BACKGROUND: Compare the differences between normal newborns and high-risk children with inherited metabolic diseases. The disease profile includes amino acidemias, fatty acid oxidation disorders, and organic acidemias.
METHODS: Data was collected on newborns and children from high-risk populations in Shanghai from December 2010 to December 2020.
RESULTS: 232,561 newborns were screened for disorders of organic, amino acid, and fatty acid metabolism. The initial positive rate was 0.66 % (1,526/232,561) and the positive recall rate was 77.85 %. The positive predictive value is 4.71 %. Among them, 56 cases were diagnosed as metabolic abnormalities. The total incidence rate is 1:4153. Hyperphenylalaninemia and short-chain acyl-CoA dehydrogenase are the most common diseases in newborns. In addition, in 56 children, 39 (69.42 %) were diagnosed by genetic sequencing. Some hotspot mutations in 14 IEMs have been observed, including PAH gene c.728G > A, c.611A > G, and ACADS gene c. 1031A > G, c.164C > T. A total of 49,860 symptomatic patients were screened, of which 185 were diagnosed with IEM, with a detection rate of 0.37 %. The most commonly diagnosed diseases in high-risk infants aremethylmalonic acidemia and hyperphenylalaninemia.
CONCLUSIONS: There are more clinical cases of congenital metabolic errors diagnosed by tandem mass spectrometry than newborn screening. The spectrum of diseases, prevalence, and genetic characteristics of normal newborns and high-risk children are quite different.

Diagnosis and management strategy of disorders of sex development (DSD) are difficult and various due to heterogeneous phenotype and genotype. Under widespread use of genomic sequencing technologies, multiple genes and mechanisms have been identified and proposed as genetic causes of 46,XY DSD. In this study, 178 46,XY DSD patients were enrolled and underwent gene sequencing (either whole-exome sequencing or targeted panel gene sequencing). Detailed clinical phenotype and genotype information were summarized which showed that the most common clinical manifestations were micropenis (56.74%, 101/178), cryptorchidism (34.27%, 61/178), and hypospadias (17.42%, 31/178). Androgen synthesis/action disorders and idiopathic hypogonadotropic hypogonadism were the most frequent clinical diagnoses, accounting, respectively, for 40.90 and 21.59%. From all next-generation sequencing results, 103 candidate variants distributed across 32 genes were identified in 88 patients. The overall molecular detection rate was 49.44% (88/178), including 35.96% (64/178) pathogenic/likely pathogenic variants and 13.48% (24/178) variants of uncertain significance. Of all, 19.42% (20/103) variants were first reported in 46,XY DSD patients. Mutation c.680G>A (p.R227Q) on SRD5A2 (steroid 5-alpha-reductase 2) (36.67%, 11/30) was a hotspot mutation in the Chinese population. Novel candidate genes related to DSD (GHR (growth hormone receptor) and PHIP (pleckstrin homology domain-interacting protein)) were identified. Overall, this was a large cohort of 46,XY DSD patients with a common clinical classification and phenotype spectrum of Chinese patients. Targeted gene panel sequencing covered most of the genes contributing to DSD, whereas whole-exome sequencing detected more candidate genes.

Microsatellite instability (MSI) is the first pan-cancer biomarker approved to guide immune checkpoint inhibitor therapy for MSI-high (MSI-H) solid tumors. In lung cancer, the MSI-H frequency is very low, and the genetic characteristics and prognosis of lung cancer with MSI-H were rarely reported.
Next-generation sequencing and immunohistochemistry were used detect MSI status, tumor mutation burden (TMB) and PD-L1 expression.
Among 12,484 lung cancer patients screened, 66 were found with MSI-H, the proportion was as low as 0.5%. Compared with Microsatellite stability (MSS), TMB was higher in MSI-H lung cancer patients, while PD-L1 expression showed no considerable difference between MSI-H and MSS. After propensity score matching, compared with MSS, the most common companion mutations in MSI-H were TP53, BRCA2, TGFBR2, PTEN and KMT2C. In MSI-H lung adenocarcinoma with EGFR mutation, TGFBR2 and ERBB2 had higher mutation frequency than in MSS.
The current study reveals the genetic characteristics of MSI-H lung cancer, which advanced our understanding of MSI-H lung cancer.

