New Horizons of Discovery on Sex Differences in Autism

John Constantino, MD, for the Intellectual and Developmental Disabilities Research Center at Washington University School of Medicine in St. Louis

August 15, 2022

AUCD's network of Intellectual and Developmental Disability Research Centers (IDDRCs) consists of 16 Centers. Fifteen Centers currently receive funding from the Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD). IDDRCs contribute to the development and implementation of evidence-based practices by evaluating the effectiveness of biological, biochemical, and behavioral interventions; developing assistive technologies; and advancing prenatal diagnosis and newborn screening.

The sex ratio for autism, 3 boys for every girl, occurs long before the time of puberty and is observed in all populations around the world, but its cause has remained a mystery. It is a very important mystery to solve because knowing what protects girls from the condition—or what makes boys more sensitive to it—could be key to developing effective treatments or therapeutic supports. Even when autism recurs in families, it recurs, on average, in a 3:1 ratio within families, and in the many families among whom autism recurs it is rare for the cause of autism to be an X-linked mutation (a type of mutation that is responsible for sex differences in some conditions, such as Fragile X Syndrome).

The Washington University Intellectual and Developmental Disabilities Research Center (IDDRC@WUSTL) has been hard at work for years trying to uncover the biology of this profoundly influential sex difference. In early analyses of accumulated data from the Baby Siblings Research Consortium, which included the involvement of five U.S. IDDRCs, it was confirmed that the sex difference in liability to the inheritance of autism was fully manifest by the start of the third year of life. A multifaceted approach to understanding the biology of the sex difference in autism (harnessing information from a large population-based epidemiologic study, brain imaging, and cellular modeling) was the focus of a principal research study of the IDDRC@WUSTL during the 2015-2020 cycle. One of the most important findings of this effort was the revelation that although boys are more sensitive and girls less sensitive to common genetic factors that influence the development of autism, neurotypical sisters of boys with autism are, on average, only 2% more likely than girls in the general population to have a child with autism—this work was published in the journal Biological Psychiatry and received honorable mention for the 2022 Somerfield-Ziskind Research Award. There are important exceptions to this relatively low offspring recurrence rate for sisters, which are discoverable through clinical genetic testing of the affected individual in the family; more details can be found here.

This year, the IDDRC@WUSTL team joined the Simons Foundation Autism Research Initiative Collaboration on Sex Differences in Autism, an international effort to combine the technologies and work of a select group of scientists around the world to further advance understanding of the biological mechanisms that distinguish males and females in the recognition, expression, and incidence of autism. Joseph Dougherty, PhD, the new co-Director of the IDDRC@WUSTL (succeeding Dr. Constantino who moved to Emory University August 1), in collaboration with colleagues at Washington University and UCSF, co- led a comprehensive synthesis of the latest knowledge surrounding sex differences in autism, published last month in the journal Neuron.