{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:43:56Z","timestamp":1787028236032,"version":"build-2736575974"},"reference-count":32,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,25]],"date-time":"2023-01-25T00:00:00Z","timestamp":1674604800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"McKusick-Nathans Department of Genetic Medicine, Baylor Hopkins center for Mendelian Genomics Baltimore"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Autosomal recessive congenital hereditary endothelial dystrophy (CHED2) may be misdiagnosed as primary congenital glaucoma (PCG) due to similar clinical phenotypes during early infancy. In this study, we identified a family with CHED2, which was previously misdiagnosed as having PCG, and followed up for 9 years. Linkage analysis was first completed in eight PCG-affected families, followed by whole-exome sequencing (WES) in family PKGM3. The following in silico tools were used to predict the pathogenic effects of identified variants: I-Mutant 2.0, SIFT, Polyphen-2, PROVEAN, mutation taster and PhD-SNP. After detecting an SLC4A11 variant in one family, detailed ophthalmic examinations were performed again to confirm the diagnosis. Six out of eight families had CYP1B1 gene variants responsible for PCG. However, in family PKGM3, no variants in the known PCG genes were identified. WES identified a homozygous missense variant c.2024A&gt;C, p.(Glu675Ala) in SLC4A11. Based on the WES findings, the affected individuals underwent detailed ophthalmic examinations and were re-diagnosed with CHED2 leading to secondary glaucoma. Our results expand the genetic spectrum of CHED2. This is the first report from Pakistan of a Glu675Ala variant with CHED2 leading to secondary glaucoma. The p.Glu675Ala variant is likely a founder mutation in the Pakistani population. Our findings suggest that genome-wide neonatal screening is worthwhile to avoid the misdiagnosis of phenotypically similar diseases such as CHED2 and PCG.<\/jats:p>","DOI":"10.3390\/genes14020310","type":"journal-article","created":{"date-parts":[[2023,1,26]],"date-time":"2023-01-26T01:57:07Z","timestamp":1674698227000},"page":"310","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Exome Sequencing Reveals SLC4A11 Variant Underlying Congenital Hereditary Endothelial Dystrophy (CHED2) Misdiagnosed as Congenital Glaucoma"],"prefix":"10.3390","volume":"14","author":[{"given":"Khazeema","family":"Yousaf","sequence":"first","affiliation":[{"name":"Department of Biotechnology, Lahore College for Women University, Lahore 54000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1912-0235","authenticated-orcid":false,"given":"Sadaf","family":"Naz","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, University of the Punjab, Quaid-i-Azam Campus, Lahore 54590, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asma","family":"Mushtaq","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Children\u2019s Hospital & the Institute of Child Health, Lahore 54000, Pakistan"},{"name":"Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Hong Kong 999077, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6189-9839","authenticated-orcid":false,"given":"Elizabeth","family":"Wohler","sequence":"additional","affiliation":[{"name":"McKusick-Nathans Department of Genetic Medicine, Baylor Hopkins Center for Mendelian Genomics, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nara","family":"Sobreira","sequence":"additional","affiliation":[{"name":"McKusick-Nathans Department of Genetic Medicine, Baylor Hopkins Center for Mendelian Genomics, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7386-3868","authenticated-orcid":false,"given":"Bo-Man","family":"Ho","sequence":"additional","affiliation":[{"name":"McKusick-Nathans Department of Genetic Medicine, Baylor Hopkins Center for Mendelian Genomics, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3500-5840","authenticated-orcid":false,"given":"Li-Jia","family":"Chen","sequence":"additional","affiliation":[{"name":"Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Hong Kong 999077, China"},{"name":"Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2903-3247","authenticated-orcid":false,"given":"Wai-Kit","family":"Chu","sequence":"additional","affiliation":[{"name":"Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Hong Kong 999077, China"},{"name":"Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rasheeda","family":"Bashir","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Lahore College for Women University, Lahore 54000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1136\/jmg.2004.020024","article-title":"CYP1B1 mutations in French patients with early-onset primary open-angle glaucoma","volume":"41","author":"Melki","year":"2004","journal-title":"J. Med. Genet."},{"key":"ref_2","first-page":"2002","article-title":"Novel CYP1B1 mutations in consanguineous Pakistani families with primary congenital glaucoma","volume":"14","author":"Firasat","year":"2008","journal-title":"Mol. Vis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/09286586.2021.1883676","article-title":"Genetic Epidemiology of Primary Congenital Glaucoma in the 22 Arab Countries: A Systematic Review","volume":"29","author":"Jemmeih","year":"2022","journal-title":"Ophthalmic Epidemiol."},{"key":"ref_4","first-page":"39","article-title":"Genetic analysis of two Indian families affected with congenital hereditary endothelial dystrophy: Two novel mutations in SLC4A11","volume":"13","author":"Kumar","year":"2007","journal-title":"Mol. Vis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2395","DOI":"10.1093\/hmg\/4.12.2395","article-title":"Linkage of congenital hereditary endothelial dystrophy to chromosome 20","volume":"4","author":"Toma","year":"1995","journal-title":"Hum. Mol. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1006\/geno.1999.5920","article-title":"Localization of the gene for autosomal recessive congenital hereditary endothelial dystrophy (CHED2) to chromosome 20 by homozygosity mapping","volume":"61","author":"Hand","year":"1999","journal-title":"Genomics"},{"key":"ref_7","first-page":"475392","article-title":"SLC4A11 and the Pathophysiology of Congenital Hereditary Endothelial Dystrophy","volume":"2015","author":"Sangita","year":"2015","journal-title":"BioMed Res. Int."