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<!DOCTYPE html> <html > <head> <meta charset="utf-8"> <meta rel="search" type="application/opensearchdescription+xml" href="/open_search.xml" title="Academia.edu"> <meta content="width=device-width, initial-scale=1" name="viewport"> <meta name="google-site-verification" content="bKJMBZA7E43xhDOopFZkssMMkBRjvYERV-NaN4R6mrs"> <meta name="csrf-param" content="authenticity_token" /> <meta name="csrf-token" content="9TWTFrQwBjpfzTeUVMYjmD80OWXsyRtreMM7XCqvWNO6uXDe0UBX2cnK2zwtMtJ6ox7nXaXmO_unK0IRY0pw9g" /> <meta name="citation_title" content="Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy" /> <meta name="citation_publication_date" content="2015/01/05" /> <meta name="citation_journal_title" content="Cell reports" /> <meta name="citation_author" content="Esra Battaloglu" /> <meta name="twitter:card" content="summary" /> <meta name="twitter:url" content="https://www.academia.edu/56909580/Exome_Sequence_Analysis_Suggests_that_Genetic_Burden_Contributes_to_Phenotypic_Variability_and_Complex_Neuropathy" /> <meta name="twitter:title" content="Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy" /> <meta name="twitter:description" content="Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous distal symmetric polyneuropathy. Whole-exome sequencing (WES) of 40 individuals from 37 unrelated families with CMT-like peripheral neuropathy refractory to molecular" /> <meta name="twitter:image" content="http://a.academia-assets.com/images/twitter-card.jpeg" /> <meta property="fb:app_id" content="2369844204" /> <meta property="og:type" content="article" /> <meta property="og:url" content="https://www.academia.edu/56909580/Exome_Sequence_Analysis_Suggests_that_Genetic_Burden_Contributes_to_Phenotypic_Variability_and_Complex_Neuropathy" /> <meta property="og:title" content="Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy" /> <meta property="og:image" content="http://a.academia-assets.com/images/open-graph-icons/fb-paper.gif" /> <meta property="og:description" content="Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous distal symmetric polyneuropathy. Whole-exome sequencing (WES) of 40 individuals from 37 unrelated families with CMT-like peripheral neuropathy refractory to molecular" /> <meta property="article:author" content="https://boun.academia.edu/EsraBattaloglu" /> <meta name="description" content="Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous distal symmetric polyneuropathy. Whole-exome sequencing (WES) of 40 individuals from 37 unrelated families with CMT-like peripheral neuropathy refractory to molecular" /> <title>(PDF) Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy</title> <link rel="canonical" href="https://www.academia.edu/56909580/Exome_Sequence_Analysis_Suggests_that_Genetic_Burden_Contributes_to_Phenotypic_Variability_and_Complex_Neuropathy" /> <script async src="https://www.googletagmanager.com/gtag/js?id=G-5VKX33P2DS"></script> <script> window.dataLayer = window.dataLayer || []; function gtag(){dataLayer.push(arguments);} gtag('js', new Date()); gtag('config', 'G-5VKX33P2DS', { cookie_domain: 'academia.edu', send_page_view: false, }); gtag('event', 'page_view', { 'controller': "single_work", 'action': "show", 'controller_action': 'single_work#show', 'logged_in': 'false', 'edge': 'unknown', // Send nil if there is no A/B test bucket, in case some records get logged // with missing data - that way we can distinguish between the two cases. // ab_test_bucket should be of the form <ab_test_name>:<bucket> 'ab_test_bucket': null, }) </script> <script> var $controller_name = 'single_work'; var $action_name = "show"; var $rails_env = 'production'; var $app_rev = '107520bac59918e2ceae62eaadd15bff3d1e7904'; var $domain = 'academia.edu'; var $app_host = "academia.edu"; var $asset_host = "academia-assets.com"; var $start_time = new Date().getTime(); var $recaptcha_key = "6LdxlRMTAAAAADnu_zyLhLg0YF9uACwz78shpjJB"; var $recaptcha_invisible_key = "6Lf3KHUUAAAAACggoMpmGJdQDtiyrjVlvGJ6BbAj"; var $disableClientRecordHit = false; </script> <script> window.require = { config: function() { return function() {} } } </script> <script> window.Aedu = window.Aedu || {}; window.Aedu.hit_data = null; window.Aedu.serverRenderTime = new Date(1741002748000); window.Aedu.timeDifference = new Date().getTime() - 1741002748000; </script> <script type="application/ld+json">{"@context":"https://schema.org","@type":"ScholarlyArticle","abstract":"Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous distal symmetric polyneuropathy. Whole-exome sequencing (WES) of 40 individuals from 37 unrelated families with CMT-like peripheral neuropathy refractory to molecular diagnosis identified apparent causal mutations in ∼45% (17/37) of families. Three