To investigate the genetic variability and the epidemiological features of respiratory syncytial virus (RSV) in Beijing during five consecutive seasons from 2015 to 2019.
We collected 36,927 samples (ages ranged from 1 day to 101 years old) from cases with acute respiratory tract infections (ARTI) using the Respiratory Pathogens Surveillance System (RPSS) in Beijing, 2015-2019. G gene sequencing and phylogenetic analysis were performed to identify RSV genotypes, clusters, and amino acid (aa) changes.
In total, 764 (2.1%, 764/36927) cases were RSV positive, 52.1% cases were children under 5 years old, and 25.8% were elderly ≥ 60 years old. We obtained 369 sequences of the G gene. ON1 and BA9 were the dominant genotypes in Beijing. Sub-lineage 4 of ON1, which contains four aa substitutions (T113I, N178G, H258Q, and H266L), emerged in 2017 and became the predominant variant in 2018-2019. Sub-lineage 4 of BA9, which contains two aa changes (A131T, T137I), emerged in 2017 and became the predominant variant in 2019. We also observed 10 rarely reported nucleotide deletions in the 3\' end of the G gene from five sequences of the ON1 genotype.
With the exception of children < 5 years old, RSV infection mainly occurred in the elderly ≥ 60 years old. Newly emerged sub-lineages have replaced existing sub-lineage over time and become predominant in Beijing. Continued surveillance of the genetic diversity of RSV is necessary.

Juvenile myelomonocytic leukaemia (JMML), a rare clonal haematopoietic disorder of childhood, is characterised as a myelodysplastic/myeloproliferative neoplasm. Despite ground-breaking genetic discoveries, JMML remains difficult to diagnose given its diverse clinical features and disease course. A total of 24 patients with JMML were diagnosed and treated at a single institution, and their genetic profiles and association with clinical and laboratory characteristics were analysed. In all, 22 of the patients received allogeneic haematopoietic stem cell transplantation after myeloablative conditioning, mostly from a haploidentical family donor. RAS pathway mutations were identified in 88% of patients: PTPN11 [nine (38%)], NRAS [nine (38%)], KRAS [two (8%)], NF1 [five (21%)] and CBL [one (4%)]. Secondary mutations were found in 25% of patients: SETBP1, JAK3, ASXL1, GATA2, KIT, KDM6A, and BCOR. Six patients showed cytogenetic abnormalities, including three with monosomy 7. The estimated 5-year event-free survival (EFS) and overall survival (± standard error) of the entire cohort were 58·9 (10·9)% and 73·5 (10·8)% respectively. NRAS (+) patients had a higher 5-year EFS than NRAS (-) patients [72·9 (16·5)% vs. 52·5 (13·1)%, P = 0·127]. NRAS (+) patients had a better 5-year EFS than PTPN11 (+) patients [41·7 (17·3)%, P = 0·071]. Our study revealed the genetic characteristics of Korean JMML patients with RAS pathway and secondary mutations.

Human respiratory syncytial virus (RSV) is a major pathogen of acute lower respiratory tract infection among young children. To investigate the prevalence and genetic characteristics of RSV in China, we performed a molecular epidemiological study during 2015-2019. A total of 964 RSV-positive specimens were identified from 5529 enrolled patients during a multi-center study. RSV subgroup A (RSV-A) was the predominant subgroup during this research period except in 2016. Totally, 535 sequences of the second hypervariable region (HVR-2) of the G gene were obtained. Combined with 182 Chinese sequences from GenBank, phylogenetic trees showed that 521 RSV-A sequences fell in genotypes ON1 (512), NA1 (6) and GA5 (3), respectively; while 196 RSV-B sequences fell in BA9 (193) and SAB4 (3). ON1 and BA9 were the only genotypes after December 2015. Genotypes ON1 and BA9 can be separated into 10 and 7 lineages, respectively. The HVR-2 of genotype ON1 had six amino acid changes with a frequency more than 10%, while two substitutions H258Q and H266L were co-occurrences. The HVR-2 of genotype BA9 had nine amino acid substitutions with a frequency more than 10%, while the sequences with T290I and T312I were all from 2018 to 2019. One N-glycosylation site at 237 was identified among ON1 sequences, while two N-glycosylation sites (296 and 310) were identified in the 60-nucleotide duplication region of BA9. To conclusion, ON1 and BA9 were the predominant genotypes in China during 2015-2019. For the genotypes ON1 and BA9, the G gene exhibited relatively high diversity and evolved continuously.

