Heterozygous Variants in LRP1 Cause a Neurodevelopmental Disorder With Congenital Heart Defects

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.

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Journal
American Journal of Medical Genetics Part A
Published
2026-08-26
DOI
https://doi.org/10.1002/ajmg.a.70261
Primary Topic
Protease and Inhibitor Mechanisms
Type
article
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article

Heterozygous Variants in LRP1 Cause a Neurodevelopmental Disorder With Congenital Heart Defects

Sureni V. Mullegama, Vinod K. Misra, Sara MacKay, Madeleine Franchi et al.
American Journal of Medical Genetics Part A
Protease and Inhibitor Mechanisms
article

Heterozygous Variants in LRP1 Cause a Neurodevelopmental Disorder With Congenital Heart Defects

Sureni V. Mullegama, Vinod K. Misra, Sara MacKay, Madeleine Franchi, Sarah Dyack, Leia A. Peterman, Tanja Frey, Gudny A. Arnadottir, Roberta Zeuli, Jorge L. Granadillo, Patrick Sulem, Cristina Peduto, Pamela Trapane, Alyssa L. Rippert, Nicola Brunetti‐Pierri, Kosuke Izumi, David Geneviève, Ian A. Glass, Erika Chick, Xin Chen, Samuel H. Zinner, Paige McDunnah, Yanmin Chen, Anita Rauch, Kelly A. Keener, Kari Stefansson, Katharina Steindl, Laura Bedinger, Cherith Somerville, Telma Sulem, Kristin G. Monaghan, Jennifer Cech
article en

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.

American Journal of Medical Genetics Part A
Seattle Children's Hospital (US), Dalhousie University (CA), deCODE Genetics (Iceland) (IS), Children's Hospital of Philadelphia (US), Inserm (FR), Central Michigan University (US), University of Iceland (IS), University of Campania "Luigi Vanvitelli" (IT), Université de Montpellier (FR), University of Washington (US), University of Zurich (CH), Washington University in St. Louis (US), Izaak Walton Killam Health Centre (CA), Jacksonville University (US), Ted Rogers Centre for Heart Research (CA), Institute for Regenerative Medicine & Biotherapy (FR), New Jersey Community College Consortium For Workforce & Economic Development (US), Nemours Children's Health System (US), Helen DeVos Children's Hospital (US), Children's Hospital of Michigan (US), Hôpital Arnaud de Villeneuve (FR), Scuola Superiore Meridionale (IT), Telethon Institute Of Genetics And Medicine (IT), Bicêtre Hospital (FR), University of Naples Federico II (IT), The University of Texas Southwestern Medical Center (US), Florida College (US)
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Protease and Inhibitor Mechanisms
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