Biochemical and genetic characteristics of patients with primary carnitine deficiency identified through newborn screening

Yiming Lin,Yanru Chen,Bangbang Lin,Qingliu Fu,Zhenzhu Zheng,Weifeng Zhang,Weihua Lin

doi:10.1186/s13023-021-02126-3

Abstract

BackgroundPrimary carnitine deficiency (PCD) is an autosomal recessive disorder of carnitine transportation that leads to impaired fatty acid oxidation. Large-scale studies on newborn screening (NBS) for PCD are limited. This study aimed to investigate the biochemical and genetic characteristics of patients with PCD detected through NBS.ResultsA total of 548 247 newborns were screened for PCD between January 2014 and June 2021; 1714 newborns with low free carnitine (C0) levels were called back and 49 patients were diagnosed with PCD. The latest incidence rate in Quanzhou, China, was estimated to be 1 in 11 189 newborns. NBS results showed that the 49 patients had varying degrees of decreased C0 levels, whereas seven patients exhibited normal C0 levels during the recall review. All patients harbored biallelic pathogenic variants of the SLC22A5 gene. Nineteen distinct SLC22A5 variants were detected in these 49 patients, and most of the detected variants were clustered in exons 1, 4, and 7. The top eight variants had an allele frequency of 86.73%. The most common variant was c.760C > T (p.R254*) with an allele frequency of 31.63%, followed by c.51C > G (p.F17L) (17.35%) and c.1400C > G (p.S467C) (16.33%). The C0 level of patients with the N/N genotype was significantly lower than that of the M/M group. The C0 levels of patients with genotypes of R254*/R254* and R254*/F17L were far lower than those of patients with the R254*/S467C genotype.ConclusionsThis study presented more than 500,000 NBS data with the latest incidence of 1:11 189 in the Quanzhou area. The SLC22A5 variant spectrum in the selected southern Chinese population has been updated. Patients with null variants were associated with low C0 levels. Combining NBS with genetic testing is critical to improve screening efficiency because patients with PCD may have normal C0 levels during NBS and recall review.

Highlights

Primary carnitine deficiency (PCD) is an autosomal recessive disorder of carnitine transportation that leads to impaired fatty acid oxidation
newborn screening (NBS) for PCD Overall, 548 247 newborns were screened for PCD during the study period
NBS results showed that 1714 newborns had low Free carnitine (C0) levels, yielding a positivity rate of 0.31% (1714/548 247)

Summary

Introduction

Primary carnitine deficiency (PCD) is an autosomal recessive disorder of carnitine transportation that leads to impaired fatty acid oxidation. Primary carnitine deficiency (PCD, OMIM #212140) is an autosomal recessive disorder of carnitine transportation that leads to impaired fatty acid oxidation. The diagnosis of PCD after NBS is confirmed by genetic analysis of the SLC22A5 gene or by verifying reduced carnitine transport activity in fibroblasts [8, 9]. The measurement of carnitine transport activity is a reliable diagnostic assay, but it is only performed in a few laboratories worldwide and requires a skin biopsy. It is noteworthy that some disease-causing pathogenic variants can escape detection because the genetic diagnostic yield for PCD has been relatively low [10]

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