A genetic investigation in fi ve Chinese families with keratoconus

Background: This study investigated the genetic characteristics of fi ve Chinese families with keratoconus (KC). Methods: In the fi ve families affected by KC, medical records, clinical observations, and blood samples were collected from all individuals. All KC family members (n n = 20) underwent both whole exome sequencing of genomic DNA and Sanger sequencing to confirm fi rm the variants. Online software was utilized to analyze all variants, and the online server I-TASSER was employed for in silico predictions of the three-dimensional protein structures of the variants. The newly discovered variants and single nucleotide polymorphisms were further examined in 322 sporadic KC patients. Results: The Pentacam tomographic composite index in those affected fi rst-degree family members of the probands showed a pathological change. Five new variants were detected in the fi ve probands and other affected members in their families: a heterozygous missense variant g.19043832C>T (p.Ser145Asn) in the homer scaffolding protein 3 ( HOMERS ) gene; a heterozygous missense variant g.99452113G>A (p.Gly483Arg) in the insulin-like growth factor 1 receptor ( IGF1R ) gene; a heterozygous missense variant g.55118280G>T (p.Trp843Leu) in the echinoderm microtubule-associated protein like 6 ( EML6 ) gene; a heterozygous frameshift variant c. 1226_1227del (p.Gln410Glufs*17) in the DOP1 leucine zipper-like protein B ( DOP1B ) gene; and a heterozygous splice-site variant c.7776 +2T>A in the neurobeachin-like protein 2 ( NBEAL2 ) gene. These variations were predicted to be potentially pathogenic and associated with KC. Conclusion: Five novel variants in HOMERS, IGF1R, EML6, DOP1B, , and NBEAL2 genes were identified fi ed in this study and may be associated with the pathogenesis of KC. This study provides new information about the gene variants and their protein changes in KC patients. The fi ndings should be explored further and could potentially be applied to the early diagnosis of KC before clinical onset.