{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T18:40:41Z","timestamp":1789756841581,"version":"4.0.1"},"reference-count":51,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2022,9,9]],"date-time":"2022-09-09T00:00:00Z","timestamp":1662681600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Primary congenital glaucoma (PCG) is a heterogeneous rare recessively inherited disorder prevalent in regions with high consanguinity. Disease phenotype is associated with increased intra ocular pressure and is a major cause of childhood blindness. Sequence variations in <jats:italic>Cytochrome P450 1B1<\/jats:italic> (<jats:italic>CYP1B1<\/jats:italic>) gene are a major cause of PCG. Current study was conducted to screen <jats:italic>CYP1B1<\/jats:italic> gene in highly consanguineous PCG affected families from Pakistani population consistent with the autosomal recessive pattern of PCG inheritance.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>For this study, patients and controls (clinically unaffected individuals of each family) from 25 consanguineous families belonging to Punjab, Baluchistan and Khyber Pakhtunkhwa, Pakistan were recruited through ophthalmologists. DNA was isolated from collected blood samples. Genetic screening of <jats:italic>CYP1B1<\/jats:italic> gene was done for all enrolled families. In-silico analysis was performed to identify and predict the potential disease-causing variations.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Pathogenicity screening revealed sequence variants segregating with disease phenotype in homozygous or compound heterozygous form in eleven out of 25 analyzed families. We identified a total of sixteen disease causing variants among which five frameshift i.e., c.629dup (p.Gly211Argfs*13), c.287dup (p.Leu97Alafs*127), c.662dup (p.Arg222Profs*2), c.758_759insA (p.Val254Glyfs*73) and c.789dup (p.Leu264Alafs*63), two silent c.1314G&gt;A, c.771T&gt;G and six missense variations c.457C&gt;G (p.Arg153Gly), c.516C&gt;A (p.Ser172Arg), c.722T&gt;A (p.Val241Glu), c.740T&gt;A (p.Leu247Gln), c.1263T&gt;A (p.Phe421Leu), and c.724G&gt;C (p.Asp242His) are previously un reported. However two frameshift c.868dup (p.Arg290Profs*37), c.247del (p.Asp83Thrfs*12) and one missense variant c.732G&gt;A (p.Met244Ile), is previously reported. Furthermore, six polymorphisms c.1347T&gt;C, c.2244_2245insT, c.355G&gt;T, c.1294G&gt;C, c.1358A&gt;G and c.142C&gt;G were also identified. In the intronic region, a novel silent polymorphism i.e., g.35710_35711insT was found in homozygous state. All the newly detected disease-causing variants were negative in 96 ethnically matched controls.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Among twenty-five screened families, eight families (PCG50, 52\u201354, 58, 59, 63 and 67) were segregating disease causing variants in recessive manner. Two families (PCG049 and PCG062) had compound heterozygosity. Our data confirms genetic heterogeneity of PCG in Pakistani population however we did not find molecular variants segregating with PCG in fifteen families in coding exons and intron-exon boundaries of <jats:italic>CYP1B1<\/jats:italic> gene. Genetic counseling was provided to families to refrain from practicing consanguinity and perform premarital screening as a PCG control measure in upcoming generations.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0274335","type":"journal-article","created":{"date-parts":[[2022,9,9]],"date-time":"2022-09-09T20:00:39Z","timestamp":1662753639000},"page":"e0274335","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Mutation screening of the CYP1B1 gene reveals thirteen novel disease-causing variants in consanguineous Pakistani families causing primary congenital glaucoma"],"prefix":"10.1371","volume":"17","author":[{"given":"Raeesa","family":"Tehreem","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anam","family":"Arooj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sorath Noorani","family":"Siddiqui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shagufta","family":"Naz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiran","family":"Afshan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4959-7832","authenticated-orcid":true,"given":"Sabika","family":"Firasat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,9,9]]},"reference":[{"issue":"4","key":"pone.0274335.ref001","doi-asserted-by":"crossref","first-page":"543vi","DOI":"10.1016\/S0896-1549(03)00062-2","article-title":"Genetics and biochemistry of primary congenital glaucoma","volume":"16","author":"M. 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Barkan","year":"1955","journal-title":"American journal of ophthalmology"},{"issue":"1","key":"pone.0274335.ref004","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-017-19113-z","article-title":"Visual field loss and vision-related quality of life in the Italian Primary Open Angle Glaucoma Study","volume":"8","author":"E. Rulli","year":"2018","journal-title":"Scientific reports"},{"key":"pone.0274335.ref005","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1146\/annurev.pharmtox.48.061807.154729","article-title":"Role of CYP1B1 in glaucoma","volume":"48","author":"V. Vasiliou","year":"2008","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"issue":"1","key":"pone.0274335.ref006","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/hgv.2016.21","article-title":"A spectrum of CYP1B1 mutations associated with primary congenital glaucoma in families of Pakistani descent","volume":"3","author":"B. 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