Metabolic associated fatty liver disease （MAFLD） is a highly prevalent chronic liver disease worldwide， and the mechanism underlying its progression to metabolic associated steatohepatitis and liver fibrosis remain unclear. Endoplasmic reticulum stress （ERS） and ferroptosis （Fer） are deeply involved in the pathological evolution of MAFLD. This article systematically reviews the core regulatory mechanisms of ERS and its role in regulating lipid metabolism， inflammation response， and cell apoptosis in MAFLD. It also analyzes the core mechanism of Fer and discusses the predisposing factors for Fer in the pathological microenvironment of MAFLD， as well as the role of Fer in exacerbating hepatocyte death and activating the progression of liver fibrosis. This article proposes that the crosstalk between ERS and Fer is a key driver for the progression of MAFLD， which provides new references and ideas for the clinical intervention of MAFLD.

Background and purpose:The colorectal cancer screening program for community residents in Shanghai has been implemented for 12 years since 2013.This study aimed to analyze the impact of screening on the colorectal cancer incidence,stage and survival outcomes based on their screening participation status.Methods:This study used registry-based cohort study method.The registered residents in Shanghai from 2013 to 2017 who met the screening age range were divided into screening group and non-screening group.The data of colorectal cancer cases after being included in groups were obtained from the Population Based Cancer Registry.We calculated age-standardized cumulative incidence and age-group cumulative incidence,diagnosis stage and survival rate of colorectal cancer by gender,age and year of diagnosis.We used the Joinpoint regression method to calculate the annual change percentage for cumulative incidence trend analysis.The life table method and EdererⅡ method were used to calculate the 5-year observed survival rates and expected survival rates of colorectal cancer cases.Finally the 5-year relative survival rates were obtained.Results:The study included 1 687 689 participants aged 50-74 in screening group and 4 713 307 participants in non-screening group.During a 5-year follow-up period,there were 10 333 and 20 904 new cases of colorectal cancer diagnosed in the two groups,respectively.The age-standardized 5-year cumulative incidence in the screening group was 555.33/105,with an average annual increase of 33.32%(P＜0.05).The age-standardized 5-year cumulative incidence in the non-screening group was 529.85/105,with an average annual increase of 48.13%(P＜0.05).There was no statistically significant difference between the screening group and the non-screening group in the age-standardized 5-year cumulative incidence(X=0.25,P=0.804).The lower the age group,the greater the difference between the screening group and the non-screening group in the annual average change percentage of the age-standardized cumulative incidence.The stages 0-Ⅰ of newly diagnosed colorectal cancer cases in the screening group and non-screening group accounted for 14.70%and 7.46%,respectively,with a statistically significant difference in composition between the two groups(P＜0.05).The 5-year relative survival rate of the screening group was 73.94%,while the non-screening group was 59.66%.The survival rate indicators of the former were significantly higher than those of the latter,and the difference was statistically significant.The survival rate of the former was significantly higher than that of the latter(73.94%vs 59.66%),and the difference was statistically significant(P＜0.05).The survival rate of females in both groups of cases was higher than that of males,and the survival rate decreased with increasing age-groups at diagnosis.Conclusion:With the implementation of the colorectal cancer screening program,the growth trend of the incidence rate of colorectal cancer among the screening participants has been curbed,and the early stages of colorectal cancer cases diagnosed and the 5-year survival rate were significantly improved.In order to reduce the incidence rate of colorectal cancer in the whole population,it is necessary to vigorously promote the screening coverage of the appropriate population,especially to increase the proportion of lower age groups participating in screening.We should also pay attention to the screening quality of the elderly groups and improve the compliance of colonoscopy in high-risk participants.At the same time,we should further optimize the refined management of screening for different genders,ages,and risk groups.

