Comparing the Phenotypic and Genetic Differences Between Autistic Regression and Autism Without Regression Using the SPARK Cohort

Regression was identified in 43% of autistic individuals in the SPARK cohort, with other domain regression occurring later than language regression and 60% of skill regain within two years.

• Why it matters: Autistic regression’s biology is poorly understood, and distinguishing its phenotypic and genetic landscape from autism without regression is needed to clarify associated neurodevelopmental morbidity.
• What they did: In 51 633 SPARK participants, parental-reported regression and ages at regression/regain were analyzed, and rare damaging coding variants were tested with TADA in 1 107 Autreg and 974 Autnreg, followed by pathway enrichment; polygenic scores were compared and validated in larger SPARK genotyping data.
• The result: Autreg showed modest phenotypic differences but was associated with lower Vineland-3 Adaptive Behavior Composite scores and increased odds of epilepsy and intellectual disability (p<0.001), with TADA implicating pathways including nucleotide catabolism, transcription, and focal adhesion and highlighting PTEN; schizophrenia PGS explained 0.087% of variance.