A New Integrated Newborn Screening Workflow Can Provide a Shortcut to Differential Diagnosis and Confirmation of Inherited Metabolic Diseases

Abstract Background: Current newborn screening (NBS) in China is mainly aimed at detecting biochemical levels of metabolites in the blood, which may generate false positive/negative results. To explore whether next-generation sequencing (NGS) for dried blood spots can increase the detecting rate of genetic disorders, we carried out a pilot study using NGS in 1,173 newborns who had been tested by traditional NBS. With a focus on inherited metabolic diseases (IMDs), our team investigated the current frequencies of genes related to common inherited metabolic diseases in this cohort. Methods: We designed an NGS panel of 573 genes related to severe diseases and performed NBS in 1,173 individuals who had been screened by tandem mass spectrometry (MS/MS) as well as for phenylalanine (Phe), thyroid-stimulating hormone (TSH), 17-α-hydroxyprogesterone (17-OHP), and glucose-6-phosphate dehydrogenase (G6PD) abnormalities in a traditional biochemical NBS conducted in September 2016. We compared the biochemical results to the genetic variants and investigated the carrier frequencies of 77 genes related to disorders by MS/MS in these newborns.Results: The biochemical results showed that four newborns (all male) were positive for G6PD by enzymatic assay, while the other biochemical findings including MS/MS, Phe, TSH and 17-OHP were negative. Genetic analysis results revealed that all the four newborns with positive G6PD values harbored hemizygous G6PD mutations. The NGS results also revealed an individual (ID 84123) carrying two SLC22A5 mutations (c.760C>T/p.R254* and c.1400C>G/p.S467C) common in Chinese patients with carnitine deficiency, which were later verified to be in trans, who was biochemically negative in 2016. The MS/MS results in 2019 showed free carnitine deficiency, consistent with the genetic analysis findings. The top five genes with the highest carrier frequencies in these newborns were PAH (1.77%), ETFDH (1.24%), MMACHC (1.15%), SLC25A13 (0.98%), and GCDH (0.80%). Conclusions: Our study provided data combing biochemical results with genetic variants in 1,173 newborns and confirmed a primary carnitine deficiency patient with false-negative biochemical results. This is also the first study to report the carrier frequencies of 77 IMD-causing genes in China.

Download Full-text

Pilot study of expanded newborn screening for 573 genes related to severe diseases in China: results from 1173 newborns

10.21203/rs.2.13332/v2 ◽

2019 ◽

Author(s):

Xiaomei Luo ◽

Yu Sun ◽

Feng Xu ◽

Jun Guo ◽

Lin Li ◽

...

Keyword(s):

Pilot Study ◽

Genetic Analysis ◽

Newborn Screening ◽

Genetic Variants ◽

Metabolic Diseases ◽

False Negative ◽

Dried Blood Spots ◽

Carnitine Deficiency ◽

Chinese Patients ◽

Inherited Metabolic Diseases

Abstract Background: Current newborn screening (NBS) in China is mainly aimed at detecting biochemical levels of metabolites in the blood, which may generate false positive/negative results. To explore whether next-generation sequencing (NGS) for dried blood spots can increase the detecting rate, we carried out a pilot study using NGS in 1,173 newborns who had been tested by traditional NBS. With a focus on inherited metabolic diseases (IMDs), our team investigated the current frequencies of genes related to common inherited metabolic diseases in this cohort. Methods: We designed an NGS panel of 573 genes related to severe diseases and performed NBS in 1,173 individuals who had been screened by tandem mass spectrometry (MS/MS) as well as for phenylalanine (Phe), thyroid-stimulating hormone (TSH), 17-α-hydroxyprogesterone (17-OHP), and glucose-6-phosphate dehydrogenase (G6PD) abnormalities in a traditional biochemical NBS conducted in September 2016. We compared the biochemical results to the genetic variants and investigated the carrier frequencies of 77 genes related to disorders by MS/MS in these newborns.Results: The biochemical results showed that four newborns (all male) were positive for G6PD by enzymatic assay, while the other biochemical findings including MS/MS, Phe, TSH and 17-OHP were negative. Genetic analysis results revealed that all the four newborns with positive G6PD values harbored hemizygous G6PD mutations. The NGS results also revealed an individual (ID 84123) carrying two SLC22A5 mutations (c.760C>T/p.R254* and c.1400C>G/p.S467C) common in Chinese patients with carnitine deficiency, which were later verified to be in trans, who was biochemically negative in 2016. The MS/MS results in 2019 showed free carnitine deficiency, consistent with the genetic analysis findings. The top five genes with the highest carrier frequencies in these newborns were PAH (1.77%), ETFDH (1.24%), MMACHC (1.15%), SLC25A13 (0.98%), and GCDH (0.80%). Conclusions: Our study provided data combing biochemical results with genetic variants in 1,173 newborns and confirmed a primary carnitine deficiency patient with false-negative biochemical results. This is also the first study to report the carrier frequencies of 77 IMD-causing genes in China.