OBJECTIVE: To explore the clinical characteristics and gene variant of a fetus with Farber lipogranulomatosis caused by ASAH1 gene variant. METHODS: A fetus with Farber lipogranulomatosis caused by ASAH1 gene variant diagnosed at Women and Children's Hospital of Ningbo University in August 2024 was selected as the subject. Clinical data and abortion tissue samples of the fetus and peripheral blood samples of its parents were collected for whole exome sequencing (WES). Sanger sequencing validation and bioinformatics analysis were performed on candidate variants. This study was approved by Women and Children's Hospital of Ningbo University (Ethics No. EC2020-048). RESULTS: Generalized skin oedema, pericardial effusion, right pleural effusion and increased bowel echogenicity of the fetus were founded by prenatal ultrasound. WES revealed that the fetus has harbored a homozygous c.101C>A (p.Ser34Ter) variation in exon 2 of the ASAH1 gene. Sanger sequencing confirmed that both parents carry the heterozygous nonsense variation c.101C>A (p.Ser34Ter) in ASAH1 gene, which has not been included in databases such as HGMD, ClinVar, 1000 Genomes, ExAC, dbSNP, and gnomAD. Based on the Standards and Guidelines for the Interpretation of Sequence Variants of the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be pathogenic (PM2_Supporting+PVS1+PM3_Supporting). The AlphaFold3 model protein structure prediction reveals that the c.101C>A variant caused the premature appearance of a termination codon, resulting in only a small partial α-helix structure in the N-terminal of the encoded ASAH1 protein, with the complete loss of the α-helix structure in the core domain, which might lead to the loss of function of this protein. CONCLUSION The c.101C>A (p.Ser34Ter) variant of the ASAH1 gene probably underlay the Farber lipogranulomatosis with hydrops fetalis in this fetus. The newly discovered c.101C>A (p.Ser34Ter) variant has enriched the mutational spectrum of Farber lipogranulomatosis.
Humans ; Female ; Pregnancy ; Acid Ceramidase/chemistry* ; Farber Lipogranulomatosis/diagnostic imaging* ; Fetus ; Exome Sequencing ; Adult

OBJECTIVE: To explore the genetic characteristics of a fetus affected with Structural heart defects and renal anomalies syndrome (SHDRA). METHODS: A pedigree with SHDRA (fetus and the parents) who had visited the Affiliated Women and Children's Hospital of Ningbo University in April 2023 was selected as the study subject. Clinical data of the family were collected. A total of 10 mL of amniotic fluid cells from the fetus and 5 mL of peripheral blood samples from the parents were collected for genomic DNA extraction. Trio whole-exome sequencing (Trio-WES) was performed, and Sanger sequencing was used to validate candidate variants in the family. The identified variants were classified according to the Standards and Guidelines for the Interpretation of Sequence Variants established by the American College of Medical Genetics and Genomics (ACMG) (hereinafter referred to as the "ACMG Guidelines). Relevant research literature on SHDRA in domestic and international databases were searched for literature review. This study was approved by the Affiliated Women and Children's Hospital of Ningbo University (Ethics No. EC2023-094). RESULTS: In this family, prenatal ultrasound at 18 weeks of gestation revealed left renal multicystic dysplasia in the fetus. After birth, the infant exhibited an ostium secundum atrial septal defect, patent ductus arteriosus, and left renal multicystic dysplasia. Trio-WES revealed that the fetus had carried c.344dup (p.L116Afs*32) and c.90_104dup (p.Ala31_Ala35dup) compound heterozygous variants in the TMEM260 gene, which were respectively inherited from its father and mother. According to the ACMG guidelines, the c.344dup (p.L116Afs*32) and c.90_104dup (p.Ala31_Ala35dup) variants were classified as pathogenic (PM2_Supporting+PVS1+PP4) and likely pathogenic (PM2_Supporting+PM4+PM3+PP4), respectively. According to the literature search strategy set for this study, a total of 6 literature was retrieved, involving 25 SHDRA patients from 20 families. Together with the patients in this study, there were 14 TMEM260 gene variants, most of which were frameshift variants (7 types) and had located in exons 3, 11 and 13. The main clinical features of SHDRA were congenital heart malformation, renal abnormality and neurodevelopmental abnormality, and there was a lack of genotype-phenotype correlation. CONCLUSION The c.344dup (p.L116Afs*32) and c.90_104dup (p.Ala31_Ala35dup) variants of the TMEM260 gene probably underlay the SHDRA in this family. Above finding has provided a basis for clinical diagnosis and genetic counseling for the family.
Humans ; Female ; Pedigree ; Membrane Proteins/genetics* ; Male ; Heart Defects, Congenital/genetics* ; Kidney/abnormalities* ; Pregnancy ; Adult ; Kidney Diseases/congenital* ; Exome Sequencing ; Mutation ; Genetic Testing

