Identifying rare genetic variants in 21 highly multiplex autism families: the role of diagnosis and autistic traits.

Autism is a highly heritable, heterogeneous, neurodevelopmental condition. Large-scale genetic studies, predominantly focussing on simplex families and clinical diagnoses of autism have identified hundreds of genes associated with autism. Yet, the contribution of these classes of genes to multiplex families and autistic traits still warrants investigation. Here, we conducted whole-genome sequencing of 21 highly multiplex autism families, with at least three autistic individuals in each family, to prioritise genes associated with autism. Using a combination of both autistic traits and clinical diagnosis of autism, we identify rare variants in genes associated with autism, and related neurodevelopmental conditions in multiple families. We identify a modest excess of these variants in autistic individuals compared to individuals without an autism diagnosis. Finally, we identify a convergence of the genes identified in molecular pathways related to development and neurogenesis. In sum, our analysis provides initial evidence to demonstrate the value of integrating autism diagnosis and autistic traits to prioritise genes.

Elevated rates of autism, other neurodevelopmental and psychiatric diagnoses, and autistic traits in transgender and gender-diverse individuals.

It is unclear whether transgender and gender-diverse individuals have elevated rates of autism diagnosis or traits related to autism compared to cisgender individuals in large non-clinic-based cohorts. To investigate this, we use five independently recruited cross-sectional datasets consisting of 641,860 individuals who completed information on gender, neurodevelopmental and psychiatric diagnoses including autism, and measures of traits related to autism (self-report measures of autistic traits, empathy, systemizing, and sensory sensitivity). Compared to cisgender individuals, transgender and gender-diverse individuals have, on average, higher rates of autism, other neurodevelopmental and psychiatric diagnoses. For both autistic and non-autistic individuals, transgender and gender-diverse individuals score, on average, higher on self-report measures of autistic traits, systemizing, and sensory sensitivity, and, on average, lower on self-report measures of empathy. The results may have clinical implications for improving access to mental health care and tailoring adequate support for transgender and gender-diverse individuals.