Primary carnitine deficiency: Estimation of prevalence in Chinese population and insights into newborn screening.

Primary carnitine deficiency (PCD) caused by pathogenic variants in the solute carrier family 22 member 5 (SLC22A5) gene is a rare autosomal recessive disease that results in defective fatty acid oxidation. PCD can be detected through tandem mass spectrometry (MS/MS), but transplacental transport of free carnitine from mothers may cause false negatives or positives during newborn screening (NBS). This study aimed to analyze the genetic characteristics of SLC22A5 and estimate the prevalence of PCD in the Chinese population, providing useful information for NBS and genetic counseling. We manually curated SLC22A5 pathogenic or likely pathogenic (P/LP) variants according to the American College of Medical Genetics and Genomics (ACMG) guidelines and identified 128 P/LP variants. Based on the China Neonatal Genomes Project (CNGP), the estimated PCD prevalence was 1:17,456, which was higher than that in other populations. The genotype-phenotype association analysis showed that patients carrying homozygous c.760C>T and c.844C>T were more likely to present cardiomyopathy, whereas those carrying homozygous c.1400C>G were more likely to be asymptomatic (all p-values < 0.05). We found that there was no significant difference in initial C0 concentrations between patients and carriers, but there was a significant difference in the second-tier screening of C0 concentration between them (p-value < 0.05). We established a cost-effective variant panel containing 10 high-frequency sites and developed a screening algorithm incorporating gene panels with MS/MS, which could rescue one more patient who was undetected from MS/MS. In conclusion, the prevalence of PCD in the Chinese population is relatively high. The combination of conventional NBS with genetic sequencing is suggested for early diagnosis of PCD.

Comprehensive spatiotemporal mapping of single-cell lineages in developing mouse brain by CRISPR-based barcoding.

A fundamental interest in developmental neuroscience lies in the ability to map the complete single-cell lineages within the brain. To this end, we developed a CRISPR editing-based lineage-specific tracing (CREST) method for clonal tracing in Cre mice. We then used two complementary strategies based on CREST to map single-cell lineages in developing mouse ventral midbrain (vMB). By applying snapshotting CREST (snapCREST), we constructed a spatiotemporal lineage landscape of developing vMB and identified six progenitor archetypes that could represent the principal clonal fates of individual vMB progenitors and three distinct clonal lineages in the floor plate that specified glutamatergic, dopaminergic or both neurons. We further created pandaCREST (progenitor and derivative associating CREST) to associate the transcriptomes of progenitor cells in vivo with their differentiation potentials. We identified multiple origins of dopaminergic neurons and demonstrated that a transcriptome-defined progenitor type comprises heterogeneous progenitors, each with distinct clonal fates and molecular signatures. Therefore, the CREST method and strategies allow comprehensive single-cell lineage analysis that could offer new insights into the molecular programs underlying neural specification.

Modeling congenital brain malformations with brain organoids: a narrative review.

Background and Objective: During embryonic development, the dysregulation of the proliferation and differentiation of neuronal progenitors triggers congenital brain malformations. These malformations are common causes of morbidity and mortality in patients younger than 2 years old. Animal models have provided considerable insights into the etiology of diseases that cause congenital brain malformations. However, the interspecies differences in brain structure limit the ability to transfer these insights directly to studies of humans. In recent years, brain organoids generated from human embryonic stem cells (hESCs) or human induced pluripotent stem cells (hiPSCs) using a 3-dimensional (3D) culture system have been used to resemble the structure and function of a developing human brain. Therefore, we aimed to summarize the different congenital brain malformations that have been modeled by organoids and discuss the ability of this model to reveal the cellular and molecular mechanisms of congenital brain malformations. Methods: A comprehensive search was performed using PubMed and Web of Science's Core Collection for literature published from July 1, 2000 to July 1, 2022. Keywords included terms related to brain organoids and congenital brain malformations, as well as names of individual malformations. Key Content and Findings: The self-assembled 3D aggregates have been used to recapitulate structural malformations of human brains, such as microcephaly, macrocephaly, lissencephaly (LIS), and periventricular nodular heterotopia (PH). The use of disease-specific brain organoids has revealed unprecedented details of mechanisms that cause congenital brain malformations. Conclusions: This review summarizes the establishment and development of brain organoid technologies and provides an overview of their applications in modeling congenital brain malformations. Although several hurdles still need to be overcome, using brain organoids has greatly expanded our ability to reveal the pathogenesis of congenital brain malformations. Compared with existing methods, the combination with cutting-edge technologies enables a more accurate diagnosis and development of increasingly personalized targeted therapy for patients with congenital brain diseases.

Human genetic basis of severe or critical illness in COVID-19.

Coronavirus Disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to considerable morbidity and mortality worldwide. The clinical manifestation of COVID-19 ranges from asymptomatic or mild infection to severe or critical illness, such as respiratory failure, multi-organ dysfunction or even death. Large-scale genetic association studies have indicated that genetic variations affecting SARS-CoV-2 receptors (angiotensin-converting enzymes, transmembrane serine protease-2) and immune components (Interferons, Interleukins, Toll-like receptors and Human leukocyte antigen) are critical host determinants related to the severity of COVID-19. Genetic background, such as 3p21.31 and 9q34.2 loci were also identified to influence outcomes of COVID-19. In this review, we aimed to summarize the current literature focusing on human genetic factors that may contribute to the observed diversified severity of COVID-19. Enhanced understanding of host genetic factors and viral interactions of SARS-CoV-2 could provide scientific bases for personalized preventive measures and precision medicine strategies.

Diagnostic utility of rapid sequencing in critically ill infants: a systematic review and meta-analysis.

BACKGROUND: Genetic disorders are a major cause of death in critically ill infants. Several studies have assessed the diagnostic yield of rapid genomic sequencing in critically ill infants. This meta-analysis aimed to summarize the diagnostic utility of rapid genomic sequencing in critically ill infants. METHODS: PubMed, Scopus, Web of Science, and Cochrane Library, were searched before 1 July 2022. Studies reported diagnostic rate of rapid genomic sequencing in critically ill infants were selected. Two authors screened and extracted data regarding the method of genetic test, total number of patients, and number of diagnosed patients. RESULTS: Twenty-three studies, comprising 1567 critically ill infants were included in the meta-analysis. In the overall analysis, the pooled diagnostic utility of rapid genomic sequencing was 0.42 (95% CI: 0.37-0.49, I2 = 79%, P < 0.1). Moreover, the pooled diagnostic rates of rapid whole-exome and rapid whole-genome sequencing were 0.50 (95% CI: 0.41-0.61; I2 = 74%; P < 0.01) and 0.37 (95% CI: 0.30-0.46; I2 = 77%; P < 0.01), respectively. Sensitive analysis showed that the results were stable in the overall analysis. Additionally, publication bias was not observed in the overall analysis. CONCLUSIONS: This meta-analysis proved that rapid genomic sequencing has a good diagnostic utility for critically ill infants.