Gene Discovery in Primary Congenital Glaucoma

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ABSTRACT Primary Congenital Glaucoma (PCG) is an autosomal recessive, typically severe form of glaucoma that presents in early childhood. PCG is characterized by high intraocular pressure, leading to glaucomatous optic neuropathy associated with enlargement of the ocular globe. Four genetic loci-GLC3A, B, C and D- have been identified and the causative genes in two of these loci have been reported. Cytochrome P450 subfamily I polypeptide 1 (CYP1B1), is located within the GLC3A locus, and mutations in this gene account for approximately 10-20% of affected individuals in the US Caucasian population. The latent transforming growth factor beta binding protein 2 (LTBP2) gene, located within the GLC3D locus, is mutated in a small number of Pakistani and gypsy families, but variants in this gene have not been found in other populations. Finally, mutations in myocilin (MYOC) and CYP1B1 acting together have been implicated PCG in a large Canadian family. These genes account for only 10-20% of the PCG cases in the US, with the genetic etiology of the majority of PCG cases remaining unexplained. We propose to find mutations that cause PCG by sequencing every coding exon of every gene in 75 families containing individuals with PCG. This process, called whole exome sequencing, rapidly and efficiently provides a complete inventory of all deleterious mutations present in an individual's genome. This technique has been used to identify causative mutations for many different diseases including Miller syndrome, non-syndromic hearing loss, and congenital chloride diarrhea. Whole exome sequencing is ideally suited to the identification of mutations in autosomal recessive diseases such as PCG. We hypothesize that most causative mutations will be homozygous or compound heterozygous rare missense mutations or stop codons. It is also possible that mutations will be disrupt gene regulatory regions such as promoters or splice sites, or will consist of duplications or deletions (copy number variants). We will screen the remainder of our PCG dataset to identify all individuals with causative mutations in any given gene. Confirmed mutations will then be replicated in two independent PCG datasets. These investigations will pave the way for the development of new treatments for multiple types of glaucoma.