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"129","DOI":"10.3109\/13816810.2010.544363","article-title":"Conditions that can be mistaken as early childhood glaucoma","volume":"32","author":"Khan","year":"2011","journal-title":"Ophthalmic Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1111\/cxo.12276","article-title":"Missense mutation in SLC4A11 in two Pakistani families affected with congenital hereditary endothelial dystrophy (CHED2)","volume":"99","author":"Kaul","year":"2016","journal-title":"Clin. Exp. Optom."},{"key":"ref_10","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":"Kardagor","year":"2013","journal-title":"Mol. Vis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1097\/APO.0000000000000205","article-title":"The Genetics and Pathophysiology of IC3D Category 1 Corneal Dystrophies: A Review","volume":"5","author":"Oliver","year":"2016","journal-title":"Asia Pac. J. Ophthalmol."},{"key":"ref_12","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_13","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1001\/archopht.126.5.700","article-title":"Identification of mutations in the SLC4A11 gene in patients with recessive congenital hereditary endothelial dystrophy","volume":"126","author":"Hemadevi","year":"2008","journal-title":"Arch. Ophthalmol."},{"key":"ref_14","first-page":"1327","article-title":"Mutational spectrum of the SLC4A11 gene in autosomal recessive congenital hereditary endothelial dystrophy","volume":"13","author":"Sultana","year":"2007","journal-title":"Mol. Vis."},{"key":"ref_15","first-page":"2955","article-title":"Congenital hereditary endothelial dystrophy-mutation 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_16","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1136\/jmg.2006.044644","article-title":"Autosomal recessive corneal endothelial dystrophy (CHED2) is associated with mutations in SLC4A11","volume":"44","author":"Jiao","year":"2007","journal-title":"J. Med. Genet."},{"key":"ref_17","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_18","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1080\/13816810701850033","article-title":"Mutation in the SLC4A11 gene associated with autosomal recessive congenital hereditary endothelial dystrophy in a large Saudi family","volume":"29","author":"Shah","year":"2008","journal-title":"Ophthalmic Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1038\/ng1824","article-title":"Mutations in sodium-borate cotransporter SLC4A11 cause recessive congenital hereditary endothelial dystrophy (CHED2)","volume":"38","author":"Vithana","year":"2006","journal-title":"Nat. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"29","DOI":"10.3928\/01913913-20100106-07","article-title":"High measured intraocular pressure in children with recessive congenital hereditary endothelial dystrophy","volume":"47","author":"Khan","year":"2010","journal-title":"J. Pediatr. Ophthalmol. Strabismus."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.gene.2015.07.014","article-title":"Homozygous p.G61E mutation in a consanguineous Pakistani family with co-existence of juvenile-onset open angle glaucoma and primary congenital glaucoma","volume":"570","author":"Bashir","year":"2015","journal-title":"Gene"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.12669\/pjms.306.5771","article-title":"Contribution of GLC3A locus to Primary Congenital Glaucoma in Pakistani population","volume":"30","author":"Bashir","year":"2014","journal-title":"Pak. J. Med. Sci."},{"key":"ref_23","first-page":"18101","article-title":"Generating exome enriched sequencing libraries from formalin-fxed, parafn-embedded tissue DNA for next-generation sequencing","volume":"92","author":"Marosy","year":"2017","journal-title":"Curr. Protoc. Hum. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2747","DOI":"10.1093\/bioinformatics\/bts526","article-title":"A robust model for read count data in exome sequencing experiments and implications for copy number variant calling","volume":"28","author":"Plagnol","year":"2012","journal-title":"Bioinformatics"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3572","DOI":"10.1093\/bioinformatics\/bty304","article-title":"AnnotSV: An integrated tool for structural variations annotation","volume":"34","author":"Geoffroy","year":"2018","journal-title":"Bioinformatics"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"321291","DOI":"10.1155\/2015\/321291","article-title":"The Genetics and the Genomics of Primary Congenital Glaucoma","volume":"2015","author":"Cascella","year":"2015","journal-title":"BioMed Res. Int."},{"key":"ref_27","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_28","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1111\/j.1755-3768.1989.tb01635.x","article-title":"Anterior mesenchymal dysgenesis of the eye. Congenital hereditary endothelial dystrophy and congenital glaucoma","volume":"67","author":"Pedersen","year":"1989","journal-title":"Acta Ophthalmol."},{"key":"ref_29","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_30","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1136\/bjo.2008.148122","article-title":"Intraocular pressures after ketamine and sevoflurane in children with glaucoma undergoing examination under anaesthesia","volume":"94","author":"Jones","year":"2010","journal-title":"Br. J. Ophthalmol."},{"key":"ref_31","first-page":"11","article-title":"Tonometry","volume":"23","author":"Ottar","year":"1998","journal-title":"Insight"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1002\/humu.23152","article-title":"SLC4A11 Three-Dimensional Homology Model Rationalizes Corneal Dystrophy-Causing Mutations","volume":"38","author":"Badior","year":"2017","journal-title":"Hum. Mutat."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/2\/310\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:15:15Z","timestamp":1760120115000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/2\/310"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,25]]},"references-count":32,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["genes14020310"],"URL":"https:\/\/doi.org\/10.3390\/genes14020310","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,25]]}}}