Distinct sub-clusters of developmental disorder-associated variants in the switch II region of RAC1.

Activating (N-terminal) vs dominant-negative (C-terminal) variants in switch II domain

Fifteen new patients with switch II RAC1 variants define two phenotypically and mechanistically distinct subclusters: the N-terminal subgroup (Q61–R68) has activating variants associated with normocephaly, while the C-terminal subgroup (P69–Q74) has dominant-negative variants associated with microcephaly. Cell-based assays and a Drosophila model confirmed opposite effects on RAC1 signaling and neuronal morphology, providing direct utility for VUS interpretation.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The demonstration that two variants in the same RAC1 functional domain have opposing effects with distinct phenotypes underscores the need for fine mapping to interpret missense VUS. A switch II RAC1 variant cannot be interpreted without knowing its precise position within this domain.

Clinical impact: 2/3 · Evidence quality: 2/3 · Novelty: 2/2 · Sample size: 0/1 · Journal quality: 1/1 → Total: 7/10