Molecular based newborn screening in Germany: Follow-up for cystinosis

Katharina Hohenfellner; Carsten Bergmann; Tobias Fleige; Nils Janzen; Siegfried Burggraf; Bernd Olgemöller; William A Gahl; Ludwig Czibere; Sonja Froschauer; Wulf Röschinger; Katharina Vill; Erik Harms; Uta Nennstiel

doi:10.1016/j.ymgmr.2019.100514

Molecular based newborn screening in Germany: Follow-up for cystinosis

Mol Genet Metab Rep. 2019 Sep 18:21:100514. doi: 10.1016/j.ymgmr.2019.100514. eCollection 2019 Dec.

Authors

Affiliations

¹ Department of Pediatrics, Pediatric Nephrology, RoMed Kliniken, Pettenkoferstr. 10, Rosenheim 83022, Germany.
² Department of Medicine, University Hospital Freiburg, Hugstetter Str. 55, Freiburg 79106, Germany.
³ Laboratory Becker & Colleagues, Führichstr. 70, Munich 81671, Germany.
⁴ Screening-Laboratory Hannover, Am Steinweg 11A/13B, Ronnenberg 30952, Germany.
⁵ Department of Clinical Chemistry, Hannover Medical School, Carl-Neuberg-str.1, Hannover 30625, Germany.
⁶ Formally Laboratory Becker, Olgemöller & Colleagues, Führichstr. 70, Munich 81671, Germany.
⁷ National Human Genome Research Institute, NIH, USA.
⁸ Cystinosis Foundation, Germany c/o Haus des Stiftens gGmbH, Landshuter Allee 11, Munich 80637, Germany.
⁹ Dr. v. Hauner Children's Hospital, Department of Pediatric Neurology and Developmental Medicine, LMU - University of Munich, Lindwurmstrasse 4, Munich 80337, Germany.
¹⁰ Formally University Hospital Münster, Children's Hospital, Albert-Schweitzer-Campus 1, Münster 48149, Germany.
¹¹ Screening Center, Bavarian Health and Food Safety Authority (LGL), Veterinaerstrasse 2, 85764 Oberschleissheim, Germany.

Abstract

Background: Newborn screening (NBS) programs for treatable metabolic disorders have been enormously successful, but molecular-based screening has not been broadly implemented so far.

Methods: This prospective pilot study was performed within the German NBS framework. DNA, extracted from dried blood cards was collected as part of the regular NBS program. As cystinosis has a prevalence of only 1:100,000-1:200,000, a molecular genetic assay for detection of the SMN1 gene mutation with a higher prevalence was also included in the screening process, a genetic defect that leads to spinal muscular atrophy (SMA). First tier multiplex PCR was employed for both diseases. The cystinosis screening employed assays for the three most common CTNS mutations covering 75% of German patients; in case of heterozygosity for one of these mutations, samples were screened by next generation sequencing (NGS) of the CTNS exons for 101 CTNS mutations. A detection rate of 98.5% is predicted using this approach.

Results: Between January 15, 2018 and May 31, 2019, 257,734 newborns were screened in Germany for cystinosis. One neonate was diagnosed with cystinosis, consistent with the known incidence of the disease. No false positive or false negatives were detected so far. Screening, communication of findings to parents, and confirmation of diagnosis were accomplished in a multi-disciplinary setting. This program was accomplished with the cooperation of hospitals, physicians, and parents. In the neonate diagnosed with cystinosis, oral cysteamine treatment began on day 18. After 16 months of treatment the child has no clinical signs of renal tubular Fanconi syndrome.

Conclusions: This pilot study demonstrates the efficacy of a molecular-based neonatal screening program for cystinosis using an existing national screening framework.

Keywords: Cystinosis; Efficacy; Follow-up; MS-MS, tandem mass spectroscopy; Molecular-based newborn screening; NBS, newborns screening; NGS, next generation sequencing; QA/QC, quality assurance, quality control; SMA, spinal muscular atrophy; SMN, survival motor neuron protein.