Identification and in silico analysis of a spectrum of SLC4A11 variations in Indian familial and sporadic cases of congenital hereditary endothelial dystrophy

Abstract

Background Congenital hereditary endothelial dystrophy (CHED) is a rare form of corneal dystrophy caused by SLC4A11 gene variations. This study aims to find the genetic alterations in SLC4A11, in two Indian familial CHED cases with affected members n = 3 and n = 2 respectively and five sporadic CHED cases using direct sequencing, followed by in silico analysis and characterization of the identified variants. Results All three affected members of the first CHED family were identified with a novel homozygous c.1514C > G (p.Ser489Trp) variation while second family showed presence of a compound heterozygous variation c.529A > C (p.Arg161Arg) + c.2461insT (p.Val805fs). Among five sporadic cases, two showed novel changes, homozygous c.1487G > T (p.Ser480Ile) and c.620-2A > G, while the other one had previously reported homozygous c.2653C > T (p.Arg869Cys) variation. The remaining two cases did not reveal the presence of SLC4A11-related pathogenic variations. The identified variations were excluded from the Indian control (n = 80). In silico analysis using homology-based protein modeling and pathogenicity prediction tools, which revealed these alterations as pathogenic, changing their protein stability, local flexibility, residue contact clashes, and the hydrogen bond interactions. Conclusions This study contributed to the CHED mutational spectrum, adding four novel variations and confirming a previously reported one. It demonstrates different type of variations in CHED cases, including coding, non-coding, homozygous, synonymous, and compound heterozygous variations. The identified variations revealed different degrees of pathogenic effects in silico. Moreover, two sporadic cases could not be identified with pathogenic variation emphasizing the involvement of other genes or genetic mechanisms. Supplementary Information The online version contains supplementary material available at 10.1186/s13023-022-02521-4.

Increasing the diagnostic yield of childhood glaucoma cases recruited into the 100,000 Genomes Project

“…All variants detected were in genes previously associated with glaucoma and are “Green” in the glaucoma panel of PanelApp except SLC4A11 and COL18A1 which are not in the glaucoma panel, but are rated “Green” in the corneal abnormalities (v1.12) and structural eye disease (v3.2) panels, respectively. However, the involvement of SLC4A11 and COL18A1 with glaucoma cases has been reported in the literature [ 88 , 112 ]. Furthermore, SOS2 is rated “Green” in the foetal anomalies panel (3.133), but recent studies have showed a probable association between variations in SOS2 and glaucoma [ 113 , 114 ].…”

Investigation of the functional impact of CHED- and FECD4-associated SLC4A11 mutations in human corneal endothelial cells

“…[OMIM] #217700) and Fuchs corneal endothelial dystrophy (FECD, OMIM #613267) belong to a group of inherited disorders that are characterized by bilateral corneal endothelial cell (CEnC) dysfunction and/or cell loss leading to corneal edema and loss of corneal clarity [1]. With an onset at birth or in early childhood, CHED has an autosomal recessive inheritance pattern and is associated with over 90 distinct mutations in the solute linked carrier family 4 member 11 (SLC4A11) gene, in which approximately 80 percent of affected individuals harbor homozygous or compound heterozygous mutations [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. FECD is a complex disease that is associated with both environmental and genetic factors, with a typical onset in the fifth decade of life, though cases of early onset FECD are also observed [21,22].…”