A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex.

2022

1284-1292

09/2022

1546-1718

The genetic etiology of autism spectrum disorder (ASD) is multifactorial, but how combinations of genetic factors determine risk is unclear. In a large family sample, we show that genetic loads of rare and polygenic risk are inversely correlated in cases and greater in females than in males, consistent with a liability threshold that differs by sex. De novo mutations (DNMs), rare inherited variants and polygenic scores were associated with various dimensions of symptom severity in children and parents. Parental age effects on risk for ASD in offspring were attributable to a combination of genetic mechanisms, including DNMs that accumulate in the paternal germline and inherited risk that influences behavior in parents. Genes implicated by rare variants were enriched in excitatory and inhibitory neurons compared with genes implicated by common variants. Our results suggest that a phenotypic spectrum of ASD is attributable to a spectrum of genetic factors that impact different neurodevelopmental processes.

10.1038/s41588-022-01064-5

Nat Genet

35654974

The Early Screening for Autism and Communication Disorders: Field-testing an autism-specific screening tool for children 12 to 36 months of age.

2021

13623613211012526

2021 May 07

1461-7005

<p><strong>LAY ABSTRACT: </strong>There is a critical need for accurate screening tools for autism spectrum disorder in very young children so families can access tailored intervention services as early as possible. However, there are few screeners designed for children 18-24 months. Developing screeners that pick up on the signs of autism spectrum disorder in very young children has proved even more challenging. In this study, we examined a new autism-specific parent-report screening tool, the Early Screening for Autism and Communication Disorders for children between 12 and 36 months of age. Field-testing was done in five sites with 471 children screened for communication delays in primary care or referred for familial risk or concern for autism spectrum disorder. The Early Screening for Autism and Communication Disorders was tested in three age groups: 12-17, 18-23, and 24-36 months. A best-estimate diagnosis of autism spectrum disorder, developmental delay, or typical development was made. Analyses examined all 46 items and identified 30 items that best discriminated autism spectrum disorder from the non-spectrum groups. Cutoffs were established for each age group with good sensitivity and specificity. Results provide preliminary support for the accuracy of the Early Screening for Autism and Communication Disorders as an autism-specific screener in children 12-36 months with elevated risk of communication delay or autism spectrum disorder.</p>

10.1177/13623613211012526

Autism

33962531