Screening 3.4 million newborns for primary carnitine deficiency in Zhejiang Province, China

Lin, Yiming; Xu, Hao; Zhou, Duo; Hu, Zhenzhen; Zhang, Chao; Hu, Lingwei; Yu, Zhen; Zhu, Lin; Lü, Bin; Zhang, Ting; Huang, Xinwen

doi:10.1016/j.cca.2020.04.039

Cited by 26 publications

(39 citation statements)

References 31 publications

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“…Based on NBS including second-tier genetic screening, the incidence of PCD in the selected population was estimated at 1:8191. This incidence is higher than that reported in most other regions of China [9,22,23]. Although there may be regional differences, our findings suggest that the true incidence of PCD in China might be underestimated.…”

Section: Discussioncontrasting

confidence: 72%

“…The designed primers were run through BLAT and modified when necessary to avoid pseudogene amplification. The designed primers cover nearly all the most common SLC22A5 gene mutation sites, based on the mutation frequencies reported in previous studies [5,9,24,26,28,29] and a local mutation database (Additional file 1: Table S1). Genotyping was performed using the MassARRAY platform according to the manufacturer's instructions.…”

Section: Multiplex Primary Carnitine Deficiency Assay Design and Genomentioning

confidence: 99%

“…Although some patients appear to be asymptomatic, PCD is a potentially lethal disease, and recent studies have shown that untreated PCD is associated with sudden death [7,8]. Fortunately, with timely treatment, the long-term prognosis is favourable, as most symptoms are reversible [9].…”

Section: Introductionmentioning

confidence: 99%

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Increased detection of primary carnitine deficiency through second-tier newborn genetic screening

Lin¹,

Zhang²,

Huang³

et al. 2021

Orphanet J Rare Dis

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Background Newborn screening for primary carnitine deficiency (NBS) is commonly implemented worldwide; however, it has poor sensitivity. This study aimed to evaluate the feasibility of improving screening by including a second-tier genetic assay. Results An Agena iPLEX assay was developed to identify 17 common SLC22A5 mutations in Chinese populations and was applied in NBS as a second-tier screening. From January 2017 to December 2018, 204,777 newborns were screened for PCD using tandem mass spectrometry. A total of 316 (0.15%) residual NBS-positive specimens with low free carnitine (C0) levels were subjected to this second-tier screening. The screening identified 20 screen-positive newborns who harboured biallelic mutations in theSLC22A5 gene, 99 carriers with one mutation, and 197 screen-negative newborns with no mutations. Among the 99 carriers, four newborns were found to have a second disease-causing SLC22A5mutation by further genetic analysis. Among the 197 screen-negatives were four newborns with persistently low C0 levels, and further genetic analysis revealed that one newborn had two novel SLC22A5 pathogenic variants. In total, 25 newborns were diagnosed with PCD, for a positive predictive value of 7.91% (25/316). Based on these data, we estimate the incidence of PCD in Quanzhou is estimated to be 1:8191.Thirteen distinct SLC22A5 variants were identified, and the most common was c.760C > T, with an allelic frequency of 32% (16/50), followed by c.1400C > G (7/50, 14%), and c.51C > G (7/50, 14%). Conclusion Data from this study revealed that 24% (6/25) of PCD cases would have been missed by conventional NBS. This high-throughput iPLEX assay is a powerful tool for PCD genotyping. The addition of this second-tier genetic screening to the current NBS program could identify missed PCD cases, thereby increasing PCD detection. However, further studies are needed to optimise the workflow of the new screening algorithm and to evaluate the cost-effectiveness of this screening approach.

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Section: Discussioncontrasting

confidence: 72%

Section: Multiplex Primary Carnitine Deficiency Assay Design and Genomentioning

confidence: 99%

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Increased detection of primary carnitine deficiency through second-tier newborn genetic screening

Lin¹,

Zhang²,

Huang³

et al. 2021

Orphanet J Rare Dis

Self Cite

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“…For new identi ed patients, genetic testing was performed by the Genetic Diagnostic Laboratory at Children's Hospital, Zhejiang University School of Medicine (Hangzhou, Zhejiang, China). Target next-generation sequencing (NGS) was done as previously described [11], all potentially pathogenic variants identi ed through NGS were validated by Sanger sequencing. One hundred healthy newborns who were screened negative for BKTD were selected to assess variant frequencies in normal controls.…”

