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.