{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T20:24:35Z","timestamp":1792009475111,"version":"4.4.0"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:p>\n                    Charcot-Marie-Tooth (CMT) is a group of inherited neuromuscular disorders with diverse clinical features such as muscle weakness and atrophy of the distal regions, foot deformities, sensory loss and decreased or absent reflexes. With the diverse inheritance patterns including dominant, recessive, and X-linked, it exhibits significant genetic heterogeneity often overlapping with other neurological disorders. Whole exome sequencing (WES) has emerged as favorable diagnostic tool for such challenging disease entities. We recruited five Pakistani families that consisted of 14 affected individuals exhibiting representative symptoms of CMT such as severe muscle weakness of the lower limbs, muscles atrophy, claw hands and feet deformities. WES data analysis revealed two novel and two already reported homozygous missense variants in\n                    <jats:italic>GDAP1<\/jats:italic>\n                    (NM_018972) c.1A\u202f&amp;gt;\u202fG (p. Met1Val), c.683A\u202f&amp;gt;\u202fG (p. Glu228Gly), c.734C\u202f&amp;gt;\u202fT (p. Thr245Ile) and c.811G\u202f&amp;gt;\u202fA (p. Gly271Arg) in families A\u2013D, respectively. While a novel homozygous\n                    <jats:italic>SBF2<\/jats:italic>\n                    variant c.2746G\u202f&amp;gt;\u202fC, p. (Gly916Arg) was identified in family E. Sanger sequencing confirm the segregation of all candidate variants in their respective pedigrees. Moreover, molecular modeling supports the destabilizing effect of these variants on final protein product of both\n                    <jats:italic>GDAP1<\/jats:italic>\n                    and\n                    <jats:italic>SBF2<\/jats:italic>\n                    by inducing modifications in overall conformation of the protein. The present study expands the mutation spectrum of the\n                    <jats:italic>GDAP1<\/jats:italic>\n                    and\n                    <jats:italic>SBF2<\/jats:italic>\n                    genes, with possible implications for improved understanding of disease pathophysiology. Furthermore, the current study highlights the importance of NGS, particularly WES, in achieving rapid and precise molecular genetic diagnosis for clinical purposes, especially in neuromuscular disorders of heterogeneous nature.\n                  <\/jats:p>","DOI":"10.3389\/fneur.2026.1920139","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T04:30:17Z","timestamp":1789014617000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Genetic basis of Charcot-Marie-Tooth disease in Pakistani consanguineous families"],"prefix":"10.3389","volume":"17","author":[{"given":"Zafar","family":"Ali","sequence":"first","affiliation":[{"name":"Department of Biotechnology, Genetics, Forensic and Microbiology, University of Swat, Charbagh","place":["Swat, Pakistan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Jameel","sequence":"additional","affiliation":[{"name":"Centre of Oncological Research in Surgery, The Aga Khan University","place":["Karachi, Pakistan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joakim","family":"Klar","sequence":"additional","affiliation":[{"name":"Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University","place":["Uppsala, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Suleman","sequence":"additional","affiliation":[{"name":"Biomedical Research Center (BRC), QU Health, Qatar University","place":["Doha, Qatar"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uswah","family":"Batool","sequence":"additional","affiliation":[{"name":"University Institute of Biochemistry and Biotechnology, Pir Mehr Ali Shah Arid Agriculture University","place":["Rawalpindi, Pakistan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hammad","family":"Yousaf","sequence":"additional","affiliation":[{"name":"Department of Biological and Biomedical Sciences, The Aga Khan University","place":["Karachi, Pakistan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farhan","family":"Ali","sequence":"additional","affiliation":[{"name":"Frontier Corps Teaching Hospital Hayatabad Phase-6","place":["Peshawar, Pakistan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ambrin","family":"Fatima","sequence":"additional","affiliation":[{"name":"Department of Biological and Biomedical Sciences, The Aga Khan University","place":["Karachi, Pakistan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahid Mahmood","family":"Baig","sequence":"additional","affiliation":[{"name":"Department of Biological and Biomedical Sciences, The Aga Khan University","place":["Karachi, Pakistan"]},{"name":"Faculty of Life Sciences, Health Services Academy","place":["Islamabad, Pakistan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niklas","family":"Dahl","sequence":"additional","affiliation":[{"name":"Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University","place":["Uppsala, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathais","family":"Toft","sequence":"additional","affiliation":[{"name":"Department of Neurology, Oslo University Hospital","place":["Oslo, Norway"]},{"name":"Institute of Clinical Medicine, University of Oslo","place":["Oslo, Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uzma","family":"Abdullah","sequence":"additional","affiliation":[{"name":"University Institute of Biochemistry and Biotechnology, Pir Mehr Ali Shah Arid Agriculture University","place":["Rawalpindi, Pakistan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zafar","family":"Iqbal","sequence":"additional","affiliation":[{"name":"Department