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Objective: To analyze the clinical and genetic characteristics of a patient with Polyglucosan body myopathy 1 (PGBM1) caused by a novel compound heterozygous variant in the RBCK1 gene. Methods: The clinical data of the patient were collected, next‐generation sequencing technology was used to determine the exome sequence of the patient, and the suspected pathogenic locus was verified by Sanger sequencing. Results: Through whole‐exome sequencing, we found that there were c.919G>T; p. (Glu307*) and c.723_730dup; p. (Glu244fs) variants of the RBCK1 gene in the patient, inherited from his parents, constituting a compound heterozygous variation. According to the guidelines of the American College of Medical Genetics and Genomics (ACMG), the two variants were rated as pathogenic, but there were no comparable cases. Previous literature reported 24 patients with RBCK1 gene variants, involving a total of 20 myocardial and 18 skeletal muscle cases. Conclusions: The patient was twice diagnosed with cardiac insufficiency, neglecting the usual manifestations of muscle weakness, resulting in misdiagnosis. Later, novel variants in the RBCK1 gene were discovered through whole‐exome sequencing, and symptomatic treatment was given after diagnosis. The importance of whole‐exome sequencing technology in disease diagnosis and genetic counseling was emphasized. [ABSTRACT FROM AUTHOR]

Objective: To analyze the clinical and genetic characteristics of a patient with long QT syndrome type 14 (long QT syndrome‐14, LQT14, OMIM # 616247) caused by a de novo CALM1 mutation. Methods: The clinical data of the patient were collected, next‐generation sequencing technology was used to determine the exome gene sequence of the patient, and the suspected pathogenic locus was verified by Sanger sequencing. Results: A 5‐year and 9‐month‐old girl was admitted to the hospital due to a syncopal episode. During the attack, the main symptoms were loss of consciousness, cyanosis of the face and lips, and weakness of limbs. The child had multiple seizures in the past, all of which occurred after emotional excitement and activity. She was diagnosed with epilepsy for more than 3 years, but the effect of antiepileptic treatment was not satisfactory. The electrocardiogram was normal in the past. A month ago, convulsions occurred again after exercise, and the electrocardiogram showed QTc 496 ms. The treadmill test showed a significant prolongation of QTc after exercise, and the genetic results suggested a new heterozygous variant of CALM1, c.395A>G; p. (Asp132Gly). Consequently, she was diagnosed with LQT14 and treated with propranolol. During a follow‐up of 15 months, there were no seizures or syncope. Conclusions: This patient had multiple episodes of convulsions or syncope after emotional stimulation or activity, with intermittent prolongation of the QTc on routine ECG, marked prolongation of the QTc after exercise, and T‐wave alternans, which differed from the LQT14 phenotype caused by the previous CALM1 mutation. [ABSTRACT FROM AUTHOR]