Section: Genetic Diagnosis and Data Analysismentioning

confidence: 99%

C4OH is a Potential Screening Marker - A Multicenter Retrospective Study of Patients with Beta-Ketothiolase Deficiency in China

Lin

Yang

Yang³

et al. 2020

Preprint

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Background: Beta-ketothiolase deficiency (BKTD) is an autosomal recessive disorder caused by biallelic mutations in ACAT1 that affects both isoleucine catabolism and ketolysis. Scant information is available regarding the incidence, newborn screening (NBS), and mutational spectrum in China.Methods: We collected NBS, biochemical, clinical, and ACAT1 mutation data from 18 provinces or municipalities in China between January 2009 and May 2020, and systematically assessed all available published Chinese BKTD patients data.Results: Totally 16,088,190 newborns were screened and 14 were identified through NBS, with an estimated incidence of 1 per 1 million newborns in China. Twenty-nine patients were genetically diagnosed as BKTD and 12 patients were newly identified. Most patients showed typical blood acylcarnitine and urinary organic acid profiles. In particular, almost all patients (15/16, 94%) showed elevated C4OH levels. Eighteen patients presented acute metabolic decompensations and displayed variable clinical symptoms. The acute episodes of 9 patients were triggered by infections, diarrhea, and vaccination. About two thirds of patients have favorable outcomes, one showed developmental delay, while three had died. Twenty-seven distinct variants were identified in ACAT1, among which 5 were found to be novel.Conclusion: This study presented the largest series of BKTD cohort in China. Our results indicated that C4OH is a useful marker for the detection of BKTD. The performance of BKTD NBS could be improved by adding C4OH to the current panel of C5OH and C5:1 markers in NBS. The mutational spectrum and molecular profiles of ACAT1 in Chinese population were expanded with 5 newly identified variants.

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“…Although some patients appear to be asymptomatic, PCD is a potentially lethal disease and recent studies have shown that untreated PCD is associated to episodes of sudden death [7,8].Fortunately, the long-term prognosis is favourable with timely treatment as most symptoms are reversible [9]. Given the potential severity of PCD and the availability of effective treatment, PCD has been included in many newborn screening (NBS) programs worldwide [10][11][12].Tandem mass spectrometry (MS/MS) is mainly used in NBS for PCD, affected newborns can be detected by measuring free carnitine (C0) levels in dried blood spot.…”

Section: Introductionmentioning

confidence: 99%

Increased primary carnitine deficiency detection through second-tier newborn genetic screening

Lin

Zhang

Huang

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Background Newborn screening for (NBS) for primary carnitine deficiency (PCD) is widely implemented worldwide, however, with poor sensitivity. This study aimed to evaluate the feasibility of improving the screening using second-tier genetic assay. Methods An Agena iPLEX assay was developed to identify 17 SLC22A5 mutations in the Chinese populations, then this assay was applied in NBS for second-tier mutation screening of newborns with low free carnitine (C0) levels. Results The Agena iPLEX assay was successfully established and performed in second-tier genetic screening. A total of316 (0.15%) residual NBS-positive specimens were subjected to second-tier genetic screening. Twenty screen-positive newborns harbored biallelic mutations in SLC22A5 gene, 99 screen-carriers with one mutation, and 197 screen-negative newborns with no mutation identified. Among 99 carriers, four newborns were found with a second disease-causing SLC22A5mutation by further genetic analysis. Four newborns were found with persistently low C0 levels among 197 screen-negatives, further genetic analysis revealed that one newborn with two novel SLC22A5 pathogenic variants. In total, 25 newborns were diagnosed with PCD, for a positive predictive value of 7.91% (25/316). The incidence of PCD in Quanzhou was estimated at 1:8191. Conclusion Data from this study revealed that 24% (6/25) of PCD cases would have been missed by conventional NBS. The high throughput iPLEX assay is a powerful tool for PCD genotyping. The incorporation of second-tier genetic screening into NBS program could increase PCD detection, however, further studies are needed to optimize the workflow of new screening algorithm.

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Screening 3.4 million newborns for primary carnitine deficiency in Zhejiang Province, China

Cited by 26 publications

References 31 publications

Increased detection of primary carnitine deficiency through second-tier newborn genetic screening

Increased detection of primary carnitine deficiency through second-tier newborn genetic screening

C4OH is a Potential Screening Marker - A Multicenter Retrospective Study of Patients with Beta-Ketothiolase Deficiency in China

Increased primary carnitine deficiency detection through second-tier newborn genetic screening

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