Lynch syndrome(LS),also known as hereditary non-polyposis colorectal cancer(HNPCC),is an inherited condition associated with a higher risk of colorectal cancer(CRC)and other cancers.It is caused by germline mutations ...Lynch syndrome(LS),also known as hereditary non-polyposis colorectal cancer(HNPCC),is an inherited condition associated with a higher risk of colorectal cancer(CRC)and other cancers.It is caused by germline mutations in DNA mismatch repair(MMR)genes,including MLH1,MSH2,MSH6 and PMS2.These mutations lead to microsatellite instability(MSI)and defective DNA repair mechanisms,resulting in increased cancer risk.Early detection of LS is crucial for effective management and cancer prevention.Endoscopic surveillance,particularly regular colonoscopy,is recommended for individuals with LS to detect CRC at early stages.Additionally,universal screening of CRC for MMR deficiency can help identify at-risk individuals.Genetic counseling plays a valuable role in LS by guiding patients and their families in understanding the genetic basis,making informed decisions regarding surveillance and prevention,and offering reproductive options to reduce the transmission of pathogenic variants of the offspring.The aim of this review is to outline current strategies for the diagnosis,surveillance,and management of LS,with a focus on the role of genetic counseling,endoscopic screening,and emerging therapeutic approaches to mitigate cancer risk in affected individuals.展开更多
Although the genetic bases of most hereditary cancer syndromes are known,and genetic tests are available for them,the incidence of the most rare of these syndromes is likely underestimated,partially because the clinic...Although the genetic bases of most hereditary cancer syndromes are known,and genetic tests are available for them,the incidence of the most rare of these syndromes is likely underestimated,partially because the clinical expression is neither fully understood nor easily diagnosed due to the variable and complex expressivity. The clinical features of a small pool of rare cancer syndromes include gastroenterological signs,though not necessarily tumors,that could require the intervention of a gastroenterologist during any of the phases of the clinical management. Herein we will attempt to spread the knowledge on these rare syndromes by summarizing the phenotype and genetic basis,and revising the peculiar gastroenterological signs whose underlying role in these rare hereditary cancer syndromes is often neglected. Close collaboration between geneticists and gastroenterologists could facilitate both the early identification of patients or relatives at-risk and the planning of multidisciplinary and tailored management of these subjects.展开更多
Pancreatic ductal adenocarcinoma(PDAC)is one of the most aggressive solid malignancies.A specific mechanism of its metastasis has not been established.In this study,we investigated whether Neural Wiskott-Aldrich syndr...Pancreatic ductal adenocarcinoma(PDAC)is one of the most aggressive solid malignancies.A specific mechanism of its metastasis has not been established.In this study,we investigated whether Neural Wiskott-Aldrich syndrome protein(N-WASP)plays a role in distant metastasis of PDAC.We found that N-WASP is markedly expressed in clinical patients with PDAC.Clinical analysis showed a notably more distant metastatic pattern in the N-WASP-high group compared to the N-WASP-low group.N-WASP was noted to be a novel mediator of epithelialmesenchymal transition(EMT)via gene expression profile studies.Knockdown of N-WASP in pancreatic cancer cells significantly inhibited cell invasion,migration,and EMT.We also observed positive association of lysyl oxidase-like 2(LOXL2)and focal adhesion kinase(FAK)with the N-WASP-mediated response,wherein EMT and invadopodia function were modulated.Both N-WASP and LOXL2 depletion significantly reduced the incidence of liver and lung metastatic lesions in orthotopic mouse models of pancreatic cancer.These results elucidate a novel role for N-WASP signaling associated with LOXL2 in EMT and invadopodia function,with respect to regulation of intercellular communication in tumor cells for promoting pancreatic cancer metastasis.These findings may aid in the development of therapeutic strategies against pancreatic cancer.展开更多
Introduction: Non-Syndromic Clefts Lip-Palates (NSCLP/CP) are most common congenital malformation in the world, with very important psychic and social impact. Formation of NSCLP/CP arises from the interaction of envir...Introduction: Non-Syndromic Clefts Lip-Palates (NSCLP/CP) are most common congenital malformation in the world, with very important psychic and social impact. Formation of NSCLP/CP arises from the interaction of environmental and genetic factors. This paper provides a review of recent progress in defining the genetic causes of NSCLP. Methods: A literature review was conducted on the Medline data by searching for the following keywords: genes, non-syndromic cleft lip-palate, and genetics of clefts lip-palates, until January 2018. Results: Various genes are identified in different population and country, with the study using case parent’s trio. The aim of this study contributes to review relative gene which has been identify in non-syndromic cleft lip and palate, and to help to have a better understanding of the inheritance pattern of this pathology and the prevention of genetic disease. Conclusion: Although three major genes have been confirmed, the genetic research is necessary to provide an understanding of the pathophysiology of the clefts lip-palates.展开更多
