A Genetics-First Approach to Dissecting the Heterogeneity of Autism: Phenotypic Comparison of Autism Risk Copy Number Variants

Abstract

Objective: Certain copy number variants (CNVs) greatly increase risk of autism. We conducted a genetics-first study to investigate whether heterogeneity in the clinical presentation of autism is underpinned by specific genotype-phenotype relationships.Methods: This international study included 566 children (12.3 years (SD=4.2), 51% male) who were ascertained on the basis of having a genetic diagnosis of a rare CNV associated with high risk of autism (83 16p11.2 deletion carriers, 50 16p11.2 duplication carriers, 380 22q11.2 deletion carriers and 53 22q11.2 duplication carriers), as well as 2027 children (9.1 years (SD=4.9), 87% male) with autism of heterogeneous aetiology. The Autism Diagnostic Interview-Revised (ADI-R) and IQ testing were conducted. Results:The four genetic variant groups differed in autism severity, autism subdomain profile as well as IQ profile. However, we found substantial variability in phenotypic outcome within individual genetic variant groups (75% to 96% of the variance depending on the trait), whereas variability between groups was low (1% to 21% depending on trait). We compared CNV carriers who met autism criteria, to children with heterogeneous autism, and a range of profile differences were identified. Using clinical cut-offs, we found that 54% of children with one of the 4CNVs who did not meet full autism diagnostic criteria nonetheless had elevated levels of autistic traits. Conclusion:Many CNV carriers do not meet full diagnostic criteria for autism, but nevertheless meet clinical cut-offs for autistic traits. Although we find profile differences between variants, there is considerable variability in clinical symptoms within the same variant..

Translational Study of Copy Number Variations in Schizophrenia

“…CNVs at 15q13.3 are associated with developmental disorders, intellectual disability, attention-deficit hyperactivity disorder, autism spectrum disorder, childhood-onset schizophrenia, and depression in addition to schizophrenia [ 32 , 36 , 45 , 46 ]. CNVs at proximal 16p11.2 are also associated with neurodevelopmental disorder, intellectual disability, attention-deficit hyperactivity disorder, depression, and autism [ 34 , 36 , 47 , 48 , 49 , 50 , 51 ]. Finally, CNVs at 22q11.2 are associated with congenital heart disease, neurodevelopmental disorders, intellectual disability, autism spectrum disorders, and other neuropsychiatric conditions [ 7 , 48 , 52 , 53 ].…”

“…CNVs at proximal 16p11.2 are also associated with neurodevelopmental disorder, intellectual disability, attention-deficit hyperactivity disorder, depression, and autism [ 34 , 36 , 47 , 48 , 49 , 50 , 51 ]. Finally, CNVs at 22q11.2 are associated with congenital heart disease, neurodevelopmental disorders, intellectual disability, autism spectrum disorders, and other neuropsychiatric conditions [ 7 , 48 , 52 , 53 ]. Together, these data indicate that clinical manifestations of CNVs at the eight loci in this study are not limited to schizophrenia; they have pleiotropic clinical effects.…”

Clinical evaluation of patients with a neuropsychiatric risk copy number variant

“…CNV carriers are also likely to experience clinically impairing symptoms which do not fit traditional categorical diagnoses, and clinicians should consider dimensional and functional domains of impairment such as attention, social functioning, affect and executive functioning [ 38 ] rather than focussing solely on categorical diagnostic criteria. One illustrative example is that many carriers do not meet criteria for autism diagnosis yet have clear functional impairments in domains such as social functioning [ 39 • ]. Also diagnosing psychiatric conditions within the context of multimorbid physical health problems can provide challenges, for instance cleft palate problems can make it difficult to assess the communication domain of autism [ 40 ].…”

Patterns of delay in early gross motor and expressive language milestone attainment in probands with genetic conditions versus idiopathic ASD from SFARI registries

“…Large-scale collaborations (e.g. Simons Simplex Collection;Fischbach & Lord, 2010;Simons VIP Consortium, 2012) have made available larger cohorts of individuals with specific genetic diagnoses associated with neurodevelopmental disorders, allowing for an approach to examining phenotypes as they relate to specific genotypes (Chawner et al, 2021). Defining the phenotypic landscape of these genetic conditions, particularly in early childhood, is important for improving identification and clinical management.…”