Future of Dutch NGS-Based Newborn Screening: Exploring the Technical Possibilities and Assessment of a Variant Classification Strategy

Author:

Kiewiet Gea1,Westra Dineke2ORCID,de Boer Eddy N.1ORCID,van Berkel Emma2,Hofste Tom G. J.2,van Zweeden Martine2,Derks Ronny C.2,Leijsten Nico F. A.2,Ruiterkamp-Versteeg Martina H. A.2,Charbon Bart1,Johansson Lennart1ORCID,Bos-Kruizinga Janneke1,Veenstra Inge J.1,de Sain-van der Velden Monique G. M.3,Voorhoeve Els4ORCID,Heiner-Fokkema M. Rebecca5ORCID,van Spronsen Francjan6ORCID,Sikkema-Raddatz Birgit1,Nelen Marcel27

Affiliation:

1. Department of Genetics, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands

2. Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands

3. Section Metabolic Diagnostics, Department of Genetics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands

4. Centre for Health Protection, National Institute for Public Health and the Environment, 3720 BA Bilthoven, The Netherlands

5. Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands

6. Division of Metabolic Diseases, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands

7. Department of Genetics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands

Abstract

In this study, we compare next-generation sequencing (NGS) approaches (targeted panel (tNGS), whole exome sequencing (WES), and whole genome sequencing (WGS)) for application in newborn screening (NBS). DNA was extracted from dried blood spots (DBS) from 50 patients with genetically confirmed inherited metabolic disorders (IMDs) and 50 control samples. One hundred IMD-related genes were analyzed. Two data-filtering strategies were applied: one to detect only (likely) pathogenic ((L)P) variants, and one to detect (L)P variants in combination with variants of unknown significance (VUS). The variants were filtered and interpreted, defining true/false positives (TP/FP) and true/false negatives (TN/FN). The variant filtering strategies were assessed in a background cohort (BC) of 4833 individuals. Reliable results were obtained within 5 days. TP results (47 patient samples) for tNGS, WES, and WGS results were 33, 31, and 30, respectively, using the (L)P filtering, and 40, 40, and 38, respectively, when including VUS. FN results were 11, 13, and 14, respectively, excluding VUS, and 4, 4, and 6, when including VUS. The remaining FN were mainly samples with a homozygous VUS. All controls were TN. Three BC individuals showed a homozygous (L)P variant, all related to a variable, mild phenotype. The use of NGS-based workflows in NBS seems promising, although more knowledge of data handling, automated variant interpretation, and costs is needed before implementation.

Funder

ZonMW

Illumina

Publisher

MDPI AG

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