ARPC1B deficiency

ARPC1B deficiency is a rare primary immunodeficiency disorder characterised by dysfunction of the ARP2/3 protein complex subunit 1B (ARPC1B), a scaffolding protein involved in actin polymerisation in cells. This dysfunction of the cellular actin-cytoskeletal pathway leads to recurrent infections and autoinflammation, and to patients’ T cells being unable to extend lamellipodia upon T-cell receptor (TCR) stimulation to allow cell migration and assemble an immunological synapse.

The main features of ARPC1B deficiency include:

• combined immunodeficiency with predisposition to severe, recurrent infections, including opportunistic infections;
• natural killer (NK) cell dysfunction, leading to recurrent viral infections;
• thrombocytopaenia with mild platelet dysfunction;
• vasculitis;
• arthritis;
• atopic dermatitis;
• autoinflammatory features, such as prolonged fever; and
• potential radiosensitivity with predisposition to malignancies.

Laboratory tests will show eosinophilia with increased levels of IgE and/or IgA. Lymphocyte subsets will show T-cell lymphopaenia and low numbers of naive T cells.

ARPC1B deficiency is caused by biallelic loss-of-function pathogenic variants in the ARPC1B gene. The gene encodes ARPC1B, which is a key molecule in cytoskeletal dynamics, essential for immune cell function.

Patients with null variants (typically frameshift, nonsense and splice variants) with complete loss of ARPC1B protein present early in life with recurrent infections and prolonged bleeding time. Homozygous missense deleterious variants disrupt the WD40 domain of ARPC1B, which is required for actin polymerisation.

There is a recognised Nepalese founder variant (c.64+2T>A).

ARPC1B deficiency can be diagnosed following clinical evaluation or through newborn blood spot screening using the T-cell receptor excision circles assay. Where either is suggestive of T-cell lymphopenia, laboratory evaluation is required. Patients may have a family history of immunodeficiency.

Other diagnostic criteria include:

• full blood count showing reduced lymphocyte count;
• eosinophilia;
• lymphocyte subset testing showing absent or very low levels of T cells, particularly CD4 naive T cells;
• reduced immunoglobulin levels with impaired antibody responses (raised IgA levels have also been described);
• T-cell proliferation assay showing impaired response; and
• absent or low ARPC1B protein expression by flow cytometry.

Genomic testing confirms the diagnosis and differentiates ARPC1B deficiency from other genetic causes of immunodeficiency.

For information about testing, see ‘Infant or child with severe, recurrent, persistent and/or unusual infections‘.

ARPC1B deficiency may be identified before any symptoms appear, for example through the Generation Study. Confirmation of the diagnosis will require referral to clinical immunology services. Please refer to the local pathway for your region for this condition.

ARPC1B deficiency is a rare primary immunodeficiency caused by biallelic pathogenic genetic variants in the ARPC1B gene. It is inherited in an autosomal recessive pattern.

A family history should be taken, and parents and other potentially affected family members should be identified and screened as appropriate. Note that de novo variants may also arise, and that heterozygous carriers are not thought to be symptomatic.

• If both parents are carriers of an autosomal recessive condition, with each pregnancy there is a:
  • 1-in-4 (25%) chance of the child inheriting both gene copies with the pathogenic variant and therefore being affected;
  • 1-in-2 (50%) chance of the child inheriting one copy of the gene with the pathogenic variant and one normal copy, and therefore being a healthy carrier themselves; and
  • 1-in-4 (25%) chance of the child inheriting both normal copies and being neither affected nor a carrier.

If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

ARPC1B deficiency is a multi-system condition and requires specialised multidisciplinary care.

Immediate management principles involve treating infection and the prevention of opportunistic infections. This includes:

• no live vaccinations;
• aggressive treatment of infections, including with anti-fungal and anti-viral agents;
• immunoglobulin replacement therapy;
• platelet transfusion with irradiated cytomegalovirus negative blood products if there is severe bleeding;
• topical emollients and corticosteroids; and
• monitoring and screening for thrombocytopaenia and malignancy.

The primary curative treatment is haematopoietic stem cell transplantation (HSCT). This involves replacing stem cells from the patient’s bone marrow with that of a compatible donor. Patients who receive allogeneic HSCT soon after birth tend to have the best outcomes with fewer complications. Five-year survival rates are >90% if HSCT is begun when the patient is less than three months old. However, this survival rate declines with increasing age of transplantation and presence of active infections at the time of transplant. Patients require long-term monitoring following HSCT to assess immune reconstitution and monitor for potential complications.

ARPC1B deficiency may be identified before any symptoms appear, for example through the Generation Study. Management of these individuals may differ from those presenting symptomatically.

For clinicians

• OMIM: 617718 Immunodeficiency 71 with inflammatory disease and congenital thrombocytopenia

References:

• Somech R, Lev A, Lee YN and others. ‘Disruption of thrombocyte and T lymphocyte development by a min ARPC1B‘. The Journal of Immunology 2017: volume 199, issue 12, pages 4,036–4,045. DOI: 10.4049/jimmunol.1700460
• Vásquez-Echeverri E, Yamazaki-Nakashimada MA, Venegas Montoya E and others. ‘Is your kid actin out? A series of six patients with inherited actin-related protein 2/3 complex subunit 1B deficiency and review of the literature‘. The Journal of Allergy and Clinical Immunology in Practice 2023: volume 11, issue 4, pages 1,261–1,280.e8. DOI: 10.1016/j.jaip.2022.12.045

For patients

• Immunodeficiency UK