Background: Congenital hereditary endothelial dystrophy (CHED) is a rare form of corneal dystrophy and is known to be caused by SLC4A11 gene mutation. The purpose of this study is to find genetic alterations in SLC4A11 using direct sequencing in two Indian familial CHED cases with affected members n=3 and n=2 respectively and five non-familial cases with a single affected member, followed by in silico characterization of identified mutations.
Results: All three affected members of the first CHED family were identified with novel hom. c.1514C>G (p.Ser489Trp) mutation while second family showed presence of novel compound heterozygous mutation- het c.529A>C (p.Arg161Arg) + het c.2461insT (p.Val805fs). Among five non-familial cases, two showed novel changes hom. c.1487G>T (p.Ser480Ile) and hom. c.620-2A>G respectively, while the other one had previously reported hom. c.2653C>T (p.Arg869Cys) mutation. The remaining two cases did not reveal the presence of SLC4A11 related pathogenic mutations. Identified mutations were excluded from a large number of controls (n=80) and analyzed in silico using homology-based protein modeling and pathogenicity prediction tools, which predicted these alterations to be pathogenic causing change in protein stability, protein local flexibility and decrease in hydrogen bond interactions.
Conclusions: Our study contributed to CHED mutational spectrum adding four novel mutations and confirming a previously reported mutation. Our study demonstrated a spectrum of mutations ranging from coding, non-coding, homozygous, and synonymous compound heterozygous in CHED cases. The identified mutations demonstrated different degrees of pathogenic effects based on in silico analysis. In addition, two non-familial cases could not be identified with pathogenic mutation emphasizing the involvement of other genes or genetic mechanisms for such cases.