Genetic testing for APDS

How to arrange genetic testing for patients with APDS

APDS is caused by a rare point mutation in the PIK3CD gene. If you think that your patient has clinical presentation that resembles APDS, sequence analysis would be advisable. We can help you to arrange it.

If you have a collection of samples from a cohort of patients with relevant phenotypes, we could help you to screen these samples for the mutation that causes APDS.

Contact details:

Sergey Nejentsev MD, PhD
Department of Medicine, University of Cambridge
Level 5, Addenbrooke’s Hospital
Hills Road
Cambridge
CB2 0QQ
UK
E-mail: sn262@cam.ac.uk

Learn about APDS

An overview of APDS for clinicians who would like to learn more about the disease

Learn about APDS

Overview

Activated PI3 Kinase Delta Syndrome (APDS) is a newly discovered cause of Primary Immunodeficiency (PID) and Hyper-IgM Syndrome. Clinicians and scientists working on exome sequencing patients with primary immunodeficiency in Cambridge, United Kingdom, observed the same missense mutation in a critical signalling kinase that is particularly highly expressed in immune cells termed PI3 kinase delta. On further testing, this mutation has been shown to be absent from over 4,000 healthy control subjects’ genomes as well as unaffected first degree relatives of affected patients, indicating that this mutation is causative of these subjects’ immunodeficiency. One subject has been identified with an apparent spontaneous mutation causing APDS, indicating that a history of inherited immunodeficiency is not absolutely required for a patient to have APDS.

To date, 17 subjects have been identified as carrying the APDS mutation out of a total of ~240 screened genomes from PID patients. Thus, although rare in the general population APDS is reasonably common among patients with PID.

Clinical features

APDS is a clinically heterogenous condition with variable penetrance among affected individuals. The most common manifestation is susceptibility to recurrent infections with Streptococcus pneumoniae and Haemophilus influenzae, particularly of the ear, sinuses and lungs. Other common features include a rise in circulating IgM, a reduction in IgG2, and lymphopaenia. Many patients also have splenomegaly. A more detailed description of the symptoms and signs seen in APDS is described here.

Diagnosing APDS

At present, and for the foreseeable future, the only way to definitively diagnose APDS is with genetic testing. APDS is never a clinical diagnosis; genotyping the PIK3CD gene is mandatory to prove or exclude the diagnosis. Patients who should be considered for screening include:

  1. Any patient with Primary Immunodeficiency;
  2. Any patient with Hyper-IgM syndrome;
  3. First degree relatives of patients with proven APDS.

Contact details to arrange genetic testing of patients who fulfil one of these criteria can be found here.

Management of APDS

Until now, patients with APDS have been treated with standard regimes used in PID. Many patients (but not all) have received treatment with regular IVIG. Prompt and aggressive management of intercurrent infection with anti-microbials is mandatory. One subject with particularly penetrant and severe disease received a bone marrow transplant at the age of eight, following which his condition markedly improved – however, APDS comprises a spectrum of clinical severity, and not all patients have disease severe enough to justify bone marrow transplantation. More details about the treatment of APDS can be found here.

Future developments

Now that the underlying mutation in APDS has been described and cheap and rapid genotyping is available for other subjects, it may be possible to conduct clinical trials of treatments that interfere in a targetted fashion with the overactive kinase in these patients. Although certain small molecule inhibitors of PI3K-delta would not be an appropriate treatment for patients with PID in general, patients with APDS may represent a subset in whom these treatments may have particular efficacy.

The APDS patient registry

Learn about the APDS patient registry

The APDS patient registry is intended to advance the research and development of treatments, therapies and care for all those diagnosed with APDS.

APDS is currently thought to be a rare disease. Many specialist units will only look after a small number of patients – or perhaps only one – and if new treatments become available it could prove hard to spread information and knowledge rapidly to patients and doctors.

If potential new treatments are developed, this registry may be used to reach as many patients as possible to discuss participation in clinical studies.

We are in the process of conducting the consent, data protection and ethical review process necessary to begin recruitment to the APDS patient registry.

Please keep checking back!

The APDSyndrome team.

Major redevelopment underway!

The APDSyndrome.org website is being comprehensively refurbished to bring patients, clinicians and scientists more up to date and authoritative information.  I hope to have this site up and running in November 2016 with a load of new information.

Keep checking back!

Dr Edward Banham-Hall MRCP PhD – the APDSyndrome.org webmaster