Combined Immunodeficiency

Gene: RAC2

Green List (high evidence)

Immunodeficiency 73A with defective neutrophil chemotaxix and leukocytosis
2 unrelated individuals; mono-allelic; loss of function; One mouse model; functional studies

Both individuals carried a de novo heterozygous missense variant (p.Asp57Asn), resulting in an impaired GTP binding domain and loss of function.

Both individuals presented from birth with recurrent perirectal/ paratracheal abscesses, failure to heal surgical wounds, and the absence of pus in infected areas, in addition to leukocytosis and neutrophilia.
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Immunodeficiency 73C with defective neutrophil chemotaxis and hypogammaglobulinaemia
Only one family (2 sibs) has been reported; bi-allelic; loss of function; one mouse model.

They were homozygous for a nonsense variant p.Trp56Ter (W56X), resulting in premature termination and loss of function.

Clinical history included recurrent respiratory infections leading to the development of bronchiectasis, urticaria, factor XI deficiency, and hypothyroidism.

Their immunologic presentation showed a progression from selective IgA deficiency to Hypogammaglobulinaemia of all classes leading to a diagnosis of CVID.
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Immunodeficiency 73B with defective neutrophil chemotaxis and lymphopaenia
13 individuals from 8 unrelated families; mono-allelic; gain of function; multiple mouse models

Mono-allelic missense variants were reported in each individual (5 x De Novo) and resulted in a gain-of -function. (E62K, P34H, N92T, G12R)

These individuals typically presented in infancy with frequent infections, profound leukopaenia, lymphopaenia diarrhoea and hypogammaglobulinaemia.
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Amber- Immunodeficiency 73A with defective neutrophil chemotaxix and leukocytosis (Mono-allelic; loss of function)
Red- Immunodeficiency 73C with defective neutrophil chemotaxis and hypogammaglobulinaemia (Bi-allelic; loss of function)
Green- Immunodeficiency 73B with defective neutrophil chemotaxis and lymphopaenia (Mono-allelic; gain of function)

Created: 24 Aug 2021, 1:27 a.m. | Last Modified: 24 Aug 2021, 2:49 a.m.

Panel Version: 0.365

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Immunodeficiency 73A with defective neutrophil chemotaxix and leukocytosis MIM# 608203; Immunodeficiency 73C with defective neutrophil chemotaxis and hypogammaglobulinaemia MIM# 618987; Immunodeficiency 73B with defective neutrophil chemotaxis and lymphopaenia MIM# 618986

Publications

• 21167572
• 10758162
• 10072071
• 25512081
• 32542921
• 31919089

Mode of pathogenicity
Other