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Nadia Carstens, Saadiah Goolam, Susan E I Williams, Trevor R Carmichael, Scott Hazelhurst, Michele Ramsay; HSPG2 mutations identified in black South African children with Primary Congenital Glaucoma. Invest. Ophthalmol. Vis. Sci. 2016;57(12):802. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Primary congenital glaucoma (PCG), a leading cause of childhood blindness worldwide, is a rare developmental autosomal recessive monogenic disorder characterised by trabecular meshwork dysgenesis. Previous linkage studies identified four PCG loci, including two known genes: CYP1B1 and LTBP2. The genetic aetiology of PCG was investigated in 22 black South African PCG cases.
Whole exome sequencing was done to an average depth of 43x. Using a tiered approach, we first investigated potentially pathogenic variants in the four known PCG loci, then novel or rare homozygous or compound heterozygous mutations with a high probability of functional impact in the rest of the exome. Sixteen genes predicted by Endeavour to have the highest likelihood of impacting the PCG phenotype are discussed.
One boy had a homozygous pathogenic variant (R390H) in CYP1B1 and none of the cases had LTBP2 pathogenic mutations. Eight of the remaining 21 PCG cases had rare, potentially disease causing compound heterozygous variants in the HSPG2 gene, which is located on chromosome 1p36, within a previously identified PCG locus (GLC3B) for which the gene is unknown. A novel HSPG2 G1260A missense mutation was found in the heterozygous state in six of the eight PCG cases in combination with different rare, potentially functional HSPG2 mutations.
Only one of the patients had a mutation in a known PCG gene. We identified potentially disease-causing variants in HSPG2 in eight PCG cases. HSPG2, which encodes perlecan, a microfibril-associated protein involved in cell-adhesion interactions and extracellular matrix integrity, has a reasonable likelihood of impacting the PCG phenotype according to the recently published microfibril hypothesis of glaucoma, which states that defective microfibrils may be an underlying cause of glaucoma. Functional studies are necessary to confirm the effect of perlecan on the PCG phenotype.
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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