Seeing the female protective effect in infant siblings of children with ASD

Dr. Daniel Messinger, University of Miami

Last year, a study in Molecular Autism published by the Baby Siblings Research Consortium, or BSRC, led by Dr. Daniel Messinger at the University of Miami, examined characteristics of male and female siblings of those with an autism spectrum disorder. These younger siblings have a 20 fold increased probability of an autism diagnosis themselves. Because of this, they are the perfect group for studying early signs and symptoms of autism, biological markers before behavioral features emerge, and risk factors.   Around 20% of the time they will develop autism, 20% of the time they show symptoms of developmental problems but not ASD, and the rest are on a normal trajectory by 36 months1, therefore this is also the perfect group to study the female protective effect. This protective effect, if it exists, is most likely to be seen in the siblings of individuals with autism, and if there is something protecting females against an autism diagnosis, possibly the female sisters is the place to start looking.

A previous study in the general population looking at the co-occurrence of symptoms in twins observed female protection through what is known as the Carter Effect. The Carter Effect is defined by the higher incidence of a disorder in relatives when the person affected is the least commonly affected by sex. In other words, since females are less commonly affected, the Carter Effect was seen in the twin of a female with autism. If the co-twin did not have autism, autism symptoms were likely to be higher if they had a sister with autism compared to a brother.2

The BSRC study on the infant siblings looked for the Carter Effect in the infant siblings by looking at ASD diagnosis, scores on instruments like the Mullen (which tests IQ in younger kids) or severity scores of autism behaviors.   They did not find that the sex of the person with autism had any effect on these variables in the sibling, and therefore did not observe the Carter Effect.

Dr. John Constantino, Washington University School of Medicine

But that does not mean a protective effect was not there. When John Constantino from Washington University in St. Louis (who is also involved in infant sibling research) took a look at the data, he found evidence of a protective effect. Despite the absence of the Carter effect, there remains a very substantial male/female difference in ASD diagnosis.3 As it turns out, while there were equal numbers of male and female siblings in the study, boys were three times more likely to be diagnosed with autism than girls. In this sample where there is a high genetic liability of autism, there is a higher probability of boys to be diagnosed with autism vs. girls. This is not the first time the nature of the female protective effect has been seen in this way. Dr. Constantino has also shown a protective effect for females in other cohorts in which the absence of the Carter effect was simultaneously observed: these include the AGRE and IAN cohorts.4-7

The female protective effect can be seen in the difference between the two arrows

The original BSRC paper also found higher Mullen scores and lower autism repetitive symptoms in high-risk girls, mirroring other studies8,9. This may contribute to a protective effect which explains some of the reason why fewer females are diagnosed. There area also questions around the age of onset of symptoms, male bias in diagnostic instruments, and social perceptions of male and female specific behaviors. However, this protective effect, if it can be defined and described biologically, may lead to treatments and prevention of debilitating symptoms seen in both males and females.

The healthy and productive debate and conversation on this issue is exactly the sort of scientific conversations that move scientific discovery forward.   Not squabbling or one-upping one another, but carefully and thoughtfully discussing these ideas on an open forum for even others to comment on.   If this had not happened, these new insights would never have been shared with the community. Thank you to the editors of the journal Molecular Autism, Simon Baron-Cohen and Joseph Buxbaum, as well as BSRC and to Dr. John Constantino for making sure this happened.v4



  1. Messinger D, Young GS, Ozonoff S, et al. Beyond autism: a baby siblings research consortium study of high-risk children at three years of age. Journal of the American Academy of Child and Adolescent Psychiatry. 2013;52(3):300-308 e301.
  2. Robinson EB, Lichtenstein P, Anckarsater H, Happe F, Ronald A. Examining and interpreting the female protective effect against autistic behavior. Proceedings of the National Academy of Sciences of the United States of America. 2013;110(13):5258-5262.
  3. Constantino JN. Data from the Baby Siblings Research Consortium confirm and specify the nature of the female protective effect in autism: A commentary on Messinger et al. Molecular autism. 2016;7:32.
  4. Goin-Kochel RP, Abbacchi A, Constantino JN, Autism Genetic Resource Exchange C. Lack of evidence for increased genetic loading for autism among families of affected females: a replication from family history data in two large samples. Autism : the international journal of research and practice. 2007;11(3):279-286.
  5. Constantino JN, Charman T. Diagnosis of autism spectrum disorder: reconciling the syndrome, its diverse origins, and variation in expression. The Lancet. Neurology. 2016;15(3):279-291.
  6. Constantino JN, Zhang Y, Frazier T, Abbacchi AM, Law P. Sibling recurrence and the genetic epidemiology of autism. The American journal of psychiatry. 2010;167(11):1349-1356.
  7. Virkud YV, Todd RD, Abbacchi AM, Zhang Y, Constantino JN. Familial aggregation of quantitative autistic traits in multiplex versus simplex autism. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics. 2009;150B(3):328-334.
  8. Szatmari P, Liu XQ, Goldberg J, et al. Sex differences in repetitive stereotyped behaviors in autism: implications for genetic liability. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics. 2012;159B(1):5-12.
  9. Hartley SL, Sikora DM. Sex differences in autism spectrum disorder: an examination of developmental functioning, autistic symptoms, and coexisting behavior problems in toddlers. Journal of autism and developmental disorders. 2009;39(12):1715-1722.


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