SHANK3-anchored reverse phenotyping identifies a rare-variant-enriched cognitive-motor subgroup of autism

Rare deleterious variants in SHANK3 are established causes of autism spectrum disorder (ASD), but the extent to which they define a phenotypically and genetically coherent ASD subgroup remains unclear. Using the SPARK cohort, we identified 132 SHANK3 variant carriers; 108 had phenotype data and were compared with 47,555 non-carrier ASD cases. SHANK3 damaging variant carriers showed lower cognitive ability, poorer motor coordination, and delayed developmental milestones. Protein-truncating variant and deletion carriers showed similarly severe phenotypic profiles, whereas duplication carriers did not differ from non-carriers. A combined threshold of intelligence quotient (IQ) < 70 and impaired motor coordination (DCDQ total score) < 35 defined a discriminative cognitive-motor phenotype among cases meeting this cognitive-motor phenotype. Beyond SHANK3 , SLC6A1 was the only additional gene reaching false discovery rate significance, while pathway analyses implicated synaptic and chromatin-related processes. Phenotype-meeting cases did not show elevated ASD polygenic risk, supporting a rare-variant-enriched cognitive-motor subgroup within ASD.