OBJECTIVE: To explore the genetic etiology of a child with Brain small vessel disease 1 with ocular anomalies. METHODS: A child who was admitted to Ningbo Women and Children's Hospital on May 28, 2022 was selected for the study. Clinical data were collected, and peripheral blood samples from the child and her parents were obtained for genomic DNA extraction. Whole exome sequencing (WES) was performed to screen for pathogenic variants. Candidate variants were validated via Sanger sequencing and subjected to bioinformatic analysis. This study was approved by the Medical Ethics Committee of Ningbo Women and Children's Hospital (Ethics No. EC2020-014). RESULTS: The child was a 7-year-old female with a diagnosis of epilepsy. WES revealed that she has carried a heterozygous missense variant in the COL4A1 gene: c.1792G>A (p.Gly598Ser). Sanger sequencing confirmed that her parents both had the wild-type genotype for this variant. Based on American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines for the Interpretation of Sequence Variants, the variant were predicted to be a likely pathogenic (PS2+PM1+PM2_Supporting+PP3). Bioinformatics predicted that amino acid 598 was highly conserved in different species, formed hydrogen bond with Asp599 after becoming Ser598. CONCLUSION The heterozygous missense variant of the COL4A1 gene c.1792T>C (p.G598S) could be the pathogenic cause of this child with Brain small vessel disease 1 with ocular anomalies.
Humans ; Female ; Child ; Collagen Type IV/genetics* ; Eye Abnormalities/genetics* ; Exome Sequencing ; Mutation, Missense ; Cerebral Small Vessel Diseases/genetics*

OBJECTIVE: To explore the clinical characteristics and genetic etiology of a patient with Fliedner-Zweier syndrome (FZS). METHODS: A pregnant woman who was diagnosed with FZS at the Affiliated Women and Children's Hospital of Ningbo University in November 2023 for "intellectual disability, epilepsy, delayed language development and facial abnormalities" was selected as the study subject. Peripheral blood samples were collected from the woman and her husband, whilst amniotic fluid sample was obtained from the fetus. Following extraction of genomic DNA, whole-exome sequencing (WES) and chromosomal karyotyping analysis were performed. Candidate variant was validated by Sanger sequencing. Pathogenicity of the variant was classified based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: EC2023-094). RESULTS: The proband, a 23-year-old woman, was at 19⁺² weeks of gestation and had a history of epilepsy, mild intellectual disability, delayed language development, and subtle facial dysmorphism. Chromosomal analysis showed the she has a normal karyotype. WES revealed that the woman and her fetus both harbored a heterozygous c.1489C>T (p.Gln497Ter) nonsense variant of the SCAF4 gene, which was verified by Sanger sequencing as de novo. Based on the ACMG guidelines, the variant was classified as pathogenic (PVS1+PM2_supporting+PS2_supporting). According to pre-set search strategy, five articles were retrieved. Together with the patient in this study, a total of 69 FZS patients were involved (including 7 from China). The main clinical features have included intellectual disability, epilepsy, behavioral abnormalities, and facial dysmorphism. CONCLUSION The heterozygous c.1489C>T (p.Gln497Ter) variant of the SCAF4 gene probably underlyay the FZS in this patient. Above finding has expanded the mutational spectrum of the SCAF4 gene.
Humans ; Female ; Intellectual Disability/genetics* ; Pregnancy ; Young Adult ; Exome Sequencing ; Epilepsy/genetics* ; Abnormalities, Multiple/genetics* ; Mutation ; Karyotyping

