Genetic Screening Revealed Latent Keratoconus in Asymptomatic Individuals.

PURPOSE: To adopt molecular screening in asymptomatic individuals at high risk of developing keratoconus as a combinative approach to prevent subclinical patients from post-refractive surgery progressive corneal ectasia. METHODS: In this study, 79 Chinese and nine Greek families with keratoconus were recruited, including 91 patients with clinically diagnosed keratoconus as well as their asymptomatic but assumptive high-risk first-degree relatives based on underlying genetic factor. Mutational screening of VSX1, TGFBI, and ZEB1 genes and full clinical assessment including Pentacam Scheimpflug tomography were carried out in these individuals. RESULTS: Five variants in VSX1 and TGFBI genes were identified in three Chinese families and one Greek family, and four of them were novel ones. Surprisingly, ultra-early corneal changes in Belin/Ambrosio Enhanced Ectasia Display of Pentacam corneal topography together with co-segregated variants were revealed in the relatives who had no self-reported symptoms. CONCLUSIONS: Variants of VSX1 and TGFBI genes identified in both the clinically diagnosed and subclinical patients may cause the keratoconus through an autosomal dominant inheritance pattern, with different variable expressivity. Combining genetic with Belin/AmbrosioEnhanced Ectasia Display can be used to identify patients with latent keratoconus. This study indicates that genetic testing may play an important supplementary role in re-classifying the disease manifestation and evaluating the preoperative examination of refractive surgery.

Trio-based exome sequencing arrests de novo mutations in early-onset high myopia.

The etiology of the highly myopic condition has been unclear for decades. We investigated the genetic contributions to early-onset high myopia (EOHM), which is defined as having a refraction of less than or equal to -6 diopters before the age of 6, when children are less likely to be exposed to high educational pressures. Trios (two nonmyopic parents and one child) were examined to uncover pathogenic mutations using whole-exome sequencing. We identified parent-transmitted biallelic mutations or de novo mutations in as-yet-unknown or reported genes in 16 probands. Interestingly, an increased rate of de novo mutations was identified in the EOHM patients. Among the newly identified candidate genes, a BSG mutation was identified in one EOHM proband. Expanded screening of 1,040 patients found an additional four mutations in the same gene. Then, we generated Bsg mutant mice to further elucidate the functional impact of this gene and observed typical myopic phenotypes, including an elongated axial length. Using a trio-based exonic screening study in EOHM, we deciphered a prominent role for de novo mutations in EOHM patients without myopic parents. The discovery of a disease gene, BSG, provides insights into myopic development and its etiology, which expands our current understanding of high myopia and might be useful for future treatment and prevention.

Genetic signatures of high-altitude adaptation in Tibetans.

Indigenous Tibetan people have lived on the Tibetan Plateau for millennia. There is a long-standing question about the genetic basis of high-altitude adaptation in Tibetans. We conduct a genome-wide study of 7.3 million genotyped and imputed SNPs of 3,008 Tibetans and 7,287 non-Tibetan individuals of Eastern Asian ancestry. Using this large dataset, we detect signals of high-altitude adaptation at nine genomic loci, of which seven are unique. The alleles under natural selection at two of these loci [methylenetetrahydrofolate reductase (MTHFR) and EPAS1] are strongly associated with blood-related phenotypes, such as hemoglobin, homocysteine, and folate in Tibetans. The folate-increasing allele of rs1801133 at the MTHFR locus has an increased frequency in Tibetans more than expected under a drift model, which is probably a consequence of adaptation to high UV radiation. These findings provide important insights into understanding the genomic consequences of high-altitude adaptation in Tibetans.

Genome-Wide Detection of Copy Number Variations in Unsolved Inherited Retinal Disease.

Purpose: Inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous group of Mendelian disorders that plays a crucial role in the etiology of blindness across the world. Molecular genetic diagnosis of IRD remains extremely complex and challenging because mutations are only detected in 40% to 60% of cases. In this study, we aimed to dissect the contributions of copy number variations (CNVs) in IRD patients. Methods: A total of 50 patients were diagnosed with IRD, all of whom previously tested negative for pathogenic mutations in known disease genes. Single-nucleotide polymorphism array analysis was performed by using the HumanCoreExome BeadChip. Analyses of CNVs were carried out by using GenomeStudio, KaryoStudio, and cnvPartition. The putative pathogenic CNVs were further confirmed by real-time quantitative PCR. Results: We identified four novel CNVs in three different genes (one duplication in USH2A gene, two duplications in CEP290 gene, and one duplication in RIMS2 gene) in total four families, at a detection rate of 8% (4/50). All of these CNVs are currently absent in all databases. Three variations are located in genes that are already known to cause inherited retinal disease: USH2A and CEP290, while the association between mutation in the RIMS2 gene and IRD is reported for the first time. Conclusions: We performed whole-genome-wide CNV analyses in a large cohort as an alternative approach to molecular diagnosis of IRDs. This study dissected the contributions of CNVs of IRDs, not only increasing the yield in genetic testing but also suggesting the CNVs should be analyzed in the patients with IRDs.