{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T23:58:21Z","timestamp":1785455901823,"version":"3.56.0"},"reference-count":33,"publisher":"Georg Thieme Verlag KG","funder":[{"DOI":"10.13039\/501100004681","name":"Higher Education Commission, Pakistan","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004681","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Thromb Haemost"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Glanzmann thrombasthenia (GT) and GT-like phenotype represent inherited platelet disorders caused by defects in platelet glycoprotein \u03b1IIb\u03b23 (encoded by ITGA2B and ITGB3) or RASGRP2- and FERMT3-mediated platelet intracellular signaling, respectively. While globally rare, prevalence of these bleeding phenotypes is notably higher in regions with high consanguinity, including Pakistan, with limited data on GT-associated variants. Compared with traditional diagnostic approaches, next-generation sequencing (NGS) offers comprehensive detection of known and novel variants, enhancing diagnostic accuracy in genetically heterogeneous disorders like GT.<\/jats:p>\n                  <jats:p>This study investigated the mutational spectrum of GT and GT-like phenotype in 67 patients from 55 unrelated Pakistani families using a targeted gene panel. Variant annotation and pathogenicity assessments were performed using established guidelines. Structural modeling and molecular dynamics simulations were used to predict the functional consequences of select novel variants.<\/jats:p>\n                  <jats:p>A total of 21 distinct variants were identified (15 in ITGA2B and 6 in ITGB3), achieving an 87.3% diagnostic yield. In all, 10 were novel, including missense, frameshift, splice-site, and copy number variants (CNVs). Two recurrent ITGA2B frameshift variants suggested possible founder effect. Analysis of RASGRP2 revealed two novel homozygous variants in GT-like cases. A genotype\u2013phenotype association analyses suggested a severe bleeding diathesis in GT patients harboring truncating mutations in an age-dependent manner, and clinical diversity among GT patients with same genetic variant.<\/jats:p>\n                  <jats:p>This study expands the mutational spectrum of GT and GT-like bleeding diathesis in Pakistani population, identifying novel and recurrent mutations, which highlights the diagnostic value of NGS.<\/jats:p>","DOI":"10.1055\/a-2906-7166","type":"journal-article","created":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T00:14:47Z","timestamp":1783124087000},"source":"Crossref","is-referenced-by-count":0,"title":["Novel\/Recurrent Variants in Pakistani Glanzmann Thrombasthenia and Glanzmann-like Bleeding Diathesis: Insights from NGS Analysis"],"prefix":"10.1055","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3240-0741","authenticated-orcid":false,"given":"Ali","family":"Amar","sequence":"first","affiliation":[{"name":"University of Health Sciences Lahore, Pakistan","place":["Lahore"],"department":["Department of Human Genetics and Molecular Biology"]},{"name":"PKLI Institute of Nursing and Allied Health Sciences, Pakistan Kidney and Liver Institute and Research Center, Pakistan","place":["Lahore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Christine","family":"Alessi","sequence":"first","affiliation":[{"name":"Aix-Marseille Universit\u00e9, Provence-Alpes-C\u00f4te d'Azur, France","place":["Marseille"],"department":["Laboratory of Hematology, Centre de R\u00e9f\u00e9rence des Pathologies Plaquettaires"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shagufta","family":"Khaliq","sequence":"first","affiliation":[{"name":"University of Health Sciences Lahore, Pakistan","place":["Lahore"],"department":["Department of Human Genetics and Molecular Biology"]},{"name":"The University of Lahore University College of Medicine and Dentistry, Pakistan","place":["Lahore"],"department":["Department of Research Cell"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madiha","family":"Shakoor","sequence":"additional","affiliation":[{"name":"University of Health Sciences Lahore, Pakistan","place":["Lahore"],"department":["Department of Human Genetics and Molecular Biology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saima","family":"Farhan","sequence":"additional","affiliation":[{"name":"The Children\u2019s Hospital and Institute of Child Health, Pakistan","place":["Lahore"],"department":["Division of Hematology and Transfusion