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Identification of ADAMTS18 as a gene mutated in Knobloch syndrome
  1. Mohammed A Aldahmesh1,
  2. Arif O Khan1,2,
  3. Jawahir Y Mohamed1,
  4. Hisham Alkuraya1,2,
  5. Hala Ahmed3,
  6. Steve Bobis3,
  7. Saleh Al-Mesfer2,
  8. Fowzan S Alkuraya1,4,5
  1. 1Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
  2. 2Department of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
  3. 3Department of Comparative Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
  4. 4Department of Pediatrics, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh, Saudi Arabia
  5. 5Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
  1. Correspondence to Dr Fowzan S Alkuraya, MD, Developmental Genetics Unit, Department of Genetics, King Faisal Specialist Hospital and Research Center, MBC-03 PO Box 3354, Riyadh 11211, Saudi Arabia; falkuraya{at}


Background Knobloch syndrome (KS) is a developmental disorder characterised by occipital skull defect, high myopia, and vitreo-retinal degeneration. Although genetic heterogeneity has been suspected, COL18A1 is the only known KS disease gene to date.

Objective To identify a novel genetic cause of KS in a cohort of Saudi KS patients enrolled in this study.

Methods When COL18A1 mutation was excluded, autozygosity mapping was combined with exome sequencing.

Results In one patient with first cousin parents, COL18A1 was excluded by both linkage and direct sequencing. By filtering variants generated on exome sequencing using runs of autozygosity in this simplex case, the study identified ADAMTS18 as the only gene carrying a homozygous protein altering mutation. It was also shown that Adamts18 is expressed in the lens and retina in the developing murine eye.

Conclusion The power of combining exome and autozygome analysis in the study of genetics of autosomal recessive disorders, even in simplex cases, has been demonstrated.

  • COL18A1
  • ADAMTS18
  • encephalocoele
  • cutis aplasia
  • lens subluxation
  • vitreoretinal degeneration
  • autozygome
  • genetics
  • genome-wide
  • glaucoma
  • ophthalmology

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  • Funding This study was funded in part by KACST grants 08-MED497-20 and 09-MED941-20 (FSA) and a Dubai Harvard Foundation for Medical Research Collaborative Grant (FSA).

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was approved by KFSHRC IRB.

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