Approximately 70% of CC cases may occur alone, and 15% of such cases may be accompanied by other ocular abnormalities, such as microphthalmia, aniridia, or retinal degeneration. In another 15% of cases, cataracts are one part of a multisystem genetic disorder. (47) To obtain clues related to the noncataractous phenotype or provide a reference for the prognosis of CC surgery, we designed a high-throughput microarray with exon-capture and NGS targeting of the 792 genes most frequently involved in common inherited eye diseases. Compared to related previous studies, our study included the largest numbers of patients and targeted genes. We achieved detection rates in familial and sporadic cases similar to those in a recent study.(37) Although the overall detection rate (46.3%) in our cohort was apparently lower than that in the other studies listed in Table 5, these rates are not comparable due to differences in the proportions of participants. Most of the studies(17-19) included only binocular cataracts, whereas we enrolled many monocular cases. Regarding the distribution of genes, our result was slightly different from those reported previously. Li et al (37) reported that variants in the crystallin genes were the most frequent mutations found in their study, whether in familial or sporadic cases. We found that variants in crystallins accounted for a similar proportion of fCC cases but only 1 sCC case (Figure 1). Structural protein genes, such as transmembrane, collagen, or microtube-associated proteins, accounted for most of the sCCs in our study.
In our study, approximately 20/30 (66.67%) variants provided clues regarding the possibility of complication with inherited ocular or systemic diseases other than CC. Among these, 7 identified loci provided additional ophthalmological diagnostic information. For instance, OPA3 mutations are associated with optic atrophy,(22) BEST1 mutations with best vitelliform macular dystrophy (BEST),(25-28) TSPAN12 mutations with familial exudative vitreoretinopathy (FEVR)(33), PAX6 mutations with aniridia and Peter’s anomaly,(48) and CYP1B1 mutations with glaucoma.(45) Six variants were associated with systemic syndrome. WFS1 is the most common causative gene in Wolfram-like syndrome, a rare autosomal dominant disease characterized by congenital progressive hearing loss, diabetes mellitus, and optic atrophy.(49) COL4A5 is one of causing genes in Alport Syndrome, a genetic condition characterized by progressive loss of kidney function, hearing, and eye abnormalities, including misshapen lenses and abnormal retina.(32) JAG1 has been associated with Alagille syndrome, which involves liver damage or a combination of heart defects. Loss-of-function mutations in the BCOR gene have been identified in individuals with oculo-facio-cardio-dental syndrome (OFCD), which comprises microcornea, CC, and facial, cardiac, and dental abnormalities.(38) Mutations in the FBN1 (fibrillin-1) gene may be diagnostic of Marfan syndrome.(46) NHS mutations have been identified in patients with Nance-Horan syndrome (NHS), an X-linked developmental disorder characterized by CC, dental anomalies, facial dysmorphism and, in some cases, mental retardation.(50) Clinically, a new diagnosis was made after surgery and with reference to genetic testing in at least two patients in our cohort. One of the sporadic cases (ID 11 in Table 2) presented some retinal abnormalities during operations after the removal of cataracts in both eyes, including settled subretinal exudates and dragging of the optic disc. Combined with this clinical manifestation, we have clarified the diagnosis of FEVR with regard for the TSPAN12 mutation, which is a pathogenic gene known to indicate FEVR. We also observed dental, facial and mental anomalies and made a new diagnosis of NHS at 2 years after the first CC operation was performed in one of the sporadic cases with an identified NHS mutation. However, whether other variants are associated with a noncataractous phenotype is difficult to confirm. The relationships between complicated phenotypes and mutations in ocular genes are not explicit. Thus, more cases should be included, and more experiments should be performed to verify these connections.
This study emphasizes the power of and the need for comprehensive parent-child NGS analyses of CC families. Such analyses have the potential to reveal a striking new landscape of inheritance in CC by identifying pathogenic heterozygous and homozygous mutations, de novo mutations, and parental mosaicism, with important implications beyond only the affected child. However, trio sequencing can reveal numerous variants of unknown significance for which thorough functional validation is mandatory, although this remains challenging. Furthermore, based on a parent-child approach, future research is required to determine the clinical implications of non-Mendelian inheritance, the complex interactions between genetic predispositions and environmental factors, and genetic and epigenetic interplay. These studies will provide important insights into the pathogenesis and the complex genotype-to-phenotype association of CC. In the future, these results may also lead to the development of novel gene therapies for some types of congenital cataracts, similar to other inherited eye diseases.
Although we sought to identify links between genotypes and prognoses after uneventful CC surgery to facilitate the provision of accurate prognoses and support clinical decision-making before invasive management, we did not find any clear correlations. Samples in which no mutations were identified in this study could be further submitted to whole-genome sequencing but rarely are because it is challenging to obtain a sufficient amount of blood from infants and young children to meet experimental needs.