Key points are not available for this paper at this time.
Abstract 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.
Udeshi et al. (Fri,) studied this question.