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Their diagnosis is challenging for two reasons: firstly, their clinical features, particularly prenatal and postnatal growth disturbance, are heterogeneous and partially overlapping; secondly, their underlying molecular defects include mutation, epimutation, copy number variation, and chromosomal errors, and can be further complicated by somatic mosaicism and multi\u2010locus methylation defects. It is currently unclear to what extent the observed phenotypic heterogeneity reflects the underlying molecular pathophysiology; in particular, the molecular and clinical diversity of multilocus methylation defects remains uncertain. To address these issues we performed comprehensive methylation analysis of imprinted genes in a research cohort of 285 patients with clinical features of imprinting disorders, with or without a positive molecular diagnosis. 20 of 91 patients (22%) with diagnosed epimutations had methylation defects of additional imprinted loci, and the frequency of developmental delay and congenital anomalies was higher among these patients than those with isolated epimutations, indicating that hypomethylation of multiple imprinted loci is associated with increased diversity of clinical presentation. Among 194 patients with clinical features of an imprinting disorder but no molecular diagnosis, we found 15 (8%) with methylation anomalies, including missed and unexpected molecular diagnoses. These observations broaden the phenotypic and epigenetic definitions of imprinting disorders, and show the importance of comprehensive molecular testing for patient diagnosis and management. \u00a9 2013 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ajmg.a.36049","type":"journal-article","created":{"date-parts":[[2013,8,2]],"date-time":"2013-08-02T18:16:03Z","timestamp":1375467363000},"page":"2174-2182","source":"Crossref","is-referenced-by-count":69,"title":["Targeted methylation testing of a patient cohort broadens the epigenetic and clinical description of imprinting disorders"],"prefix":"10.1002","volume":"161","author":[{"given":"Rebecca L.","family":"Poole","sequence":"first","affiliation":[{"name":"Faculty of Medicine University of Southampton Southampton UK"},{"name":"Wessex Genetics Service, University Hospital Trust Southampton, and Salisbury Hospital NHS Foundation Trust Salisbury UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise E.","family":"Docherty","sequence":"additional","affiliation":[{"name":"Faculty of Medicine University of Southampton Southampton UK"},{"name":"Wessex Genetics Service, University Hospital Trust Southampton, and Salisbury Hospital NHS Foundation Trust Salisbury UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abeer","family":"Al Sayegh","sequence":"additional","affiliation":[{"name":"Faculty of Medicine University of Southampton Southampton UK"},{"name":"Wessex Genetics Service, University Hospital Trust Southampton, and Salisbury Hospital NHS Foundation Trust Salisbury UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Almuth","family":"Caliebe","sequence":"additional","affiliation":[{"name":"Faculty of Medicine University of Southampton Southampton UK"},{"name":"Wessex Genetics Service, University Hospital Trust Southampton, and Salisbury Hospital NHS Foundation Trust Salisbury UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Turner","sequence":"additional","affiliation":[{"name":"Peninsula Genetic Service Royal Devon and Exeter Hospital Exeter UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Baple","sequence":"additional","affiliation":[{"name":"Centre for Human Genetics St. George's, University of London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Wakeling","sequence":"additional","affiliation":[{"name":"North West Thames Regional Genetics Service North West London Hospitals NHS Trust Harrow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy","family":"Harrison","sequence":"additional","affiliation":[{"name":"Faculty of Medicine University of Southampton Southampton UK"},{"name":"Wessex Genetics Service, University Hospital Trust Southampton, and Salisbury Hospital NHS Foundation Trust Salisbury UK"},{"name":"Comprehensive Local Research Network (Hampshire &amp; Isle of Wight) Hampshire UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Lehmann","sequence":"additional","affiliation":[{"name":"Faculty of Medicine University of Southampton Southampton UK"},{"name":"Wessex Genetics Service, University Hospital Trust Southampton, and Salisbury Hospital NHS Foundation Trust Salisbury UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I. 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