Heterozygous Variants in LRP1 Cause a Neurodevelopmental Disorder With Congenital Heart Defects
Year: 2026
Type: article
Study design: Observational Study
Abstract: LRP1 encodes the low-density lipoprotein (LDL) receptor-related protein 1 (LRP1), a transmembrane protein involved in endocytosis and activation of multiple signaling pathways. LRP1 variants have been implicated in the pathogenesis of congenital heart defects (CHD), Alzheimer's disease, and neurodevelopmental disorders (NDD). Biallelic LRP1 variants have also been reported in two siblings with CHD, hypotonia, dysmorphology, corneal clouding, and ascites. However, conclusive evidence supporting the role of LRP1 in human disease is still lacking. Individuals with heterozygous variants in LRP1 (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-of-function (pLOF) or missense variants in LRP1 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 LRP1 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.
DOI: 10.1002/ajmg.a.70261
Authors: Alyssa L. Rippert, Gudny Anna Arnadottir, Laura Bedinger, Nicola Brunetti‐Pierri, Jennifer Cech, Xin Chen, Yanmin Chen, Erika Chick, Sarah Dyack, Madeleine Franchi, Tanja Frey, David Genevieve, Ian Glass, Jorge Granadillo, Kelly A. Keener, Sara B. MacKay, Paige McDunnah, Vinod K. Misra, Kristin G. Monaghan, Sureni V. Mullegama, Cristina Peduto, Leia Peterman‐Prather, Anita Rauch, Cherith Somerville, Kari Stefansson, Katharina Steindl, Patrick Sulem, Telma Sulem, Pamela Trapane, Roberta Zeuli, Samuel Zinner, Kosuke Izumi
Institutions: Children's Hospital of Philadelphia, deCODE Genetics (Iceland), Helen DeVos Children's Hospital, Corewell Health, Federico II University Hospital, Scuola Superiore Meridionale, Telethon Institute Of Genetics And Medicine, University of Naples Federico II, Seattle Children's Hospital, Hospital for Sick Children, Ted Rogers Centre for Heart Research, Children's Hospital of Michigan, Dalhousie University, University of Florida Health Science Center, University of Zurich, Inserm, Université de Montpellier, Institute for Regenerative Medicine & Biotherapy, Hôpital Arnaud de Villeneuve, University of Washington, Washington University in St. Louis, Izaak Walton Killam Health Centre, Central Michigan University, University of Campania "Luigi Vanvitelli", Bicêtre Hospital, University of Iceland, The University of Texas Southwestern Medical Center
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,710
OpenAlex ID: W7204459143