BACKGROUND Familial adenomatous polyposis(FAP)is a disorder of autosomal dominant inheritance that is responsible for around 1%of colorectal cancer(CRC)cases.AIM To determine the mutation profile of FAP-specific to th...BACKGROUND Familial adenomatous polyposis(FAP)is a disorder of autosomal dominant inheritance that is responsible for around 1%of colorectal cancer(CRC)cases.AIM To determine the mutation profile of FAP-specific to the Hungarian population.METHODS This prospective single-center study enrolled patients with clinically suspected FAP or attenuated FAP(aFAP).Whole-exome next-generation sequencing was performed to detect variants of 50 FAP priority genes and 173 CRC predisposing genes or other CRC disease-associated genes.To identify larger deletions and insertions,a multiplex amplifiable probe hybridization technique was used.The identified genes were then classified according to the American College of Medical Genetics and Genomics guidelines.RESULTS A total of 26 index patients with clinically suspected FAP(n=21)and aFAP(n=5)were enrolled.APC gene alterations were confirmed in 92.31%of the cases(region 1B deletion,n=2;whole-gene deletion,n=4;frameshift mutation,n=2;nonsense mutation,n=5,and splice mutation,n=1),with the remaining two cases having CHEK2 and MSH3 gene alterations.According to pathogenicity,21 cases had pathogenic mutations,6 cases had likely pathogenic mutations,and 16 cases had variants of unknown significance(VUS).The most frequent of the latter were the POLE(n=5)and PIEZO1(n=4)gene variants.CONCLUSION Germline mutations in the APC gene were confirmed in more than 90%of Hungarian patients with clinically suspected FAP.Although the role of VUS genes is unclear,they are highly likely to play a role in the development of CRC.展开更多
Childhood survivors of acute lymphoblastic leukemia (ALL) are increased risk of several chronic complications, such as second cancers, pulmonary, metabolic complications and cardiovascular disease. Obesity and metabol...Childhood survivors of acute lymphoblastic leukemia (ALL) are increased risk of several chronic complications, such as second cancers, pulmonary, metabolic complications and cardiovascular disease. Obesity and metabolic syndrome is one of the most common treatment related complication in children surviving cancer, which concurs with our nations childhood epidemic [1-3] Recent research has identified the role of genetics in the development of obesity and metabolic syndrome in childhood survivors of ALL. Growth hormone deficiency, Leptin regulation, fat mass obesity (FTO) gene and the insulin resistant ENPP1 variants disorders has been associated adverse effects of chemotherapeutic treatment and the cause of clinical manifestations of metabolic syndrome [4-8]. The illumination of the role of genetic variants can shed insights into obesity within high risk population, as well as, a target to prevent disease.展开更多
AIM:To investigate the genetic basis of Weill-Marchesani syndrome(WMS)in a Chinese family and clarify the pathogenic mechanism of novel ADAMTS17 mutations.METHODS:Comprehensive clinical assessments and genetic analyse...AIM:To investigate the genetic basis of Weill-Marchesani syndrome(WMS)in a Chinese family and clarify the pathogenic mechanism of novel ADAMTS17 mutations.METHODS:Comprehensive clinical assessments and genetic analyses were performed on a Chinese family with two affected siblings.Whole-exome sequencing(WES)was conducted for the proband and other family members.Bioinformatics tools were used to evaluate the conservation,predicted pathogenicity,and structural effects of the identified ADAMTS17 variants.In addition,protein structure modeling was applied to assess the functional impacts of the mutations.RESULTS:The proband(a 32-year-old male)and his elder sister(42y)presented typical clinical features of WMS,including short stature,brachydactyly,high myopia,ectopia lentis,and secondary glaucoma.WES identified a novel compound heterozygous mutation in ADAMTS17:a splicing mutation(c.451-2A>G)inherited from the father and a missense mutation(c.1043G>A;p.C348Y)inherited from the mother.The splicing mutation disrupted normal mRNA splicing and processing,leading to premature translation termination.The missense mutation,which is located in the metalloprotease catalytic domain,was predicted to abolish a critical disulfide bond,thereby impairing protein stability.Both mutations exhibited high evolutionary conservation and were predicted to be pathogenic by multiple bioinformatics algorithms.CONCLUSION:A novel compound heterozygous mutation in ADAMTS17 is identified in this WMS-affected Chinese family,and its pathogenicity is verified via bioinformatics analysis and protein structural modeling.These findings are expected to facilitate the genetic diagnosis of WMS and deepen the understanding of its molecular pathogenesis.展开更多
