirming that individual's diagnosis (searched: LD_0807 and LD0807). (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    SNORD118 variants were found as part of a targeted cohort study and concomitantly found in our genome sequencing cohort.

    “SNORD118 variants were found as part of a targeted cohort study and concomitantly found in our genome sequencing cohort.18”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [18] Jenkinson EM, Rodero MP, Kasher PR, et al. Mutations in SNORD118 cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts. Nat Genet 2016; 48: 1185– 1192. 27571260 PMC5045717 source

  • May combine two claims.

    Findingcitation

    Reanalysis identified a de novo missense variant in H3F3B, a hemizygous synonymous variant in AIFM1, and biallelic variants in HIKESHI, NKX6-2, and SPATA5, all previously associated with prominent white matter disease in multiple affected individuals.

    “These included a de novo missense variant in H3F3B (OMIM:601058) (LD_0246), 11 a hemizygous, synonymous variant in AIFM1 (OMIM:300169) (LD_0500),12 and biallelic variants in HIKESHI (OMIM:614908) (LD_0162),13 NKX6‐2 (OMIM:605955) (LD_0527), 14 and SPATA5 (OMIM:613940) (LD_0808),15 all previously associated with prominent white matter disease in multiple affected individuals.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [11] Farwell Hagman KD, Shinde DN, Mroske C, et al. Candidate‐gene criteria for clinical reporting: diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnosed diseases. Genet Med 2017; 19: 224– 235. 27513193 PMC5303763 source

      Split into 2 atoms — 0 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 2 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [12] Miyake N, Wolf NI, Cayami FK, et al. X‐linked hypomyelination with spondylometaphyseal dysplasia (H‐SMD) associated with mutations in AIFM1. Neurogenetics 2017; 18: 185– 194. 28842795 PMC5705759 source
    • cites [13] Edvardson S, Kose S, Jalas C, et al. Leukoencephalopathy and early death associated with an Ashkenazi‐Jewish founder mutation in the Hikeshi gene. J Med Genet 2016; 53: 132– 137. 26545878 source

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Putatively causal variants were assessed as per the American College of Medical Genetics (ACMG) guidelines.

    “Putatively causal variants were assessed as per the American College of Medical Genetics (AGMC) guidelines.9”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [9] Richards S, Aziz N, Bale S, et al. 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. Genet Med 2015; 17: 405– 424. 25741868 PMC4544753 source

  • May combine two claims.

    Findingcitation

    LD_0498 was found to have impaired peroxisomal β-oxidation of C26:0 and genome sequencing revealed a homozygous, 7.5kb deletion in ACBD5 causing loss of exons 7 and 8, confirmed by Sanger sequencing.

    “LD_0498 was found to have impaired peroxisomal β‐oxidation of C26:0 and genome sequencing revealed a homozygous, 7.5kb deletion in ACBD5 (OMIM:616618) causing loss of exons 7 and 8, confirmed by Sanger sequencing.22”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Ferdinandusse S, Falkenberg KD, Koster J, et al. ACBD5 deficiency causes a defect in peroxisomal very long‐chain fatty acid metabolism. J Med Genet 2016; 54: 330– 337. 27799409 source

  • May combine two claims.

    Findingown data

    The c.916_928dupGCCTCCGCCCCCG GJC2 variant called by genome sequencing was supported by six of 19 genome sequencing reads covering the position, and was confirmed by Sanger sequencing.

    “The c.916_928dupGCCTCCGCCCCCG GJC2 variant called by genome sequencing was supported by six of 19 genome sequencing reads covering the position (Fig. 1C), and was confirmed by Sanger sequencing (Fig. 1D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Nineteen families were subsequently lost to follow-up, leaving 71 families able to be tested by NGS.

    “Nineteen families were subsequently lost to follow‐up, leaving 71 families able to be tested by NGS.”
    Quote in the paperSubstantial claim

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

    Findingnone given

    One case was considered clinically resolved following multidisciplinary review.

