Abstract
RAC2 encodes Ras-related C3 botulinum toxin substrate 2, a member of the Rho family of GTPases that are essential for regulating cell signalling and actin cytoskeleton reorganisation. Heterozygous mutations causing dominant activating phenotype were first described in 2019. To date, the majority of reported patients have had severe combined immunodeficiency (SCID) and/or severe dis- ease in association with their combined immunodeficiency (CID) necessitating haematopoietic stem cell transplantation (HSCT).
We present clinical and laboratory features of 4 New Zealand patients from the same family with a novel heterozygous missense variant in RAC2 [c.62T>G, p.Ile21Ser(121S)].
The index patient (P1 - age 8 y, M) has a history of infectious gastroenteritis. Staphylococcal aureus conjunctivitis, recurrent otitis media and recurrent Herpes simplex virus (HSV)-1 cutaneous infections. His 2 siblings (P2 - age 9y, M; P3- age 6 y, F) and his mother (P4 age 42 y, F) all have a history of recurrent viral (HSV-1) and bacterial (Staphylococcal aureus. Streptococcal pyogenes) cutaneous infections and/or recurrent sinopulmonary infections that respond to empiric antimicrobial therapy. Affected family members have chronic lymphopenia involving predominantly CD4+ T (range 53-361 x 106/L) and B (range 20-181 x 106/L) cell compartments. P1, P2 and P3 all have CD4+ naïve (CD45RA+/CD62L+) T cells (range 40-60% of CD4+ T cells) and normal lymphocyte proliferative response to mitogens. P1, P2 and P3 all have reduced IgM but normal IgG and IgA. Antibody responses to protein antigens are preserved. P1 underwent diagnostic laboratory gene panel evaluation (Blueprint Genetics Primary Immunodeficiency Panel, v3) which identified a heterozygous missense variant I21S in RAC2. The variant has not been observed in a large reference population cohort (gnomAD). Sanger sequencing confirmed presence of the variant in the 3 siblings (P1, P2, P3) and their mother (P4). Affected individuals in this family all have neutrophil vacuolation and an abnormal neutrophil granulation pattern. Their neutrophils all had enhanced superoxide production in response to stimulation by fMLP and PMA as compared to healthy controls’. These findings suggest that RAC2 I21S is an activating mutation causing notable abnormalities in neutrophil morphology and NADPH oxidase activation similar to other recently reported mutations.
This novel mutation expands the phenotypic spectrum of RAC2 activating mutations. Clinical management of affected patients needs to be tailored to their phenotype and disease severity.