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Cited by 24Genomics and Rare DiseasesGenomic variations and chromosomal abnormalitiesGenetics and Neurodevelopmental Disorders

Genome sequencing and comprehensive rare-variant analysis of 465 families with neurodevelopmental disorders

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Sanchis-Juan, Alba, Megy, Karyn, Stephens, Jonathan, Armirola Ricaurte, Camila, Dewhurst, Eleanor, Low, Kayyi, French, Courtney E., Grozeva, Detelina +23 more·2023·The American Journal of Human Genetics
DOI 10.1016/j.ajhg.2023.07.007PMC PMC10432178

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Abstract

Despite significant progress in unraveling the genetic causes of neurodevelopmental disorders (NDDs), a substantial proportion of individuals with NDDs remain without a genetic diagnosis after microarray and/or exome sequencing. Here, we aimed to assess the power of short-read genome sequencing (GS), complemented with long-read GS, to identify causal variants in participants with NDD from the National Institute for Health and Care Research (NIHR) BioResource project. Short-read GS was conducted on 692 individuals (489 affected and 203 unaffected relatives) from 465 families. Additionally, long-read GS was performed on five affected individuals who had structural variants (SVs) in technically challenging regions, had complex SVs, or required distal variant phasing. Causal variants were identified in 36% of affected individuals (177/489), and a further 23% (112/489) had a variant of uncertain significance after multiple rounds of re-analysis. Among all reported variants, 88% (333/380) were coding nuclear SNVs or insertions and deletions (indels), and the remainder were SVs, non-coding variants, and mitochondrial variants. Furthermore, long-read GS facilitated the resolution of challenging SVs and invalidated variants of difficult interpretation from short-read GS. This study demonstrates the value of short-read GS, complemented with long-read GS, in investigating the genetic causes of NDDs. GS provides a comprehensive and unbiased method of identifying all types of variants throughout the nuclear and mitochondrial genomes in individuals with NDD.

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  • Another nonsense variant, p.Gln520Ter, has also been reported in one individual.

    “Another nonsense variant, p.Gln520Ter, has also been reported in one individual98,99.”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [98]

    The cohort-results section reports variants in individuals, but the passages in our copy do not identify p.Gln520Ter. Searches for “p.Gln520Ter,” “Gln520*,” and “520Ter” found no passage establishing that this nonsense variant was reported in one individual. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Sanchis-Juan, A., Megy, K., Stephens, J., Armirola Ricaurte, C., Dewhurst, E., Low, K., French, C. E., Grozeva, D., Stirrups, K., Erwood, M., McTague, A., Penkett, C. J., Shamardina, O., Tuna, S., Daugherty, L. C., Gleadall, N., Duarte, S. T., Hedrera-Fernández, A., Vogt, J., Ambegaonkar, G., Chitre, M., Josifova, D., Kurian, M. A., Parker, A., Rankin, J., Reid, E., Wakeling, E., Wassmer, E., Woods, C. G., Raymond, F. L., & Carss, K. J.
Affiliations
  • University of Cambridge (GB)
  • National Health Service (GB)
  • Unidade Local de Saúde de São José (PT)
  • Hospital Universitario Central de Asturias (ES)
  • Birmingham Women's Hospital (GB)
  • Cambridge University Hospitals NHS Foundation Trust (GB)
  • Guy's Hospital (GB)
  • Great Ormond Street Hospital for Children NHS Foundation Trust (GB)
  • Royal Devon University Healthcare NHS Foundation Trust (GB)
  • AstraZeneca (United Kingdom) (GB)
Corresponding author
  • Raymond, F. Lucy
  • Carss, Keren J.
ORCID
Venue
The American Journal of Human Genetics
Publisher
Elsevier BV
Published
2023-08
Volume
110
Issue
8
Pages
1343-1355
ISSN
0002-9297 (ISSN-L)
DOI
10.1016/j.ajhg.2023.07.007
PMC
PMC10432178
OpenAlex
W4385546089
Cited by
24
References
6
Citations by year
2026: 7 · 2025: 9 · 2024: 8
FWCI
3.97
Type
journal article
Language
en
Open access
Licence
Locations
  • The American Journal of Human Genetics (publishedVersion)
  • medRxiv (acceptedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Royal Devon and Exeter Research Repository (Royal Devon and Exeter) (submittedVersion)
Funders
  • NIHR Cambridge Biomedical Research Centre (BRC-1215-20014)
  • AstraZeneca
  • NIHR Great Ormond Street Hospital Biomedical Research Centre
  • NIHR BioResource (RG65966)
  • National Institute for Health and Care Research
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
neurodevelopmental disorders, rare variants, long-read genome sequencing, structural variants, variant phasing, variants of uncertain significance, causal variant identification, mitochondrial DNA variants
MeSH terms
Base Sequence, Chromosome Mapping, Humans, Genome, Human, INDEL Mutation, Neurodevelopmental Disorders

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