    “One case was considered clinically resolved following multidisciplinary review.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The biallelic CSF1R variant affects a cryptic splice site and results in the inclusion of a novel 99nt pseudo-exon, with an in-frame stop codon p.(Pro658Serfs*24) resulting in nonsense-mediated decay of the truncated protein.

    “This biallelic variant affects a cryptic splice site and results in the inclusion of a novel 99nt pseudo‐exon, with an in‐frame stop codon p.(Pro658Serfs*24) resulting in nonsense‐mediated decay of the truncated protein.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Biallelic variants were identified in LD_0617 in GJC2, causative of Pelizaeus-Merzbacher-like disease (PMLD), a maternally inherited missense variant c.203A>G, p.(Tyr68Cys), and a 13 base paternally inherited duplication c.916_928dupGCCTCCGCCCCCG, p.(Ala310fs).

    “Biallelic variants were identified in LD_0617 in GJC2 (OMIM:608803), causative of Pelizaeus‐Merzbacher‐like disease (PMLD [OMIM:608804]), a maternally inherited missense variant c.203A>G, p.(Tyr68Cys), and a 13 base paternally inherited duplication c.916_928dupGCCTCCGCCCCCG, p.(Ala310fs).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    No recurring diagnoses were made in the current cohort of n=41, and only a minority across all tiers of NGS testing (20%) were associated with canonical leukodystrophy genes.

    “Notably, no recurring diagnoses were made in the current cohort of n = 41, and only a minority across all tiers of NGS testing (20%) were associated with canonical leukodystrophy genes.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    The study had approval from the institutional review boards at collaborating institutions.

    “The study had approval from the institutional review boards at collaborating institutions.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    White matter abnormalities are a rare association with L1CAM-related disorder.

    “White matter abnormalities are a rare association with L1CAM‐related disorder.16”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Tsurusaki Y, Okamoto N, Suzuki Y, et al. Exome sequencing of two patients in a family with atypical X‐linked leukodystrophy. Clin Genet 2011; 80: 161– 166. 21644943 source

  • May combine two claims.

    Study design and conductown data

    The mean read depth in probands was 34X and on average, 91% of the genome had coverage depth greater than 20X.

    “The mean read depth in probands was 34X and on average, 91% of the genome had coverage depth greater than 20X (Appendix S1).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Candidate splice-altering variants were validated using a minigene splicing assay.

    “Candidate splice‐altering variants were validated using a minigene splicing assay (Appendix S1).8”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Gaildrat P, Killian A, Martins A, et al. Use of splicing reporter minigene assay to evaluate the effect on splicing of unclassified genetic variants. Methods Mol Biol 2010; 653: 249– 257. 20721748 source

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Cases with variants in known disease genes meeting ACMG criteria for pathogenic or likely pathogenic, and whose clinical features were concordant with the established gene-disease relationship (including MRI patterns), were classified as resolved.

    “Cases with variants in known disease genes meeting the ACMG criteria for pathogenic or likely pathogenic, and whose clinical features were concordant with the established gene–disease relationship (including magnetic resonance imaging (MRI) patterns) were classified as resolved.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    This is consistent with multiple recent studies that have shown increases of up to 10% in diagnostic yield with reanalysis within 24-36 months.

    “This is consistent with multiple recent studies that have shown increases of up to 10% in diagnostic yield with reanalysis within 24–36 months.10”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Costain G, Jobling R, Walker S, et al. Periodic reanalysis of whole‐genome sequencing data enhances the diagnostic advantage over standard clinical genetic testing. Eur J Hum Genet 2018; 26: 740– 744. 29453418 PMC5945683 source

  • May combine two claims.

    Interpretationreasoning

    In our exome analysis, these variants were not found due to limitations of either sequencing or analysis, some of which will be difficult to overcome due to limitations of the assay (e.g. GC-rich regions) or the ability of exome to accurately detect large genomic alterations in single cases.

    “In our exome analysis, however, these variants were not found due to limitations of either sequencing or analysis, some of which will be difficult to overcome due to limitations of the assay (e.g. GC‐rich regions) or the ability of exome to accurately detect large genomic alterations in single cases.”
    Quote in the paperSubstantial claim
26 of 26

  • The paper relies on this without support.

