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

Abstract

Background Although 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. Methods We 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. Results All 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. Conclusions Individual 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.

Mid‐childhood autism sibling recurrence in infants with a family history of autism

“…If the sibling recurrence rate in prospective family history infant studies lies somewhere between the ~20% from multi‐site studies of 3‐year outcomes (Messinger et al, 2015; Ozonoff et al, 2011), the ~25% recurrence rate based on mid‐childhood community diagnosis and the ~ 35% recurrence rate based on mid‐childhood research diagnosis we report, it has implications for families and clinicians. Individual recurrence likelihood will depend on a number of genetic, familial and environmental factors, not all of which will be known (Marrus et al, 2021). In our study children who were only given an autism research diagnosis at the mid‐childhood but not at the 3‐year assessment were more likely to be girls and have higher IQ at the earlier assessment.…”

The Potential Usefulness of the Expanded Carrier Screening to Identify Hereditary Genetic Diseases: A Case Report from Real-World Data

“…This supports the hypothesis that there is a variable expressivity linked to the RBFOX1 gene [ 29 ]. Although most of the molecular genetic variants strongly associated with neurodevelopmental disorders, particularly with ASD, are de novo, also variants inherited from unaffected parent can contribute to ASD [ 37 ].…”