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.