Abstract
Purpose To identify likely pathogenic variants in three families with congenital cataracts via panel-based exome sequencing. Methods A panel containing 153 genes associated with congenital cataracts was designed. Genes were selected through reference to databases including the Human Gene Mutation Database (HGMD), Online Mendelian Inheritance in Man (OMIM), Genetic Home Reference, and the latest peer-reviewed publications on the genetics of hereditary cataracts. Panel-based exome sequencing was performed with the Illumina HiSeq X-Ten platform, and then the identified variants were confirmed with Sanger sequencing and evaluated according to the American College of Medical Genetics and Genomics (ACMG) criteria. Results Three likely pathogenic variants were found. A novel CRYBB2: c.230G > T p.G77V variant was identified in family A, a novel CRYBB2: c.230G > A p.G77D variant was identified in family B, and a novel CRYGD: c.475delG p.A159Pfs∗9 variant was identified in family C. Conclusion Panel-based exome sequencing revealed three likely pathogenic variants in three unrelated Chinese families with congenital cataracts. These data expand the genetic spectrum associated with congenital cataracts.
Highlights
Autosomal dominant congenital cataracts (ADCCs) are congenital eye abnormalities with phenotypic variability from congenital cataracts, and some but not all lead to early visual impairment
Sequencing results and biological analysis are described in the supplementary materials, and sequencing data statistics are shown in Table 2. e predictive analysis of variant function is presented in Table 3, and candidate variants are shown in Table S2. e sequencing chromatograms of the three family members are shown in supplementary outcomes 1(Sanger A, Sanger B, and Sanger C) and the sequencing biological analysis results of the three families are shown in supplementary outcomes 2
Raw_data_bases (Mb) Clean_data_bases (Mb) Aligned_bases (Mb) Aligned (%) Initial bases on target Base covered on target Coverage of target region (%) Effective bases on target Fraction of effective bases on target (%) Average sequencing depth on target Fraction of target covered with at least 4X (%) Fraction of target covered with at least 10X (%) Fraction of target covered with at least 20X (%) Duplication rate (%)
Summary
Autosomal dominant congenital cataracts (ADCCs) are congenital eye abnormalities with phenotypic variability from congenital cataracts, and some but not all lead to early visual impairment. ADCCs may impede visual development by affecting lens transparency and may develop before or after birth. Hereditary factors can account for 10–25% of all congenital cataracts [1]. Congenital cataracts are responsible for 5–20% of blindness in individuals living in developed countries and 22–30% in those living in developing countries [2]. Congenital or developmental cataracts demonstrate significant genotypic and phenotypic variability. Recent studies have identified an increasing number of loci and genes associated with congenital cataracts. Until May 12, 2021, the Online Mendelian Inheritance in Man (OMIM) database included 42 non-syndrome-related genes and 27 syndrome-related genes, including genes encoding α-, β-, and c-crystallins, such as CRYAA (NG_009823.1), CRYBB2 (NG_009827.1), and CRYGD (NG_008039.1); α-connexins, such as GJA3 (NG_016399.1) and GJA8 (NG_016242.1); other lens membrane or cytoskeletal proteins genes, such as MIP (NG_021397.2) and BFSP2 (NG_ and 012425.1); several transcription factors, such as HSF4 (NG_009294.1) and PITX3 (NG_008147.1); and an expanding group of functionally divergent genes, including EPHA2 (NG_021396.1), TDRD7 (NG_028984.1), and FYCO1 (NG_031955.1) [1, 3,4,5]
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