Identifying rare genetic variants in 21 highly multiplex autism families: the role of diagnosis and autistic traits

Abstract

Autism is a highly heritable, heterogeneous, neurodevelopmental condition. Large-scale genetic studies, predominantly focussing on simplex families and clinical diagnoses of autism have identified hundreds of genes associated with autism. Yet, the contribution of these classes of genes to multiplex families and autistic traits still warrants investigation. Here, we conducted whole-genome sequencing of 21 highly multiplex autism families, with at least three autistic individuals in each family, to prioritise genes associated with autism. Using a combination of both autistic traits and clinical diagnosis of autism, we identify rare variants in genes associated with autism, and related neurodevelopmental conditions in multiple families. We identify a modest excess of these variants in autistic individuals compared to individuals without an autism diagnosis. Finally, we identify a convergence of the genes identified in molecular pathways related to development and neurogenesis. In sum, our analysis provides initial evidence to demonstrate the value of integrating autism diagnosis and autistic traits to prioritise genes.

Fig. 1. Overview of the rare inherited SNP/INDEL and de novo variants analysis pipeline used in this study.

The separate variant calling and filtering were conducted for de novo and inherited variants. After this, variants were grouped into three tiers. SNV single nucleotide variant, Indel insertion or deletion, NFE Non-Finish European, GATK The Genome Analysis Toolkit, pLI Loss-of-function intolerant, LOEUF Loss-of-function observed/expected upper bound fraction, SIFT Sorting Intolerant From Tolerant, PolyPhen-2 Polymorphism Phenotyping v2, BAP Broad Autistic Phenotype, MAP Medium Autistic Phenotype, NAP Narrow Autistic Phenotype.

Fig. 2. Identified prioritised genes in the phenotype trait and diagnosis approaches in multiplex autism families.

A Variants harbouring genes across all chromosomes. B Venn diagram showing the common and unique genes identified in phenotypic traits and diagnosis. Tier-1 genes are highlighted in red colour. C The distribution of the Tier 1 genes identified in BAP, MAP, and NAP phenotypic trait categories.

Fig. 3. Protein–protein interaction (PPI) Gene network analysis based on the STRING database of prioritised genes in pedigrees.

Protein–protein interaction (PPI) analysis was conducted using all genes identified in the current study across all tiers (both inherited and de novo).