{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T04:15:36Z","timestamp":1745381736392,"version":"3.40.4"},"reference-count":28,"publisher":"The Endocrine Society","issue":"5","license":[{"start":{"date-parts":[[2024,7,30]],"date-time":"2024-07-30T00:00:00Z","timestamp":1722297600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome","doi-asserted-by":"publisher","award":["223187\/Z\/21\/Z"],"award-info":[{"award-number":["223187\/Z\/21\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health and Care Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Exeter Biomedical Research Centre"},{"DOI":"10.13039\/100010381","name":"European Society for Paediatric Endocrinology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010381","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005744","name":"Foundation for Paediatric Research Postdoctoral Fellowship","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005744","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,4,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Context<\/jats:title>\n                  <jats:p>Hyperinsulinemic hypoglycemia (HI) can be the presenting feature of Kabuki syndrome (KS), which is caused by loss-of-function variants in KMT2D or KDM6A. As these genes play a critical role in maintaining methylation status in chromatin, individuals with pathogenic variants have a disease-specific epigenomic profile\u2014an episignature.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>We evaluated the pathogenicity of 3 novel partial KDM6A duplications identified in 3 individuals presenting with neonatal-onset HI without typical features of KS at the time of genetic testing.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Three different partial KDM6A duplications were identified by routine targeted next-generation sequencing for HI and initially classified as variants of uncertain significance (VUS) as their location, and hence their impact on the gene, was not known. Whole-genome sequencing (WGS) was undertaken to map the breakpoints of the duplications with DNA methylation profiling performed in 2 individuals to investigate the presence of a KS-specific episignature.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>WGS confirmed the duplication in proband 1 as pathogenic as it caused a frameshift in the normal copy of the gene leading to a premature termination codon. The duplications identified in probands 2 and 3 did not alter the reading frame, and therefore their significance remained uncertain after WGS. Subsequent DNA methylation profiling identified a KS-specific episignature in proband 2 but not in proband 3.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Our findings confirm a role for KDM6A partial gene duplications in the etiology of KS and highlight the importance of performing in-depth molecular genetic analysis to properly assess the clinical significance of VUS' in the KDM6A gene.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/clinem\/dgae524","type":"journal-article","created":{"date-parts":[[2024,7,31]],"date-time":"2024-07-31T01:10:59Z","timestamp":1722388259000},"page":"e1524-e1530","source":"Crossref","is-referenced-by-count":0,"title":["Congenital Hyperinsulinism and Novel <i>KDM6A<\/i> Duplications -Resolving Pathogenicity With Genome and Epigenetic Analyses"],"prefix":"10.1210","volume":"110","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0596-0719","authenticated-orcid":false,"given":"Jonna M E","family":"M\u00e4nnist\u00f6","sequence":"first","affiliation":[{"name":"Department of Clinical and Biomedical Science, University of Exeter Medical School , Exeter EX2 5DW ,","place":["UK"]},{"name":"Kuopio Pediatric Research Unit, Faculty of Health Sciences, School of Medicine, University of Eastern Finland , 70211 Kuopio ,","place":["Finland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jasmin J","family":"Hopkins","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biomedical Science, University of Exeter Medical School , Exeter EX2 5DW ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas I","family":"Hewat","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biomedical Science, University of Exeter Medical School , Exeter EX2 5DW ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fatima","family":"Nasser","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biomedical Science, University of Exeter Medical School , Exeter EX2 5DW ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph","family":"Burrage","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biomedical Science, University of Exeter Medical School , Exeter EX2 5DW ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6332-3136","authenticated-orcid":false,"given":"Antonia","family":"Dastamani","sequence":"additional","affiliation":[{"name":"Endocrinology Department, Great Ormond Street Hospital for Children , London WC1N 3JH ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alice","family":"Mirante","sequence":"additional","affiliation":[{"name":"Pediatric Endocrinology, Hospital Pedi\u00e1trico de Coimbra, ULS de Coimbra , 3000-602 Coimbra ,","place":["Portugal"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nuala","family":"Murphy","sequence":"additional","affiliation":[{"name":"Department of Paediatric Endocrinology, CHI Temple St , Dublin, D01 XD99 ,","place":["Ireland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica","family":"Rzasa","sequence":"additional","affiliation":[{"name":"Verspeeten Clinical Genome Centre, London Health Sciences Centre , London, ON N6C 2R6 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer","family":"Kerkhof","sequence":"additional","affiliation":[{"name":"Verspeeten Clinical Genome Centre, London Health Sciences Centre , London, ON N6C 2R6 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raissa","family":"Relator","sequence":"additional","affiliation":[{"name":"Verspeeten Clinical Genome Centre, London Health Sciences Centre , London, ON N6C 2R6 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew B","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biomedical Science, University of Exeter Medical School , Exeter EX2 5DW ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas W","family":"Laver","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biomedical Science, University of Exeter Medical School , Exeter EX2 5DW ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luke","family":"Weymouth","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biomedical Science, University of Exeter Medical School , Exeter EX2 5DW ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jayne A L","family":"Houghton","sequence":"additional","affiliation":[{"name":"Exeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust , Exeter EX2 5DW ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew N","family":"Wakeling","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biomedical Science, University of Exeter Medical School , Exeter EX2 5DW ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bekim","family":"Sadikovic","sequence":"additional","affiliation":[{"name":"Verspeeten Clinical Genome Centre, London Health Sciences Centre , London, ON N6C 2R6 ,","place":["Canada"]},{"name":"Department of Pathology and Laboratory Medicine, Western University , London, ON N6A 5C1 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