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Objective The loss of LOXL1 expression reportedly leads to the prolapse of pelvic organs or to exfoliation syndrome glaucoma. Increasing evidence suggests that LOXL1 deficiency is associated with the pathogenesis of several other diseases. However, the characterization of the systemic functions of LOXL1 is limited by the lack of relevant investigative technologies. Materials and Methods To determine the functions of LOXL1, a novel method for body‐wide organ transcriptome profiling, combined with single‐cell mass cytometry, was developed. A body‐wide organ transcriptomic (BOT) map was created by RNA‐Seq of tissues from 17 organs from both Loxl1 knockout (KO) and wild‐type mice. Results The BOT results indicated the systemic upregulation of genes encoding proteins associated with the immune response and proliferation processes in multiple tissues of KO mice, and histological and immune staining confirmed the hyperplasia and infiltration of local immune cells in the tissues of KO mice. Furthermore, mass cytometry analysis of peripheral blood samples revealed systemic immune changes in KO mice. These findings were well correlated with results obtained from cancer databases. Patients with tumours had higher Loxl1 mutation frequencies, and patients with Loxl1‐mutant tumours showed the upregulation of immune processes and cell proliferation and lower survival rates. Conclusion This study provides an effective strategy for the screening of gene functions in multiple organs and also illustrates the important biological roles of LOXL1 in the cells of multiple organs as well as in systemic immunity., A new method for body‐wide organ transcriptome profiling, combined with single‐cell mass cytometry was developed to perform RNA‐seq of 17 organs from both Loxl1 knockout and wide type (WT) mice reveal body wide pathology (including hyperplasia and infiltration of immune cells) induced by Loxl1 deficiency, which provided a powerful strategy to screen body‐wide organ functions of a particular gene, and also illustrated important biological roles of LOXL1 on multiple organ cells and systemic immunity.

Background Congenital myasthenic syndrome 22 (CMS22) is a rare autosomal recessive disorder due to isolated PREPL deficiency and characterized by neonatal hypotonia, muscular weakness, and feeding difficulties. Eight such cases have already been reported, while maternal uniparental disomy with a PREPL pathogenic mutation has never been involved. Methods Trio whole‐exome sequencing (WES), comparative genomic hybridization microarray (arry‐CGH), and Sanger sequencing were performed on a 6‐month‐old girl with severe neonatal hypotonia and feeding difficulties. Also, the phenotype and genotype of reported CMS22 patients were reviewed. Results In this female infant, we identified a novel homozygous frameshift mutation in PREPL (c.1282_1285delTTTG, p.Phe428Argfs*18) by trio‐WES. Sanger sequencing confirmed that her mother was heterozygous and her father was normal. Trio‐WES data showed that 96.70% (1668/1725) variants on chromosome 2 were homozygous and maternally inherited, suggesting maternal uniparental disomy of chromosome 2 [UPD(2)mat]. Array‐CGH did not show copy number variants (CNVs) but revealed complete UPD(2). Conclusion To date, nine patients with CMS22 have been reported including our patient, and we report the youngest and the first UPD(2)mat with PREPL novel homozygous pathogenic mutation case, which expand the mutation spectrum of PREPL gene., Congenital myasthenic syndrome 22 (CMS22) is a rare autosomal recessive disorder due to isolated PREPL deficiency and characterized by neonatal hypotonia, muscular weakness and feeding difficulties. Eight cases have been reported, while maternal uniparental disomy with a PREPL pathogenic mutation has never been involved. Here, we report the first and the youngest CMS22 patient of UPD(2)mat with a novel homozygous frameshift mutation in PREPL, which expanded the mutation spectrum of the PREPL gene.

Objective We aimed to use next‐generation sequencing (NGS) for the early diagnosis of primary immunodeficiency diseases (PIDs) and define its effects on medical management for an infant cohort in early life. Methods A single‐centre study was conducted from November 2015 to April 2018. Infants less than 3 months old with infections or abnormal white blood cell counts were enrolled in the study. Gene variants were analysed by NGS, and once a mutation was found in a PID‐associated gene, the immune functions associated with this mutation were detected. The diagnosis rate of PIDs in the cohort was the main outcome. The patients received corresponding management and follow‐up treatments. Results Among 2392 patients who were genetically tested with NGS, 51 infants were diagnosed with PIDs. Seven types of PIDs were detected, and the most common (25/51, 49%) were combined immunodeficiencies with associated or syndromic features. Thirty‐five patients (68.6%) were cured or had improved outcomes after being diagnosed with PID. The NGS cost was US$280 per case. Conclusions This study not only highlighted the potential of NGS to rapidly deliver molecular diagnoses of PIDs but also indicated that the prevalence of PIDs is underestimated. With broader use, this approach has the potential to alter clinical strategies., This study highlights advantages of next‐generation sequencing for primary immunodeficiency diseases (PID) screening in early life infants. Based on the diagnosis, early precision therapy improved the prognosis of individuals with PIDs.

