Arar, Claude Edel (2022) Preparing for a new two-tier strategy in Newborn Screening for Inborn Metabolic Diseases: Follow-up biochemical confirmation of abnormal first-tier Next-Generation Sequencing results. thesis, Medicine.
Full text available on request.Abstract
Expanding the current dried blood spot (DBS)-based newborn screening (NBS) to more treatable inborn metabolic diseases (IMDs) is crucial, to prevent morbidity and mortality in more children. This approach is limited by a lack of trustworthy DBS-biomarkers and relatively high false-result rates. Instead, using a genetic-based first-tier test such as Next-Generation Sequencing (NGS) can overcome this, provide more precise results and include more IMDs. However, use of biochemical markers for follow-up is still required to confirm the clinical relevance of NGS-variants that are challenging to interpret, especially in the absence of symptoms. To systematize this two-tier approach, an action plan following abnormal or unclear first-tier NGS results is proposed for 100 treatable IMDs, using a second-tier biochemical-based confirmation in DBS or another biomaterial, if available, to reach diagnosis. Biochemical analysis in DBS is feasible for 58/100 selected IMDs and can be readily used as a second-tier test. Referral to a metabolic committee is needed for biochemical confirmation in other biomaterials for 33/100 and for other investigations for 9/100 IMDs. Last, 15 samples from deceased children from the BURDEN study were used to apply this strategy. The genetic variants and biochemical profiles were gathered aiming to reach diagnosis but failed to identify a causative IMD. Such a two-tier strategy theoretically allows safe triage of patients to avoid false results and expand NBS but further investigations in more samples are required.
| Item Type: | Thesis (UNSPECIFIED) |
|---|---|
| Supervisor name: | Heiner-Fokkema, Dr. Rebecca and van Spronsen, Prof. dr. Francjan |
| Faculty: | Medical Sciences |
| Date Deposited: | 16 May 2023 12:58 |
| Last Modified: | 16 May 2023 12:58 |
| URI: | https://umcg.studenttheses.ub.rug.nl/id/eprint/3521 |
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