Pancytopenia, Recurrent Infection, Poor Wound Healing, Heterotopia of the Brain Probably Associated with A Candidate Novel de Novo CDC42 Gene Defect: Expanding the Molecular and Phenotypic Spectrum

Abstract

: CDC42 (cell division cycle protein 42) belongs to the Rho GTPase family that is known to control the signaling axis that regulates several cellular functions, including cell cycle progression, migration, and proliferation. However, the functional characterization of the CDC42 gene in mammalian physiology remains largely unclear. Here, we report the genetic and functional characterization of a non-consanguineous Saudi family with a single affected individual. Clinical examinations revealed poor wound healing, heterotopia of the brain, pancytopenia, and recurrent infections. Whole exome sequencing revealed a de novo missense variant (c.101C > A, p.Pro34Gln) in the CDC42 gene. The functional assays revealed a substantial reduction in the growth and motility of the patient cells as compared to the normal cells control. Homology three-dimensional (3-D) modeling of CDC42 revealed that the Pro34 is important for the proper protein secondary structure. In conclusion, we report a candidate disease-causing variant, which requires further confirmation for the etiology of CDC42 pathogenesis. This represents the first case from the Saudi population. The current study adds to the spectrum of mutations in the CDC42 gene that might help in genetic counseling and contributes to the CDC42-related genetic and functional characterization. However, further studies into the molecular mechanisms that are involved are needed in order to determine the role of the CDC42 gene associated with aberrant cell migration and immune response.

The clinical phenotype with gastrostomy and abdominal wall infection in a pediatric patient with Takenouchi-Kosaki syndrome due to a heterozygous c.191A > G (p.Tyr64Cys) variant in CDC42: a case report

“…The ever-increasing use of the next-generation sequencing (NGS) approach enabling uncovering molecular genetic diagnosis underpinning the clinical symptomatology has led to better recognition of variable CDC42 gene alterations and the spectrum of clinical immunophenotypes. A variable degree of immunodeficiency has been primarily linked to the variants affecting the switch II domain in the CDC42 gene ( Takenouchi et al, 2015 ; Takenouchi et al, 2016 ; Martinelli et al, 2018 ; Motokawa et al, 2018 ; Uehara et al, 2019 ; Bucciol et al, 2020 ; Asiri et al, 2021 ; Ishikawa et al, 2021 ; Kashani et al, 2021 ; Santoro et al, 2021 ). In the reported patients, the antibody immune response ranged from normal referenced serum immunoglobulin levels to panhypogammaglobulinemia affecting the production of all immunoglobulin isotypes with low specific antibody response to diphtheria, tetanus, and mumps vaccine antigens.…”

Congenital disorder of glycosylation with defective fucosylation 2 (FCSK gene defect): The third report in the literature with a mild phenotype

“…The selected structure was optimized using UCSF Chimera version1 via the AMBERff14 SB force field3D. The overall quality of the model was evaluated using an ERRAT plot (Asiri et al, 2021 ).…”

Case Report: Bi-allelic missense variant in the desmocollin 3 gene causes hypotrichosis and recurrent skin vesicles

“…All disease-causing variants reported in the HGMD and ClinVar were considered. Furthermore, all variants in the gnomAD database with a minor allele frequency of less than 1% were considered ( Alhamoudi et al, 2020 ; Asiri et al, 2021 ).…”