Genetic diagnostic outcomes from a 10-year research programme in autism in Aotearoa New Zealand

Abstract

Autism is a relatively common neurodevelopmental difference with considerable phenotypic heterogeneity impacting cognitive, sensory, and social processing, and often co-occurs with other conditions. Therefore, there is not a one-size-fits-all clinical support pathway for autistic individuals following diagnosis. DNA sequencing technology has enabled the discovery of genes causative of, or associated with, autism. Unsurprisingly, genetic heterogeneity goes hand-in-hand with the phenotypic heterogeneity for this condition; with causative genetic variation ranging from single base pair changes to complex chromosomal rearrangements in more than 100 different genes. This study captures a snapshot (201 individuals) of the autistic population (both clinically referred and self-referred) in Aotearoa New Zealand and documents a decade's research effort to refine diagnosis using a flexible and customised genome-wide sequencing approach. The diagnostic yield in this phenotypically disparate cohort was 12.9%, with an additional 15.9% of individuals harbouring 'likely causal' variants, providing the groundwork to tailor clinical, social, and educational care. Importantly, this study reveals the diagnostic utility of customised genetic screening for autism across a phenotypically diverse autistic population.

Keywords: Neurodevelopmental conditions; diagnostic yield; genome-wide sequencing; self-referred; whole exome sequencing; whole genome sequencing.

Figure 1.

Key cohort demographics. (A) Age of participants at time of registration (reported in 178 participants). (B) Reported ethnicity of participants. Participants could choose multiple ethnicities (reported in 176 participants). (C) Frequency of co-occurring self – or carer-reported conditions in participants (reported for 179 participants). Colour-coding categories adapted from ICD-11. For both ethnicity and co-occurring conditions, ‘Other’ refers to participants selecting ‘other’ as an answer, or to ethnicities/conditions present in two or fewer participants. ADHD, Attention Deficit Hyperactivity Disorder; GDD, Global Developmental Delay; Intellectual Disability; OCD, Obsessive Compulsive Disorder.

Figure 2.

Variants identified in the cohort. (A) Identified variants for all participants. Variants are classified as causal, likely causal or candidate. (B) Identified variants in female and male participants. 8/55 (14.6%) females and 18/146 (12.3%) males had a causal variant (P = 0.6450, Fisher’s exact test (two tailed)).