{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T04:18:17Z","timestamp":1787804297738,"version":"build-2784847793"},"reference-count":40,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K02NS140483"],"award-info":[{"award-number":["K02NS140483"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002426","name":"Fondazione Telethon","doi-asserted-by":"publisher","award":["GSP15001"],"award-info":[{"award-number":["GSP15001"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","award":["U24HG006834"],"award-info":[{"award-number":["U24HG006834"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    <jats:italic>LRP1<\/jats:italic>\n                    encodes the low\u2010density lipoprotein (LDL) receptor\u2010related protein 1 (LRP1), a transmembrane protein involved in endocytosis and activation of multiple signaling pathways.\n                    <jats:italic>LRP1<\/jats:italic>\n                    variants have been implicated in the pathogenesis of congenital heart defects (CHD), Alzheimer's disease, and neurodevelopmental disorders (NDD). Biallelic\n                    <jats:italic>LRP1<\/jats:italic>\n                    variants have also been reported in two siblings with CHD, hypotonia, dysmorphology, corneal clouding, and ascites. However, conclusive evidence supporting the role of\n                    <jats:italic>LRP1<\/jats:italic>\n                    in human disease is still lacking. Individuals with heterozygous variants in\n                    <jats:italic>LRP1<\/jats:italic>\n                    (NM_002332.3) were identified through genetic testing. GeneMatcher facilitated identification of participants and international collaboration. Comprehensive clinical and genotypic data were collected. Fifteen participants with heterozygous predicted loss\u2010of\u2010function (pLOF) or missense variants in\n                    <jats:italic>LRP1<\/jats:italic>\n                    were identified. The most common phenotypes include NDD, CHD, musculoskeletal and gastrointestinal issues, and dysmorphic features. CHD was more common in participants with pLOF variants. Our findings suggest that\n                    <jats:italic>LRP1<\/jats:italic>\n                    haploinsufficiency is associated with a syndromic NDD. Phenotypic differences in cardiac and neurologic involvement between participants with pLOF and missense variants suggest the possibility of alternate disease mechanisms.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.70261","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T03:25:13Z","timestamp":1787801113000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Heterozygous Variants in\n                    <scp>\n                      <i>LRP1<\/i>\n                    <\/scp>\n                    Cause a Neurodevelopmental Disorder With Congenital Heart Defects"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4735-5223","authenticated-orcid":false,"given":"Alyssa L.","family":"Rippert","sequence":"first","affiliation":[{"name":"Division of Human Genetics Children's Hospital of Philadelphia  Philadelphia Pennsylvania 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(SSM, School of Advanced Studies), Genomics and Experimental Medicine Program University of Naples Federico II  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Cech","sequence":"additional","affiliation":[{"name":"Seattle Children's Hospital  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1871-4477","authenticated-orcid":false,"given":"Xin","family":"Chen","sequence":"additional","affiliation":[{"name":"Cardiac Genome Clinic, Ted Rogers Centre for Heart Research, the Hospital for Sick Children  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanmin","family":"Chen","sequence":"additional","affiliation":[{"name":"GeneDx, LLC  Gaithersburg Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Chick","sequence":"additional","affiliation":[{"name":"Division of Genetic, Genomic, and 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