of Neurology, Oslo University Hospital","place":["Oslo, Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1038\/s41572-025-00679-2","article-title":"Charcot-Marie-Tooth disease and related neuropathies","volume":"12","author":"Burns","year":"2026","journal-title":"Nat Rev Dis Primers"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1111\/j.1399-0004.1974.tb00638.x","article-title":"Genetic and clinical aspects of Charcot-Marie-Tooth's disease","volume":"6","author":"Skre","year":"1974","journal-title":"Clin Genet"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1093\/brain\/103.2.259","article-title":"The clinical features of hereditary motor and sensory neuropathy types I and II","volume":"103","author":"Harding","year":"1980","journal-title":"Brain J Neurol"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.expneurol.2010.09.006","article-title":"Mitochondrial dysfunction and pathophysiology of Charcot-Marie-Tooth disease involving GDAP1 mutations","volume":"227","author":"Cassereau","year":"2011","journal-title":"Exp Neurol"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1097\/WCO.0000000000000131","article-title":"Recent advances in Charcot-Marie-Tooth disease","volume":"27","author":"Baets","year":"2014","journal-title":"Curr Opin Neurol"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"644","DOI":"10.1038\/s41582-019-0254-5","article-title":"Next-generation sequencing in Charcot-Marie-Tooth disease: opportunities and challenges","volume":"15","author":"Pipis","year":"2019","journal-title":"Nat Rev Neurol"},{"key":"ref7","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcad139","article-title":"Whole-genome sequencing in clinically diagnosed Charcot-Marie-Tooth disease undiagnosed by whole-exome sequencing","volume":"5","author":"Kim","year":"2023","journal-title":"Brain Commun"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1038\/ejhg.2009.31","article-title":"Charcot-Marie-Tooth disease","volume":"17","author":"Szigeti","year":"2009","journal-title":"Eur J Hum Genet"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"e72042","DOI":"10.1002\/hsr2.72042","article-title":"Research trends and insights of Charcot-Marie-Tooth disease (CMT): a visualization analysis (2000\u20132025)","volume":"9","author":"Cao","year":"2026","journal-title":"Health Sci Rep"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/j.pneurobio.2012.03.003","article-title":"Charcot-Marie-Tooth disease and intracellular traffic","volume":"99","author":"Bucci","year":"2012","journal-title":"Prog Neurobiol"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"443","DOI":"10.3889\/oamjms.2016.079","article-title":"The role of rehabilitation in the management of patients with Charcot-Marie-Tooth disease: report of two cases","volume":"4","author":"Dimitrova","year":"2016","journal-title":"Open Access Maced J Med Sci"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1136\/jnnp-2014-308826","article-title":"CMT subtypes and disease burden in patients enrolled in the inherited neuropathies consortium natural history study: a cross-sectional analysis","volume":"86","author":"Fridman","year":"2015","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1111\/cge.13101","article-title":"Whole-exome sequencing is a valuable diagnostic tool for inherited peripheral neuropathies: outcomes from a cohort of 50 families","volume":"93","author":"Hartley","year":"2018","journal-title":"Clin Genet"},{"key":"ref14","volume-title":"Molecular cloning","author":"Sambrook","year":"1989"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"848","DOI":"10.1038\/ejhg.2017.54","article-title":"A missense variant in ITPR1 provides evidence for autosomal recessive SCA29 with asymptomatic cerebellar hypoplasia in carriers","volume":"25","author":"Klar","year":"2017","journal-title":"Eur J Hum Genet"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"2076","DOI":"10.1093\/bioinformatics\/btu168","article-title":"Variant annotation: a bioconductor package for exploration and annotation of genetic variants","volume":"30","author":"Obenchain","year":"2014","journal-title":"Bioinformatics"},{"key":"ref18","doi-asserted-by":"publisher","DOI":"10.3390\/genes13091667","article-title":"A novel nonsense variant in GRM1 causes autosomal recessive spinocerebellar ataxia 13 in a consanguineous Pakistani family","volume":"13","author":"Yousaf","year":"2022","journal-title":"Genes (Basel)"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with alpha fold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"1049","DOI":"10.1006\/jmbi.1993.1351","article-title":"Main-chain bond lengths and bond angles in protein structures","volume":"231","author":"Laskowski","year":"1993","journal-title":"J Mol Biol"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"669","DOI":"10.2174\/092986607781483912","article-title":"Ramachandran plot on the web (2.0)","volume":"14","author":"Gopalakrishnan","year":"2007","journal-title":"Protein Pept Lett"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1093\/bioinformatics\/btt691","article-title":"mCSM: predicting the effects of mutations in proteins using graph-based signatures","volume":"30","author":"Pires","year":"2013","journal-title":"Bioinformatics"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"5.6.1","DOI":"10.1002\/cpbi.3","article-title":"Comparative protein structure modeling using modeller","volume":"54","author":"Webb","year":"2016","journal-title":"Curr Protoc Bioinform"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"105893","DOI":"10.1016\/j.compbiomed.2022.105893","article-title":"Screening of immune epitope in the proteome of the Dabie bandavirus, SFTS, to