Genotype/phenotype correlation studies in French-Canadian glaucoma families co-segregating myocilin and WDR36 mutations/variations

¹Karine Lebel, ¹Pascal Belleau, ¹Rose Arseneault, ²Jean-Louis Anctil, ¹Annie Duchesne, ¹Marc-André Rodrigue, ²Gilles Côté, ³Marcel Amyot, ¹The Québec Glaucoma Network, ^1,2Vincent Raymond
¹Ocular Genetics and Genomics, Molecular Endocrinology and Oncology, Laval University Hospital (CHUL) Research Ctr, Quebec City, PQ, Canada, ²Dept. of Ophthalmology, Laval University, Quebec City, PQ, Canada, ³Dept. of Ophthalmology, University of Montreal, Montreal, PQ, Canada

Glaucoma is the 2nd cause of blindness. Its most common form, primary open-angle glaucoma (POAG), is genetically heterogenous. Three POAG genes have been characterized: myocilin (MYOC), optineurin (OPTN) and WDR36. Myocilin mutations cause about 4% of all POAG cases. On the other hand, contributions of WDR36 variations to the glaucoma phenotype are less understood. Several variations are considered disease-associated mutations while others may modify the phenotype. To assess if WDR36 acted as a modifier gene, we determined the distribution of its variations in French-Canadian families in which myocilin mutations were the primary cause for glaucoma. Genotype/phenotype studies were performed in kindreds showing co-segregation of variations in both genes. 180 myocilin mutation carriers, members of 7 families, were screened for WDR36 variations. One kindred was the huge CA pedigree in which the K423E myocilin mutation caused autosomal dominant POAG; age at onset (AAO) of the disease ranged from 7 to 63 years old in its 142 heterozygotic carriers. Overall, 22 sequence alterations were detected in WDR36 coding exons and flanking introns. Six of the 9 exon variations encoded non-synonymous amino acid changes. In myocilin mutant carriers, 11 harbored the L25P WDR36 variant; 4, the D33E variant; 5, the H212P; 68, the I264V; 2, the A449T; and 5 harbored the D658G variants. Co-segregation of the L25P WDR36 variation with the K423E myocilin mutation was observed in 2 branches of the CA pedigree. To assess for an effect of WDR36 variations on age at onset (AAO) of POAG, we compared the AAO for the disease in carriers of WDR36 variations to the median of the AAO in non-WDR36 carriers using myocilin mutant carriers who shared a kinship coefficient of 0,625 or higher. Ten WDR36 carriers had a younger AAO than their close relatives compared to 5 WDR36 carriers who had an older AAO than their neighbourhood. Three WDR36 carriers had similar AAO. In a qualitative phenotypic assessment of our kindreds, several WDR36 variations may exacerbate the disease by lowering AAO and/or by accelerating optic nerve degeneration or visual field defects. In conclusion, WDR36 was a highly polymorphic gene in our French-Canadian myocilin pedigrees. WDR36 variations displayed a trend to lower age at onset of the disease trait. This study suggests that WDR36 variants may contribute to the glaucoma phenotype by interacting with myocilin mutations as a modifier gene.