At the Norwegian National Unit for Newborn Screening in Oslo, Dr. Asbjørg Stray-Pedersen has lead a research programme integrating next generation sequencing in newborn screening. In January 2018, screening for severe combined immunodeficiency (SCID) and other severe T cell deficiencies became national in Norway. On June 11, 2018, they detected their first SCID patient, and within 2 days they had the molecular diagnosis which had direct implications for deciding the appropriate treatment, involving a complete cure via bone marrow transplantation.
Newborn screening (NBS) commonly involves taking a blood drop from a pinprick of the newborn baby’s heel and applying it to a piece of filter paper. Small, 3 mm discs are punched from the blood spots to detect a variety of rare but potentially serious genetic disorders such as phenylketonuria (PKU), cystic fibrosis, and congenital hypothyroidism. If a disorder is identified, early treatment can prevent permanent organ damage or death.
With genetic tests becoming more common, a wide variety of tests may use the blood collected by this method. One such disorder is SCID, the most severe form of primary immunodeficiencies. Babies with this disorder, popularly known as “bubble baby disease”, are extremely vulnerable to infectious diseases, requiring them to stay within a sterile environment. The condition is the result of a highly compromised immune system to the extent that it is almost absent. If untreated, babies with this condition may die within one year due to infections, unless they have undergone successful hematopoietic stem cell transplantation.
Currently we know of more than 40 different genes in which mutations lead to a form of SCID or severe T cell deficiency, and a further 300 genes that contribute to other forms of primary immunodeficiencies.
Newborn screening in Norway
Newborns across Norway are now offered screening for 25 rare, congenital disorders for which early treatment is vital. The Norwegian newborn screening program includes testing for 2 endocrinological conditions, 21 metabolic disorders, SCID and other severe T-cell deficiencies, and cystic fibrosis*.
The Norway lab heel prick test approach follows 2 main steps: First a biomarker test such as biochemical measures, then secondly sequencing the disease genes using DNA the same filter card to quickly confirm the disorder in the child.
In SCID screening, the first measures a DNA product resulting from T-cell development, (T-cell Receptor Excision Circles)1. This TREC test is run using a quantitative PCR testing approach.
If the TREC result falls below a standard threshold, a second step is performed, using next generation gene panel sequencing on the same DNA-extract from the newborn screening filter card punch, using a custom, 160-gene panel containing all known disease genes for SCID and T cell deficiencies, cystic fibrosis, and the metabolic disorders included in the screening, plus genes for disorders belonging to the recommended US´ NBS disorders, and genes for disorders expected to be included in the near-future NBS programmes. Crucially, the gene results are delivered within 2 days. This enables the fast response which is so critical to save a SCID baby’s life.
The approach has also been adopted and published by King Faisal Specialist Hospital, Riyadh2.
“Last week we identified the first SCID patient, and within 2 days we had the molecular diagnosis which will have direct implications for treatment and preconditioning regimen prior to bone marrow transplantation.” – Dr Asbjørg Stray-Pedersen
Learn more about human genetic analysis here.
1. T-cell receptor and K-deleting recombination excision circles in newborn screening of T- and B-cell defects: review of the literature and future challenges. Chiarini, M et al 2013
2. High incidence of severe combined immunodeficiency disease in Saudi Arabia detected through combined T Cell Receptor Excision Circle and next genreration sequencing of newborn dried spots Al-Mouse H et al 2018 doi: 10.3389/fimmu.2018.00782