Background Rubinstein–Taybi syndrome (RSTS) is a rare genetic disease characterized by broad thumbs and halluces, facial dysmorphisms, short stature, and intellectual disability. RSTS is mainly caused by de novo variants in epigenetics‐associated gene, CREBBP. To date, there is no cohort study of CREBBP variants in Chinese RSTS patients. Methods In this study, 18 kids who meet the main criteria of RSTS were recruited. Molecular diagnoses were analyzed by clinical exome sequencing (CES), and the medical records were reviewed retrospectively. Results Nineteen novel CREBBP variants in 18 RSTS patients were identified, including two missense, four nonsense, five frameshift, one splicing variants, and seven intragenic deletions. A higher incidence (37%, 7/19) of intragenic deletions was detected. One patient who had two de novo missense variants c.[4112T > A, 4118C > A] in cis and one patient who had a de novo frameshift variant c.5837delC in homozygous state (90%) were found in this study. Compared with the previously reported populations, seven clinical features were different, including the higher incidence of polydactyly, syndactyly, microcephaly, and micrognathia, and the lower incidence of angulated thumbs, autistic behavior, and epilepsy. One patient with obesity in the first year was diagnosed with CREBBP gene exon 2 deletion, was initially suspected of Prader–Willi syndrome. Conclusion We reported the genetic and clinical information of 18 RSTS patients from Chinese population with novel CREBBP variants. This study provides a new insight into RSTS and illustrates the value of applying CES which increases the diagnostic yields and enhances the clinical care of RSTS patients., We reported 18 RSTS cases with novel CREBBP variants, including two missense, four nonsense, six frameshift, one splicing variants, and seven deletions. Two special de novo variants were reported in this study: one patient was detected with two missense variants in cis and another patient confirmed with a frameshift variant (c.5837delC) in homozygous state (90%). Interesting, one patient had obesity was diagnosed with CREBBP gene exon 2 deletion, who was initially suspected of Prader‐Willi syndrome (PWS), while PWS DNA methylation testing revealed negative.

In article number 2000938, Zi Yin, Junxin Lin, and co‐workers identify a novel musculoskeletal stem cell population by single‐cell transcriptional profiling with lineage tracing data during limb development. The differentiation potential and trajectory of musculoskeletal stem cells showed they could contribute to soft and hard connective tissues, as well as muscular tissue. These results suggest an indispensable role of limb Scx+ musculoskeletal stem cell population in musculoskeletal system morphogenesis. [Image: see text]

HFM1 is a meiosis-specific gene and expressed in germ-line tissues. More recently, evidence has indicated that variations in HFM1 gene could be causative for primary ovarian insufficiency (POI), also known as premature ovarian failure. The aim of this study was to investigate the association between HFM1 gene variants and sporadic POI in Chinese women. A total of 138 POI patients and 316 healthy controls (matched for ethnic background, sex, and age of the patients) were recruited in this study. We screened the entire HFM1 coding region by direct sequencing in all subjects and identified six variants of HFM1 gene in POI group, namely c.148G>A/p.Glu50Lys, c.1241A>C/p.His414Pro, c.2325C>A/p.Phe775Leu, c.3367T>C/p.Ser1123Pro, c.3580C>T/p.Arg1194Cys, and c.1686-1G>C. The variation rate of HFM1 in POI group is significantly higher than control group (p < 0.01). The p.His414Pro and p.Arg1194Cys were predicted to be probably damaging to the HFM1 protein function, while p.Glu50Lys, p.Phe775Leu and p.Ser1123Pro mutants might not have any deleterious effect on the structure or function of the protein by online predictors. Taken together, our data suggested that HFM1 gene might be associated with primary ovarian insufficiency in Chinese population.

A multicellular organism's development is coupled with cellular self-organization, which is regulated by cell-cell interactions and cell-extracellular matrix (ECM) crosstalk. Testicular cells from different species such as mouse, rat, and porcine can self-organize into seminiferous tubules both in vitro and in vivo, but the understanding of the functional role of the ECM during this process is limited. Here, it is shown that mouse testicular cells encapsulated with the biomaterial Matrigel can self-organize into seminiferous tubules with blood-testis barrier (BTB) formation and Leydig cell differentiation. By varying the encapsulation method, a combination of sodium alginate and collagen is used to promote reorganization of seminiferous tubules, which resemble those in vivo. In addition, the self-organization ability of testicular cells declines with advanced cell age, and those germ cells play a pivotal role in this process. These findings will be helpful to understand the self-organization process of testicular cells and provide insights for the reconstruction of testes.