OBJECTIVE: To explore the clinical characteristics and genetic etiology of STISS syndrome (an autosomal dominant disorder characterized by ubiquitin-proteasome system dysfunction) in a child. METHODS: A child with STISS syndrome diagnosed at the Affiliated Women and Children's Hospital of Ningbo University in September 2024 due to "abnormal development of external genitalia" was selected as the study subject. Clinical data were retrospectively collected. Peripheral blood samples were obtained from the child and his family members. Following genomic DNA extraction, whole-exome sequencing (WES) and Sanger sequencing validation were carried out. Pathogenicity of the candidate variants was assessed based on the guidelines from American College of Medical Genetics and Genomics (ACMG). The study was approved by the Ethics Committee of the hospital (Ethics No.: EC2023-094). RESULTS: The proband, a 16-year-old boy, presented with micropenis, testicular hypoplasia, delayed sexual development, insulin resistance, diabetes mellitus, and obesity. WES revealed that he has harbored a c.934del; p.Met312TrpfsTer3 frameshifting variant of the PSMD12 gene, which was unreported previously. Sanger sequencing confirmed that the variant to be de novo in origin. Based on the guidelines from the ACMG, the variant was classified as pathogenic (PVS1+PM2_supporting+PM6_supporting). The variant was predicted to result in a premature termination codon. Bioinformatics analysis suggested that the amino acid at position 312 is highly conserved, and the variant may therefore affect the protein structure. CONCLUSION Patients with STISS syndrome exhibit clinical features including psychomotor retardation, intellectual disability, distinctive facial features, and urogenital abnormalities. The c.934del (p.Met312TrpfsTer3) frameshift variant of the PSMD12 gene probably underlay the pathogenesis in the proband. Above finding has enriched the mutational spectrum of the PSMD12 gene.
Adolescent ; Humans ; Male ; Exome Sequencing ; Mutation ; Proteasome Endopeptidase Complex/genetics* ; Syndrome

Objective To analyze the epidemiological characteristics and trends of the incidence and mortality of biliary tract cancer in Shanghai from 2002 to 2020. Methods Data on new cases and deaths of malignant tumors of the gallbladder, extrahepatic bile ducts, and other biliary tract organs from 2002 to 2020 were obtained from the Population-based Cancer Registry and Vital Statistics System of Shanghai Municipal Center for Disease Control and Prevention. Cases or deaths, proportion, crude rate, age-specific rate, age-standardized rate (ASR) and others were calculated stratified by year of diagnosis or death, gender and age-group. ASRs were calculated using Segi′s 1960 world standard population. Trends of the annual percent change (APC) of ASRs, age-specific rates and proportions of new cases with selected diagnostic character of biliary tract cancer stratified by different groups were analyzed by Joinpoint analysis software. Results Annual new cases of biliary tract cancer in Shanghai increased from 963 in 2002 to 1 537 in 2020, with ASR of incidence changing from 3.91/10⁵ to 3.59/10⁵. Annual deaths increased from 830 to 1 225, with ASR of mortality decreased from 3.36/10⁵ to 2.69/10⁵. In 2020, the crude rate of incidence of biliary tract cancer was 10.43/10⁵ (9.54/10⁵ in males and 11.30/10⁵ in females) in Shanghai, and the ASR was 3.59/10⁵ (3.54/10⁵ in males and 3.61/10⁵ in females), with no statistically significant gender difference (P=0.731). The crude rate of mortality was 8.31/10⁵ (7.60/10⁵ in males and 9.00/10⁵ in females), and the ASR was 2.69/10⁵ (2.69/10⁵ in males and 2.66/10⁵ in females), also with no significant gender difference (P=0.874). Age-specific nunbers and rates of incidence and mortality generally increased with aging. Stratified by gender, the trend of ASRs of incidence of biliary tract cancer in Shanghai in males showed no significant change (P=0.179) from 2002 to 2020, nor did that of ASRs of mortality (P=0.738). In females, the ASRs of incidence decreased at an average annual rate of 1.58% (P<0.001), while the trend of ASRs of mortality showed no significant change from 2002 to 2011 (P=0.774), but ASRs decreased at an average annual rate of 3.72% from 2011 to 2020 (P<0.001). Among new cases, the proportions of morphological verification increased, while the proportions of imaging verification decreased. The gallbladder was the most common site, but its proportions decreased significantly, whereas the proportions of extrahepatic bile duct increased from 25.75% to 42.88%. Over 60% of cases were unknown stage at diagnosis, while the combined proportions of stages Ⅰ-Ⅲ remained less than that of stage Ⅳ. Conclusions The ASRs for incidence and mortality of biliary tract cancer in Shanghai remain relatively high, with distinct epidemiological characteristics. The improvement in the diagnosis and treatment of biliary diseases maybe have impact on the incidence patterns of biliary tract cancer in Shanghai, but the effect on increasing survival rates and reducing mortality rates is relatively lagging. It needs a big progress to advance the screening, diagnosis, and survival of biliary tract cancer in Shanghai. This study provides a foundation for further research and prevention strategies for biliary tract cancer.

