Biochemical, Molecular, and Clinical Characterization of Patients With Primary Carnitine Deficiency via Large-Scale Newborn Screening in Xuzhou Area

Zhou, Weili; Li, Huizhong; Huang, Ting; Zhang, Yan; Wang, Chuanxia; Gu, Maosheng

doi:10.3389/fped.2019.00050

Cited by 17 publications

(22 citation statements)

References 27 publications

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“…However, if maternal carnitine deficiency was included in the analysis, it could be concluded that carnitine deficiency was more common in the region. c.1400C>G in the SLC22A5 gene for PCD and c.1031A>G in the ACADS gene for SCADD were common mutations, consistent with previous reports 10 – 12 , 34 . However, of the 3 cases diagnosed with MCADD, 2 cases with dizygotic twins carried a homozygous c.985A>G (66.7%) mutation in the ACADM gene, so we think that the mutation frequency of c.985A>G seems to be overestimated in this study.…”

Section: Discussionsupporting

confidence: 92%

Spectrum analysis of inborn errors of metabolism for expanded newborn screening in a northwestern Chinese population

Zhang

Qiang

Song

et al. 2021

Sci Rep

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Expanded newborn screening facilitates early identification and intervention of patients with inborn errors of metabolism (IEMs), There is a lack of disease spectrum data for many areas in China. To determine the disease spectrum and genetic characteristics of IEMs in Xi'an city of Shaanxi province in northwest China, 146152 newborns were screening by MSMS from January 2014 to December 2019 and 61 patients were referred to genetic analysis by next generation sequencing (NGS) and validated by Sanger sequencing. Seventy-five newborns and two mothers were diagnosed with IEMs, with an overall incidence of 1:1898 (1:1949 without mothers). There were 35 newborns with amino acidemias (45.45%, 1:4176), 28 newborns with organic acidurias (36.36%, 1:5220), and 12 newborns and two mothers with FAO disorders (18.18%; 1:10439 or 1:12179 without mothers). Phenylketonuria and methylmalonic acidemia were the two most common disorders, accounting for 65.33% (49/75) of all confirmed newborn. Some hotspot mutations were observed for several IEMs, including PAH gene c.728G>A for phenylketonuria; MMACHC gene c.609G>A and c.567dupT, MMUT gene c.323G>A for methylmalonic acidemia and SLC25A13 gene c.852_855del for citrin deficiency. Our study provides effective clinical guidance for the popularization and application of expanded newborn screening, genetic screening, and genetic counseling of IEMs in this region.

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Section: Discussionsupporting

confidence: 92%

Spectrum analysis of inborn errors of metabolism for expanded newborn screening in a northwestern Chinese population

Zhang

Qiang

Song

et al. 2021

Sci Rep

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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%

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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“…The incidence of PCD in selected population was estimated at 1:8191 by incorporating second-tier genetic screening into NBS programs. The incidence is higher than that reported in most region of China [9,27,28]. Of course there may be regional differences, but our ndings suggest that the true incidence of PCD in China might be much underestimated.…”

Section: Discussioncontrasting

confidence: 58%

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

Lin

Zhang

Huang

et al. 2021

Preprint

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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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Biochemical, Molecular, and Clinical Characterization of Patients With Primary Carnitine Deficiency via Large-Scale Newborn Screening in Xuzhou Area

Cited by 17 publications

References 27 publications

Spectrum analysis of inborn errors of metabolism for expanded newborn screening in a northwestern Chinese population

Spectrum analysis of inborn errors of metabolism for expanded newborn screening in a northwestern Chinese population

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

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

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