FGD1 encodes a guanine nucleotide exchange factor (GEF) that stimulates the GDP-GTP exchange of the Rho GTPase Cdc42. When activated by FGD1, Cdc42 participates in multiple cellular processes including RUNX2 mediated osteoblast differentiation, neuronal polarity, extracellular matrix remodeling and cytoskeleton remodeling.
Reported pathogenic variants in FGD1 are loss-of-function variants, mostly truncating variants (around 65%). In the largest study reported to date, they comprised missense (≈ 35%), nonsense (≈ 10%), frameshift (≈ 26%) and splice-site (≈ 18%) variants in addition to a few intragenic and large-scale deletions (≈ 10%), and one case of intragenic duplication. These variants were mostly inherited from a carrier mother and occurred de novo in a minority of individuals (≈ 11%). To date, no hotspot of variants has been reported and no genotype-phenotype correlation has been highlighted.
Pathogenic variants may be detected by FGD1 targeted analysis when the diagnosis is clinically obvious or strongly suspected, or by analysis of a panel of genes dedicated to congenital malformations and/or neurodevelopment problems. However, nowadays, they are more often detected by pangenomic analysis such as exome or whole genome sequencing. In case of a negative result although the diagnosis is obvious, the molecular lab must be aware of the possibility of intragenic or large-scale duplications and use an appropriate method of detection.
FGD1