Primary carnitine deficiency: Estimation of prevalence in Chinese population and insights into newborn screening

Xiaoshan Ji; Yanzhuang Ge; Qi Ni; Suhua Xu; Zhongmeng Xiong; Lin Yang; Liyuan Hu; Yun Cao; Yulan Lu; Qiufen Wei; Wenqing Kang; Deyi Zhuang; Wenhao Zhou; Xinran Dong

doi:10.3389/fgene.2023.1304458

Primary carnitine deficiency: Estimation of prevalence in Chinese population and insights into newborn screening

Front Genet. 2023 Dec 6:14:1304458. doi: 10.3389/fgene.2023.1304458. eCollection 2023.

Authors

Xiaoshan Ji^#^{1

2}, Yanzhuang Ge^#^{1

3}, Qi Ni^#¹, Suhua Xu⁴, Zhongmeng Xiong^{1

2}, Lin Yang¹, Liyuan Hu², Yun Cao², Yulan Lu¹, Qiufen Wei⁵, Wenqing Kang⁶, Deyi Zhuang⁷, Wenhao Zhou^{1

2

3

8}, Xinran Dong¹

Affiliations

¹ Center for Molecular Medicine, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
² Division of Neonatology, National Children's Medical Center, Children's Hospital of Fudan University, Shanghai, China.
³ Center for Molecular Medicine, Children's Hospital of Fudan University, National Children's Medical Center, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
⁴ Children's Hospital of Shanghai, Shanghai, China.
⁵ Division of Neonatology, Maternal and Child Health Care Hospital of Guangxi Zhuang Autonomous Region, Nanning, China.
⁶ Division of Neonatology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, China.
⁷ Division of Pediatrics, Xiamen Children's Hospital, Xiamen, China.
⁸ Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.

^# Contributed equally.

Abstract

Primary carnitine deficiency (PCD) caused by pathogenic variants in the solute carrier family 22 member 5 (SLC22A5) gene is a rare autosomal recessive disease that results in defective fatty acid oxidation. PCD can be detected through tandem mass spectrometry (MS/MS), but transplacental transport of free carnitine from mothers may cause false negatives or positives during newborn screening (NBS). This study aimed to analyze the genetic characteristics of SLC22A5 and estimate the prevalence of PCD in the Chinese population, providing useful information for NBS and genetic counseling. We manually curated SLC22A5 pathogenic or likely pathogenic (P/LP) variants according to the American College of Medical Genetics and Genomics (ACMG) guidelines and identified 128 P/LP variants. Based on the China Neonatal Genomes Project (CNGP), the estimated PCD prevalence was 1:17,456, which was higher than that in other populations. The genotype-phenotype association analysis showed that patients carrying homozygous c.760C>T and c.844C>T were more likely to present cardiomyopathy, whereas those carrying homozygous c.1400C>G were more likely to be asymptomatic (all p-values < 0.05). We found that there was no significant difference in initial C0 concentrations between patients and carriers, but there was a significant difference in the second-tier screening of C0 concentration between them (p-value < 0.05). We established a cost-effective variant panel containing 10 high-frequency sites and developed a screening algorithm incorporating gene panels with MS/MS, which could rescue one more patient who was undetected from MS/MS. In conclusion, the prevalence of PCD in the Chinese population is relatively high. The combination of conventional NBS with genetic sequencing is suggested for early diagnosis of PCD.

Keywords: SLC22A5; genotype–phenotype analysis; newborn screening; prevalence estimation; primary carnitine deficiency.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This research was supported by the National Key R&D Program of China (Grant No. 2022ZD0116003) and the Shanghai Committee of Science and Technology, China (Grant No. 20Z11900601).