Genetic Testing for IEIs in the Netherlands
Genetic testing for inborn errors of immunity (IEI) in the Netherlands is performed at most of the University Medical Centers. The most commonly used techniques include whole-exome sequencing (WES) and (short- and long-read) whole-genome sequencing (WGS). Sanger sequencing is used in some centers for the targeted analysis of familial genetic variants or for the analyses of a single gene instead of a panel of genes.
In the Netherlands, WES/WGS analyses are typically based on a predefined IEI gene panel. The minimum required content of this national gene panel is determined collectively during the national PID (Primary Immunodeficiency) genetics committee, which takes place four times per year. This multidisciplinary meeting includes clinical geneticists, clinical laboratory geneticists, pediatric immunologists, and clinical immunologists, who jointly decide which genes must be included based on genes listed by the IUIS, and current scientific and clinical evidence. Depending on the clinical phenotype, different gene panels can be requested, e.g.:
- Primary immunodeficiency (PID)
- Severe combined immunodeficiency (SCID)
- Autoinflammatory diseases
- Hemophagocytic lymphohistiocytosis (HLH)
- Bone marrow failure
- Early onset enteropathy/congenital diarrhea
Basic health insurance is mandatory in the Netherlands. However, genetic testing is reimbursed only when medically indicated and initiated through a referral by a physician. For individuals aged 18 years and older, a statutory deductible applies, whereas children under the age of 18 are exempt from any deductible.
Pre-test counselling is provided by a clinical geneticist, a pediatrician or an immunologist with expertise in genetics. The specialist ordering the test is responsible for obtaining informed consent.
Genetic laboratories report pathogenic or likely pathogenic variants, as well as variants of uncertain significance (VUS) that correspond to the patient’s clinical presentation. Genetic results can be reviewed in a multidisciplinary team meeting, where clinicians and laboratory experts jointly integrate genetic data with clinical features, laboratory findings, and family history to reach a diagnostic interpretation.
When genetic findings remain inconclusive, or when a VUS requires further clarification, national or international laboratories may be consulted for functional testing e.g. via the “list of functional testing” (https://ern-rita.org/working-group/molecular-testing/) of the European reference network RITA (https://ern-rita.org/).
Newborn screening for SCID
From April 2018 to December 2020, a pilot study for newborn screening for Severe Combined Immunodeficiency (SCID) was conducted in three provinces in the Netherlands. As of January 1, 2021, SCID screening using T-cell receptor excision circles (TRECs) has been incorporated into the Dutch national newborn screening program.
Abnormal screening results are communicated to parents by their general practitioner, after which the child is referred to a pediatric immunologist at one of the academic hospitals. If laboratory results indicate Tcell lymphopenia, a genetic test is offered to investigate the underlying cause.
Report prepared by:
Dr. Hanna IJspeert and Dr. Lars van der Veken (on behalf of the Dutch PID genetics committee)
