Mutations in known disease genes account for the majority of autosomal recessive retinal dystrophies.

Retinal dystrophies (RDs) are hereditary blinding eye conditions that are highly variable in their clinical presentation. The remarkable genetic heterogeneity that characterizes RD was a major challenge in establishing the molecular diagnosis in these patients until the recent advent of next-generation sequencing. It remains unclear, however, what percentage of autosomal recessive RD remain undiagnosed when all established RD genes are sequenced. We enrolled 75 families in which RD segregates in an apparently autosomal recessive manner. We show that the yield of a multigene panel that contains known RD genes is 67.5%. The higher yield (82.3%) when whole exome sequencing was implemented instead was often due to hits in genes that were not included in the original design of the panel. We also show the value of homozygosity mapping even during the era of exome sequencing in uncovering cryptic mutations. In total, we describe 45 unique likely deleterious variants (of which 18 are novel including one deep intronic and one genomic deletion mutation). Our study suggests that the genetic heterogeneity of autosomal recessive RD is approaching saturation and that any new RD genes will probably account for only a minor role in the mutation burden.

Genetic investigation of 93 families with microphthalmia or posterior microphthalmos.

Microphthalmia is a developmental eye defect that is highly variable in severity and in its potential for systemic association. Despite the discovery of many disease genes in microphthalmia, at least 50% of patients remain undiagnosed genetically. Here, we describe a cohort of 147 patients (93 families) from our highly consanguineous population with various forms of microphthalmia (including the distinct entity of posterior microphthalmos) that were investigated using a next-generation sequencing multi-gene panel (i-panel) as well as whole exome sequencing and molecular karyotyping. A potentially causal mutation was identified in the majority of the cohort with microphthalmia (61%) and posterior microphthalmos (82%). The identified mutations (55 point mutations, 15 of which are novel) spanned 24 known disease genes, some of which have not or only very rarely been linked to microphthalmia (PAX6, SLC18A2, DSC3 and CNKSR1). Our study has also identified interesting candidate variants in 2 genes that have not been linked to human diseases (MYO10 and ZNF219), which we present here as novel candidates for microphthalmia. In addition to revealing novel phenotypic aspects of microphthalmia, this study expands its allelic and locus heterogeneity and highlights the need for expanded testing of patients with this condition.

Association of serum cytokines levels, interleukin 10 -1082G/A and interferon-γ +874T/A polymorphisms with atopic asthma children from Saudi Arabia.

The aim of this study was to clarify the role of IL-4, IL-10, IL-13 and interferon (IFN) -γ levels in atopic asthma patients by studying the relation between their serum levels and severity of the disease. The effect of IL-10 -1082G/A and IFN-γ +874T/A SNPs was also studied. The study included 200 atopic children with asthma and 50 age- and gender matched healthy children as controls. The levels of both IL-4 and IL-13 were significantly (p<0.001) higher, while IFN-γ was significantly (p<0.001) lower in patients compared to that of the controls. There was a significant effect of gene polymorphisms of IL-10 (p<0.05) and IFN-γ (p<0.001) in occurrence of atopic asthma and increased IgE level. Polymorphism of IFN-γ gene had an effect on the serum level of IFN-γ. In conclusion, IFN-γ gene polymorphism at position +874 and IL-10 gene polymorphism at position -1082A/G are genetic determinants which contribute to susceptibility to atopic asthma in children from Saudi Arabia.