Abstract
Purpose :
Primary congenital glaucoma (PCG) is a rare genetic disorder and accounts for 5% of childhood blindness worldwide. Increased intraocular pressure (IOP) leads to corneal clouding, globe size expansion, and optic nerve damage. Genetic studies to date only explain approximately 60% of the mutation etiology. We sought to find the causal mutation in a collection of PCG families prescreened and determined to be negative for mutations in known PCG genes CYP1B1, MYOC, and TEK.
Methods :
After consent was obtained, medical histories and blood samples for DNA extraction were acquired from available members of 4 non-consanguineous families (African and European descent) with non-syndromic PCG. Exome sequencing was performed on the 4 affected probands utilizing either a Sure Select Human All Exon capture kit or a Roche/Nimblegen SeqCap EZ v2.0 capture kit, and an Illumina HiSeq platform. Golden Helix SVS software was used to remove variants that were outside of coding/splice site regions, synonymous, or with an allele frequency greater than 0.002 (gnomAD global data). Sanger sequencing validated the candidate variants and the genotypes of additional family members. Gene expression in ocular tissues was interrogated using the Iowa Ocular Tissue Database.
Results :
Exome sequencing identified 4 rare heterozygous missense variants within either the extracellular LDL-receptor class A repeat domain (p.Gln1025His), B repeat domain (p.Arg2276His and p.Arg2577His) or linker region (p.Asp2101Gly) of the low density lipoprotein receptor 2 gene LRP2. Global and ethnically matched population allele counts were low for all variants (gnomAD database). FATHMM, SIFT, Polyphen2, and CADD algorithms predicted variants to be functionally detrimental. Vertebrate protein sequence alignments showed strong conservation of the reference residues at all 4 missense variant locations. LRP2 ocular gene expression was identified as high in the optic nerve, retina, and ciliary body.
Conclusions :
We provide evidence for autosomal dominant PCG with reduced penetrance caused by heterozygous missense mutations in LRP2. Human LRP2 mutations residing in the same protein domains as our variants have been associated with high myopia with normal IOP. Our findings suggest that LRP2 may also play a role in early-onset glaucoma. Increased suspicion for glaucoma is advised with clinical inspection of individuals with high myopia.
This is a 2021 ARVO Annual Meeting abstract.