Linked-read genome sequencing identifies biallelic pathogenic variants in DONSON as a novel cause of Meier-Gorlin syndrome
By K. Knapp, Rosie Sullivan, J. Murray, Gregory Gimenez, P. Arn, Precilla D’Souza, A. Gezdirici, W. Wilson, A. Jackson, C. Ferreira and 1 more. 2019
41 citations recorded by the source corpus.
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.
Subfields: Molecular Biology, Oncology
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Citations in the corpus
- In silico protein interaction screening uncovers DONSON’s role in replication initiation (2023, background): “DONSON ’ s role in CMG assembly provides a mechanistic explanation for DONSON mutations discovered in MGS patients ( 50 , 51 ).”
- The expanding genetic and clinical landscape associated with Meier-Gorlin syndrome (2023, background): “The identification of replication fork stabiliser DONSON as a new MGORS gene challenges this idea [9, 16, 17], since DONSON has no known role during early DNA replication processes.”