candidate disease genes are proposed, supported by a combination of genetic and in vivo studies. Aggregate analysis of mutation data revealed a significantly increased number of rare variants across 58 neuropathy-associated genes in subjects versus controls, confirmed in a second ethnically discrete neuropathy cohort, suggesting that mutation burden potentially contributes to phenotypic variability. Neuropathy genes shown to have highly penetrant Mendelizing variants (HPMVs) and implicated by burden in families were shown to interact genetically in a zebrafish assay exacerbating the phenotype established by the suppression of single genes. Our findings suggest...","author":[{"@context":"https://schema.org","@type":"Person","name":"Esra Battaloglu","url":"https://boun.academia.edu/EsraBattaloglu","sameAs":[]}],"contributor":[],"dateCreated":"2021-10-10","dateModified":"2021-10-10","datePublished":"2015-01-05","headline":"Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy","image":"https://attachments.academia-assets.com/72064185/thumbnails/1.jpg","inLanguage":"en","keywords":["Humans","Mutation","Female","Animals","Male","Pedigree","Phenotype","Genetic variation","Zebrafish","Charcot Marie Tooth Disease","Exome"],"publication":"Cell 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Whole-exome sequencing (WES) of 40 individuals from 37 unrelated families with CMT-like peripheral neuropathy refractory to molecular diagnosis identified apparent causal mutations in ∼45% (17/37) of families. Three candidate disease genes are proposed, supported by a combination of genetic and in vivo studies. Aggregate analysis of mutation data revealed a significantly increased number of rare variants across 58 neuropathy-associated genes in subjects versus controls, confirmed in a second ethnically discrete neuropathy cohort, suggesting that mutation burden potentially contributes to phenotypic variability. Neuropathy genes shown to have highly penetrant Mendelizing variants (HPMVs) and implicated by burden in families were shown to interact genetically in a zebrafish assay exacerbating the phenotype established by the suppression of single genes. Our findings suggest...","publication_date":"2015,1,5","publication_name":"Cell reports"},"document_type":"paper","pre_hit_view_count_baseline":null,"quality":"high","language":"en","title":"Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy","broadcastable":false,"draft":null,"has_indexable_attachment":true,"indexable":true,"seo_quality":null}}["work"]; window.loswp.workCoauthors = [83451]; window.loswp.locale = "en"; window.loswp.countryCode = "SG"; window.loswp.cwvAbTestBucket = ""; window.loswp.designVariant = "ds_vanilla"; window.loswp.fullPageMobileSutdModalVariant = "full_page_mobile_sutd_modal"; window.loswp.useOptimizedScribd4genScript = false; window.loginModal = {}; window.loginModal.appleClientId = 'edu.academia.applesignon'; window.userInChina = "false";</script><script defer="" src="https://accounts.google.com/gsi/client"></script><div class="ds-loswp-container"><div class="ds-work-card--grid-container"><div class="ds-work-card--container js-loswp-work-card"><div class="ds-work-card--cover"><div class="ds-work-cover--wrapper"><div class="ds-work-cover--container"><button class="ds-work-cover--clickable js-swp-download-button" data-signup-modal="{"location":"swp-splash-paper-cover","attachmentId":72064185,"attachmentType":"pdf"}"><img alt="First page of “Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy”" class="ds-work-cover--cover-thumbnail" src="https://0.academia-photos.com/attachment_thumbnails/72064185/mini_magick20211010-26223-16lm1lx.png?1633864250" /><img alt="PDF Icon" class="ds-work-cover--file-icon" src="//a.academia-assets.com/images/single_work_splash/adobe_icon.svg" /><div class="ds-work-cover--hover-container"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">download</span><p>Download Free PDF</p></div><div class="ds-work-cover--ribbon-container">Download Free PDF</div><div class="ds-work-cover--ribbon-triangle"></div></button></div></div></div><div class="ds-work-card--work-information"><h1 class="ds-work-card--work-title">Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy</h1><div class="ds-work-card--work-authors ds-work-card--detail"><a class="ds-work-card--author js-wsj-grid-card-author ds2-5-body-md ds2-5-body-link" data-author-id="83451" href="https://boun.academia.edu/EsraBattaloglu"><img alt="Profile image of Esra Battaloglu" class="ds-work-card--author-avatar" src="//a.academia-assets.com/images/s65_no_pic.png" />Esra Battaloglu</a></div><div class="ds-work-card--detail"><p class="ds-work-card--detail ds2-5-body-sm">2015, Cell reports</p><div class="ds-work-card--work-metadata"><div