{Reference Type}: Case Reports
{Title}: Case report: Phenotype expansion and analysis of TRIO and CNKSR2 variations.
{Author}: Liu Y;Liang Z;Cai W;Shao Q;Pan Q;Liu Y;Liang Z;Cai W;Shao Q;Pan Q;
{Journal}: Front Neurol
{Volume}: 13
{Issue}: 0
{Year}: 2022
{Factor}: 4.086
{DOI}: 10.3389/fneur.2022.948877
{Abstract}: <B>UNASSIGNED: </B>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.<BR><B>UNASSIGNED: </B>Here, we reported two cases with TRIO variation from one family and three cases with CNKSR2 variation from another family. The family with TRIO 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 CNKSR2 family carries a novel hemizygous non-sense variant c.1282C>T (p. Arg428*). Concurrently, we identified a novel phenotype never reported in known pathogenic CNKSR2 variants, that hydrocephalus and widening lateral ventricle in a 6-year-old male of this family. Furthermore, the genotype-phenotype relationship for TRIO, CNKSR2, and RAC1 was explored through a literature review.<BR><B>UNASSIGNED: </B>The novel variants and unique clinical features of these two pedigrees will help expand our understanding of the genetic and phenotypic profile of TRIO- and CNKSR2-related diseases.