{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T02:31:28Z","timestamp":1788834688342,"version":"build-2803163510"},"reference-count":29,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2020,7,28]],"date-time":"2020-07-28T00:00:00Z","timestamp":1595894400000},"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":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2020,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Classical Ehlers\u2013Danlos syndrome (cEDS) is a connective tissue disorder mainly caused by heterozygous <jats:italic>COL5A1<\/jats:italic> or <jats:italic>COL5A2<\/jats:italic> variants encoding type V collagen and rarely by the p.(Arg312Cys) missense substitution in <jats:italic>COL1A1<\/jats:italic> encoding type I collagen. The current EDS nosology specifies that minimal suggestive criteria are marked skin hyperextensibility plus atrophic scarring together with either generalized joint hypermobility or at least three minor criteria comprising additional cutaneous and articular signs. To reach a final diagnosis, molecular testing is required. Herein, we report on a 3\u2010year\u2010old female who came to our attention with an inconclusive next generation sequencing (NGS) panel comprising all cEDS\u2010associated genes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Despite the patient did not formally fulfill the nosological criteria because the skin was only slightly hyperextensible, we made a cEDS diagnosis, mainly for the presence of typical atrophic scars. We investigated <jats:italic>COL5A1<\/jats:italic> intragenic deletions\/duplications by Multiplex Ligation\u2010dependent Probe Amplification (MLPA), excluded the recessive classical\u2010like EDS type 2 by <jats:italic>AEBP1<\/jats:italic> Sanger analysis, and retested <jats:italic>COL5A1<\/jats:italic> with the Sanger method.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Molecular analyses revealed the novel <jats:italic>COL5A1<\/jats:italic> c.3369_3431dup p.(Glu1124_Gly1144dup) intermediate\u2010sized duplication with a predicted dominant negative effect that was missed both by NGS and MLPA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This report highlights that some cEDS patients might not display overt skin hyperextensibility and the importance of clinical expertise to make such a diagnosis in patients with an incomplete presentation. Our results also exemplify that NGS is not a fool\u2010proof technology and that Sanger sequencing achieves the diagnostic goal when there is a sufficiently clear phenotypic indication.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.1422","type":"journal-article","created":{"date-parts":[[2020,7,28]],"date-time":"2020-07-28T10:20:27Z","timestamp":1595931627000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Identification of the novel <i>COL5A1<\/i> c.3369_3431dup, p.(Glu1124_Gly1144dup) variant in a patient with incomplete classical Ehlers\u2013Danlos syndrome: The importance of phenotype\u2010guided genetic testing"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7025-2495","authenticated-orcid":false,"given":"Marco","family":"Ritelli","sequence":"first","affiliation":[{"name":"Division of Biology and Genetics Department of Molecular and Translational Medicine University of Brescia Brescia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1545-4801","authenticated-orcid":false,"given":"Valeria","family":"Cinquina","sequence":"additional","affiliation":[{"name":"Division of Biology and Genetics Department of Molecular and Translational Medicine University of Brescia Brescia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Venturini","sequence":"additional","affiliation":[{"name":"Division of Dermatology Department of Clinical and Experimental Sciences Spedali Civili University Hospital Brescia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3105-5990","authenticated-orcid":false,"given":"Marina","family":"Colombi","sequence":"additional","affiliation":[{"name":"Division of Biology and Genetics Department of Molecular and Translational Medicine University of Brescia Brescia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,7,28]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19980428)77:1<31::AID-AJMG8>3.0.CO;2-O"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.02.018"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31548"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31550"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31425"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31429"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2017.10.005"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13052"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.38035"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/26.1.253"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp324"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2017.01.004"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20107"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31552"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20429"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-019-0609-8"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.21037\/acs.2017.11.03"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13683"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.3109\/03009741003781977"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes10020135"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-8-58"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.38004"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes10110843"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa002939"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-23978-z"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22137"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddz024"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31538"}],"container-title":["Molecular Genetics &amp; 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