A pilot study of expanded newborn screening for 573 genes related to severe inherited disorders in China: results from 1,127 newborns

Background: Newborn screening (NBS) in China is mainly aimed at detecting biochemical levels of metabolites in the blood, which may generate false-positive/negative results. Current biochemical NBS includes tandem mass spectrometry (MS/MS) screening for metabolites as well as phenylalanine (Phe), thyroid-stimulating hormone (TSH), 17-alpha-hydroxyprogesterone (17-OHP), and glucose-6-phosphate dehydrogenase (G6PD) test. This study intended to explore whether next-generation sequencing (NGS) for dried blood spots combining with biochemical screening could improve the current screening efficiency and to investigate the carrier frequencies of mutations in causative genes related to amino acid metabolism, organic acid metabolism, and fatty acid oxidation in this cohort. Methods: We designed a panel of 573 genes related to severe inherited disorders and performed NGS in 1,127 individuals who had undergone biochemical NBS. The NGS screening results of neonates were used to compare with the biochemical results. Results: NGS screening results revealed that all the four newborns with abnormal G6PD values carried hemizygous G6PD mutations, which were consistent with the decreased G6PD enzymatic activity. The NGS results revealed an individual with compound heterozygous mutations of SLC22A5, who was biochemically negative in 2016. The MS/ MS screening results in 2019 showed free carnitine deficiency, which was consistent with the genetic findings. The top five genes with the highest carrier frequencies of mutations in these newborns were PAH (1:56, 1.79%), ETFDH (1:81, 1.23%), MMACHC (1:87, 1.15%), SLC25A13 (1:102, 0.98%), and GCDH (1:125, 0.80%). Conclusions: Our study highlighted that combining NGS screening with biochemical screening could improve the current NBS efficiency. This is the first study to investigate carrier frequencies of mutations in 77 genes causing inherited metabolic diseases (IMDs) in China.