Medicine"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aisha","family":"Hameed","sequence":"additional","affiliation":[{"name":"University of Health Sciences Lahore, Pakistan","place":["Lahore"],"department":["Department of Hematology"]},{"name":"Gujranwala Medical College, Pakistan","place":["Gujranwala"],"department":["Department of Pathology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad Asif","family":"Naveed","sequence":"additional","affiliation":[{"name":"University of Health Sciences Lahore, Pakistan","place":["Lahore"],"department":["Department of Hematology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khansa","family":"Qamar","sequence":"additional","affiliation":[{"name":"University of Health Sciences Lahore, Pakistan","place":["Lahore"],"department":["Department of Hematology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad Imran","family":"Qadeer","sequence":"additional","affiliation":[{"name":"Sundas Foundation Hematology and Blood Transfusion Center Lahore, Pakistan","place":["Lahore"]},{"name":"Stoke Mandeville Hospital, Buckinghamshire Healthcare NHS Trust, England, United Kingdom of Great Britain and Northern Ireland","place":["Aylesbury"],"department":["Department of Blood Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manal","family":"Ibrahim-Kosta","sequence":"additional","affiliation":[{"name":"Aix-Marseille Universit\u00e9, Provence-Alpes-C\u00f4te d'Azur, France","place":["Marseille"],"department":["Laboratory of Hematology, Centre de R\u00e9f\u00e9rence des Pathologies Plaquettaires"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"194","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"issue":"02","key":"ref1","doi-asserted-by":"crossref","first-page":"213","DOI":"10.3390\/cells12020213","article-title":"Glanzmann thrombasthenia in Pakistani patients: identification of 7 novel pathogenic variants in the fibrinogen receptor \u03b1IIb\u03b23","volume":"12","author":"M YJ Siddiqi","year":"2023","journal-title":"Cells"},{"issue":"03","key":"ref2","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1007\/s12288-020-01368-8","article-title":"Next-generation sequencing based approach to identify underlying genetic defects of Glanzmann thrombasthenia","volume":"37","author":"R Sharma","year":"2021","journal-title":"Indian J Hematol Blood Transfus"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1038\/s41525-019-0079-6","article-title":"Molecular yield of targeted sequencing for Glanzmann thrombasthenia patients","volume":"4","author":"T Owaidah","year":"2019","journal-title":"NPJ Genom Med"},{"issue":"01","key":"ref4","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1186\/s12905-022-01704-2","article-title":"Consanguineous marriages and their association with women's reproductive health and fertility behavior in Pakistan: secondary data analysis from Demographic and Health Surveys, 1990-2018","volume":"22","author":"S Iqbal","year":"2022","journal-title":"BMC Womens Health"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"100026","DOI":"10.1016\/j.gpeds.2022.100026","article-title":"Glanzmann thrombasthenia\u2014a not so rare platelet function disorder in Pakistan","volume":"2","author":"R Mahmood","year":"2022","journal-title":"Glob Pediatr"},{"issue":"05","key":"ref6","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1002\/humu.22776","article-title":"Expanding the mutation spectrum affecting \u03b1IIb\u03b23 integrin in Glanzmann thrombasthenia: screening of the ITGA2B and ITGB3 genes in a large international cohort","volume":"36","author":"A T Nurden","year":"2015","journal-title":"Hum Mutat"},{"issue":"09","key":"ref7","doi-asserted-by":"crossref","first-page":"2063","DOI":"10.1111\/j.1538-7836.2010.03975.x","article-title":"ISTH\/SSC bleeding assessment tool: a standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders","volume":"8","author":"F Rodeghiero","year":"2010","journal-title":"J Thromb Haemost"},{"issue":"01","key":"ref8","doi-asserted-by":"crossref","first-page":"4455","DOI":"10.1101\/pdb.prot4455","article-title":"Purification of nucleic acids by extraction with phenol:chloroform","volume":"2006","author":"J Sambrook","year":"2006","journal-title":"Cold Spring Harb Protoc"},{"issue":"02","key":"ref9","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1182\/bloodadvances.2020003712","article-title":"Specifications of the variant curation guidelines for ITGA2B\/ITGB3: ClinGen platelet disorder variant curation