Non-Specific Inherited Background Susceptibilities for Autism Spectrum Disorder

Background: Previous studies have demonstrated that autism spectrum disorder (ASD) is highly heritable and may arise from the highly deleterious effects of genetic variants as occur in monogenic and oligogenic ASD syndromes. Besides the direct genetic effects, indirect background ASD susceptibilities may amplify the effects of these genetic mutations. For example, it has been shown that the risk for clinical-level ASD affectation in offspring is strengthened when parents exhibit subclinical ASD traits. Many previous studies have demonstrated the aggregation of non-ASD-specific neurodevelopmental impairments in individuals with ASD, such as attention-deficit/hyperactivity disorder (ADHD) symptoms and motor impairments. Although these problems are not part of the DSM5 diagnostic criteria for ASD, these impairments often co-occur in children affected by ASD. Studies strongly suggest genetic overlap between ASD and ADHD and between ASD and motor impairment, but findings from genetic studies are mixed and remain inconclusive. Supporting genetic overlap though, studies have revealed the highly pleiotropic effect of rare mutations in monogenic syndromes, such as the FMR1, TSC1/TSC2 and NF1 mutations, which have all three been associated with both ASD, ADHD and motor impairments.

Objectives: In this talk, both direct genetic effects as well as non-ASD-specific inherited background susceptibilities that amplify the level of ASD impairment will be discussed.

Methods: The first part of this talk describes a retrospective study in 114 males with a clinical diagnosis of ASD and 114 of their male siblings. In all children, quantitative autistic traits (QAT) were assessed, as well as ADHD symptoms and motor coordination. We examined the extent to which these two—non-ASD-specific—neurodevelopmental traits might contribute to ASD recurrence in the siblings. The second part of this talk portrays the direct genetic effect, and describes (preliminary) data on the neurodevelopmental profile (including ASD and ADHD traits) of children with rare monogenic syndromes, such as Fragile X syndrome, Tuberous Sclerosis Complex and Neurofibromatosis type I.

Results: In siblings of ASD-affected probands over 50% of the variation in autistic impairment—whether ascertained quantitatively or categorically—was predicted by sibling ADHD and motor problems. Preliminary data in children with rare monogenic syndromes demonstrates that neurodevelopmental difficulties such as ASD and ADHD are highly prevalent and often co-occur in these patients.

Conclusions: These studies suggest that background ASD susceptibilities that are inherited but non-specific (“BASINS”) play a significant role in the development of ASD, and may contribute to additive genetic liability in the same manner that ASD-specific susceptibilities (such as deleterious mutations) engender ASD risk (Figure 1).