class="ds-work-card--work-metadata__stat"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">visibility</span><p class="ds2-5-body-sm" id="work-metadata-view-count">…</p></div><div class="ds-work-card--work-metadata__stat"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">description</span><p class="ds2-5-body-sm">16 pages</p></div><div class="ds-work-card--work-metadata__stat"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">link</span><p class="ds2-5-body-sm">1 file</p></div></div><script>(async () => { const workId = 56909580; 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Whole-exome sequencing (WES) of 40 individuals from 37 unrelated families with CMT-like peripheral neuropathy refractory to molecular diagnosis identified apparent causal mutations in ∼45% (17/37) of families. Three candidate disease genes are proposed, supported by a combination of genetic and in vivo studies. Aggregate analysis of mutation data revealed a significantly increased number of rare variants across 58 neuropathy-associated genes in subjects versus controls, confirmed in a second ethnically discrete neuropathy cohort, suggesting that mutation burden potentially contributes to phenotypic variability. Neuropathy genes shown to have highly penetrant Mendelizing variants (HPMVs) and implicated by burden in families were shown to interact genetically in a zebrafish assay exacerbating the phenotype established by the suppression of single genes. Our findings suggest...</p></div></div><div class="ds-top-related-works--grid-container"><div class="ds-related-content--container ds-top-related-works--container"><h2 class="ds-related-content--heading">Related papers</h2><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="0" data-entity-id="1123081" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/1123081/Whole_genome_sequencing_in_a_patient_with_Charcot_Marie_Tooth_neuropathy">Whole-genome sequencing in a patient with CharcotMarieTooth neuropathy</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="993990" href="https://regeneron.academia.edu/ClaudiaGonzagaJauregui">Claudia Gonzaga-Jauregui</a></div><p class="ds-related-work--metadata ds2-5-body-xs">New England Journal …, 2010</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Whole-genome sequencing in a patient with CharcotMarieTooth neuropathy","attachmentId":6927594,"attachmentType":"pdf","work_url":"https://www.academia.edu/1123081/Whole_genome_sequencing_in_a_patient_with_Charcot_Marie_Tooth_neuropathy","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/1123081/Whole_genome_sequencing_in_a_patient_with_Charcot_Marie_Tooth_neuropathy"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="1" data-entity-id="23790762" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/23790762/Improved_inherited_peripheral_neuropathy_genetic_diagnosis_by_whole_exome_sequencing">Improved inherited peripheral neuropathy genetic diagnosis by whole-exome sequencing</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="45955266" href="https://independent.academia.edu/GarthNicholson">Garth Nicholson</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Molecular Genetics & Genomic Medicine, 2015</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Improved inherited peripheral neuropathy genetic diagnosis by whole-exome sequencing","attachmentId":44219745,"attachmentType":"pdf","work_url":"https://www.academia.edu/23790762/Improved_inherited_peripheral_neuropathy_genetic_diagnosis_by_whole_exome_sequencing","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/23790762/Improved_inherited_peripheral_neuropathy_genetic_diagnosis_by_whole_exome_sequencing"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="2" data-entity-id="87120753" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/87120753/Whole_Genome_Sequencing_Identifies_a_78_kb_Insertion_from_Chromosome_8_as_the_Cause_of_Charcot_Marie_Tooth_Neuropathy_CMTX3">Whole Genome Sequencing Identifies a 78 kb Insertion from Chromosome 8 as the Cause of Charcot-Marie-Tooth Neuropathy CMTX3</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="102899656" href="https://independent.academia.edu/NicholsonGarth">Garth Nicholson</a></div><p class="ds-related-work--metadata ds2-5-body-xs">PLOS Genetics, 2016</p><p class="ds-related-work--abstract ds2-5-body-sm">With the advent of whole exome sequencing, cases where no pathogenic coding mutations can be found are increasingly being observed in many diseases. In two large, distantly-related families that mapped to the Charcot-Marie-Tooth neuropathy CMTX3 locus at chromosome Xq26.3-q27.3, all coding mutations were excluded. Using whole genome sequencing we found a large DNA interchromosomal insertion within the CMTX3 locus. The 78 kb insertion originates from chromosome 8q24.3, segregates fully