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Eyvind Rodahl, Per M. Knappskog, Jacek Majewski, Wenche Telstad, Jostein Kråkenes, Helge Boman; Variants Of Anterior Segment Dysgenesis In A Large Family With A Novel COL4A1 Mutation. Invest. Ophthalmol. Vis. Sci. 2011;52(14):68.
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To investigate the diverse ocular manifestations and identify the causative mutation in a large family with anterior segment dysgenesis.
Forty-five family members in four generations underwent ophthalmic examination. Twenty-six family members and five spouses were subjected to molecular genetic investigation. These studies included genome wide mapping with microsatellite and SNP markers, linkage analysis and DNA sequencing.
A broad range of ocular manifestations were observed. Typical cases presented with a combination of abnormalities including corneal opacities, anterior synechiae, and iris hypoplasia. Embryotoxon posterior, corectopia and early cataract development were also seen, but less frequently. Some parents of affected children had eyes with minimal anomalies that could classified as normal variants, or even indistinguishable from normal eyes. The first genomewide screening with microsatellite markers failed to yield any significant LOD-scores, most likely due to misclassification. We then screened definitely affected individuals with SNP markers followed by haplotype mapping. Definitely affected individuals shared (among other segments) a 14 cM region of chromosome 13qter that included COL4A1. DNA sequencing revealed a sequence variant c.4881C>G present only in affected individuals, but not in 190 local blood donors. The predicted amino acid substitution (p.Asn1627Lys) is localized in the non-collagenous domain of the protein.
Highly heterogenous presentation of anterior segment dysgenesis can be seen in individuals with mutations in COL4A1. Problems with variable expressivity and incomplete penetrance may explain failed attempts to identify causative COL4A1 mutations in families with anterior segment dysgenesis.
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