{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T09:34:31Z","timestamp":1787045671698,"version":"build-2736575974"},"reference-count":19,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>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&gt;A; p.A600E, c.2623C&gt;T; p.R875*, and c.670dup; p.W224Lfs*7. Seven variants recurred, and the canonical splice donor change c.2018+1G&gt;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.<\/jats:p>","DOI":"10.3390\/ijms27167220","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T09:31:09Z","timestamp":1786613469000},"page":"7220","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Complete SLC4A11 Detection in Saudi Congenital Hereditary Endothelial Dystrophy: A Transmembrane Glycine Hotspot and a Recurrent Splice Donor Allele in Consanguineous Patients"],"prefix":"10.3390","volume":"27","author":[{"given":"Khaled K.","family":"Abu-Amero","sequence":"first","affiliation":[{"name":"Research Department, King Khaled Eye Specialist Hospital and Research Center, Riyadh 11462, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rizwan","family":"Malik","sequence":"additional","affiliation":[{"name":"Research Department, King Khaled Eye Specialist Hospital and Research Center, Riyadh 11462, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara M.","family":"AlHilali","sequence":"additional","affiliation":[{"name":"Anterior Segment Division, King Khaled Eye Specialist Hospital and Research Center, Riyadh 11462, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2112-8196","authenticated-orcid":false,"given":"Deema E.","family":"Jomar","sequence":"additional","affiliation":[{"name":"Anterior Segment Division, King Khaled Eye Specialist Hospital and Research Center, Riyadh 11462, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1097\/ICO.0000000000003420","article-title":"IC3D Classification of Corneal Dystrophies-Edition 3","volume":"43","author":"Weiss","year":"2024","journal-title":"Cornea"},{"key":"ref_2","first-page":"1694","article-title":"Mutation analysis of the SLC4A11 gene in Indian families with congenital hereditary endothelial dystrophy 2 and a review of the literature","volume":"19","author":"Kodaganur","year":"2013","journal-title":"Mol. Vis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1186\/s13023-022-02521-4","article-title":"Identification and in silico analysis of a spectrum of SLC4A11 variations in Indian familial and sporadic cases of congenital hereditary endothelial dystrophy","volume":"17","author":"Salman","year":"2022","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_4","first-page":"2955","article-title":"Congenital hereditary endothelial dystrophy\u2014Mutation analysis of SLC4A11 and genotype-phenotype correlation in a North Indian patient cohort","volume":"16","author":"Paliwal","year":"2010","journal-title":"Mol. Vis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4142","DOI":"10.1167\/iovs.08-3006","article-title":"Mutational spectrum of SLC4A11 in autosomal recessive CHED in Saudi Arabia","volume":"50","author":"Aldahmesh","year":"2009","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"12751","DOI":"10.1038\/s41598-025-97873-9","article-title":"Clinicopathological characterization of non-guttata corneal endothelial dystrophy in Saudi patients with idiopathic endothelial failure","volume":"15","author":"Alkatan","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1016\/j.survophthal.2022.07.010","article-title":"Update on pediatric corneal diseases and keratoplasty","volume":"67","author":"Vanathi","year":"2022","journal-title":"Surv. Ophthalmol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1111\/cge.12191","article-title":"Genetics of the corneal endothelial dystrophies: An evidence-based review","volume":"84","author":"Aldave","year":"2013","journal-title":"Clin. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"148","DOI":"10.3109\/13816810.2016.1151901","article-title":"Homozygous SLC4A11 mutation in a large Irish CHED2 pedigree","volume":"38","author":"Hand","year":"2017","journal-title":"Ophthalmic Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4579","DOI":"10.1093\/hmg\/ddt307","article-title":"Transmembrane water-flux through SLC4A11: A route defective in genetic corneal diseases","volume":"22","author":"Vilas","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"ref_11","first-page":"1621","article-title":"Observation of nine previously reported and 10 non-reported SLC4A11 mutations among 20 Iranian CHED probands and identification of an MPDZ mutation as possible cause of CHED and FECD in one family","volume":"104","author":"Moazzeni","year":"2020","journal-title":"Br. J. Ophthalmol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Yousaf, K., Naz, S., Mushtaq, A., Wohler, E., Sobreira, N., Ho, B.M., Chen, L.J., Chu, W.K., and Bashir, R. (2023). Exome Sequencing Reveals SLC4A11 Variant Underlying Congenital Hereditary Endothelial Dystrophy (CHED2) Misdiagnosed as Congenital Glaucoma. Genes, 14.","DOI":"10.3390\/genes14020310"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"553795","DOI":"10.2147\/OPTH.S553795","article-title":"Congenital Hereditary Endothelial Dystrophy: A Review of the Molecular Pathogenesis, Genetic Basis, and Emerging Treatments","volume":"20","author":"Jomar","year":"2026","journal-title":"Clin. Ophthalmol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Iqbal, A., Naz, S., Kaul, H., Sharif, S., Khushbakht, A., Naeem, M.A., Iqtedar, M., Kaleem, A., Firasat, S., and Manzoor, F. (2022). Mutational analysis in sodium-borate cotransporter SLC4A11 in consanguineous families from Punjab, Pakistan. PLoS ONE, 17, Correction in PLoS ONE\u00a02023, 18, e0293769. https:\/\/doi.org\/10.1371\/journal.pone.0293769.","DOI":"10.1371\/journal.pone.0293769"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4330","DOI":"10.1167\/iovs.13-11929","article-title":"Ion transport function of SLC4A11 in corneal endothelium","volume":"54","author":"Jalimarada","year":"2013","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/S0161-6420(95)31037-8","article-title":"Congenital hereditary endothelial dystrophy associated with glaucoma","volume":"102","author":"Mullaney","year":"1995","journal-title":"Ophthalmology"},{"key":"ref_17","unstructured":"Moshirfar, M., Drake, T.M., and Ronquillo, Y. (2026). Congenital Hereditary Endothelial Dystrophy. StatPearls, StatPearls Publishing."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.1016\/j.ajhg.2022.10.013","article-title":"Calibration of computational tools for missense variant pathogenicity classification and ClinGen recommendations for PP3\/BP4 criteria","volume":"109","author":"Pejaver","year":"2022","journal-title":"Am. J. Hum. Genet."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/16\/7220\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T09:06:59Z","timestamp":1787044019000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/16\/7220"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,13]]},"references-count":19,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27167220"],"URL":"https:\/\/doi.org\/10.3390\/ijms27167220","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,13]]}}}