with the disease in the two families, and is absent from the general population as well as 627 neurologically normal chromosomes from in-house controls. Large insertions into chromosome Xq27.1 are known to cause a range of diseases and this is the first neuropathy phenotype caused by an interchromosomal insertion at this locus. The CMTX3 insertion represents an understudied pathogenic structural variation mechanism for inherited peripheral neuropathies. Our finding highlights the importance of considering all structural variation types when PLOS Genetics |</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Whole Genome Sequencing Identifies a 78 kb Insertion from Chromosome 8 as the Cause of Charcot-Marie-Tooth Neuropathy CMTX3","attachmentId":91422502,"attachmentType":"pdf","work_url":"https://www.academia.edu/87120753/Whole_Genome_Sequencing_Identifies_a_78_kb_Insertion_from_Chromosome_8_as_the_Cause_of_Charcot_Marie_Tooth_Neuropathy_CMTX3","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/87120753/Whole_Genome_Sequencing_Identifies_a_78_kb_Insertion_from_Chromosome_8_as_the_Cause_of_Charcot_Marie_Tooth_Neuropathy_CMTX3"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="3" data-entity-id="14870694" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/14870694/Unraveling_the_genetic_landscape_of_autosomal_recessive_Charcot_Marie_Tooth_neuropathies_using_a_homozygosity_mapping_approach">Unraveling the genetic landscape of autosomal recessive Charcot-Marie-Tooth neuropathies using a homozygosity mapping approach</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="33843518" href="https://kuleuven.academia.edu/PDamme">Philip Van Damme</a></div><p class="ds-related-work--metadata ds2-5-body-xs">neurogenetics, 2014</p><p class="ds-related-work--abstract ds2-5-body-sm">Autosomal recessive forms of Charcot-Marie-Tooth disease (ARCMT) are rare but severe disorders of the peripheral nervous system. Their molecular basis is poorly understood due to the extensive genetic and clinical heterogeneity, posing considerable challenges for patients, physicians, and researchers. We report on the genetic findings from a systematic study of a large collection of 174 independent ARCMT families. Initial sequencing of the three most common ARCMT genes (ganglioside-induced differentiation protein 1-GDAP1, SH3 domain and tetratricopeptide repeatscontaining protein 2-SH3TC2, histidine-triad nucleotide binding protein 1-HINT1) identified pathogenic mutations Peter De Jonghe and Albena Jordanova are equally contributing last co-authors.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Unraveling the genetic landscape of autosomal recessive Charcot-Marie-Tooth neuropathies using a homozygosity mapping approach","attachmentId":43822594,"attachmentType":"pdf","work_url":"https://www.academia.edu/14870694/Unraveling_the_genetic_landscape_of_autosomal_recessive_Charcot_Marie_Tooth_neuropathies_using_a_homozygosity_mapping_approach","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/14870694/Unraveling_the_genetic_landscape_of_autosomal_recessive_Charcot_Marie_Tooth_neuropathies_using_a_homozygosity_mapping_approach"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="4" data-entity-id="5945296" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/5945296/Charcot_Marie_Tooth_disease_and_related_neuropathies_Mutation_distribution_and_genotype_phenotype_correlation">Charcot-Marie-Tooth disease and related neuropathies: Mutation distribution and genotype-phenotype correlation</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="8845901" href="https://007.academia.edu/johnjohnson">john johnson</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Annals of Neurology, 2002</p><p class="ds-related-work--abstract ds2-5-body-sm">Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous disorder that has been associated with alterations of several proteins: peripheral myelin protein 22, myelin protein zero, connexin 32, early growth response factor 2, periaxin, myotubularin related protein 2, N-myc downstream regulated gene 1 product, neurofilament light chain, and kinesin 1B. To determine the frequency of mutations in these genes among patients with CMT or a related peripheral neuropathy, we identified 153 unrelated patients who enrolled prior to the availability of clinical testing, 79 had a 17p12 duplication (CMT1A duplication), 11 a connexin 32 mutation, 5 a myelin protein zero mutation, 5 a peripheral myelin protein 22 mutation, 1 an early growth response factor 2 mutation, 1 a periaxin mutation, 0 a myotubularin related protein 2 mutation, 1 a neurofilament light chain mutation, and 50 had no identifiable mutation; the N-myc downstream regulated gene 1 and the kinesin 1B gene were not screened for mutations. In the process of screening the above cohort of patients as well as other patients for CMT-causative mutations, we identified several previously unreported mutant alleles: two for connexin 32, three for myelin protein zero, and two for peripheral myelin protein 22. The peripheral myelin protein 22 mutation W28R was associated with CMT1 and profound deafness. One patient with a CMT2 clinical phenotype had three myelin protein zero mutations (I89N+V92M+I162M). Because one-third of the mutations we report arose de novo and thereby caused chronic sporadic neuropathy, we conclude that molecular diagnosis is a necessary adjunct for clinical diagnosis and management of inherited and sporadic neuropathy.