Case report: Phenotype expansion and analysis of and variations.

Introduction: TRIO and CNKSR2 have been demonstrated as the important regulators of RAC1. TRIO is a guanine exchange factor (GEF) and promotes RAC1 activity by accelerating the GDP to GTP exchange. CNKSR2 is a scaffold and adaptor protein and helps to maintain Rac1 GTP/GDP levels at a concentration conducive for dendritic spines formation. Dysregulated RAC1 activity causes synaptic function defects leading to neurodevelopmental disorders (NDDs), which manifest as intellectual disability, learning difficulties, and language disorders.

Case Presentation: Here, we reported two cases with variation from one family and three cases with variation from another family. The family with variation carries a novel heterozygous frameshift variant c.3506delG (p. Gly1169AlafsTer11), where a prenatal case and an apparently asymptomatic carrier mother with only enlarged left lateral ventricles were firstly reported. On the other hand, the family carries a novel hemizygous non-sense variant c.1282C>T (p. Arg428). Concurrently, we identified a novel phenotype never reported in known pathogenic variants, that hydrocephalus and widening lateral ventricle in a 6-year-old male of this family. Furthermore, the genotype-phenotype relationship for , and was explored through a literature review.

Conclusion: The novel variants and unique clinical features of these two pedigrees will help expand our understanding of the genetic and phenotypic profile of - and -related diseases.