{"id":892,"date":"2024-10-09T11:49:10","date_gmt":"2024-10-09T11:49:10","guid":{"rendered":"http:\/\/sebigec.es\/blog\/?guid=7414440d74b28352eb7f2f057733e20b"},"modified":"2024-10-09T11:49:10","modified_gmt":"2024-10-09T11:49:10","slug":"genetic-analyses-of-a-large-consanguineous-south-indian-family-reveal-novel-variants-in-nagpa-and-four-hitherto-unreported-genes-in-developmental-stuttering","status":"publish","type":"post","link":"https:\/\/sebigec.es\/blog\/index.php\/2024\/10\/09\/genetic-analyses-of-a-large-consanguineous-south-indian-family-reveal-novel-variants-in-nagpa-and-four-hitherto-unreported-genes-in-developmental-stuttering\/","title":{"rendered":"Genetic analyses of a large consanguineous south Indian family reveal novel variants in NAGPA and four hitherto unreported genes in developmental stuttering"},"content":{"rendered":"\n<h2>Abstract<\/h2>\n<h2>Background<\/h2>\n<p>Developmental stuttering, a multifactorial speech disorder with remarkable rate of spontaneous recovery pose challenges for gene discoveries. Exonic variants in <i>GNPTAB, GNPTG<\/i>, and <i>NAGPA<\/i> involved in lysosomal pathway and <i>AP4E1, IFNAR1<\/i>, and <i>ARMC3-<\/i>signaling genes reported till date explain only \u223c2.1% \u2013 3.7% of persistent stuttering cases.<\/p>\n<h2>Aim<\/h2>\n<p>We aimed to identify additional genetic determinants of stuttering in a multiplex family by exome sequencing (<i>n<\/i>\u00a0=\u00a027) and further validation on additional extended family members (<i>n<\/i>\u00a0=\u00a021).<\/p>\n<h2>Materials &amp; Methods<\/h2>\n<p>We employed hypothesis-free and pathway-based analyses.<\/p>\n<h2>Results<\/h2>\n<p>A novel heterozygous exonic variant NM_016256.4:c.322G\u00a0&gt;\u00a0A in <i>NAGPA<\/i> with reduced penetrance and predicted pathogenicity segregated with the phenotype in a large subset of the family. Reanalysis to identify additional disease-causing variant(s) revealed exonic heterozygous variants each in <i>RIMS2<\/i> and <i>XYLT1<\/i> in severely affected members; and <i>IGF2R<\/i> variant in a small subset of the family. Furthermore, pathway-based analysis uncovered NM_022089.4:c.3529G\u00a0&gt;\u00a0A in <i>ATP13A2<\/i> (<i>PARK9<\/i>) in affected members; and variants in G<i>NPTAB<\/i> and <i>GNPTG<\/i> of minor significance in a few affected members.<\/p>\n<h2>Discussion<\/h2>\n<p>Genotype\u2013phenotype correlation efforts suggest that the combined effect of gene variants at multiple loci or variants in a single gene in different subsets of the pedigree (genetic heterogeneity) may be contributing to stuttering in this family. More importantly, variants identified in <i>ATP13A2<\/i>, a Parkinson's disease gene also implicated in lysosomal dysfunction, and <i>RIMS2<\/i> suggests for the first time a likely role of dopamine signaling in stuttering.<\/p>\n<h2>Conclusion<\/h2>\n<p>Screening for these variants in independent stuttering cohorts would be astute.<\/p>","protected":false},"excerpt":{"rendered":"<p>Annals of Human Genetics, EarlyView.<\/p>\n","protected":false},"author":0,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[60,6,42],"tags":[43],"class_list":["post-892","post","type-post","status-publish","format-standard","hentry","category-annals-of-human-genetics","category-articulos","category-original-article","tag-annhumgenet"],"_links":{"self":[{"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts\/892","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/types\/post"}],"replies":[{"embeddable":true,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/comments?post=892"}],"version-history":[{"count":1,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts\/892\/revisions"}],"predecessor-version":[{"id":893,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts\/892\/revisions\/893"}],"wp:attachment":[{"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/media?parent=892"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/categories?post=892"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/tags?post=892"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}