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Charcot-Marie-Tooth disease and related neuropathies: Mutation distribution and genotype-phenotype correlation","attachmentId":49080851,"attachmentType":"pdf","work_url":"https://www.academia.edu/5945296/Charcot_Marie_Tooth_disease_and_related_neuropathies_Mutation_distribution_and_genotype_phenotype_correlation","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/5945296/Charcot_Marie_Tooth_disease_and_related_neuropathies_Mutation_distribution_and_genotype_phenotype_correlation"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="5" data-entity-id="55039988" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/55039988/Molecular_Diagnosis_of_Hereditary_Neuropathies_by_Whole_Exome_Sequencing_and_Expanding_the_Phenotype_Spectrum">Molecular Diagnosis of Hereditary Neuropathies by Whole Exome Sequencing and Expanding the Phenotype Spectrum</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="42106596" href="https://uswr.academia.edu/MarziehMohseni">Marzieh Mohseni</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Archives of Iranian Medicine</p><p class="ds-related-work--abstract ds2-5-body-sm">Background: Inherited peripheral neuropathies (IPNs) are a group of neuropathies affecting peripheral motor and sensory neurons. Charcot-Marie-Tooth (CMT) disease is the most common disease in this group. With recent advances in next-generation sequencing (NGS) technologies, more than 100 genes have been implicated for different types of CMT and other clinically and genetically inherited neuropathies. There are also a number of genes where neuropathy is a major feature of the disease such as spinocerebellar ataxia (SCA) and hereditary spastic paraplegia (HSP). We aimed to determine the genetic causes underlying IPNs in Iranian families. Methods: We performed whole exome sequencing (WES) for 58 PMP22 deletion-/duplication-negative unrelated Iranian patients with a spectrum of phenotypes and with a preliminary diagnosis of hereditary neuropathies. Results: Twenty-seven (46.6%) of the cases were genetically diagnosed with pathogenic or likely pathogenic variants. In this study, we iden...</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Molecular Diagnosis of Hereditary Neuropathies by Whole Exome Sequencing and Expanding the Phenotype Spectrum","attachmentId":71105405,"attachmentType":"pdf","work_url":"https://www.academia.edu/55039988/Molecular_Diagnosis_of_Hereditary_Neuropathies_by_Whole_Exome_Sequencing_and_Expanding_the_Phenotype_Spectrum","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/55039988/Molecular_Diagnosis_of_Hereditary_Neuropathies_by_Whole_Exome_Sequencing_and_Expanding_the_Phenotype_Spectrum"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="6" data-entity-id="3861791" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/3861791/Exome_sequencing_resolves_apparent_incidental_findings_and_reveals_further_complexity_of_SH3TC2_variant_alleles_causing_Charcot_Marie_Tooth_neuropathy">Exome sequencing resolves apparent incidental findings and reveals further complexity of SH3TC2 variant alleles causing Charcot-Marie-Tooth neuropathy</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="993990" href="https://regeneron.academia.edu/ClaudiaGonzagaJauregui">Claudia Gonzaga-Jauregui</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Genome medicine, 2013</p><p class="ds-related-work--abstract ds2-5-body-sm">Background: The debate regarding the relative merits of whole genome sequencing (WGS) versus exome sequencing (ES) centers around comparative cost, average depth of coverage for each interrogated base, and their relative efficiency in the identification of medically actionable variants from the myriad of variants identified by each approach. Nevertheless, few genomes have been subjected to both WGS and ES, using multiple next generation sequencing platforms. In addition, no personal genome has been so extensively analyzed using DNA derived from peripheral blood as opposed to DNA from transformed cell lines that may either accumulate mutations during propagation or clonally expand mosaic variants during cell transformation and propagation.