Primary Immunodeficiencies:
immunological and genetic background in relation to clinical complications

Background.
Primary immunodeficiencies (PIDs) are rare diseases that affect the immune
system. Major issues for these diseases are
1. The lack of detailed knowledge of the (natural) course of disease in PID;
2. The need for improved diagnostics. This project will address both issues.

Project aims
1. To provide a more precise overview of prevalence, presenting symptoms,
referral routes, clinical complications and evolution during follow-up of PIDs
in The Netherlands by registration and analysis of prospective patient data
derived from (structured) routine patient care
2.To discover new genetic and immunophenotypic causes of PID by advanced
genetic analysis and by functional characterization of novel genetic causes of
PID. To implement improved diagnostic techniques to diagnose (genetic) causes
of PID and to collaborate in this respect with other consortia which are active
in or outside of the field of PID research.

Methods:
The study consist of a prospective follow up study in N=1000-1500 patients,
combined with a cross sectional study for genetic causes of PID in a subset of
N=200 patients. For certain aspects of the study, healthy family or houshold
members and/or friends of patients will be included (up to N=200).

Ad 1. Prospective follow up study. Data derived from routine patient care
(yearly follow up visits) will be entered into a database and analysed on a
yearly basis. In this part of the study, 600 patients will participate. Data
entered include medical history, physical examination, laboratory values,
radiological findings, and results from microbiological evaluation. Apart from
these data derived from routine medical care, patients will be asked to
complete a yearly questionnaire on quality of life issues. Data will be coded
and protected according to privacy guidelines.

Ad 2. Improved diagnostics. PID patients who lack a genetic diagnosis will be
entered in this part of the study. DNA and RNA will be analysed using next
generation sequencing. One part of the study will use a targeted array for all
known PID genes. Another part will use whole exome sequencing. The technique
used will depend on clinical presentation, the availability of affected family
members, and the descriptive diagnosis. Results from genetic analyses will be
combined with those of functional- and phenotypical analyses.

Ad 1. Prospective follow up study.
- Minimal burden: for patients an annual questionnair (30 minutes), healthy
controls are asked to fill out a questionnaire (15 minutes) once. Parents of
patients < 12 years can be asked to fill out a daily symptom record taking up a
approixmately 1 minute per day with a maximum of 7 extra questions once per
month. Controls > 18 years will be asked to donate blood (max. 20mL) once and
controls of IgA deficient patients < 18 years will be asked to donate blood
(max. 8 ml) once. Both groups are asked to donate noninvasive samples such as
saliva, faeces, skin and/or oro-/nasopharyngeal swabs (up to max. 5 times
annually in patients).

Ad 2. Improved diagnostics.
- The donation of extra blood during a venapuncture for standard (normal)
diagnostics (once). Alternative: the donation of a small amount of salive for
dna extraction.
- In some patients: the donation of a maximum of 4 extra blood samples per year
for a maximum of 5 years during venapunctures meant for standard care.

These are all considered minimal burdens associated with participation.

There are no direct benefits associated with participation.