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

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.

SUBMITTER: Hohenfellner K

PROVIDER: S-EPMC6796768 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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

Hohenfellner Katharina K Bergmann Carsten C Fleige Tobias T Janzen Nils N Burggraf Siegfried S Olgemöller Bernd B Gahl William A WA Czibere Ludwig L Froschauer Sonja S Röschinger Wulf W Vill Katharina K Harms Erik E Nennstiel Uta U

Molecular genetics and metabolism reports 20190918

<h4>Background</h4>Newborn screening (NBS) programs for treatable metabolic disorders have been enormously successful, but molecular-based screening has not been broadly implemented so far.<h4>Methods</h4>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 ...[more]

PMID: 31641587

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Project description:BACKGROUND:Mucopolysaccharidoses (MPS) are lysosomal storage diseases in which mutations of genes encoding for lysosomal enzymes cause defects in the degradation of glycosaminoglycans (GAGs). The accumulation of GAGs in lysosomes results in cellular dysfunction and clinical abnormalities. The early initiation of enzyme replacement therapy (ERT) can slow or prevent the development of severe clinical manifestations. MPS I and II newborn screening has been available in Taiwan since August 2015. Infants who failed the recheck at recall were referred to MacKay Memorial Hospital for a detailed confirmatory diagnosis. METHODS:From August 2015 to November 2017, 294,196 and 153,032 infants were screened using tandem mass spectrometry for MPS I and MPS II, respectively. Of these infants, 84 suspected cases (eight for MPS I; 76 for MPS II) were referred for confirmation. Urinary first-line biochemistry examinations were performed first, including urinary GAG quantification, two-dimensional electrophoresis, and tandem mass spectrometry assay for predominant disaccharides derived from GAGs. If the results were positive, a confirmative diagnosis was made according to the results of leukocyte enzymatic assay and molecular DNA analysis. Leukocyte pellets were isolated from EDTA blood and used for fluorescent ?-iduronidase (IDUA) or iduronate-2-sulfatase (IDS) enzymatic assay. DNA sequencing analysis was also performed. RESULTS:Normal IDS and IDUA enzyme activities were found in most of the referred cases except for four who were strongly suspected of having MPS I and three who were strongly suspected of having MPS II. Of these infants, three with novel mutations of the IDS gene (c.817C?>?T, c.1025A?>?G, and c.311A?>?T) and four with two missense mutations of the IDUA gene (C.300-3C?>?G, c.1874A?>?C; c.1037 T?>?G, c.1091C?>?T) showed significant deficiencies in IDS and IDUA enzyme activities (<?5% of mean normal activity), respectively. Urinary dermatan sulfate and heparan sulfate quantitative analyses by tandem mass spectrometry also demonstrated significant elevations. The prevalence rates of MPS I and MPS II in Taiwan were 1.35 and 1.96 per 100,000 live births, respectively. CONCLUSIONS:The early initiation of ERT for MPS can result in better clinical outcomes. An early confirmatory diagnosis increases the probability of receiving appropriate medical care such as ERT quickly enough to avoid irreversible manifestations. All high risk infants identified in this study so far remain asymptomatic and are presumed to be affected with the attenuated disease variants.

Dataset Information

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

Publications

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

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