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Exome sequencing resolves apparent incidental findings and reveals further complexity of SH3TC2 variant alleles causing Charcot-Marie-Tooth neuropathy","attachmentId":50113186,"attachmentType":"pdf","work_url":"https://www.academia.edu/3861791/Exome_sequencing_resolves_apparent_incidental_findings_and_reveals_further_complexity_of_SH3TC2_variant_alleles_causing_Charcot_Marie_Tooth_neuropathy","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/3861791/Exome_sequencing_resolves_apparent_incidental_findings_and_reveals_further_complexity_of_SH3TC2_variant_alleles_causing_Charcot_Marie_Tooth_neuropathy"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="7" data-entity-id="23790731" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/23790731/Refined_localization_of_dominant_intermediate_Charcot_Marie_Tooth_neuropathy_and_exclusion_of_seven_known_candidate_genes_in_the_region">Refined localization of dominant intermediate Charcot-Marie-Tooth neuropathy and exclusion of seven known candidate genes in the region</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="45955266" href="https://independent.academia.edu/GarthNicholson">Garth Nicholson</a></div><p class="ds-related-work--metadata ds2-5-body-xs">neurogenetics, 2003</p><p class="ds-related-work--abstract ds2-5-body-sm">Charcot-Marie-Tooth (CMT) neuropathy is one of the most common hereditary disorders of the human peripheral nervous system. The CMT syndrome includes weakness and atrophy of distal muscles, high arched feet (pes cavus), depressed or absent deep tendon reflexes, and mild sensory loss. Dominant intermediate CMT (DI-CMT) neuropathy is a form of CMT with intermediate median motor nerve conduction velocities. We previously localized the DI-CMT locus to a 16.8-cM region on chromosome 19p12-p13.2. Extended haplotype analysis and clinical assessment of additional family members and a report of a second family linked to this locus has enabled us to narrow the candidate region to a 6-cM interval flanked by D19S558 and D19S432. Selection of positional candidate genes for screening was performed on the basis of neural expression and microarray analysis of Schwann cell differentiation in vivo. Seven candidate genes have been investigated. These include six genes localized in the original linkage interval and one in the newly refined region. They are excluded as a cause for DI-CMT neuropathy.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Refined localization of dominant intermediate Charcot-Marie-Tooth neuropathy and exclusion of seven known candidate genes in the region","attachmentId":44219750,"attachmentType":"pdf","work_url":"https://www.academia.edu/23790731/Refined_localization_of_dominant_intermediate_Charcot_Marie_Tooth_neuropathy_and_exclusion_of_seven_known_candidate_genes_in_the_region","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/23790731/Refined_localization_of_dominant_intermediate_Charcot_Marie_Tooth_neuropathy_and_exclusion_of_seven_known_candidate_genes_in_the_region"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="8" data-entity-id="55713161" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/55713161/The_genetic_convergence_of_Charcot_Marie_Tooth_disease_types_1_and_2_and_the_role_of_genetics_in_sporadic_neuropathy">The genetic convergence of Charcot-Marie-Tooth disease types 1 and 2 and the role of genetics in sporadic neuropathy</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="12550575" href="https://ubc.academia.edu/CorneliusBoerkoel">Cornelius Boerkoel</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Current neurology and neuroscience reports, 2002</p><p class="ds-related-work--abstract ds2-5-body-sm">Charcot-Marie-Tooth (CMT) disease represents a clinically and genetically heterogeneous group of inherited neuropathies caused by aberration of the intimate relationship between the myelin sheath and the axon; disorders causing demyelination are classified as CMT1 and those causing axonal loss as CMT2. The mechanisms by which mutations disturb the relationship of the myelin sheath and axon are not fully understood; however, we hypothesize that some mutations affect this relationship more profoundly than others, and thus account for the paradox that mutation of a &quot;myelin gene&quot; can present with electrophysiologic features of CMT2 and vice versa. Also, contrary to popular understanding, inherited neuropathies account for a substantial number of chronic peripheral neuropathies. Because of this observation, we propose that molecular diagnosis is a necessary adjunct for differentiating genetic and acquired peripheral neuropathies, even in sporadic chronic neuropathy.