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Susan E I Williams, Nadia Carstens, Saadiah Goolam, Scott Hazelhurst, Trevor R Carmichael, Michele Ramsay; FBN1 mutations implicated in PCG in a South African family. Invest. Ophthalmol. Vis. Sci. 2016;57(12):801.
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© ARVO (1962-2015); The Authors (2016-present)
Primary congenital glaucoma (PCG), an important cause of childhood blindness, has known genetic associations with CYP1B1 and LTBP2, however mutations in these genes are uncommon in South Africans with PCG. The aim of this study was to identify the cause of PCG in an admixed South African family with two affected children.
The affected children were phenotyped and their DNA was extracted for genetic analysis as was that from both parents and two of their unaffected siblings. Microscopy was performed on the skin of the mother and one of the affected children. Whole exome sequencing on the six family members, to an average depth of 43x, was used for mutation identification. Variant filtering to identify the PCG-causal mutation included the inheritance pattern (autosomal recessive), variant minor allele frequency and potential functional impact.
Both affected children had isolated bilateral primary infantile glaucoma. Neither had systemic features to suggest Marfan or Weill-Marchesani syndromes; however both were found to be osteopenic on bone densitometry. Light and electron microscopy on skin samples revealed extracellular matrix abnormalities and sparser collagen fibres compared to controls. The findings were more severe in the child than his mother. There were no potentially pathogenic homozygous mutations identified within the exome by variant filtering. Twelve compound heterozygous mutations in five genes were identified and evaluated. The most likely causal gene was FBN1 that contained two extremely rare splice-site mutations that segregated with PCG in this family.
FBN1 codes for an ubiquitous extracellular matrix glycoprotein, fibrillin-1. Mutations in FBN1 are mainly causal for Marfan syndrome but have also been described in Weill-Marchesani syndrome and in isolated ectopia lentis. They have not before been implicated in PCG, but fibrillin-1 is a member of a superfamily of extracellular matrix proteins that includes LTBP2 and it interacts with LTBP2. PCG-causing LTBP2 mutations are associated with extracellular matrix and bone mineral density variations similar to the ones identified in this family. FBN1 is therefore an important candidate gene for PCG. We are currently investigating the effects of the FBN1 mutations on splicing and nonsense-mediated decay. Gene expression studies are underway. Our findings could potentially increase current understanding of the disease mechanisms underlying PCG.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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