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Original research
Whole-genome analysis as a diagnostic tool for patients referred for diagnosis of Silver-Russell syndrome: a real-world study
  1. Ahmed S N Alhendi1,
  2. Derek Lim2,
  3. Shane McKee3,
  4. Meriel McEntagart4,
  5. Katriona Tatton-Brown4,
  6. I Karen Temple1,
  7. Justin H Davies1,
  8. Deborah J G Mackay1,5
  1. 1Human Genetics and Genomic Medicine, Faculty of Medicine, University Hospital Southampton NHS Foundation Trust, Southampton, UK
  2. 2Department of Clinical Genetics, Birmingham Women's and Children's Hospital, Birmingham, UK
  3. 3Department of Genetic Medicine, Belfast City Hospital, Belfast, UK
  4. 4Department of Clinical Genetics, St George's Healthcare NHS Trust, London, UK
  5. 5Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury, UK
  1. Correspondence to Professor Deborah J G Mackay, University of Southampton, Southampton SO17 1BJ, UK; djgm{at}soton.ac.uk

Abstract

Background Silver-Russell syndrome (SRS) is an imprinting disorder characterised by prenatal and postnatal growth restriction, but its clinical features are non-specific and its differential diagnosis is broad. Known molecular causes of SRS include imprinting disturbance, single nucleotide variant (SNV), CNV or UPD affecting several genes; however, up to 40% of individuals with a clinical diagnosis of SRS currently receive no positive molecular diagnosis.

Methods To determine whether whole-genome sequencing (WGS) could uncover pathogenic variants missed by current molecular testing, we analysed data of 72 participants recruited to the 100,000 Genomes Project within the clinical category of SRS.

Results In 20 participants (27% of the cohort) we identified genetic variants plausibly accounting for SRS. Coding SNVs were identified in genes including CDKN1C, IGF2, IGF1R and ORC1. Maternal-effect variants were found in mothers of five participants, including two participants with imprinting disturbance and one with multilocus imprinting disorder. Two regions of homozygosity were suggestive of UPD involving imprinted regions implicated in SRS and Temple syndrome, and three plausibly pathogenic CNVs were found, including a paternal deletion of PLAGL1. In 48 participants with no plausible pathogenic variant, unbiased analysis of SNVs detected a potential association with STX4.

Conclusion WGS analysis can detect UPD, CNV and SNV and is potentially a valuable addition to diagnosis of SRS and related growth-restricting disorders.

  • genetics
  • medical
  • genomics

Data availability statement

No data are available. WGS data and associated clinical data are held within the 100,000 Genomes Project Research Environment. These data can be accessed by any researcher by application to join a GeCIP domain (www.genomicsengland.co.uk/join-a-gecip-domain/). Informatic scripts are available upon request.

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Data availability statement

No data are available. WGS data and associated clinical data are held within the 100,000 Genomes Project Research Environment. These data can be accessed by any researcher by application to join a GeCIP domain (www.genomicsengland.co.uk/join-a-gecip-domain/). Informatic scripts are available upon request.

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Footnotes

  • Contributors ASNA performed bioinformatic analysis and cowrote the manuscript. DL, SM, MM, KT-B and IKT recruited patients and contributed to the manuscript. IKT, JHD and DJGM secured funding, supervised the informatic and laboratory studies, and cowrote the manuscript. DJGM coordinated the study.

  • Funding ASNA was funded by the Child Growth Foundation, UK. IKT is supported by the NIHR Biomedical Research Centre (BRC), Southampton. The Wellcome Trust, Cancer Research UK and the Medical Research Council funded the research infrastructure. The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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