Biological barrier plays a crucial role for organisms against the possible toxicity from engineered nanomaterials (ENMs). Graphene oxide (GO) has been proven to cause potential toxicity on organisms. However, the molecular mechanisms for intestinal barrier of animals against GO toxicity are largely unclear. Usingin vivoassay system ofCaenorhabditis elegans, we found that mutation of genes encoding core p38 mitogen-activated protein kinase (MAPK) signaling pathway caused susceptible property to GO toxicity and enhanced translocation of GO into the body of nematodes. Genetic assays indicated that SKN-1/Nrf functioned downstream of p38 MAPK signaling pathway to regulate GO toxicity and translocation. Transcription factor of SKN-1 could regulate GO toxicity and translocation at least through function of its targeted gene ofgst-4encoding one of phase II detoxification proteins. Moreover, intestine-specific RNA interference (RNAi) assay demonstrated that the p38 MAPK-SKN-1/Nrf signaling cascade could function in intestine to regulate GO toxicity and intestinal permeability in GO exposed nematodes. Therefore, p38 MAPK-SKN-1/Nrf signaling cascade may act as an important molecular basis for intestinal barrier against GO toxicity in organisms. Exposure to GO induced significantly increased expression of genes encoding p38 MAPK-SKN-1/Nrf signaling cascade, which further implies that the identified p38 MAPK-SKN-1/Nrf signaling cascade may encode a protection mechanism for nematodes in intestine to be against GO toxicity. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to describe the genetic and clinical characteristics of paediatric cardiomyopathy in a cohort of Chinese patients., Methods: We retrospectively reviewed the clinical history and mutation spectrum of 75 unrelated Chinese paediatric patients who were diagnosed with cardiomyopathy and referred to our hospital between January 2016 and December 2022., Results: Seventy-five children with cardiomyopathy were enrolled, including 32 (42.7%) boys and 43 (57.3%) girls. Dilated cardiomyopathy was the most prevalent cardiomyopathy (61.3%) in the patients, followed by hypertrophic cardiomyopathy (17.3%), ventricular non-compaction (14.7%), restrictive cardiomyopathy (5.3%) and arrhythmogenic right ventricular cardiomyopathy (1.3%). Whole-exome sequencing and targeted next-generation sequencing identified 34 pathogenic/likely pathogenic variants and 1 copy number variant in 14 genes related to cardiomyopathy in 30 children, accounting for 40% of all patients. TNNC1 p.Asp65Asn and MYH7 p.Glu500Lys have not been reported previously. The follow-up time ranged from 2 months to 6 years. Twenty-two children died (mortality rate 29%)., Conclusions: Comprehensive genetic testing was associated with a 40% yield of causal genetic mutations in Chinese cardiomyopathy cases. We found diversity in the mutation profile in different patients, which suggests that the mutational background of cardiomyopathy in China is heterogeneous, and the findings may be helpful to those counselling patients and families., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To explore the clinical and genetic characteristics of eight children with Primary hypertrophic cardiomyopathy (HCM)., Methods: Eight children with HCM admitted to the Department of Cardiology of Henan Children's Hospital from January 2018 to December 2021 were selected as the study subjects. Clinical data of the children were collected. Whole exome sequencing was carried out on two children, and trio whole exome sequencing was carried out on the remainder 6 children. Sanger sequencing was used to verify the candidate variants in the children and their parents, and the pathogenicity of the variants was evaluated based on the guidelines from the American College of Medical Genetics and Genomics (ACMG)., Results: The patients had included 5 males and 3 females, with their ages ranging from 5 to 13 years old. The average age of diagnosis was (7.87 ± 4.8) years old, and the cardiac phenotype showed non-obstructive HCM in all of the patients. WES has identified variants of the MYH7 gene in 4 children, including c.2155C>T (p.Arg719Trp), c.1208G>A (p.Arg403Gln), c.1358G>A (p.Arg453His), and c.1498G>A (p.Glu500Lys). Based on the guidelines from the ACMG, the first 3 variants were classified as pathogenic, while c.1498G>A (p.Glu500Lys) was classified as likely pathogenic (PM1+PM2_Supporting+PM6+PP3), which was also unreported previously. The remaining four children had all harbored maternal variants, including MYL2: c.173G>A (p.Arg58Gln; classified as pathogenic), TPM1: c.574G>A (p.Glu192Lys) and ACTC1: c.301G>A (p.Glu101Lys)(both were classified as likely pathogenic), and MYBPC3: c.146T>G (p.Ile49Ser; classified as variant of uncertain significance). Seven children were treated with 0.5 ~ 3 mg/(kg·d) propranolol, and their symptoms had improved significantly. They were followed up until September 30, 2022 without further cardiac event., Conclusion: Genetic testing can clarify the molecular basis for unexplained cardiomyopathy and provide a basis for clinical diagnosis and genetic counseling. Discovery of the c.1498G>A (p.Glu500Lys) variant has also expanded the spectrum of MYH7 gene mutations underlying HCM.

