Sex Differences in Extended Pedigrees with ASD

Background:  The sex ratio of four boys to every girl with ASD is well known but little understood. Several theories have been advanced to explain this discrepancy including reduced penetrance in girls of a rare dominant genetic variant, hormonal influences during pregnancy, and epigenetic variants, though little evidence exists for any of these models. Several studies have shown that girls with ASD show fewer repetitive stereotyped behaviours than boys.  But more convincing evidence of reduced penetrance would require large families with many affected individuals.

Objectives:  The objective of this presentation is to investigate the sex ratio in large extended pedigrees with multiply affected individuals with ASD. Relatives are stratified into those that are affected with ASD, those that are identified as having broader autism phenotypes (BAP) and those that are assumed to be “obligate” carriers of a genetic risk variant from a common relative.

Methods:  Twenty-seven extended pedigrees were identified through an on-going family-genetic study of ASD conducted at McMaster University, Memorial University and the University of North Carolina. An extended pedigree was defined as a pedigree with at least three affected individuals from three separate nuclear families within that pedigree. Cases of ASD were diagnosed using the ADI-R, ADOS and clinical best-estimate. Relatives with the BAP were identified by using the self-report and/or informant versions of the Broader Autism Phenotype Questionnaire. An individual scoring above the self-report, informant or best estimate (the mean of the self-report and informant scores) thresholds on the aloof, pragmatic language or rigid subtests was classified as having the BAP. Obligate carriers were identified by isolating pairs of nuclear families with ASD relatives. The relatives connecting those ASD individuals were identified as “obligate carriers”. If a relative was classified as both BAP and an obligate carrier, the classification as obligate carrier took precedence so no relative was counted twice.

Results:  Among the 27 pedigrees there were 89 males and 23 females with ASD giving a sex ratio of 3.9 males to 1 female. Among adult relatives with the BAP, there were 18 males and 21 females, (ratio: 0.9:1). Among obligate carriers, there were 28 males compared to 45 females (ratio: 0.6:1).  The sex ratio varies significantly as a function of classification as affected, BAP or obligate carrier (chi-square=35.12, df=2, p<.001).

Conclusions:  In these highly familial pedigrees with ASD, there is a clear gradient in the sex ratio going from affected status to BAP to obligate carrier. The sex ratio among affected cases was as expected. However, there were an equal number of males and females with the BAP and most obligate carriers were female. Assuming a model of autosomal dominant inheritance, this would suggest reduced penetrance in female relatives allowing for an increased number of those relatives to become obligate carriers with or without the BAP. The study of extended pedigrees with ASD has the potential to shed considerable light on the genetic architecture of this disorder including the investigation of protective factors among female relatives.