Complete SLC4A11 Detection in Saudi Congenital Hereditary Endothelial Dystrophy: A Transmembrane Glycine Hotspot and...

Congenital hereditary endothelial dystrophy (CHED) is a rare autosomal recessive disorder of the corneal endothelium caused by biallelic variants in the SLC4A11 gene. Its genetic spectrum is well described in the Indian subcontinent, but poorly characterized in the Saudi population, where high rates of consanguinity may concentrate specific alleles. We performed whole-exome sequencing in 47 clinically diagnosed CHED patients from consanguineous Saudi families and classified the resulting variants by their predicted effect on the protein. A homozygous SLC4A11 variant was identified in every patient, and no compound heterozygotes were found. The 47 patients carried 20 unique variants, three of which were novel: c.1799C>A; p.A600E, c.2623C>T; p.R875*, and c.670dup; p.W224Lfs*7. Seven variants recurred, and the canonical splice donor change c.2018+1G>A alone accounted for 14 patients. The variants resolved into two mechanistic groups: 22 patients with missense substitutions predicted to misfold the protein and cause endoplasmic reticulum retention, and 25 with truncating or splice variants predicted to abolish the protein. Among those, only the p.R875* sequence variant removes only the final 17 residues, is predicted to escape nonsense-mediated decay, and likely leaves a near-full-length protein. Five of the nine missense variants were glycine-to-arginine substitutions clustered between residues 378 and 413, within the first transmembrane region. The complete detection rate supports genetic homogeneity of CHED in this population and contrasts with the substantial fraction of unsolved cases reported elsewhere. The concentration of variants in a few regions of the gene suggests that a targeted Sanger protocol covering these hotspots could serve as an affordable first-line diagnostic test, with exome sequencing reserved for hotspot-negative patients.