Identification of homozygous RAPGEF1 variant in patients with neuropsychiatric phenotype
The two siblings (IV.2 and IV.3) of a consanguineous family of Pakistani descent showed moderate intellectual disability, mood swings from a depressive to a jolly mood, repetitive behavior, visual impairment and no speech development in one individual (IV.3) (Figure 1 (A) and (C)). By using whole exome sequencing on one of the patients (IV.2) and the father (III.4), we detected the missense variant c.423G>A (NM_198679.1, NP_941372.1:p.(M141I)) in the RAPGEF1 gene. Targeted PCR and subsequent Sanger sequencing confirmed that this variant was homozygous in the patient and heterozygous in the father, matching a presumed recessive inheritance mode (Figure 1 (B)).
RAPGEF1 encodes a RAP guanine nucleotide exchange factor (OMIM#600303). The expression of this gene starts early in mice embryos where it reaches its climax by E15.5 with enrichment in the murine forebrain (https://www.ebi.ac.uk/gxa/home). The variant identified in this gene has a very low frequency in the population databases, is predicted to be pathogenic by various algorithms (Figure 2 (A)) and to cause an alteration of a conserved amino acid, which is located in a protein domain (Figure 2 (B) and (C)). The structural modeling of RAPGEF1 indicates a dramatic decrease of protein stability, which we propose to account for a dysfunction in the patients (Figure 2 (D)). Interestingly, the protein-protein interaction network plus KEGG pathway analysis reveals three functional modules in which RAPGEF1 plays important roles (Figure 2 (E)).