{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,10]],"date-time":"2026-11-10T04:25:16Z","timestamp":1794284716119,"version":"4.9.0"},"reference-count":16,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:00:00Z","timestamp":1779235200000},"content-version":"vor","delay-in-days":139,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP24ek0109760"],"award-info":[{"award-number":["JP24ek0109760"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["25K19217"],"award-info":[{"award-number":["25K19217"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Congenital Anomalies"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The\n                    <jats:italic>HDAC8<\/jats:italic>\n                    variant is causative for X\u2010linked Cornelia de Lange syndrome (CdLS) and shows skewed X\u2010inactivation in heterozygous female patients, who tend to present with milder phenotypes than hemizygous male patients. We report a slightly deep intronic\n                    <jats:italic>HDAC8<\/jats:italic>\n                    variant, NM_018486.3:c.112\u201015C&gt;A, in a family with CdLS. Patient 1 (male) had a hemizygous\n                    <jats:italic>HDAC8<\/jats:italic>\n                    variant, showed a severe CdLS phenotype including profound developmental delay and multiple congenital abnormalities, and was deceased at 7\u2009years old. Patient 2 (female) was a younger sister of Patient 1 and revealed mild developmental delay and consistent dysmorphic features with CdLS. Patient 2 and their mother (Patient 3) had heterozygous variants and showed a skewed X\u2010inactivation pattern. cDNA deep sequencing of peripheral blood indicated aberrantly spliced transcripts in 0.53% of sequence reads in Patient 2, but not in Patient 3. This aberrant splicing likely results in nonsense\u2010mediated mRNA decay with loss\u2010of\u2010function effects. In Patient 3, the mutated allele was strongly inactivated, and normal transcripts from the reference allele were predominant. cDNA deep sequencing was required to evaluate the pathogenicity of the intronic variants. This report suggests that leaky splicing, as well as X\u2010inactivation, may contribute to the variation in familial phenotypic severity of\n                    <jats:italic>HDAC8<\/jats:italic>\n                    \u2010related CdLS.\n                  <\/jats:p>","DOI":"10.1002\/cga.70064","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T08:13:52Z","timestamp":1779264832000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Aberrant Splicing From an\n                    <scp>\n                      <i>HDAC8<\/i>\n                    <\/scp>\n                    Intronic Variant c.112\u2010\n                    <scp>15C<\/scp>\n                    &gt;A Causes Familial Cornelia de Lange Syndrome in Heterozygous and Hemizygous Individuals"],"prefix":"10.1002","volume":"66","author":[{"given":"Yukiko","family":"Kuroda","sequence":"first","affiliation":[{"name":"Division of Medical Genetics Kanagawa Children's Medical Center  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koki","family":"Nagai","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics Kanagawa Children's Medical Center  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoko","family":"Saito","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics Kanagawa Children's Medical Center  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyuki","family":"Shimokaze","sequence":"additional","affiliation":[{"name":"Division of Neonatology Kanagawa Children's Medical Center  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriko","family":"Aida","sequence":"additional","affiliation":[{"name":"Division of Radiology Kanagawa Children's Medical Center  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3380-8121","authenticated-orcid":false,"given":"Tomoko","family":"Satake","sequence":"additional","affiliation":[{"name":"Clinical Research Institute Kanagawa Children's Medical Center  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuya","family":"Naruto","sequence":"additional","affiliation":[{"name":"Clinical Research Institute Kanagawa Children's Medical Center  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6817-7748","authenticated-orcid":false,"given":"Kenji","family":"Kurosawa","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics Kanagawa Children's Medical Center  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,20]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11316"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00247\u2010015\u20103300\u20105"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41372\u2010019\u20100451\u20105"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2020.18109"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41436\u2010018\u20100085\u20106"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12564"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.63247"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0188578"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13951"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/pd.6095"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet\u20102012\u2010100921"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejogrb.2023.03.005"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010020\u201078205\u20105"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41436\u2010019\u20100741\u20105"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2019.00203"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu002"}],"container-title":["Congenital 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