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LDS is usually caused by heterozygous sequence variants in the <jats:italic>FOXC2<\/jats:italic> gene located at 16q24, but in one previous instance LDS has resulted from a balanced reciprocal translocation with a breakpoint at 16q24, 120\u2009kb distal to the <jats:italic>FOXC2<\/jats:italic> gene suggesting a position effect. Here, we describe a second family with LDS caused by a translocation involving 16q24. The family were ascertained after detection of a paternally inherited balanced reciprocal translocation t(16;22)(q24;q13.1) in a pregnancy complicated by severe fetal hydrops. There was a past history of multiple miscarriages in the father's family, and a personal and family history of lymphedema and distichiasis, consistent with the diagnosis of LDS. Using whole genome amplified DNA from single sperm of the male proband, bead array analysis demonstrated that the <jats:italic>FOXC2<\/jats:italic> gene was intact and the chromosome 16 breakpoint mapped to the same region 120Kb distal to the <jats:italic>FOXC2<\/jats:italic> gene. This case highlights the clinical consequences that can arise from a translocation of genomic material without dosage imbalance, and that it is increasingly feasible to predict and characterize possible effects with improved access to molecular techniques.<\/jats:p>","DOI":"10.1002\/ajmg.a.61935","type":"journal-article","created":{"date-parts":[[2020,10,27]],"date-time":"2020-10-27T08:18:34Z","timestamp":1603786714000},"page":"150-156","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Lymphedema distichiasis syndrome may be caused by <scp>FOXC2<\/scp> promoter\u2010enhancer dissociation and disruption of a topological associated domain"],"prefix":"10.1002","volume":"185","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5441-1732","authenticated-orcid":false,"given":"Mathew","family":"Wallis","sequence":"first","affiliation":[{"name":"Tasmanian Clinical Genetics Service, Tasmanian Health Service, C\/\u2010 The Royal Hobart Hospital  Hobart Tasmania Australia"},{"name":"School of Medicine and Menzies Institute for Medical Research, University of Tasmania  Hobart Tasmania Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel","family":"Pope\u2010Couston","sequence":"additional","affiliation":[{"name":"Tasmanian Clinical Genetics Service, Tasmanian Health Service, C\/\u2010 The Royal Hobart Hospital  Hobart Tasmania Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia","family":"Mansour","sequence":"additional","affiliation":[{"name":"Tasmanian Clinical Genetics Service, Tasmanian Health Service, C\/\u2010 The Royal Hobart Hospital  Hobart Tasmania Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David J.","family":"Amor","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Melbourne"},{"name":"Murdoch Children's Research Institute, Royal Children's Hospital  Parkville Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paisu","family":"Tang","sequence":"additional","affiliation":[{"name":"Virtus Diagnostics  East Melbourne Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sharyn","family":"Stock\u2010Myer","sequence":"additional","affiliation":[{"name":"Virtus Diagnostics  East Melbourne Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,10,27]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2008.02.012"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s004390100528"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1196-353"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi295"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.39.7.478"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygeno.2003.11.010"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2007.052787"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.02.007"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.38.11.761"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1159\/000134099"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1086\/316915"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2008.02.007"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1997.5127"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.04.005"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2008.01.011"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2004.03.031"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0423-1"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.29.2.103"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1086\/426833"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.2007.00758.x"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/35097076"},{"issue":"2","key":"e_1_2_10_23_1","first-page":"85","article-title":"From childhood onset lymphedema to fatal fetal hydrops: Possible modifying genes for a FOXC2 mutation","volume":"51","author":"Lai L. 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