Burden of de novo mutations and inherited rare single nucleotide variants in children with sensory processing dysfunction

Elysa Jill Marco,Gilberto Da Gente,Molly Rae Gerdes,Leyla Bologlu,Elliott H Sherr,Vishnu Prakas Nair,Sean Thomas,Anne Brandes Aitken

doi:10.1186/s12920-018-0362-x

Elysa Jill Marco, Gilberto Da Gente + Show 6 more

Open Access

https://doi.org/10.1186/s12920-018-0362-x

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Abstract

BackgroundIn children with sensory processing dysfunction (SPD), who do not meet criteria for autism spectrum disorder (ASD) or intellectual disability, the contribution of de novo pathogenic mutation in neurodevelopmental genes is unknown and in need of investigation. We hypothesize that children with SPD may have pathogenic variants in genes that have been identified as causing other neurodevelopmental disorders including ASD. This genetic information may provide important insight into the etiology of sensory processing dysfunction and guide clinical evaluation and care.MethodsEleven community-recruited trios (children with isolated SPD and both biological parents) underwent WES to identify candidate de novo variants and inherited rare single nucleotide variants (rSNV) in genes previously associated with ASD. Gene enrichment in these children and their parents for transmitted and non-transmitted mutation burden was calculated. A comparison analysis to assess for enriched rSNV burden was then performed in 2377 children with ASD and their families from the Simons Simplex Collection.ResultsOf the children with SPD, 2/11 (18%), were identified as having a de novo loss of function or missense mutation in genes previously reported as causative for neurodevelopmental disorders (MBD5 and FMN2). We also found that the parents of children with SPD have significant enrichment of pathogenic rSNV burden in high-risk ASD candidate genes that are inherited by their affected children. Using the same approach, we confirmed enrichment of rSNV burden in a large cohort of children with autism and their parents but not unaffected siblings.ConclusionsOur findings suggest that SPD, like autism, has a genetic basis that includes both de novo single gene mutations as well as an accumulated burden of rare inherited variants from their parents.

Highlights

In children with sensory processing dysfunction (SPD), who do not meet criteria for autism spectrum disorder (ASD) or intellectual disability, the contribution of de novo pathogenic mutation in neurodevelopmental genes is unknown and in need of investigation
We identified 12 candidate genes with de novo loss of function and/or missense variants in our 11 SPD probands
We found that the children with SPD show trend level enrichment of inherited high risk ASD rare single nucleotide variants (rSNV) (p < 0.068, approximately 1/14 chance of false positive) with all individual children showing the same direction of rSNV burden for this gene set

Summary

Introduction

In children with sensory processing dysfunction (SPD), who do not meet criteria for autism spectrum disorder (ASD) or intellectual disability, the contribution of de novo pathogenic mutation in neurodevelopmental genes is unknown and in need of investigation. We hypothesize that children with SPD may have pathogenic variants in genes that have been identified as causing other neurodevelopmental disorders including ASD. This genetic information may provide important insight into the etiology of sensory processing dysfunction and guide clinical evaluation and care. We have recently shown that children with SPD, who do not meet criteria for ASD, have measurable differences in white matter microstructure predominantly in the posterior brain regions, which are critical to sensory perception and processing [5].

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