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J Psychiatry Neurosci. 2019 Sep 1;44(5):350-359.

Truncating variant burden in high-functioning autism and pleiotropic effects of LRP1 across psychiatric phenotypes

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From the Departament de Genètica, Microbiologia i Estadística, Universitat de Barcelona, Spain (Torrico, Vivó-Luque, Fernàndez-Castillo, Cormand, Toma); the Institute of Biomedicine, University of Barcelona, Barcelona, Spain (Torrico, Fernàndez-Castillo, Cormand, Toma); the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain (Torrico, Fernàndez-Castillo, Cormand, Toma); the Institut de Recerca Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain (Torrico, Fernàndez-Castillo, Cormand); the Neuroscience Research Australia, Sydney, NSW, Australia (Shaw, Fullerton, Toma); the School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia (Shaw, Fullerton, Toma); the Institute for Research in Biomedicine (IRB Barcelona) and the Barcelona Institute of Science and Technology, Barcelona, Spain (Mosca, Aloy); the Child and Adolescent Mental Health Unit, Hospital Universitari Mútua de Terrassa, Spain (Hervás); the Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain (Aloy); and the Centro Nacional de Análisis Genómico (CNAG), Barcelona, Spain (Bayés).



Previous research has implicated de novo and inherited truncating mutations in autism-spectrum disorder. We aim to investigate whether the load of inherited truncating mutations contributes similarly to high-functioning autism, and to characterize genes that harbour de novo variants in high-functioning autism.


We performed whole-exome sequencing in 20 high-functioning autism families (average IQ = 100).


We observed no difference in the number of transmitted versus nontransmitted truncating alleles for high-functioning autism (117 v. 130, p = 0.78). Transmitted truncating and de novo variants in high-functioning autism were not enriched in gene ontology (GO) or Kyoto Encyclopedia of Genes and Genomes (KEGG) categories, or in autism-related gene sets. However, in a patient with high-functioning autism we identified a de novo variant in a canonical splice site of LRP1, a postsynaptic density gene that is a target for fragile X mental retardation protein (FRMP). This de novo variant leads to in-frame skipping of exon 29, removing 2 of 6 blades of the β-propeller domain 4 of LRP1, with putative functional consequences. Large data sets implicate LRP1 across a number of psychiatric disorders: de novo variants are associated with autism-spectrum disorder (p = 0.039) and schizophrenia (p = 0.008) from combined sequencing projects; common variants using genome-wide association study data sets from the Psychiatric Genomics Consortium show gene-based association in schizophrenia (p = 6.6 × E−07) and in a meta-analysis across 7 psychiatric disorders (p = 2.3 × E−03); and the burden of ultra-rare pathogenic variants has been shown to be higher in autism-spectrum disorder (p = 1.2 × E−05), using whole-exome sequencing from 6135 patients with schizophrenia, 1778 patients with autism-spectrum disorder and 7875 controls.


We had a limited sample of patients with high-functioning autism, related to difficulty in recruiting probands with high cognitive performance and no family history of psychiatric disorders.


Previous studies and ours suggest an effect of truncating mutations restricted to severe autism-spectrum disorder phenotypes that are associated with intellectual disability. We provide evidence for pleiotropic effects of common and rare variants in the LRP1 gene across psychiatric phenotypes.

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