Objective: To analyze the clinical and genetic characteristics of a child with restricted cardiomyopathy (RCM) and phenylketonuria (PKU), and summarize the clinical characteristics and genetic diversity of RCM in children through a literature review., Methods: A child with RCM in conjunct with PKU who was admitted to the Children's Hospital Affiliated to Zhengzhou University in June 2020 due to edema of eyelids and lower limbs for 1 year and aggravation for over 1 month was selected as the study subject. Relevant clinical data were collected. Peripheral blood samples of the child and his parents were collected for whole exome sequencing (WES). Candidate variants were validated by Sanger sequencing and bioinformatic analysis. Childhood, TNNI3 gene and restricted cardiomyopathy were used as the keywords to search the Wanfang data knowledge service platform, Chinese Journal Full-text database and PubMed database, and the search period was limited to from the time of establishment till August 2022. Clinical manifestations and characteristics of the TNNI3 gene variants were summarized., Results: The child, a 2-year-old-and-4-month-old male, had normal intelligence, facial features and normal hair and skin color, but his motor and physical development was delayed, in addition with edema of bilateral eyelids and lower limbs. The results of WES and Sanger sequencing revealed that he has harbored compound heterozygous variants of the PAH gene, namely c.331C>T (p.R111X) and c.940C>A (p.P341T), which were inherited from his father and mother, respectively. In addition, he has also harbored a de novo heterozygous variant of c.508C>T (p.R170W) of the TNNI3 gene. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the TNNI3: c.508C>T (p.R170W) was classified as a pathogenic variant (PS2+PS4+PM2_Supporting+PM5), PAH: c.331C>T (p.R111X) as a pathogenic variant (PVS1+PM2_Supporting+PM3+PP4), and c.940C>A (p.P341T) as a likely pathogenic variant (PM2_Supporting+PM3+PM5+PP4). In total 30 children with RCM caused by TNNI3 gene variants were retrieved, with a male-to-female ratio of 1 : 1.55 and manifestations including heart failure, sinus rhythm, bi-atrial enlargement, ST-T wave change, ventricular restricted filling, and decreased ventricular diastolic function. In total 16 variants of the TNNI3 gene were identified, among which c.575G>A was the most common, and all cases had conformed to an autosomal dominant inheritance., Conclusion: Phenylalanine hydroxylase deficiency and RCM are rare diseases with complex clinical manifestations. The PAH: c.331C>T (p.R111X)/c.940C>A (p.P341T) and TNNI3: c.508C>T (p.R170W) variants probably underlay the RCM and PKU in this child.

Objective: To explore the clinical and genetic characteristics of five children with Catecholaminergic polymorphic ventricular tachycardia (CPVT)., Methods: Five children with clinical manifestations consistent with CPVT admitted to the Department of Cardiology of Children's Hospital Affiliated to Zhengzhou University from November 2019 to November 2021 were selected as the study subjects. Their clinical data were collected. Potential variants were detected by whole exome sequencing, and Sanger sequencing was used to verify the candidate variants. All patients were treated with β-blocker propranolol and followed up., Results: All patients had developed the disease during exercise and presented with syncope as the initial clinical manifestation. Electrocardiogram showed sinus bradycardia. The first onset age of the 5 patients were (10.4 ± 2.19) years, and the time of delayed diagnosis was (1.6 ± 2.19) years. All of the children were found to harbor de novo heterozygous missense variants of the RYR2 gene, including c.6916G>A (p.V2306I), c.527G>C (p.R176P), c.12271G>A (p.A4091T), c.506G>T (p.R169L) and c.6817G>A (p.G2273R). Among these, c.527G>C (p.R176P) and c.6817G>A (p.G2273R) were unreported previously. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.527G>C (p.R176P) was classified as a pathogenic variant (PS2+PM1+PM2_Supporting+PM5+PP3+PP4), and the c.6817G>A (p.G2273R) was classified as a likely pathogenic variant (PS2+PM2_Supporting+PP3+PP4). The symptoms of all children were significantly improved with the propranolol treatment, and none has developed syncope during the follow up., Conclusion: Discovery of the c.527G>C (p.R176P) and c.6817G>A (p.G2273R) variants has expanded the mutational spectrum of the RYR2 gene. Genetic testing of CPVT patients can clarify the cause of the disease and provide a reference for their genetic counseling.

