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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., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Microphthalmia is an important inborn error of eye development that can be associated with multisystem involvement. Anophthalmia is more severe and rarer. Single mutations in an expanding list of genes are known to cause this spectrum of anomaly. In one branch of a multiplex family with microphthalmia and anophthalmia, autozygome analysis excluded all known microphthalmia genes at the time of doing this study. Exome sequencing and autozygome filtration identified a novel homozygous variant in ALDH1A3. Subsequently, we identified another homozygous variant in 2 of the 10 probands with microphthalmia we specifically screened for mutations in ALDH1A3. Interestingly, the other branch of the original family was found to segregate anophthalmia/syndactyly with a novel homozygous SMOC1 variant. Our data support the very recent and independent identification of ALDH1A3 as a disease gene in microphthalmia. Locus heterogeneity should be considered in consanguineous families even for extremely rare phenotypes., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)