Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Sep 16;13(1):39.
doi: 10.1186/s11689-021-09389-8.

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

Natasha Marrus  1 , Tychele N Turner  2 , Elizabeth Forsen  3 , Drew Bolster  3 , Alison Marvin  4 , Andrew Whitehouse  5 , Laura Klinger  6 , Christina A Gurnett  7 , J N Constantino  3
Affiliations

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

Natasha Marrus et al. J Neurodev Disord. .

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.

Keywords: Early detection; Family studies; Genetic counseling; Personalized medicine; Reproductive health planning.

PubMed Disclaimer

Conflict of interest statement

Dr. John Constantino has received royalties from Western Psychological Services for the Social Responsiveness Scale.

Figures

Fig. 1
Fig. 1
Mean parental QATs according to presence of ASD-associated pathogenic variants in offspring. QAT distributions for either mothers, fathers, or averaged parental SRS-2 scores have a slightly higher mean and wider range (encompassing higher scores) in families for which an ASD-affected child does not have known ASD-associated de novo variants, versus families in which the ASD-affected child has a known de novo variant. For parents of a child with known de novo variant, correlation of parental SRS-2 scores are as follows: r=0.26 (0.15, 0.36), p<.001; for parents of a child with unknown variants: r=0.31 (0.27, 0.34), p<.001)
Fig. 2
Fig. 2
Relationship of maternal and paternal age to offspring de novo variant burden. Parental age at the time of birth of a child with ASD (a) or an unaffected sibling (b) is plotted in relationship to the number of ASD-associated de novo variants in these offspring. Similar correlations are observed for both ASD-affected and unaffected offspring, suggesting the observed relationship is not specific to ASD
See this image and copyright information in PMC

References

    1. Sandin S, Lichtenstein P, Kuja-Halkola R, Hultman C, Larsson H, Reichenberg A. The heritability of autism spectrum disorder. JAMA. 2017;318(12):1182–1184. doi: 10.1001/jama.2017.12141. - DOI - PMC - PubMed
    1. Iossifov I, Ronemus M, Levy D, Wang Z, Hakker I, Rosenbaum J, Yamrom B, Lee YH, Narzisi G, Leotta A, Kendall J, Grabowska E, Ma B, Marks S, Rodgers L, Stepansky A, Troge J, Andrews P, Bekritsky M, Pradhan K, Ghiban E, Kramer M, Parla J, Demeter R, Fulton LL, Fulton RS, Magrini VJ, Ye K, Darnell JC, Darnell RB, Mardis ER, Wilson RK, Schatz MC, McCombie WR, Wigler M. De novo gene disruptions in children on the autistic spectrum. Neuron. 2012;74(2):285–299. doi: 10.1016/j.neuron.2012.04.009. - DOI - PMC - PubMed
    1. Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T, Yamrom B, Yoon S, Krasnitz A, Kendall J, Leotta A, Pai D, Zhang R, Lee YH, Hicks J, Spence SJ, Lee AT, Puura K, Lehtimaki T, Ledbetter D, Gregersen PK, Bregman J, Sutcliffe JS, Jobanputra V, Chung W, Warburton D, King MC, Skuse D, Geschwind DH, Gilliam TC, Ye K, Wigler M. Strong association of de novo copy number mutations with autism. Science. 2007;316(5823):445–449. doi: 10.1126/science.1138659. - DOI - PMC - PubMed
    1. Gaugler T, Klei L, Sanders SJ, Bodea CA, Goldberg AP, Lee AB, Mahajan M, Manaa D, Pawitan Y, Reichert J, Ripke S, Sandin S, Sklar P, Svantesson O, Reichenberg A, Hultman CM, Devlin B, Roeder K, Buxbaum JD. Most genetic risk for autism resides with common variation. Nat Genet. 2014;46(8):881–885. doi: 10.1038/ng.3039. - DOI - PMC - PubMed
    1. Klei L, Sanders SJ, Murtha MT, Hus V, Lowe JK, Willsey AJ, Moreno-de-Luca D, Yu TW, Fombonne E, Geschwind D, Grice DE, Ledbetter DH, Lord C, Mane SM, Martin CL, Martin DM, Morrow EM, Walsh CA, Melhem NM, Chaste P, Sutcliffe JS, State MW, Cook EH, Jr, Roeder K, Devlin B. Common genetic variants, acting additively, are a major source of risk for autism. Mol Autism. 2012;3(1):9. doi: 10.1186/2040-2392-3-9. - DOI - PMC - PubMed

Publication types