Autism Spectrum Disorder Phenotype Profiles in Probands From Simplex Versus Multiplex Families

Background: Twin and family studies find that the risk of developing autism spectrum disorder (ASD) rises dramatically as the level of shared genes increases.  However, most children with ASD are the only individuals in their family with the diagnosis.  These simplex families have recently received attention from genetic researchers.  Sebat and colleagues (2007) examined genetic markers in ASD families and found that de novo copy number variant mutations were significantly more likely to occur in simplex than in either multiplex or control families.   Together, these findings suggest that the genetic etiologies of ASD may vary between single-incidence and multiple-incidence ASD families.  

Objectives: Given the potential differences in genetic etiologies for ASD, it is plausible that differences in phenotype exist as well.  The current study seeks to compare phenotype profiles in probands within multiplex versus simplex families.   

Methods: Probands from simplex families were ascertained from the ongoing Simons Simplex Collection (SSC) project and The Autism Simplex Collection (TASC). Probands in these studies are carefully screened for a family history of ASD and families are excluded if any immediate biological family member has or is suspected to have a diagnosis of ASD. 154 probands from simplex families in the UW studies were included in these analyses. Data for the multiplex family sample was obtained from the Collaborative Programs of Excellence in Autism study.  Multiplex families were included if two or more children in the family had a diagnosis of ASD, as assessed by study clinicians.  One proband from each multiplex family was selected at random to participate in this study, resulting in 226 probands eligible for analysis. Diagnosis of ASD for both samples was based on meeting cutoffs on the ADI and ADOS as well as a clinical diagnosis made by experienced clinicians.  Measures analyzed included the Aberrant Behavior Checklist (ABC), the social domain of the Vineland Adaptive Behavior Scales (VABS), ADOS severity score (Gotham et al, 2009), and either the Wechsler scales or the Differential Abilities Scale to assess IQ.

Results: Preliminary results suggest that multiplex probands scored significantly lower than simplex probands on both verbal, t (344)= 8.23, p <.001, and full scale IQ, t (356)= 6.77, p <.001.  Given that IQ often correlates with social deficits in ASD, we controlled for IQ when analyzing scores on the social domain of the VABS.  After controlling for IQ, multiplex probands scored lower than simplex probands on this domain, t (336) = 3.90, p <.001.  Scores did not differ between the groups on any composite of the ABC nor on the nonverbal IQ composite. Analyses concerning the ADOS severity scores are ongoing.

Conclusions: Phenotypic differences between probands from multiplex versus simplex families were found in a number of areas, including IQ and social skills.  These findings lend further support that different genetic mechanisms underlying simplex and multiplex families may have demonstrable effect on phenotypic presentation. Such findings may be important in further examinations of genetic risk markers potentially specific to each family-type.