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"The genetic convergence of Charcot-Marie-Tooth disease types 1 and 2 and the role of genetics in sporadic neuropathy","attachmentId":71454569,"attachmentType":"pdf","work_url":"https://www.academia.edu/55713161/The_genetic_convergence_of_Charcot_Marie_Tooth_disease_types_1_and_2_and_the_role_of_genetics_in_sporadic_neuropathy","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/55713161/The_genetic_convergence_of_Charcot_Marie_Tooth_disease_types_1_and_2_and_the_role_of_genetics_in_sporadic_neuropathy"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="9" data-entity-id="56909581" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/56909581/Novel_mutations_in_genes_causing_hereditary_spastic_paraplegia_and_Charcot_Marie_Tooth_neuropathy_identified_by_an_optimized_protocol_for_homozygosity_mapping_based_on_whole_exome_sequencing">Novel mutations in genes causing hereditary spastic paraplegia and Charcot-Marie-Tooth neuropathy identified by an optimized protocol for homozygosity mapping based on whole-exome sequencing</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="83451" href="https://boun.academia.edu/EsraBattaloglu">Esra Battaloglu</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Genetics in Medicine, 2015</p><p class="ds-related-work--abstract ds2-5-body-sm">Purpose: Homozygosity mapping is an effective approach for detecting molecular defects in consanguineous families by delineating stretches of genomic DNA that are identical by descent. Constant developments in next-generation sequencing created possibilities to combine whole-exome sequencing (WES) and homozygosity mapping in a single step. Methods: Basic optimization of homozygosity mapping parameters was performed in a group of families with autosomal-recessive (AR) mutations for which both single-nucleotide polymorphism (SNP) array and WES data were available. We varied the criteria for SNP extraction and PLINK thresholds to estimate their effect on the accuracy of homozygosity mapping based on WES. Results: Our protocol showed high specificity and sensitivity for homozygosity detection and facilitated the identification of novel mutations in GAN, GBA2, and ZFYVE26 in four families affected by hereditary spastic paraplegia or Charcot-Marie-Tooth disease. Filtering and mapping with optimized parameters was integrated into the HOMWES (homozygosity mapping based on WES analysis) tool in the GenomeComb package for genomic data analysis. We present recommendations for detection of homozygous regions based on WES data and a bioinformatics tool for their identification, which can be widely applied for studying AR disorders.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Novel mutations in genes causing hereditary spastic paraplegia and Charcot-Marie-Tooth neuropathy identified by an optimized protocol for homozygosity mapping based on whole-exome sequencing","attachmentId":72064182,"attachmentType":"pdf","work_url":"https://www.academia.edu/56909581/Novel_mutations_in_genes_causing_hereditary_spastic_paraplegia_and_Charcot_Marie_Tooth_neuropathy_identified_by_an_optimized_protocol_for_homozygosity_mapping_based_on_whole_exome_sequencing","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/56909581/Novel_mutations_in_genes_causing_hereditary_spastic_paraplegia_and_Charcot_Marie_Tooth_neuropathy_identified_by_an_optimized_protocol_for_homozygosity_mapping_based_on_whole_exome_sequencing"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div></div></div><div class="ds-sticky-ctas--wrapper js-loswp-sticky-ctas hidden"><div class="ds-sticky-ctas--grid-container"><div class="ds-sticky-ctas--container"><button class="ds2-5-button js-swp-download-button" data-signup-modal="{"location":"continue-reading-button--sticky-ctas","attachmentId":72064185,"attachmentType":"pdf","workUrl":null}">See full PDF</button><button class="ds2-5-button ds2-5-button--secondary js-swp-download-button" data-signup-modal="{"location":"download-pdf-button--sticky-ctas","attachmentId":72064185,"attachmentType":"pdf","workUrl":null}"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">download</span>Download PDF</button></div></div></div><div class="ds-below-fold--grid-container"><div class="ds-work--container js-loswp-embedded-document"><div class="attachment_preview" data-attachment="Attachment_72064185" style="display: none"><div class="js-scribd-document-container"><div class="scribd--document-loading js-scribd-document-loader" style="display: block;"><img alt="Loading..." src="//a.academia-assets.com/images/loaders/paper-load.gif" /><p>Loading Preview</p></div></div><div style="text-align: center;"><div class="scribd--no-preview-alert js-preview-unavailable"><p>Sorry, preview is currently unavailable. You can download the paper by clicking the button above.