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.