Genetic counseling as preventive intervention: toward individual specification of transgenerational autism risk

Natasha Marrus,Christina A Gurnett,Andrew Whitehouse,Tychele N Turner,Drew Bolster,Laura Klinger,Alison Marvin,J N Constantino,Elizabeth Forsen

doi:10.1186/s11689-021-09389-8

Abstract

BackgroundAlthough autism spectrum disorders (ASD) are among the most heritable of all neuropsychiatric syndromes, most affected children are born to unaffected parents. Recently, we reported an average increase of 3–5% over general population risk of ASD among offspring of adults who have first-degree relatives with ASD in a large epidemiologic family sample. A next essential step is to investigate whether there are measurable characteristics of individual parents placing them at higher or lower recurrence risk, as this information could allow more personalized genetic counseling.MethodsWe assembled what is to our knowledge the largest collection of data on the ability of four measurable characteristics of unaffected prospective parents to specify risk for autism among their offspring: (1) sub clinical autistic trait burden, (2) parental history of a sibling with ASD, (3) transmitted autosomal molecular genetic abnormalities, and (4) parental age. Leveraging phenotypic and genetic data in curated family cohorts, we evaluate the respective associations between these factors and child outcome when autism is present in the family in the parental generation.ResultsAll four characteristics were associated with elevation in offspring risk; however, the magnitude of their predictive power—with the exception of isolated rare inherited pathogenic variants —does not yet reach a threshold that would typically be considered actionable for reproductive decision-making.ConclusionsIndividual specification of risk to offspring of adults in ASD-affected families is not straightforwardly improved by ascertainment of parental phenotype, and it is not yet clear whether genomic screening of prospective parents in families affected by idiopathic ASD is warranted as a clinical standard. Systematic screening of affected family members for heritable pathogenic variants, including rare sex-linked mutations, will identify a subset of families with substantially elevated transmission risk. Polygenic risk scores are only weakly predictive at this time but steadily improving and ultimately may enable more robust prediction either singly or when combined with the risk variables examined in this study.

Highlights

Autism spectrum disorders (ASD) are among the most heritable of all neuropsychiatric syndromes, most affected children are born to unaffected parents
Maternal Quantitative Autistic Traits (QATs) in simplex versus multiplex families (Analysis 1a) We first explored the difference in phenotypic characteristics of women with a single child with autism spectrum disorders (ASD) versus women with multiple ASD-affected children
We tested whether the groups differed with respect to the proportion of mothers above and below an Social Responsiveness Scale-2 (SRS-2) T-score cutoff of 45 for mild trait levels, and there was no significant difference between simplex and multiplex mothers (x2(1) = 0.36, p = .54)

Summary

Introduction

Autism spectrum disorders (ASD) are among the most heritable of all neuropsychiatric syndromes, most affected children are born to unaffected parents. Many sporadic cases of ASD have been associated with rare, highly-penetrant de novo pathogenic variants [2, 3], inheritance of the condition is believed to be mediated principally by polygenic risk, i.e., the aggregation of numerous common allelic variants, each individually of negligible main effect [4, 5]. In support of this model, rare, deleterious de novo variants are more frequently observed in simplex families with a single sporadic case of ASD versus multiplex families with multiple cases of ASD [6], and family members in multiplex families exhibit higher levels of sub clinical quantitative autistic traits (QATs) relative to simplex families [7, 8], consistent with higher polygenic liability. The increasingly recognized intersections between contributions of rare and common variants to ASD’s inherited liability and underlying neurobiology suggests that identifying measurable parental characteristics linked to these factors (e.g., ASD trait liability, genetic profiles) could provide more individualized specification of transgenerational ASD risk, with clinical implications for genetic counseling

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