@article{a15760d8eae0433a9b8d474650a041ff,
title = "Quantitative autism symptom patterns recapitulate differential mechanisms of genetic transmission in single and multiple incidence families",
abstract = "Background: Previous studies have demonstrated aggregation of autistic traits in undiagnosed family members of children with autism spectrum disorder (ASD), which has significant implications for ASD risk in their offspring. This study capitalizes upon a large, quantitatively characterized clinical-epidemiologic family sample to establish the extent to which family transmission pattern and sex modulate ASD trait aggregation. Methods: Data were analyzed from 5515 siblings (2657 non-ASD and 2858 ASD) included in the Interactive Autism Network. Autism symptom levels were measured using the Social Responsiveness Scale (SRS) and by computing Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) symptom scores based on items from the SRS and Social Communication Questionnaire. Generalized estimating equation models evaluated the influence of family incidence types (single versus multiple incidence families; male-only ASD-affected families versus families with female ASD-affected children), diagnostic group (non-ASD children with and without a history of language delay with autistic speech and ASD-affected children), and sibling sex on ASD symptom levels. Results: Non-ASD children manifested elevated ASD symptom burden when they were members of multiple incidence families - this effect was accentuated for male children in female ASD-containing families - or when they had a history of language delay with autistic qualities of speech. In this sample, ASD-affected children from multiple incidence families had lower symptom levels than their counterparts in single incidence families. Recurrence risk for ASD was higher for children from female ASD-containing families than for children from male-only families. Conclusions: Sex and patterns of family transmission modulate the risk of autism symptom burden in undiagnosed siblings of ASD-affected children. Identification of these symptoms/traits and their molecular genetic causes may have significant implications for genetic counseling and for understanding inherited liabilities that confer risk for ASD in successive generations. Autism symptom elevations were more dramatic in non-ASD children from multiple incidence families and those with a history of language delay and autistic qualities of speech, identifying sub-groups at substantially greater transmission risk. Higher symptom burden and greater recurrence in children from female ASD-containing families indicate that familial aggregation patterns are further qualified by sex-specific thresholds, supportive of the notion that females require a higher burden of deleterious liability to cross into categorical ASD diagnosis.",
keywords = "Autism spectrum disorder, Autism symptoms, DSM-5, Genetic epidemiology, Multiple incidence families",
author = "Frazier, {Thomas W.} and Youngstrom, {Eric A.} and Hardan, {Antonio Y.} and Stelios Georgiades and Constantino, {John N.} and Charis Eng",
note = "Funding Information: Data used in the preparation of this article were obtained from the Interactive Autism Network (IAN) Research Database at the Hugo W. Moser Research Institute at Kennedy Krieger Inc., version 2013-01-28. For up-to-date information, see http://www.ianproject.org. The authors wish to acknowledge the important contribution of the participants with autism, their siblings, and their families. This publication was made possible by the Stephan and Allison Cole Family Research Fund; Case Western Reserve University/Cleveland Clinic CTSA Grant Number UL1 RR024989 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health and NIH roadmap for Medical Research; and the Developmental Synaptopathies Consortium (U54NS092090), a part of NCATS Rare Disease Clinical Research Network (RDCRN), an initiative of the Office of Rare Disease Research (ORDR). The Developmental Synaptopathies Consortium is funded through the collaboration between NCATS and the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health. The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. CE is the Sondra J. and Stephen R. Hardis Chair of Cancer Genomic Medicine at the Cleveland Clinic and an American Cancer Society Clinical Research Professor. Funding Information: Dr. Frazier has received federal funding or research support from, acted as a consultant to, received travel support from, and/or received a speaker{\textquoteright}s honorarium from the Cole Family Research Fund, Simons Foundation, Ingalls Foundation, Forest Laboratories, Ecoeos, IntegraGen, Kugona LLC, Shire Development, Bristol-Myers Squibb, National Institutes of Health, and the Brain and Behavior Research Foundation. Dr. John Constantino receives royalties from Western Psychological Services for the commercial distribution of one of the metrics used in this study, the Social Responsiveness Scale. Dr. Eng received research support from IntegraGen, is an unpaid member of the External Scientific Advisory Boards of Ecoeos and GenomOncology, serves on the External Strategic Advisory Board of N-of-One, and serves on the External Advisory Boards of the Center for Personalized Medicine, Mission Health, NC, CareSource and Medical Mutual of Ohio. Drs. Youngstrom, Hardan, and Georgiades have no competing interests to disclose. No authors have non-financial competing interests to disclose. Publisher Copyright: {\textcopyright} 2015 Frazier et al.",
year = "2015",
month = oct,
day = "27",
doi = "10.1186/s13229-015-0050-z",
language = "English",
volume = "6",
journal = "Molecular Autism",
issn = "2040-2392",
number = "1",
}