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.
"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 , 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  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. "
[Show abstract][Hide abstract] 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.
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.
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.
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.
[Show abstract][Hide abstract] ABSTRACT: Very-long-chain fatty acids (VLCFAs) play important roles in membrane structure and cellular signaling, and their contribution to human health is increasingly recognized. Fatty acid elongases catalyze the first and rate-limiting step in VLCFA synthesis. Heterozygous mutations in ELOVL4, the gene encoding one of the elongases, are known to cause macular degeneration in humans and retinal abnormalities in mice. However, biallelic ELOVL4 mutations have not been observed in humans, and murine models with homozygous mutations die within hours of birth as a result of a defective epidermal water barrier. Here, we report on two human individuals with recessive ELOVL4 mutations revealed by a combination of autozygome analysis and exome sequencing. These individuals exhibit clinical features of ichthyosis, seizures, mental retardation, and spasticity-a constellation that resembles Sjögren-Larsson syndrome (SLS) but presents a more severe neurologic phenotype. Our findings identify recessive mutations in ELOVL4 as the cause of a neuro-ichthyotic disease and emphasize the importance of VLCFA synthesis in brain and cutaneous development.
The American Journal of Human Genetics 11/2011; 89(6):745-50. DOI:10.1016/j.ajhg.2011.10.011 · 10.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Split hand and foot malformation (SHFM) refers to a genetically heterogeneous developmental disorder of the hands and feet that presents as median ray deficiency of varying severity. 7q21.3 (SHFM1) is one of six loci described to date, and although DLX5 and DLX6 are compelling candidates in that locus, no intragenic mutations have been described in either of these genes.
The authors combined autozygome analysis and exome sequencing to study a consanguineous family with a highly unusual SHFM phenotype, where there is associated dorsalisation of the hands.
A novel missense mutation in a highly conserved residue of the homeobox domain of DLX5 was identified. Unlike previously reported position effect mutations in SHFM1, this first documented intragenic DLX5 mutation is also accompanied by abnormal dorsal-ventral patterning.
This study identified the first intragenic DLX5 mutation in SHFM and raises interesting possibilities about a dual role for DLX5 in limb development.
Journal of Medical Genetics 11/2011; 49(1):16-20. DOI:10.1136/jmedgenet-2011-100556 · 6.34 Impact Factor
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