design a protein-specific and proteome-wide vaccine for immune response instigation using an immunoinformatics approaches","volume":"148","author":"Suleman","year":"2022","journal-title":"Comput Biol Med"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"1244","DOI":"10.3760\/cma.j.cn511374-20191210-00630","article-title":"Identification of a novel c.1A>G variant of GDAP1 gene in a pedigree affected with autosomal recessive fibula atrophy","volume":"37","author":"Liu","year":"2020","journal-title":"Zhonghua Yi Xue Yi Chuan Xue Za Zhi"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"720","DOI":"10.1016\/S0960-8966(03)00093-2","article-title":"Identification of novel GDAP1 mutations causing autosomal recessive Charcot-Marie-Tooth disease","volume":"13","author":"Ammar","year":"2003","journal-title":"Neuromuscul Disord"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"1087","DOI":"10.1093\/hmg\/ddi121","article-title":"GDAP1, the protein causing Charcot-Marie-Tooth disease type 4A, is expressed in neurons and is associated with mitochondria","volume":"14","author":"Pedrola","year":"2005","journal-title":"Hum Mol Genet"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.1083\/jcb.200507087","article-title":"Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network: new implications for Charcot-Marie-Tooth disease","volume":"170","author":"Niemann","year":"2005","journal-title":"J Cell Biol"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1016\/j.nbd.2009.09.011","article-title":"GDAP1 mutations differ in their effects on mitochondrial dynamics and apoptosis depending on the mode of inheritance","volume":"36","author":"Niemann","year":"2009","journal-title":"Neurobiol Dis"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1007\/s10048-008-0166-9","article-title":"Mitochondrial complex I deficiency in GDAP1-related autosomal dominant Charcot-Marie-Tooth disease (CMT2K)","volume":"10","author":"Cassereau","year":"2009","journal-title":"Neurogenetics"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1093\/hmg\/ddr450","article-title":"Charcot-Marie-Tooth disease CMT4A: GDAP1 increases cellular glutathione and the mitochondrial membrane potential","volume":"21","author":"Noack","year":"2012","journal-title":"Hum Mol Genet"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1016\/j.nmd.2017.01.008","article-title":"Phenotypical features of a new dominant GDAP1 pathogenic variant (p.R226del) in axonal Charcot-Marie-Tooth disease","volume":"27","author":"Garc\u00eda-Sobrino","year":"2017","journal-title":"Neuromuscul Disord"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"113069","DOI":"10.1016\/j.expneurol.2019.113069","article-title":"Oxidative stress contributes differentially to the pathophysiology of Charcot-Marie-Tooth disease type 2K","volume":"323","author":"Cassereau","year":"2020","journal-title":"Exp Neurol"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.neulet.2015.04.001","article-title":"Mitochondrial dynamics and inherited peripheral nerve diseases","volume":"596","author":"Pareyson","year":"2015","journal-title":"Neurosci Lett"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"e1005115","DOI":"10.1371\/journal.pgen.1005115","article-title":"Lack of GDAP1 induces neuronal calcium and mitochondrial defects in a knockout mouse model of Charcot-Marie-Tooth neuropathy","volume":"11","author":"Barneo-Mu\u00f1oz","year":"2015","journal-title":"PLoS Genet"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"6529","DOI":"10.1038\/s41598-026-37808-0","article-title":"Molecular characterization of recessively inherited ataxic and neuropathic disorders in consanguineous Pakistani families","volume":"16","author":"Aslam","year":"2026","journal-title":"Sci Rep"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1186\/s43141-023-00568-9","article-title":"Mutational screening of GDAP1 in dysphonia associated with Charcot-Marie-Tooth disease: clinical insights and phenotypic effects","volume":"21","author":"Manzoor","year":"2023","journal-title":"J Genet Eng Biotechnol"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1186\/s12883-024-03882-y","article-title":"Expanding the genetic spectrum of hereditary motor sensory neuropathies in Pakistan","volume":"24","author":"Ahmed","year":"2024","journal-title":"BMC Neurol"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1089\/dna.2023.0169","article-title":"Homozygous mutations in GDAP1 and MFN2 genes resulted in autosomal recessive forms of Charcot-Marie-Tooth disease in consanguineous Pakistani families","volume":"42","author":"Asif","year":"2023","journal-title":"DNA Cell Biol"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1093\/hmg\/ddg030","article-title":"Mutation of the SBF2 gene, encoding a novel member of the myotubularin family, in Charcot-Marie-Tooth neuropathy type 4B2\/11p15","volume":"12","author":"Senderek","year":"2003","journal-title":"Hum Mol Genet"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"eadg7492","DOI":"10.1126\/science.adg7492","article-title":"Accurate proteome-wide missense variant effect prediction with alpha missense","volume":"381","author":"Cheng","year":"2023","journal-title":"Science"}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2026.1920139\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T04:30:29Z","timestamp":1789014629000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2026.1920139\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,10]]},"references-count":41,"alternative-id":["10.3389\/fneur.2026.1920139"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2026.1920139","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,10]]},"article-number":"1920139"}}