</p></div></div></div></div><div class="ds-sidebar--container js-work-sidebar"><div class="ds-related-content--container"><h2 class="ds-related-content--heading">Related topics</h2><div class="ds-research-interests--pills-container"><a class="js-related-research-interest ds-research-interests--pill" data-entity-id="74780" rel="nofollow" href="https://www.academia.edu/Documents/in/Mutation">Mutation</a><a class="js-related-research-interest ds-research-interests--pill" data-entity-id="188349" rel="nofollow" href="https://www.academia.edu/Documents/in/Pedigree">Pedigree</a><a class="js-related-research-interest ds-research-interests--pill" data-entity-id="213897" rel="nofollow" href="https://www.academia.edu/Documents/in/Phenotype">Phenotype</a><a class="js-related-research-interest ds-research-interests--pill" data-entity-id="577933" rel="nofollow" href="https://www.academia.edu/Documents/in/Genetic_variation">Genetic variation</a><a class="js-related-research-interest ds-research-interests--pill" data-entity-id="598117" rel="nofollow" href="https://www.academia.edu/Documents/in/Zebrafish">Zebrafish</a><a class="js-related-research-interest ds-research-interests--pill" data-entity-id="1143279" rel="nofollow" href="https://www.academia.edu/Documents/in/Charcot_Marie_Tooth_Disease">Charcot Marie Tooth Disease</a><a class="js-related-research-interest ds-research-interests--pill" data-entity-id="1634669" rel="nofollow" href="https://www.academia.edu/Documents/in/Exome">Exome</a></div></div></div></div></div><div class="footer--content"><ul class="footer--main-links hide-on-mobile"><li><a href="https://www.academia.edu/about">About</a></li><li><a href="https://www.academia.edu/press">Press</a></li><li><a href="https://www.academia.edu/documents">Papers</a></li><li><a href="https://www.academia.edu/topics">Topics</a></li><li><a href="https://www.academia.edu/hiring"><svg style="width: 13px; height: 13px; position: relative; bottom: -1px;" aria-hidden="true" focusable="false" data-prefix="fas" data-icon="briefcase" class="svg-inline--fa fa-briefcase fa-w-16" role="img" xmlns="http://www.w3.org/2000/svg" viewBox="0 0 512 512"><path fill="currentColor" d="M320 336c0 8.84-7.16 16-16 16h-96c-8.84 0-16-7.16-16-16v-48H0v144c0 25.6 22.4 48 48 48h416c25.6 0 48-22.4 48-48V288H320v48zm144-208h-80V80c0-25.6-22.4-48-48-48H176c-25.6 0-48 22.4-48 48v48H48c-25.6 0-48 22.4-48 48v80h512v-80c0-25.6-22.4-48-48-48zm-144 0H192V96h128v32z"></path></svg> <strong>We're Hiring!</strong></a></li><li><a href="https://support.academia.edu/hc/en-us"><svg style="width: 12px; height: 12px; position: relative; bottom: -1px;" aria-hidden="true" focusable="false" data-prefix="fas" data-icon="question-circle" class="svg-inline--fa fa-question-circle fa-w-16" role="img" xmlns="http://www.w3.org/2000/svg" viewBox="0 0 512 512"><path fill="currentColor" d="M504 256c0 136.997-111.043 248-248 248S8 392.997 8 256C8 119.083 119.043 8 256 8s248 111.083 248 248zM262.655 90c-54.497 0-89.255 22.957-116.549 63.758-3.536 5.286-2.353 12.415 2.715 16.258l34.699 26.31c5.205 3.947 12.621 3.008 16.665-2.122 17.864-22.658 30.113-35.797 57.303-35.797 20.429 0 45.698 13.148 45.698 32.958 0 14.976-12.363 22.667-32.534 33.976C247.128 238.528 216 254.941 216 296v4c0 6.627 5.373 12 12 12h56c6.627 0 12-5.373 12-12v-1.333c0-28.462 83.186-29.647 83.186-106.667 0-58.002-60.165-102-116.531-102zM256 338c-25.365 0-46 20.635-46 46 0 25.364 20.635 46 46 46s46-20.636 46-46c0-25.365-20.635-46-46-46z"></path></svg> <strong>Help Center</strong></a></li></ul><ul class="footer--research-interests"><li>Find new research papers in:</li><li><a href="https://www.academia.edu/Documents/in/Physics">Physics</a></li><li><a href="https://www.academia.edu/Documents/in/Chemistry">Chemistry</a></li><li><a href="https://www.academia.edu/Documents/in/Biology">Biology</a></li><li><a href="https://www.academia.edu/Documents/in/Health_Sciences">Health Sciences</a></li><li><a href="https://www.academia.edu/Documents/in/Ecology">Ecology</a></li><li><a href="https://www.academia.edu/Documents/in/Earth_Sciences">Earth Sciences</a></li><li><a href="https://www.academia.edu/Documents/in/Cognitive_Science">Cognitive Science</a></li><li><a href="https://www.academia.edu/Documents/in/Mathematics">Mathematics</a></li><li><a href="https://www.academia.edu/Documents/in/Computer_Science">Computer Science</a></li></ul><ul class="footer--legal-links hide-on-mobile"><li><a href="https://www.academia.edu/terms">Terms</a></li><li><a href="https://www.academia.edu/privacy">Privacy</a></li><li><a href="https://www.academia.edu/copyright">Copyright</a></li><li>Academia ©2025</li></ul></div> </body> </html>