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Scientific advances<\/p>\n
[\/et_pb_fullwidth_header][\/et_pb_section][et_pb_section fb_built=”1″ _builder_version=”4.16″ global_colors_info=”{}”][et_pb_row _builder_version=”4.16″ background_size=”initial” background_position=”top_left” background_repeat=”repeat” global_colors_info=”{}”][et_pb_column type=”4_4″ _builder_version=”4.16″ custom_padding=”|||” global_colors_info=”{}” custom_padding__hover=”|||”][et_pb_text _builder_version=”4.27.6″ vertical_offset_tablet=”0″ horizontal_offset_tablet=”0″ hover_enabled=”0″ z_index_tablet=”0″ text_text_shadow_horizontal_length_tablet=”0px” text_text_shadow_vertical_length_tablet=”0px” text_text_shadow_blur_strength_tablet=”1px” link_text_shadow_horizontal_length_tablet=”0px” link_text_shadow_vertical_length_tablet=”0px” link_text_shadow_blur_strength_tablet=”1px” ul_text_shadow_horizontal_length_tablet=”0px” ul_text_shadow_vertical_length_tablet=”0px” ul_text_shadow_blur_strength_tablet=”1px” ol_text_shadow_horizontal_length_tablet=”0px” ol_text_shadow_vertical_length_tablet=”0px” ol_text_shadow_blur_strength_tablet=”1px” quote_text_shadow_horizontal_length_tablet=”0px” quote_text_shadow_vertical_length_tablet=”0px” quote_text_shadow_blur_strength_tablet=”1px” header_text_shadow_horizontal_length_tablet=”0px” header_text_shadow_vertical_length_tablet=”0px” header_text_shadow_blur_strength_tablet=”1px” header_2_text_shadow_horizontal_length_tablet=”0px” header_2_text_shadow_vertical_length_tablet=”0px” header_2_text_shadow_blur_strength_tablet=”1px” header_3_text_shadow_horizontal_length_tablet=”0px” header_3_text_shadow_vertical_length_tablet=”0px” header_3_text_shadow_blur_strength_tablet=”1px” header_4_text_shadow_horizontal_length_tablet=”0px” header_4_text_shadow_vertical_length_tablet=”0px” header_4_text_shadow_blur_strength_tablet=”1px” header_5_text_shadow_horizontal_length_tablet=”0px” header_5_text_shadow_vertical_length_tablet=”0px” header_5_text_shadow_blur_strength_tablet=”1px” header_6_text_shadow_horizontal_length_tablet=”0px” header_6_text_shadow_vertical_length_tablet=”0px” header_6_text_shadow_blur_strength_tablet=”1px” box_shadow_horizontal_tablet=”0px” box_shadow_vertical_tablet=”0px” box_shadow_blur_tablet=”40px” box_shadow_spread_tablet=”0px” global_colors_info=”{}” _module_preset=”dc6ab383-11a3-454b-8ba1-6554be6042b4″ sticky_enabled=”0″]<\/p>\n
Genome sequencing is increasingly being used for the investigation of developmental disorders, cancer and also in prenatal screening.\u00a0 While holding great promise for identifying genetic disorders, the use of these techniques has some pitfalls.\u00a0 The enormous volume of generated data makes variant interpretation challenging for clinical geneticists and counsellors.\u00a0 As a consequence, this can increase stress and uncertainty for patients, particularly in the setting of prenatal testing. Therefore, it is vital to provide comprehensive functional information about emerging genetic targets so that clinicians can distinguish pathogenic changes from benign ones and counsel patients accordingly<\/p>\n
This study now published in Genome Medicine<\/i>\u00a0reveals the\u00a0clinical application of a novel research technique that allows to distinguish between pathogenic and neutral genetic duplications associated with a rare growth disorder<\/b>. The research, led by an international team from the Humanitas University in Milan (Italy), the Andalusian Center for Developmental Biology (CABD) in Seville (Spain), and the University Hospital Center of Li\u00e8ge (Belgium), demonstrates how advanced chromatin conformation capture (3C) techniques can refine the diagnosis of X-linked acrogigantism (X-LAG), a severe childhood-onset form of pituitary gigantism caused by abnormal expression of the gene,\u00a0GPR101<\/i>.<\/p>\n
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Giampolo\u00a0Trivellin, Adrian Daly and Martin Franke, the senior authors from this work.<\/em><\/p>\n In 2022, the research team discovered that the underlying cause of X-LAG was due to duplications that disrupted the local 3D architecture of the X chromosome.\u00a0 This disruption affects a chromatin region – called a topologically associating domain (TAD) \u2013 at the\u00a0GPR101<\/i>\u00a0gene, which is separated from nearby genes by a border. The duplication in X-LAG places the normally-insulated gene under control by abnormal ectopic enhancers, forming what is known as a \u201cneo-TAD\u201d.\u00a0 This disorder, called a TADopathy, leads directly to tumoral growth hormone over-secretion and gigantism in affected children.<\/p>\n X-LAG is the only known clinical condition associated with\u00a0GPR101<\/i>\u00a0duplications, and as it is fully penetrant – meaning that all who carry the duplication develop the disease – the finding of a\u00a0GPR101\u00a0<\/i>duplication should herald a diagnosis of X-LAG.\u00a0 However, when clinical geneticists who were faced with\u00a0GPR101\u00a0<\/i>duplications without evidence of gigantism contacted the researchers provoked great surprise.