PCD is the most common fatty acid metabolic disorder in China. NBS for PCD has been successfully implemented in most parts of China, patients usually had better prognosis following early L-carnitine therapy. The incidence of PCD varies greatly throughout China, ranging from 1:8,938 to 1:48,717 [13–15]. The largest scale NBS study in China showed that the incidence of PCD was 1:30,182 in Zhejiang province [8]. This study presented more than 500,000 NBS data, indicating that the latest incidence in Quanzhou area was 1:11,189, which is similar to the incidence recently reported in Guangzhou (1:13,345) and Ningbo (1:16,595) areas [15, 16]. It is noteworthy that the actual incidence of PCD should be higher since current MS/MS-based NBS with poor sensitivity [17, 18].
NBS results showed that all patients with low C0 levels, while some patients may have normal C0 levels during recall review. These patients would have been excluded from conventional NBS, but could be identified by incorporating second-tier genetic screening [19]. However, it is noteworthy that PCD patients are also easily missed during NBS because the C0 levels at birth could be affected by the maternal concentration and therefore cannot reflect the true levels of the newborns themselves. Luo et al. recently conducted a pilot study in which genetic screening was performed on only 1,127 neonates using targeted NGS, and one PCD case of false-negative (C0=11.6 µmol/L) was identified [20]. Therefore, NBS for PCD NBS is facing challenges, and it is necessary to combine genetic testing to improve screening efficiency.
This study have updated the SLC22A5 variant spectrum of a southern Chinese population. The top eight variants together had an allele frequency of 86.73%, which provided an important evidence for the rapid screening of targeted SLC22A5 variants in the Chinese population. Many studies have shown that c.51C>G (p.F17L), c.760C>T (p.R254*), and c.1400C>G (p.S467C) are the three most common variants in the Chinese population, but which variant has the highest frequency varies among diverse regions. For instance, c.1400C>G (p.S467C) was the most frequent variant in Jining, Suzhou, Guangzhou, Xuzhou, and Ningbo areas [12, 15, 16, 21, 22]; c.51C>G (p.F17L) was the most common variant in Liuzhou area [23]. By contrast, our data revealed that c.760C>T (p.R254*) was the most common variant in this cohort of patients, and its allele frequency was almost equal to the sum of the other two variants. c.760C>T (p.R254*) is a loss-of-function variant that can cause severe clinical symptoms, it was common in southern China but was rarely detected in northern China [14, 22, 24–26], indicating this variant presented different geographic distribution. Whereas c.1400C>G (p.S467C) with residual function may result in a milder phenotype, it was common in both southern and northern China [14, 22, 24, 26], suggesting this variant was common in the general Chinese population.
Regarding the relationship between genotype and biochemical phenotype, significant difference was observed in C0 levels between patients with N/N and M/M genotypes, and most patients with N/N genotype had low C0 levels compared to the N/M group, indicating patients with null variants were associated with low C0 levels. Notably, patients with N/M genotype may also have very low C0 levels if the missense variant with significantly impaired transport activity. As demonstrated in Figure 1b, no significant difference was observed in C0 levels between patients with genotypes of R254*/R254* and R254*/F17L. In contrast, significant difference was observed in C0 levels between patients with genotypes of R254*/R254* and R254*/S467C because c.1400C>G (p.S467C) retained residual carnitine transport activity.
In summary, this study presented more than 500,000 NBS data with the latest incidence of 1:11,189 in Quanzhou area. The SLC22A5 variant spectrum in the selected southern Chinese population was updated, the top eight variants together had an allele frequency of 86.73%, and c.760C>T (p.R254*) was the most common variant. Patients with null variants were associated with low C0 levels. It is necessary to combine genetic testing to improve screening efficiency due to PCD patients may have normal C0 levels during NBS and recall review.