As a crucial gene associated with diseases, the SLC29A3 gene encodes the equilibrative nucleoside transporter 3 (ENT3). ENT3 plays an essential regulatory role in transporting intracellular hydrophilic nucleosides, nucleotides, hydrophilic anticancer and antiviral nucleoside drugs, energy metabolism, subcellular localization, protein stability, and signal transduction. The mutation and inactivation of SLC29A3 are intimately linked to the occurrence, development, and prognosis of various human tumors. Moreover, many hereditary human diseases, such as H syndrome, pigmentary hypertrichosis and non-autoimmune insulin-dependent diabetes mellitus (PHID) syndrome, Faisalabad histiocytosis (FHC), are related to SLC29A3 mutations. This review explores the mechanisms of SLC29A3 mutations and expression alterations in inherited disorders and cancers. Additionally, we compile studies on the inhibition of ENT3, which may serve as an effective strategy to potentiate the anticancer activity of chemotherapy. Thus, the synopsis of genetics, permeant function and drug therapy of ENT3 provides a new theoretical and empirical foundation for the diagnosis, prognosis of evaluation and treatment of various related diseases.

Newborn screening (NBS) has been implemented for neonatal inborn disorders using various technology platforms, but false-positive and false-negative results are still common. In addition, target diseases of NBS are limited by suitable biomarkers. Here we sought to assess the feasibility of further improving the screening using next-generation sequencing technology.
We designed a newborn genetic sequencing (NBGS) panel based on multiplex PCR and next generation sequencing to analyze 134 genes of 74 inborn disorders, that were validated in 287 samples with previously known mutations. A retrospective cohort of 4986 newborns was analyzed and compared with the biochemical results to evaluate the performance of this panel.
The accuracy of the panel was 99.65% with all samples, and 154 mutations from 287 samples were 100% detected. In 4986 newborns, a total of 113 newborns were detected with biallelic or hemizygous mutations, of which 36 newborns were positive for the same disorder by both NBGS and conventional NBS (C-NBS) and 77 individuals were NBGS positive/C-NBS negative. Importantly, 4 of the 77 newborns were diagnosed currently including 1 newborn with methylmalonic acidemia, 1 newborn with primary systemic carnitine deficiency and 2 newborns with Wilson\'s disease. A total of 1326 newborns were found to be carriers with an overall carrier rate of 26.6%.
Analysis based on next generation sequencing could effectively identify neonates affected with more congenital disorders. Combined with C-NBS, this approach may improve the early and accurate identification of neonates with inborn disorders. Our study lays the foundation for prospective studies and for implementing NGS-based analysis in NBS.

Magnesium (Mg2+) is an important intracellular cation and essential to maintain cell function including cell proliferation, immunity, cellular energy metabolism, protein and nucleic acid synthesis, and regulation of ion channels. Consequences of hypomagnesemia affecting multiple organs can be in overt or subtle presentations. Besides detailed history and complete physical examination, the assessment of urinary Mg2+ excretion is help to differentiate renal from extra-renal (gastrointestinal, tissue sequestration, and shifting) causes of hypomagnesemia. Renal hypomagnesemia can be caused by an increased glomerular filtration and impaired reabsorption in proximal tubular cells, thick ascending limb of the loop of Henle or distal convoluted tubules. A combination of renal Mg2+ wasting, familial history, age of onset, associated features, and exclusion of acquired etiologies point to inherited forms of renal hypomagnesemia. Based on clinical phenotypes, its definite genetic diagnosis can be simply grouped into specific, uncertain, and unknown gene mutations with a priority of genetic approach methods. An unequivocal molecular diagnosis could allow for prediction of clinical outcome, providing genetic counseling, avoiding unnecessary studies or interventions, and possibly uncovering the pathogenic mechanism. Given numerous identified genes responsible for Mg2+ transport in renal hypomagnesemia over the past two decades, several potential and specific molecular and cellular therapeutic strategies to correct hypomagnesemia are promising.

UNASSIGNED: 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-α-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.
UNASSIGNED: 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.
UNASSIGNED: 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%).
UNASSIGNED: 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.

BACKGROUND: Cystine stone is the only clinical manifestation in patients with cystinuria, which is an autosomal recessive inheritable disease. However, clinical and genetic data vary among patients in different countries.
OBJECTIVE: To investigate the characteristics of Chinese pediatric cystine stone patients.
METHODS: Thirteen pediatric patients with cystine stones were evaluated in our clinic between 2012 and 2015. Gene mutations in SLC3A1 and SLC7A9 were investigated. Metabolic evaluation was also performed. Thirteen pediatric patients with calcium oxalate stones were selected as controls.
RESULTS: Of these patients, eight were males and five were females. Average age at detection of the first stone was 6.8 ± 5.2 years. Urinary stones in three of the 13 cystine patients were composed of cystine and calcium oxalate. The 63.6% of patients with upper urinary stones had bilateral stones. A total of 17 different missense mutations were identified, and 12 of these mutations were first reported in this study. Metabolic abnormalities could be detected in 77% of cystine stone patients. The most common metabolic abnormality was hyperoxaluria, followed by hypercalciuria and hypocitraturia. Compared with calcium stone patients, our cystine stone patients had a higher rate of bilateral stones, larger stone size, higher levels of serum BUN and Cr, urine citrate excretion (Table), and higher mean value of surgeries per patient. By contrast, the opposite was true for urine oxalate excretion and AP (CaOx) index EQ. The urine excretion of cystine was not correlated with other urinary constituents.
CONCLUSIONS: Patients with cystinuria frequently suffer recurrent renal stones and may subsequently need a series of stone removal procedures during their lifetime. This condition is likely to affect their overall renal function. SLC3A1 and SLC7A9 have been extensively investigated, but a detection rate of 100% in cystinuric patients has yet to be obtained. In our study, we found 14 missense mutations in 18 of 26 alleles except four mutation polymorphisms. Most of the gene mutations found in our study were their first reports. Metabolic abnormalities were frequently found in cystine stone patients, but their risk of calcium oxalate stone formation was relatively lower than that of patients with calcium oxalate stones.
CONCLUSIONS: Cystine stone patients are at risk of impaired renal function and the formation of calcium oxalate stones. Most of the gene mutations identified in our patients were first reported in this study. Therefore, cystinuria possibly exhibits genetic and allelic heterogeneity in Chinese pediatric cystine stone patients.