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

Haploinsufficiency of LRP1, which encodes a transmembrane protein involved in endocytosis and activation of multiple signaling pathways; phenotypic differences between truncating and missense variants suggest distinct mechanisms.

LRP1 encodes low-density lipoprotein receptor-related protein 1, a transmembrane protein involved in endocytosis and activation of multiple signaling pathways, and its variants had already been implicated in congenital heart defects, Alzheimer's disease and neurodevelopmental disorders without conclusive evidence of a role in human disease. Biallelic LRP1 variants had been reported in two siblings with congenital heart defects, hypotonia, dysmorphology, corneal clouding and ascites. Through GeneMatcher and international collaboration the authors assembled fifteen participants carrying a heterozygous LRP1 variant (NM_002332.3), either predicted loss-of-function or missense, with comprehensive clinical and genotypic data. The most common phenotypes combine neurodevelopmental disorder, congenital heart defects, musculoskeletal and gastrointestinal issues and dysmorphic features, with congenital heart defects more frequent in carriers of loss-of-function variants.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Fifteen independent individuals are enough to move LRP1 from a gene merely implicated to one worth serious consideration when a neurodevelopmental disorder coexists with congenital heart defects, a frequent and often unexplained combination. The practical issue is not sequencing more but annotating: LRP1 is already covered by every exome, and it is missense classification that remains open, all the more so as phenotypic correlation differs between truncating and missense variants. With no functional study and no documented de novo status here, the evidence remains that of a collaborative series, to be consolidated before reporting an isolated missense variant as causal.

Analysis by Dr Thibaut Benquey