Identification of ADAMTS18 as a gene mutated in Knobloch syndrome

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Journal of Medical Genetics (Impact Factor: 6.34). 09/2011; 48(9):597-601. DOI: 10.1136/jmedgenet-2011-100306
Source: PubMed


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.
To identify a novel genetic cause of KS in a cohort of Saudi KS patients enrolled in this study.
When COL18A1 mutation was excluded, autozygosity mapping was combined with exome sequencing.
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.
The power of combining exome and autozygome analysis in the study of genetics of autosomal recessive disorders, even in simplex cases, has been demonstrated.

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    • "This is the second report that describes a putative pathogenic role of the ADAMTS18 gene in human genetic diseases that affect the eye and the central nervous system (CNS). Due to the recent description of another ADAMTS18 homozygous missense mutation, i.e., the p.S179L, in a family with Knobloch syndrome [25], we carefully revised the clinical history and phenotype of patient A24 to detect a possible overlap with the Knobloch phenotype. However, the lack of any detectable occipital defect as well as the lack of myopia (the patient is actually hypermetropic) and of the classical signs of vitreoretinal degeneration [29] prompted us to exclude the diagnosis of Knobloch syndrome in patient A24 (Figure 1A and data not shown) thus suggesting that the ADAMTS18 gene is also responsible for non-Knobloch forms of retinal diseases. "
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    ABSTRACT: Background Inherited retinal dystrophies, including Retinitis Pigmentosa and Leber Congenital Amaurosis among others, are a group of genetically heterogeneous disorders that lead to variable degrees of visual deficits. They can be caused by mutations in over 100 genes and there is evidence for the presence of as yet unidentified genes in a significant proportion of patients. We aimed at identifying a novel gene for an autosomal recessive form of early onset severe retinal dystrophy in a patient carrying no previously described mutations in known genes. Methods An integrated strategy including homozygosity mapping and whole exome sequencing was used to identify the responsible mutation. Functional tests were performed in the medaka fish (Oryzias latipes) model organism to gain further insight into the pathogenic role of the ADAMTS18 gene in eye and central nervous system (CNS) dysfunction. Results This study identified, in the analyzed patient, a homozygous missense mutation in the ADAMTS18 gene, which was recently linked to Knobloch syndrome, a rare developmental disorder that affects the eye and the occipital skull. In vivo gene knockdown performed in medaka fish confirmed both that the mutation has a pathogenic role and that the inactivation of this gene has a deleterious effect on photoreceptor cell function. Conclusion This study reveals that mutations in the ADAMTS18 gene can cause a broad phenotypic spectrum of eye disorders and contribute to shed further light on the complexity of retinal diseases.
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