15873
Increased Risk of Autism Spectrum Disorders in Boys with XYY
A known, highly penetrant genetic risk factor for Autism Spectrum Disorders (ASD) is the presence of a second Y chromosome, as found in the male sex chromosome aneuploidy disorder, 47,XYY syndrome (XYY). XYY occurs in ~0.1% of population-based males but is reported in 1% of males with ASD. Approximately 19 to 36% of males with XYY are reported to satisfy ASD diagnostic criteria.
Objectives: Characterize the autism phenotype in boys with XYY and evaluate the impact of prenatal versus postnatal ascertainment on the phenotype.
Methods: We performed a detailed ASD evaluation in 36 boys with karyotype-confirmed XYY (mean age 9.7±3.1 y [range 4-16 y]) using the Social Communications Questionnaire (SCQ, all 36 subjects), the Social Responsiveness Scale (SRS, 29 subjects), the Autism Diagnostic Interview-Revised (ADI-R, 29 subjects), and the Autism Diagnostic Observation Scale (ADOS, 15 subjects). Verbal abilities were evaluated with the Differential Ability Scales (DAS, all 36 subjects). We also evaluated possible ASD modulating factors including age, verbal abilities, socioeconomic status (SES), and timing of XYY diagnosis (prenatal versus postnatal).
Results: Diagnosis of XYY was made prenatally in 17 (47%) boys and in childhood (for developmental/ behavioral issues) in 19 (53%) boys. Intellectual functioning was, on average, within the normal range (mean DAS General Conceptual Ability standard score 92±14). A total of 91% had received speech and/or reading therapy, and 91% received occupational and/or physical therapy. Sixteen of 36 (44%) scored above the SCQ cutoff score for screening for ASD. Fourteen of 29 (48%) had scores in the clinical range (>mean+2.6 SD) on the SRS autistic behavior subscale. Of 29 boys with XYY, 9 (31%) met ADI-R ASD criteria, indicating a much higher rate of probable ASD than that of the general population. Seven of 15 (47%) boys with XYY met ADOS ASD criteria and 4 of these 7 also met Autism criteria. Age, SES, and verbal DAS scores were not correlated with SCQ, ADI-R, or SRS scores. ASD metrics were more severe in the postnatally ascertained boys, but there was a significantly increased ASD risk in both XYY cohorts. The proportion of boys meeting ASD criteria on the ADOS was similar in the prenatally versus postnatally diagnosed cohorts (43% vs. 50%).
Conclusions: These data strongly support the group-wide findings of increased ASD risk in XYY, and indicate that the prevalence of ASD in prenatally diagnosed XYY is similar to that in fragile X syndrome, the most common known genetic cause of autism. XYY represents a relatively well-defined genetic ASD model, compared to idiopathic ASD, which is more heterogeneous with regard to etiological/risk factors and pathogenesis. The strong likelihood that increased Y-chromosome dosage and increased risk of ASD are significantly associated deserves further investigation and may identify a genetic component of the marked male predominance in ASD.