panel","volume":"5","author":"J E Ross","year":"2021","journal-title":"Blood Adv"},{"issue":"05","key":"ref10","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":"S Richards","year":"2015","journal-title":"Genet Med"},{"issue":"03","key":"ref11","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1007\/s00439-019-01978-x","article-title":"Gene panel sequencing identifies a likely monogenic cause in 7% of 235 Pakistani families with nephrolithiasis","volume":"138","author":"A Amar","year":"2019","journal-title":"Hum Genet"},{"issue":"12","key":"ref12","doi-asserted-by":"crossref","first-page":"2258","DOI":"10.1002\/humu.23840","article-title":"Novel ACTN1 variants in cases of thrombocytopenia","volume":"40","author":"A Vincenot","year":"2019","journal-title":"Hum Mutat"},{"issue":"07","key":"ref13","doi-asserted-by":"crossref","first-page":"3022","DOI":"10.1093\/molbev\/msab120","article-title":"MEGA11: molecular evolutionary genetics analysis version 11","volume":"38","author":"K Tamura","year":"2021","journal-title":"Mol Biol 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Pakistan: molecular analysis and identification of novel mutations","volume":"89","author":"A Haghighi","year":"2016","journal-title":"Clin Genet"},{"issue":"08","key":"ref19","doi-asserted-by":"crossref","first-page":"3082","DOI":"10.1182\/blood.V90.8.3082","article-title":"A Leu117\u2013>Trp mutation within the RGD-peptide cross-linking region of \u03b23 results in Glanzmann thrombasthenia by preventing alphaIIb \u03b23 export to the platelet surface","volume":"90","author":"R B Basani","year":"1997","journal-title":"Blood"},{"issue":"04","key":"ref20","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1002\/humu.20304","article-title":"Molecular diversity of Glanzmann thrombasthenia in southern India: new insights into mRNA splicing and structure-function correlations of alphaIIbbeta3 integrin (ITGA2B, ITGB3)","volume":"27","author":"H Peretz","year":"2006","journal-title":"Hum Mutat"},{"issue":"03","key":"ref21","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1055\/s-0038-1649830","article-title":"Molecular study of Glanzmann thrombasthenia in 3 patients issued from 2 different families","volume":"74","author":"C Vinciguerra","year":"1995","journal-title":"Thromb Haemost"},{"issue":"11","key":"ref22","doi-asserted-by":"crossref","first-page":"1878","DOI":"10.1111\/j.1538-7836.2009.03579.x","article-title":"Molecular defects in ITGA2B and ITGB3 genes in patients with Glanzmann thrombasthenia","volume":"7","author":"M Kannan","year":"2009","journal-title":"J Thromb Haemost"},{"issue":"01","key":"ref23","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1186\/s13023-019-1042-4","article-title":"Molecular genetic diagnosis of Glanzmann syndrome in Iranian population; reporting novel and recurrent mutations","volume":"14","author":"F Zafarghandi Motlagh","year":"2019","journal-title":"Orphanet J Rare 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Mol Dis"},{"issue":"03","key":"ref33","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1002\/humu.21179","article-title":"AlphaIIbbeta3 integrin: new allelic variants in Glanzmann thrombasthenia, effects on ITGA2B and ITGB3 mRNA splicing, expression, and structure-function","volume":"31","author":"V Jallu","year":"2010","journal-title":"Hum Mutat"},{"issue":"05","key":"ref34","doi-asserted-by":"crossref","first-page":"401","DOI":"10.3109\/09537104.2011.604808","article-title":"Evaluation of the gene encoding calcium and diacylglycerol regulated guanine nucleotide exchange factor I (CalDAG-GEFI) in human patients with congenital qualitative platelet disorders","volume":"23","author":"J Puetz","year":"2012","journal-title":"Platelets"}],"container-title":["Thrombosis and Haemostasis"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.thieme-connect.de\/products\/ejournals\/pdf\/10.1055\/a-2906-7166.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T23:08:22Z","timestamp":1785452902000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.thieme-connect.de\/DOI\/DOI?10.1055\/a-2906-7166"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,3]]},"references-count":33,"URL":"https:\/\/doi.org\/10.1055\/a-2906-7166","archive":["Portico","CLOCKSS"],"relation":{},"ISSN":["0340-6245","2567-689X"],"issn-type":[{"value":"0340-6245","type":"print"},{"value":"2567-689X","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,7,3]]},"published":{"date-parts":[[2026,7,3]]}}}