Objective:To explore the clinical characteristics and gene variant of a fetus with Farber lipogranulomatosis caused by ASAH1 gene variant. Methods:A fetus with Farber lipogranulomatosis caused by ASAH1 gene variant diagnosed at Women and Children′s Hospital of Ningbo University in August 2024 was selected as the subject. Clinical data and abortion tissue samples of the fetus and peripheral blood samples of its parents were collected for whole exome sequencing (WES). Sanger sequencing validation and bioinformatics analysis were performed on candidate variants. This study was approved by Women and Children′s Hospital of Ningbo University (Ethics No. EC2020-048). Results:Generalized skin oedema, pericardial effusion, right pleural effusion and increased bowel echogenicity of the fetus were founded by prenatal ultrasound. WES revealed that the fetus has harbored a homozygous c. 101C>A(p.Ser34Ter) variation in exon 2 of the ASAH1 gene. Sanger sequencing confirmed that both parents carry the heterozygous nonsense variation c. 101C>A (p.Ser34Ter) in ASAH1 gene, which has not been included in databases such as HGMD, ClinVar, 1000 Genomes, ExAC, dbSNP, and gnomAD. Based on the Standards and Guidelines for the Interpretation of Sequence Variants of the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be pathogenic (PM2_Supporting+ PVS1+ PM3_Supporting). The AlphaFold3 model protein structure prediction reveals that the c. 101C>A variant caused the premature appearance of a termination codon, resulting in only a small partial α-helix structure in the N-terminal of the encoded ASAH1 protein, with the complete loss of the α-helix structure in the core domain, which might lead to the loss of function of this protein. Conclusion:The c. 101C>A(p.Ser34Ter) variant of the ASAH1 gene probably underlay the Farber lipogranulomatosis with hydrops fetalis in this fetus. The newly discovered c. 101C>A(p.Ser34Ter) variant has enriched the mutational spectrum of Farber lipogranulomatosis.

Objective:To explore the genetic etiology of a child with brain small vessel disease 1 with ocular anomalies.Methods:A child who was adwstted to Ningbo Women and Children′s Hospital on May 28, 2022, was selected for the study. Clinical data were collected, and peripheral blood samples from the child and her parents were obtained for genomic DNA extraction. Whole exome sequencing (WES) was performed to screen for pathogenic variants. Candidate variants were validated via Sanger sequencing and subjected to bioinformatic analysis. This study was approved by the Medical Ethics Committee of Ningbo Women and Children′s Hospital (Ethics No. EC2020-048).Results:① The child was a 7-year-old female with a diagnosis of epilepsy. ② WES revealed that she has carried a heterozygous missense variant in the COL4A1 gene: c. 1792G>A (p.Gly598Ser). Sanger sequencing confirmed that her parents both had the wild-type genotype for this variant. Based on American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines for the Interpretation of Sequence Variants, the variant were predicted to be a likely pathogenic (PS2+ PM1+ PM2_Supporting+ PP3). ③ Bioinformatics predicted that amino acid 598 was highly conserved in different species, formed hydrogen bond with Asp599 after becoming Ser598. Conclusion:The heterozygous missense variant of the COL4A1 gene c. 1792G>A (p.G598S) could be the pathogenic cause of this child with Brain small vessel disease 1 with ocular anomalies.