26/07/2025
Can autism present in biologically distinct subtypes?
A new study in Nature Genetics suggests it can — identifying four robust phenotypic clusters, each with its own genetic fingerprint.
Using item-level data from over 5,000 autistic children in the SPARK cohort, researchers applied unsupervised clustering to 239 behavioural and developmental items from parent-report questionnaires, without relying on diagnostic scores or subscale totals.
🧩 They found four subtypes:
Social/Behavioural (37%) – High core autism traits (social communication and restricted behaviours), plus elevated ADHD, mood, and disruptive symptoms, but no developmental delay.
🔹 Genetically enriched for ADHD polygenic scores; rare mutations in genes linked to chromatin structure, DNA repair, and microtubule activity.
Moderate Challenges (34%) – Milder, balanced profile with low severity across domains.
🔹 Served as the reference group; no specific polygenic or rare variant enrichments.
Mixed ASD with Developmental Delay (19%) – Core symptoms plus language and cognitive delays, and elevated self-injury.
🔹 Higher burden of rare mutations in genes affecting neuronal firing and sodium channel activity; lower polygenic scores for cognition and educational attainment.
Broadly Affected (10%) – Severe difficulties across all domains: social, cognitive, behavioural, and emotional.
🔹 Genetically enriched for major depressive disorder; widespread rare variant impact with no dominant pathway, consistent with broad impairment.
🧬 Each subtype also showed distinct gene expression patterns across developmental stages and brain cell types, some prenatal, others postnatal, further supporting divergent biological underpinnings.
This is one of the clearest demonstrations to date that autism is not biologically monolithic, but rather, a construct encompassing multiple genetically and developmentally distinct profiles.
👉 Notably, the largest group showed clear overlap with ADHD traits and polygenic architecture, raising the possibility that ADHD research may also benefit from similar subtype-focused methodologies, helping move beyond broad diagnostic labels toward more precise, biologically grounded frameworks.
🔬 These findings offer robust support for the existence of distinct autism subtypes, each underpinned by specific genetic and developmental mechanisms, challenging the notion of autism as a single, uniform condition and opening the door to more biologically grounded classifications and targeted interventions.
📖 Litman et al. Nature Genetics (2025)
PMID: 40634707
If you are seeking clarity about Autism, we are here to support you
https://cambridgeadhdclinic.com/
