Exfoliation syndrome (XFS) is the commonest known risk factor for secondary glaucoma and a significant cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A have been previously associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results between populations, and to identify new variants associated with XFS. We identified a rare, protective allele at LOXL1 (p.407Phe, OR = 25, P =2.9 × 10−14) through deep resequencing of XFS cases and controls from 9 countries. This variant results in increased cellular adhesion strength compared to the wild-type (p.407Tyr) allele. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 × 10−8). Index variants at the new loci map to chromosomes 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS, and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 × 10(-15)), CHAT rs1258267 (OR = 1.22, P = 2.85 × 10(-16)), GLIS3 rs736893 (OR = 1.18, P = 1.43 × 10(-14)), FERMT2 rs7494379 (OR = 1.14, P = 3.43 × 10(-11)), and DPM2-FAM102A rs3739821 (OR = 1.15, P = 8.32 × 10(-12)). We also confirmed significant association at three previously described loci (P < 5 × 10(-8) for each sentinel SNP at PLEKHA7, COL11A1, and PCMTD1-ST18), providing new insights into the biology of PACG.

Cone-rod degeneration (CRD) belongs to the disease spectrum of retinal degenerations, a group of hereditary disorders characterized by an extreme clinical and genetic heterogeneity. It mainly differentiates from other retinal dystrophies, and in particular from the more frequent disease retinitis pigmentosa, because cone photoreceptors degenerate at a higher rate than rod photoreceptors, causing severe deficiency of central vision. After exome analysis of a cohort of individuals with CRD, we identified biallelic mutations in the orphan gene CEP78 in three subjects from two families: one from Greece and another from Sweden. The Greek subject, from the island of Crete, was homozygous for the c.499+1G>T (IVS3+1G>T) mutation in intron 3. The Swedish subjects, two siblings, were compound heterozygotes for the nearby mutation c.499+5G>A (IVS3+5G>A) and for the frameshift-causing variant c.633delC (p.Trp212Glyfs(∗)18). In addition to CRD, these three individuals had hearing loss or hearing deficit. Immunostaining highlighted the presence of CEP78 in the inner segments of retinal photoreceptors, predominantly of cones, and at the base of the primary cilium of fibroblasts. Interaction studies also showed that CEP78 binds to FAM161A, another ciliary protein associated with retinal degeneration. Finally, analysis of skin fibroblasts derived from affected individuals revealed abnormal ciliary morphology, as compared to that of control cells. Altogether, our data strongly suggest that mutations in CEP78 cause a previously undescribed clinical entity of a ciliary nature characterized by blindness and deafness but clearly distinct from Usher syndrome, a condition for which visual impairment is due to retinitis pigmentosa.

This study confirms that CYP1B1 mutations are associated with POAG and PCG in the Pakistani population.

BackgroundCYP1B1 is the most commonly mutated gene in primary congenital glaucoma (PCG). This study was undertaken to identify mutations in CYP1B1 in the Western region of Saudi Arabia.MethodsBlood of patients who had typical findings of PCG, were screened by direct sequencing of all coding exons and splice junctions of the CYP1B1 gene.Results34 patients were studied; 18 patients belonged to 8 families, and 16 patients were non-familial, isolated PCG. Consanguinity was found in 27/34 (79.4%) of cases. All patients were diagnosed to have bilateral PCG at birth except one child, who had glaucoma in the right eye. More males (61.8%) were affected than females (38.2%). 79.4% (27/34) of patients were solved with pathogenic mutations and 20.6% (7/34) remained unsolved. Of the solved ones, 22.2% (6/27) of patients carry a pathogenic allele on one allele while the other allele remained yet to be determined. Direct sequencing of exon 2 revealed two pathogenic variants (p.Gly61Glu, p.Glu229Lys). P.Gly61Glu substitution was found both homozygously in 63% (17/27) of cases, and heterozygously in one patient. P.Glu229Lys variant was found heterozygous in 3.7% (1/27) of cases. One pathogenic variant (p.Arg469Trp) was found in exon 3, and is present homozygously in 14.8% (4/27) of cases while four patients have this variant heterozygously. All mutations were reported previously in the Saudi population, except p.Glu229Lys. Severe cases were associated with p.Gly61Glu, and p.Arg469Trp in 50% and 30% of ten patients respectively.ConclusionsThis study confirms that CYP1B1 mutations are the most frequent cause of PCG in the Saudi population, with p.Gly61Glu being the major disease-associated mutation. P.Glu229Lys is a newly discovered mutation in our PCG patients. Patient lacking mutation in CYP1B1 gene seems likely, to have another genetic loci involved in the pathogenesis of the disease, and need further study. Genetic studies of recessive diseases such as PCG is important in consanguineous populations, since it will increase awareness and allows genetic counseling to be offered to patients and their relatives. This will not only reduce the disease to be inherited to future generations, but will also reduce the disease burden in the community.