What Is Already Known About This Topic?: Hypersomnia is an atypical characteristic of unipolar depression (UD), indicating a high risk of bipolar depression. Identifying the symptom should be prioritized in patients with UD. However, the status and correlated factors of hypersomnia greatly varied across investigations., What Is Added by This Report?: Among inpatients with UD, the rate of hypersomnia was roughly 28.1% (39/139). Younger age (18-35 years) and recurrent depression were independent correlates of hypersomnia in hospitalized patients with UD., What Are the Implications for Public Health Practice?: Understanding the high rate and independent correlates of hypersomnia in hospitalized patients with UD will help clinicians and policymakers to identify characteristics of depression, strengthen the management capacity and improve the quality of treatment and control programs., Competing Interests: No conflicts of interest declared., (Copyright and License information: Editorial Office of CCDCW, Chinese Center for Disease Control and Prevention 2021.)

ADP Ribosylation Factor 6 (ARF6) is a part of the RAS superfamily and regulates vesicular trafficking, remodeling of membrane lipids, and signaling pathways. Our previous study has found that ARF6, functioned as a downstream of Kras/ERK signaling pathway, could promote proliferation and Warburg effect in pancreatic cancer cells. Moreover, ARF6 is promising to be a biomarker for predicting prognosis of pancreatic cancer. Ferroptosis is a new defined iron-dependent form of nonapoptotic cell death, which is closely related to Kras mutation. Therefore, it is urgent to further explore the relationship between ARF6 and ferroptosis. Our study demonstrated that ARF6 did not directly regulate lipid peroxidation, but endowed pancreatic cancer cells to a status that is sensitive to oxidative stress, especially RSL3-induced lipid peroxidation. Further study revealed that ARF6 could also regulate gemcitabine resistance via multiple pathways. In conclusion, ARF6 has a profound effect on pancreatic cancer development., Competing Interests: None., (AJCR Copyright © 2020.)

The secreted fibroblast growth factor (FGF) binding protein (FGF-BP), which is an extracellular chaperone molecule for FGFs, has been demonstrated to enhance the biological and biochemical activities of FGFs and to be closely related to the growth of several cancers. However, the role of FGFBP1 in pancreatic adenocarcinoma (PDAC) has not been studied extensively. We previously reported that decreased FBW7 could induce pancreatic cancer proliferation and progression. In the present study, we investigated whether FBW7 inhibited cell proliferation and metastasis by decreasing the expression of FGFBP1 in pancreatic cancer. We initially confirmed that pancreatic cancer patients with higher FGFBP1 expression had a worse prognosis. Next, we demonstrated that FGFBP1 silencing inhibited the proliferation and metastasis of PANC-1 and Mia PaCa-2 cells. Mechanistically, FGFBP1 was negatively correlated with FBW7 but positively correlated with c-Myc in PDAC tissue samples, and FBW7 regulated FGFBP1 in a c-Myc-dependent manner. We also found that FBW7 silencing could partly reverse the effect of FGFBP1 silencing on proliferation and metastasis. In summary, FGFBP1 is a prognostic marker for overall survival and is required for pancreatic cancer cell proliferation and metastasis, which is mediated by FBW7 in a c-Myc-dependent manner. Thus, targeting the FBW7/c-Myc/FGFBP1 axis might suppress recurrence and metastasis and provide novel treatment strategies for PDAC., Competing Interests: None., (AJCR Copyright © 2019.)