\u00a0 Moreover, these included cases identified during prenatal screening and workup, where a potential diagnosis of X-LAG was considered.<\/p>\n Dr. Adrian Daly, lead author and endocrinologist at the University Hospital Center of Li\u00e8ge, explained the background of the study: \u201cThese findings challenged our model of how X-LAG occurs. We immediately saw an opportunity to turn our laboratory research methods into a clinical tool to explain these findings.\u00a0 We wanted to provide our genetics colleagues and parents with medically useful information.\u00a0 The first clue we focused on was the smaller size of the\u00a0GPR101<\/i>\u00a0duplications in these new cases compared with X-LAG patients.\u201d<\/p>\n The researchers employed 3D genomic techniques, which map the organization of chromatin in the nucleus. The authors compared the 3D chromatin architecture at\u00a0GPR101<\/i>\u00a0in the new cases to that the researchers had observed in patients with X-LAG.\u00a0 In contrast to X-LAG, where the disrupted TAD border of\u00a0GPR101<\/i>\u00a0led to a pathogenic neo-TAD, the smaller duplications in the new cases preserved the TAD border and did not form a neo-TAD.\u00a0 Without the involvement of the ectopic enhancers,\u00a0GPR101\u00a0<\/i>was not over-expressed, thereby explaining why X-LAG did not develop.<\/p>\n Dr. Giampaolo Trivellin, senior author and corresponding researcher at the Humanitas University, emphasized the practical implications of these findings: \u201cThis study shows how 3C techniques can be used to aid diagnostic decision making in conditions associated with TAD disruption. By understanding the structural impacts of these duplications, we have shown that we can distinguish pathogenic from neutral\u00a0GPR101\u00a0<\/i>duplications, allowing for informed clinical decisions and genetic counselling.\u201d<\/p>\n Dr. Martin Franke, senior and corresponding author from the CABD in Seville, concluded, \u201cBy applying our toolkit to study the 3D genome in a clinical context, we are opening new avenues for understanding genetic disorders linked to TAD disruption, the so-called TADopathies.\u00a0 The findings of our new research provide a roadmap for interrogating the potential pathogenicity of genetic changes associated with other TADopathies.\u201d<\/p>\n This research provides a proof-of-concept for the use of chromatin mapping as a diagnostic tool, highlighting its potential application in diagnosing other genetic disorders in the future.\u00a0 In addition, it underscores the potential of 3D genome mapping techniques for increasing the accuracy of prenatal screening, thereby improving the mental load for families and streamlining genetic diagnostics.<\/p>\n <\/p>\n Daly, A.F., Dunnington, L.A., Rodriguez-Buritica, D.F.\u00a0et al.<\/em>\u00a0Chromatin conformation capture in the clinic: 4C-seq\/HiC distinguishes pathogenic from neutral duplications at the\u00a0<\/strong>GPR101<\/strong><\/em>\u00a0locus.\u00a0<\/strong>Genome Med<\/em>\u00a0 112 (2024).DOI:\u00a0\u00a0https:\/\/doi.org\/10.1186\/s13073-024-01378-5<\/a><\/p>\n This press release was written in collaboratio with CSIC Andalucia and CSIC communication departments<\/p>\n [\/et_pb_text][\/et_pb_column][\/et_pb_row][\/et_pb_section]<\/p>\n","protected":false},"excerpt":{"rendered":" Scientific advancesImproved diagnosis of a rare genetic disease using a 3D genome technology Genome sequencing is increasingly being used for the investigation of developmental disorders, cancer and also in prenatal […]<\/p>\n","protected":false},"author":2997,"featured_media":18881,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_et_pb_use_builder":"on","_et_pb_old_content":"","_et_gb_content_width":"","footnotes":""},"categories":[184],"tags":[],"class_list":["post-21226","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-scientific-advances"],"_links":{"self":[{"href":"https:\/\/cabd.es\/en\/wp-json\/wp\/v2\/posts\/21226","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/cabd.es\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/cabd.es\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/cabd.es\/en\/wp-json\/wp\/v2\/users\/2997"}],"replies":[{"embeddable":true,"href":"https:\/\/cabd.es\/en\/wp-json\/wp\/v2\/comments?post=21226"}],"version-history":[{"count":6,"href":"https:\/\/cabd.es\/en\/wp-json\/wp\/v2\/posts\/21226\/revisions"}],"predecessor-version":[{"id":26918,"href":"https:\/\/cabd.es\/en\/wp-json\/wp\/v2\/posts\/21226\/revisions\/26918"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/cabd.es\/en\/wp-json\/wp\/v2\/media\/18881"}],"wp:attachment":[{"href":"https:\/\/cabd.es\/en\/wp-json\/wp\/v2\/media?parent=21226"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/cabd.es\/en\/wp-json\/wp\/v2\/categories?post=21226"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/cabd.es\/en\/wp-json\/wp\/v2\/tags?post=21226"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}