Familial aggregation of quantitative autistic traits in multiplex versus simplex autism

Abstract

Recent research has suggested that the mode of inheritance for simplex autism (SA, one individual in the family affected) may be distinct from that for multiplex autism (MA, two or more individuals affected). Since sub clinical autistic traits have been observed in "unaffected" relatives of children with autism, we explored whether the distributions of such traits in families supported differential modes of genetic transmission for SA and MA autism. We measured patterns of familial aggregation of quantitative autistic traits (QAT) in children and parents in 80 SA families and 210 MA families, using the Social Responsiveness Scale. When considering all SA and MA siblings who scored below a uniform quantitative (clinical-level) severity threshold, MA brothers exhibited a distinct pathological shift in the distribution, compared to SA brothers (P < 0.0001). Such aggregation of QAT was also observed in fathers but not among females in MA families. Significant spousal correlations for QAT-suggestive of assortative mating-were observed in both SA and MA families, but neither group was characterized by a greater-than-chance level of concordant elevation among spousal pairs in this volunteer sample. Among male first degree relatives, there exist distinct patterns of QAT manifestation for simplex versus multiplex autism. These findings are consistent with the results of molecular genetic studies that have suggested differential modes of intergenerational transmission for SA and MA. Characterization of QAT and other endophenotypes among close relatives may be useful for reducing sample heterogeneity in future genetic and neurobiologic studies of autism.

Figure 1

Distribution of RAW teacher-report Social Responsiveness Scale (SRS) scores for ALL assessed children in each family type (all of the boys in the simplex families, all of the boys in the multiplex families, all of the girls in the same set of multiplex families). A teacher-report SRS T-score of 60, the quantitative threshold used for comparison of less-affected / unaffected male siblings in multiplex versus simplex families (see text) is denoted by the hatched line in each panel. Each bin is color-coded to depict the respective numbers of children categorically-designated as affected or unaffected on the basis of physician screening and/or ADI-R result, as described in Methods.