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Original research
Linked-read genome sequencing identifies biallelic pathogenic variants in DONSON as a novel cause of Meier-Gorlin syndrome
  1. Karen M Knapp1,
  2. Rosie Sullivan1,
  3. Jennie Murray2,
  4. Gregory Gimenez1,
  5. Pamela Arn3,
  6. Precilla D'Souza4,
  7. Alper Gezdirici5,
  8. William G Wilson6,
  9. Andrew P Jackson2,
  10. Carlos Ferreira7,
  11. Louise S Bicknell1
  1. 1 Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
  2. 2 MRC HGU, Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, Edinburgh, UK
  3. 3 Nemours Children's Clinic, Jacksonville, Florida, USA
  4. 4 Office of the Clinical Director, National Human Genome Research Institute, Bethesda, Maryland, USA
  5. 5 Department of Medical Genetics, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey
  6. 6 Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, Virginia, USA
  7. 7 Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, Bethesda, Maryland, USA
  1. Correspondence to Dr Louise S Bicknell, Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand; louise.bicknell{at}otago.ac.nz

Abstract

Material Linked-read whole genome sequencing (WGS) presents a new opportunity for cost-efficient singleton sequencing in place of traditional trio-based designs while generating informative-phased variants, effective for recessive disorders when parental DNA is unavailable.

Methods We have applied linked-read WGS to identify novel causes of Meier-Gorlin syndrome (MGORS), a condition recognised by short stature, microtia and patella hypo/aplasia. There are eight genes associated with MGORS to date, all encoding essential components involved in establishing and initiating DNA replication.

Results Our successful phasing of linked-read data led to the identification of biallelic rare variants in four individuals (24% of our cohort) in DONSON, a recently established DNA replication fork surveillance factor. The variants include five novel missense and one deep intronic variant. All were demonstrated to be deleterious to function; the missense variants all disrupted the nuclear localisation of DONSON, while the intronic variant created a novel splice site that generated an out-of-frame transcript with no residual canonical transcript produced.

Conclusion Variants in DONSON have previously been associated with extreme microcephaly, short stature and limb anomalies and perinatal lethal microcephaly-micromelia syndrome. Our novel genetic findings extend the complicated spectrum of phenotypes associated with DONSON variants and promote novel hypotheses for the role of DONSON in DNA replication. While our findings reiterate that MGORS is a disorder of DNA replication, the pathophysiology is obviously complex. This successful identification of a novel disease gene for MGORS highlights the utility of linked-read WGS as a successful technology to be considered in the genetic studies of recessive conditions.

  • linked-read genome sequencing
  • meier-gorlin syndrome
  • donson
  • DNA replication
  • microcephaly
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Footnotes

  • Contributors LSB established and supervised the project. KMK, GG and LSB undertook the bioinformatics analysis. KMK and RS undertook the molecular genetics experiments. JM, PA, PD, AG, WGW, APJ and CF provided patient samples and clinical information. LSB wrote the manuscript with assistance from KMK.

  • Funding This research, KMK and LSB are supported by the Marsden Fund; LSB is supported by a Rutherford Discovery Fellowship, both administered by the Royal Society of New Zealand. The lab of APJ is supported by the Medical Research Council, UK (MRC, U127580972) and the European Union's Horizon 2020 research and innovation programme ERC Advanced Grant (Grant agreement No: 788093).

  • Competing interests None declared.

  • Patient consent for publication Parental/guardian consent obtained.

  • Ethics approval Ethical approval for this study was provided by the New Zealand Health and Disability Ethics Committee (16/STH/3) and Scottish Multicentre Research Ethics Committee (05/MRE00/74).

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

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.