{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T22:13:19Z","timestamp":1757628799786,"version":"3.44.0"},"reference-count":31,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T00:00:00Z","timestamp":1748563200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Synpolydactyly (SPD) is a heterogeneous distal\u2010limb malformation syndrome, characterized by webbing and duplication of adjacent digits. SPD1, the most common type, is attributed to disease\u2010causing variants in HOXD13, a transcription factor in the HOXD cluster that is essential for limb development. Here, we present a challenging exome\u2010negative case of familial SPD. The case was resolved using long\u2010read genome sequencing, which revealed a microdeletion in a conserved noncoding regulatory region upstream of the HOXD cluster. Oxford Nanopore WGS\u2010LRS was pursued on two affected sisters, followed by CMA\u2010Cytoscan HT validation. WGS\u2010LRS for two affected siblings revealed a shared microdeletion of ~5.6\u2009kb upstream of EVX2 and HOXD13 [chr2:176073523\u2013176,079,120 (hg38)]. The deletion is predicted to affect the enhancer of several HOXD genes (EH38E2053988) and overlaps with a short stretch of high\u2010sequence homology between human and mouse, called R1. CMA\u2010Cytoscan HT analysis and PCR validation approved segregation of the deletion in the siblings and revealed a paternal inheritance. Our findings expand the genotype\u2013phenotype correlation of the regulatory region upstream of HOXD13 in SPD and highlight the utility of long\u2010read WGS for detecting noncoding variants that are undetectable by exome sequencing.<\/jats:p>","DOI":"10.1002\/ajmg.a.64130","type":"journal-article","created":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T08:59:04Z","timestamp":1748595544000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Long\u2010Read Whole\u2010Genome Sequencing Uncovers a Deletion Upstream to <scp>HOXD13<\/scp> Causing Synpolydactyly"],"prefix":"10.1002","volume":"197","author":[{"given":"Jonathan","family":"Rips","sequence":"first","affiliation":[{"name":"Department of Genetics Hadassah Medical Center  Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rivka","family":"Birnbaum","sequence":"additional","affiliation":[{"name":"Department of Genetics Hadassah Medical Center  Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chaim","family":"Jalas","sequence":"additional","affiliation":[{"name":"Bonei Olam Center for Rare Jewish Genetic Disorders  Brooklyn New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayala","family":"Frumkin","sequence":"additional","affiliation":[{"name":"Department of Genetics Hadassah Medical Center  Jerusalem Israel"},{"name":"Hebrew University of Jerusalem  Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shamir","family":"Zenvirt","sequence":"additional","affiliation":[{"name":"Department of Genetics Hadassah Medical Center  Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia","family":"Rachanaev","sequence":"additional","affiliation":[{"name":"Department of Genetics Hadassah Medical Center  Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Avraham","family":"Shaag","sequence":"additional","affiliation":[{"name":"Department of Genetics Hadassah Medical Center  Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3595-7075","authenticated-orcid":false,"given":"Tamar","family":"Harel","sequence":"additional","affiliation":[{"name":"Department of Genetics Hadassah Medical Center  Jerusalem Israel"},{"name":"Hebrew University of Jerusalem  Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Orly","family":"Elpeleg","sequence":"additional","affiliation":[{"name":"Department of Genetics Hadassah Medical Center  Jerusalem Israel"},{"name":"Hebrew University of Jerusalem  Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6631-0376","authenticated-orcid":false,"given":"Hagar","family":"Mor\u2010Shaked","sequence":"additional","affiliation":[{"name":"Department of Genetics Hadassah Medical Center  Jerusalem Israel"},{"name":"Hebrew University of Jerusalem  Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,5,30]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/gox.0000000000001549"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1234167"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks1193"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.281055.116"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.24465"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12920\u2010019\u20100647\u20108"},{"key":"e_1_2_9_8_1","first-page":"143","article-title":"Developmental Expression of the Mouse Evx\u20102 Gene: Relationship With the Evolution of the HOM\/Hox Complex","volume":"1994","author":"Doll\u00e9 P.","year":"1994","journal-title":"Development. 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