Newborn screening of primary carnitine deficiency: clinical and molecular genetic characteristics.

Background: Primary carnitine deficiency (PCD) is a rare autosomal recessive fatty acid oxidation disorder caused by variants in the SLC22A5 gene, with its prevalence and the spectrum of mutations in SLC22A5 varying across races and regions. This study aimed to analyze the clinical and genetic characteristics of PCD patients, including newborns and their mothers, identified by newborn screening (NBS) in Hefei, China.

Methods: The dried blood spot samples from newborns were analyzed using tandem mass spectrometry (MS/MS) from July 2015 to December 2024. Newborns and their mothers with low free carnitine (C0) levels identified during initial screening were subsequently recalled. Next-generation sequencing was employed to analyze gene mutations in patients whose rescreening results indicated that C0 levels remained below the critical reference value.

Results: A total of 897,050 newborns were screened for PCD, and 46 cases were diagnosed, resulting in an incidence rate of 1 in 19,501. Among the screened population, 34 mothers were identified as PCD patients. A total of 26 different variants were detected in the SLC22A5 gene, including four novel variants found in both PCD newborns and their mothers (c.253 C > T, c.976_977delinsAGCAGT, c.384dup, and c.236_271del). Of the 44 PCD newborns tested at our center, seven exhibited homozygous mutations, 35 exhibited compound heterozygous mutations, and two cases showed no detectable gene mutation. The most common mutation was c.1400 C > G (45.88%), followed by c.51 C > G (16.47%) and c.760 C > T (8.24%). Among the 34 PCD mothers, 15 had homozygous mutations and 19 had compound heterozygous mutations; 60.29% of the mutations were c.1400 C > G. The C0 levels in patients with SLC22A5 truncation mutations were significantly lower than those in the non-truncation mutation group (P < 0.05). Furthermore, within the truncation mutation group, the C0 levels of patients with the S467C mutation were higher than those of patients without the S467C mutation (P < 0.05).

Conclusions: MS/MS combined with genetic testing could effectively enhance the diagnostic accuracy of PCD. Our study identified four novel mutations, expanding the variant spectrum of the SLC22A5 gene.