Download Full-text

Expanded Newborn Screening for Inherited Metabolic Diseases

Nutrition Management of Inherited Metabolic Diseases ◽

10.1007/978-3-319-14621-8_2 ◽

2015 ◽

pp. 15-23

Author(s):

Erica L. Wright

Keyword(s):

Newborn Screening ◽

Metabolic Diseases ◽

Inherited Metabolic Diseases ◽

Expanded Newborn Screening

Download Full-text

SUMA Technology and Newborn Screening Tests for Inherited Metabolic Diseases in Cuba

Journal of Inborn Errors of Metabolism and Screening ◽

10.1177/2326409816661356 ◽

2016 ◽

Vol 4 ◽

pp. 232640981666135 ◽

Cited By ~ 3

Author(s):

Ernesto Carlos González Reyes ◽

Elisa M. Castells ◽

Amarilys Frómeta ◽

Ana Luisa Arteaga ◽

Lesley Del Río ◽

...

Keyword(s):

Newborn Screening ◽

Metabolic Diseases ◽

Screening Tests ◽

Inherited Metabolic Diseases

Download Full-text

Newborn Screening for Inherited Metabolic Diseases Using Tandem Mass Spectrometry in China: outcome and cost-utility analysis

10.21203/rs.3.rs-124404/v1 ◽

2020 ◽

Author(s):

Zixuan Zhao ◽

Chi Chen ◽

Xueshan Sun ◽

Duo ZHOU ◽

Xinwen Huang ◽

...

Keyword(s):

Mass Spectrometry ◽

Tandem Mass Spectrometry ◽

Newborn Screening ◽

Metabolic Diseases ◽

Life Time ◽

Cost Utility ◽

Acid Oxidation ◽

Cost Ratio ◽

Tandem Mass ◽

Inherited Metabolic Diseases

Abstract BackgroundFew studies in China have focused on economic evaluation of newborn screening(NBS) for inherited metabolic diseases (IMDs) by tandem mass spectrometry (MS/MS). This study assessed the total costs, benefits, benefit-cost ratio(BCR), cost-utility ratio(CUR) and incremental cost-utility ratio(ICUR) of NBS using MS/MS compared to non-screening group for the first time.MethodsThis study was conducted as a retrospective piece. Newborns who underwent MS/MS screening for IMDs from 2009 to 2018 were included. All records were extracted from a screening management system in NBS Center of Zhejiang province. All costs, including indirect cost, were discounted at a rate of 5% for the whole life-time. The putative benefit of clinical outcomes related to early-diagnosis through screening was assumed as improvements in quality of life and potential life expectancy in screening group.ResultsOf the 3,040,815 newborns screened, 26,297(0.86%) newborns were suspected positive after first-round screening and called back to take another MS/MS screening. 25,670(97.62%) of them followed the latter procedures and finally 735(2.86%) cases were diagnosed through gene sequence analysis. The most frequent cause of IMD was amino acid diseases(n=276), in most cases fatty acid oxidation disorders (n=248), followed by organic acidemias (n=211). The difference of QALYs ranged from 0.78-15.4. The CUR was CNY¥86,155.80/QALY in screening group and CNY¥303,9517.32/QALY in non-screening group. The ICUR was CNY¥-795,686.47/QALY, and the BCR was 1:8.11.ConclusionsNBS using MS/MS can be considered as cost-effective. Nationwide promotion of NBS using MS/MS deserves priority consideration and sufficient publicity.

Download Full-text