    The 19 families lost to follow-up do not differ systematically in diagnostic outcome from the 172 families available for testing.

    “Nineteen families were subsequently lost to follow‐up, leaving 71 families able to be tested by NGS.”

  • The paper relies on this without support.

    The m.3243A>G variant in MT-TL1 is associated with MELAS.

    “This variant has been previously associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke‐like episodes (MELAS [OMIM:540000]).”

  • The paper relies on this without support.

    Heterozygous CSF1R variants are associated with hereditary diffuse leukoencephalopathy with spheroids.

    “Heterozygous CSF1R variants are associated with another leukodystrophy, hereditary diffuse leukoencephalopathy with spheroids (OMIM:221820).”
3 of 3

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Earlier overall diagnostic rate does not match the reported case counts

    Minor

    The paper reports 101 standard-of-care diagnoses and 30 exome diagnoses among 172 families available for testing. That is 131/172, or 76.2%, rather than the stated 77%.

1 of 1

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Authors
Helman, G., Lajoie, B. R., Crawford, J., Takanohashi, A., Walkiewicz, M., Dolzhenko, E., Gross, A. M., Gainullin, V. G., Bent, S. J., Jenkinson, E. M., Ferdinandusse, S., Waterham, H. R., Dorboz, I., Bertini, E., Miyake, N., Wolf, N. I., Abbink, T. E. M., Kirwin, S. M., Tan, C. M., Hobson, G. M., Guo, L., Ikegawa, S., Pizzino, A., Schmidt, J. L., Bernard, G., Schiffmann, R., van der Knaap, M. S., Simons, C., Taft, R. J., & Vanderver, A.
Affiliations
  • Royal Children's Hospital (AU)
  • Illumina (United States) (US)
  • The University of Queensland (AU)
  • Children's Hospital of Philadelphia (US)
  • Commonwealth Scientific and Industrial Research Organisation (AU)
  • University of Manchester (GB)
  • Amsterdam University Medical Centers (NL)
  • Inserm (FR)
  • Bambino Gesù Children's Hospital (IT)
  • Yokohama City University (JP)
  • Emma Kinderziekenhuis (NL)
  • Alfred I. duPont Hospital for Children (US)
  • RIKEN Center for Integrative Medical Sciences (JP)
  • Departments of Neurology and Neurosurgery, Pediatrics, and Human Genetics McGill University Montreal Canada
  • Baylor Scott & White Research Institute (US)
  • Department of Child Neurology Emma Children’s Hospital Amsterdam University Medical Centers Vrije Universiteit Amsterdam and Amsterdam Neuroscience Amsterdam The Netherlands
Corresponding author
  • Simons, Cas
  • Taft, Ryan J.
  • Vanderver, Adeline
ORCID
Venue
Annals of Clinical and Translational Neurology
Publisher
Wiley
Published
2020-01
Volume
7
Issue
1
Pages
144-152
ISSN
2328-9503 (ISSN-L)
DOI
10.1002/acn3.50957
PMC
PMC6952322
OpenAlex
W3000498499
Semantic Scholar
6d54028268d4835ae67037510bbdf2956b56410d
Cited by
39
References
24
Citations by year
2025: 4 · 2024: 8 · 2023: 7 · 2022: 7 · 2021: 9 · 2020: 4
FWCI
3.53
Type
journal article
Language
en
Update notices
correction (2022-12-05)
Open access
Licence
Locations
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  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (publishedVersion, other-oa)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • VU Research Portal (submittedVersion, other-oa)
Funders
Canadian Institutes of Health Research
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
  • Health Sciences › Medicine › Neurology › Cerebrovascular and genetic disorders
Keywords
white matter disease, genetic diagnosis, genome sequencing, diagnostic yield, copy number variation, deep intronic variants, variant curation, variant annotation
MeSH terms
Whole Genome Sequencing, Adolescent, Child, Child, Preschool, Female, Humans, Male, Pedigree, Registries, Leukoencephalopathies

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 2026-10-20.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-20.

Cited sources are checked by gpt-6-sol.

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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