UNASSIGNED: Staphylococcus aureus is endowed with a repertoire of virulence factors potentially implicated in its pathogenicity and ability to cause invasive disease. The main objective of this study was to describe the bacterial genotype, including virulence genes and affiliation to clonal complexes (CCs), encountered in severe pneumonia.
UNASSIGNED: DNA microarray was used to analyse 18 S. aureus isolates from patients hospitalized with severe pneumonia between 2017 and 2019.
UNASSIGNED: Among 18 S. aureus isolates, 14 were methicillin-susceptible S. aureus (MSSA), and 4 methicillin-resistant S. aureus (MRSA). There were 14 community-acquired, 3 healthcare-associated, and 1 hospital-acquired infections. Different radiological presentations were observed: necrotizing pneumonia (n = 8, 44%), alveolar consolidation (n = 7, 39%), alveolar-interstitial infiltrates (n = 3, 17%). Sixteen patients (89%) required ICU hospitalization, 13 (72%) an invasive mechanical ventilation, and 12 (67%) a vasopressor support. Mortality affected 6 patients (33%). Panton-Valentine leukocidin (PVL), staphylococcal enterotoxins, toxic shock syndrome toxine-1 (TSST-1) encoding genes were documented in nine (50%), 12 (67%), one (6%) of the isolates, respectively. Accessory regulator gene group I was the most reported (n = 9, 50%) and was found in five deaths. The majority of isolates were affiliated to CC152 (n = 6), followed by CC15 (n = 3), CC45 (n = 2), CC30 (n = 2), CC1 (n = 2), CC8 (n = 1), CC9 (n = 1), and CC25 (n = 1). All the CC152 isolates were PVL-positive.
UNASSIGNED: CC152-PVL positive S. aureus strains were the most prevalent in severe pneumonia. Other virulence gene profiles were found coupled to additional clonal lineages. A genotyping strategy contributes to describe the current circulating strains and bacterial genetic backgrounds.

Chinese newborns have been screened for inborn errors of metabolism (IEM) for over 20 years. Although China features 56 different ethnic groups, there are no specific data describing the incidence of such genetic errors across difference ethnicities. To understand the ethnic preference distribution of the incidence and variants of IEM in the Ningxia Hui Autonomous Region of China, 189,354 newborns from 2016 to 2019 were screened by tandem mass spectrometry, including 87,482 from the Han ethnic population, 88,229 from the Hui population, 1,103 from other ethnicities, and 12,540 infants without ethnic registration. Suspected cases then underwent specific genetic profiling by targeted next generation sequencing. In total, 160 patients were diagnosed with 17 types of IEM, with a significant higher incidence in Hui infants (1/1,003) than in Han infants (1/1,232). Five diseases (eight patients) were specifically detected in Han infants, while three were exclusively diagnosed in six Hui infants. For shared diseases, the variants of keys genes also showed ethnic preference. Our findings enhance our understanding of the genetics underlying IEM, thus promoting the development of treatment plans for patients from different areas or ethnicities in China.

Background: Children with Down syndrome (DS) have increased risk of myeloid leukemia (ML), but specific treatment protocols ensure excellent outcome. This study was a retrospective analysis of the treatment results and genetic characteristics of ML of DS (ML-DS) in Poland from 2005 to 2019. Methods: All 54 patients with ML-DS registered in the Polish Pediatric Leukemia and Lymphoma Study Group in analyzed period were enrolled to the study. There were 34 children treated with Acute Myeloid Leukemia-Berlin-Frankfurt-Munster 2004 Interim Protocol (group I) and 20 patients treated with ML-DS 2006 Protocol (group II). In the first protocol, there was reduction of the antracyclines doses and intrathecal treatment for ML-DS compared to non-DS patients. In the second protocol, further reduction of the treatment was introduced (omission of etoposide in the last cycle, no maintenance therapy). Results: Probabilities of 5-year overall survival (OS), event-free survival (EFS), and relapse-free survival in the whole analyzed group were 0.85 ± 0.05, 0.83 ± 0.05, and 0.97 ± 0.03, respectively. No significant differences were found between two protocols in the terms of OS and EFS (0.79 ± 0.07 vs. 0.95 ± 0.05, p = 0.14, and 0.76 ± 0.07 vs. 0.95 ± 0.05, p = 0.12, respectively). All deaths were caused by the treatment-related toxicities. Reduction of the treatment-related mortality was noticed (20% in group I and 5% in group II). The only one relapse in the whole cohort occurred in the patient from group I, older than 4 years, without GATA1 gene mutation. He was treated successfully with IdaFLA cycle followed by hematopoietic stem cell transplantation from matched sibling donor. No significant prognostic factor was found in the study group probably due to low number of patients in the subgroups. Conclusions: The study confirms that the reduced intensity protocols are very effective in ML-DS patients. The only cause of deaths was toxicities; however, systematic decrease of the treatment-related mortality was noticed.