Genetics is rapidly evolving and is actively playing a role in how we diagnose and manage epilepsy.The definition of an epilepsy syndrome has changed throughout the years.The International League Against Epilepsy(ILAE...Genetics is rapidly evolving and is actively playing a role in how we diagnose and manage epilepsy.The definition of an epilepsy syndrome has changed throughout the years.The International League Against Epilepsy(ILAE)has developed a classification of the epilepsies and has recently described specific epilepsy syndromes taking into account emerging genetic information which is rapidly evolving as well as etiology-specific syndromes.Understanding genetics can help clarify the syndrome and its treatment.This review provides a history of the definition of a syndrome,and the evolving contribution of genetic information that is part of the syndromic classification.We provide few examples of several phenotypes/genotypes of epilepsy syndromes in infancy and childhood and treatment issues that may arise from the available genetic information.Epilepsy syndromes and their genetics have been rapidly changing as new gene technologies are being developed.Understanding genetics can help clarify the syndrome,its treatment,and will help change the field of epilepsy to improve patients qualify of life by creating new means of preventing,controlling,and curing epilepsy.展开更多
Brugada syndrome(BrS)is a life-threatening cardiac rhythm disorder characterized by persistent STsegment elevation in leads V1–V3 and right bundle branch block on electrocardiograms(ECG),and by syncope and sudden dea...Brugada syndrome(BrS)is a life-threatening cardiac rhythm disorder characterized by persistent STsegment elevation in leads V1–V3 and right bundle branch block on electrocardiograms(ECG),and by syncope and sudden death from ventricular tachycardia(VT)and ventricular fibrillation(VF).BrS is responsible for nearly 4%of sudden cardiac deaths and considered to be the most common cause of natural death in males younger than 50 years in some Asian countries.Since the first diseasecausing gene for BrS(the cardiac sodium channel gene SCN5A)was identified in 1998,extensive investigations on both clinical and basic aspects of BrS have occurred rapidly.SCN5A mutations remain the most common cause of BrS;nearly 300 SCN5A mutations have been identified and are responsible for 20%–30%of BrS cases.Commercial genetic testing is available for SCN5A.Recently,seven other disease-causing genes for BrS have been identified and include GPD1L(BrS2),CACNA1C(Cav1.2,BrS3),CACNB2(Cavβ2,BrS4),SCN1B(Navβ1,BrS5),KCNE3(MiRP2,BrS6),SCN3B(Navβ3,BrS7),and HCN4(BrS8).This article will briefly review the progress made over the past decade in our understanding of the clinical,genetic and molecular aspects of BrS.展开更多
BACKGROUND Birt-Hogg-Dubé(BHD)syndrome is a rare genetic disorder associated with mutations in the BHD gene,which can manifest symptoms at any age,including dermatological and pulmonary complications,as well as r...BACKGROUND Birt-Hogg-Dubé(BHD)syndrome is a rare genetic disorder associated with mutations in the BHD gene,which can manifest symptoms at any age,including dermatological and pulmonary complications,as well as renal tumors.This study presents a case of a BHD patient who experienced spontaneous pneumothorax,aiming to enhance the understanding of this syndrome.CASE SUMMARY A 42-year-old female patient presented with left-sided chest pain and tightness lasting three days.Chest computed tomography scans revealed left-sided pneumothorax and multiple pulmonary bullae.Physical examination indicated decreased vocal fremitus and tympanic percussion on the left side.A thorough family history revealed a pattern of pulmonary disorders,including emphysema,spontaneous pneumothorax,and lung cancer among relatives.Genetic testing identified a heterozygous frameshift mutation in the FLCN gene at the 17p11.2 locus.Based on the clinical presentation,imaging findings,family history,and genetic results,the patient was suspected to have BHD syndrome.CONCLUSION We present a case of a heterozygous mutation in the FLCN gene in a patient with BHD syndrome,aiming to review the associated clinical characteristics and genetic mechanisms of this condition.This case serves as a reference point to offer insights into the diagnosis of multiple pulmonary cysts and spontaneous pneumo-thorax of unknown etiology in clinical practice.展开更多
BACKGROUND Floating-harbor syndrome(FHS)is a rare genetic disorder caused by pathogenic variants in the SRCAP gene.Most individuals with FHS have short stature,delayed speech and language development,and dysmorphic fa...BACKGROUND Floating-harbor syndrome(FHS)is a rare genetic disorder caused by pathogenic variants in the SRCAP gene.Most individuals with FHS have short stature,delayed speech and language development,and dysmorphic facial features.However,the patients with FHS are not easy to diagnose due to the overlap of clinical phenotypes with other disorders.CASE SUMMARY We reported a 10-year-old boy who presented with severe short stature,developmental delay and distinctive facial features.Exome sequencing was provided for the proband and his parents.We identified a novel frameshift variant c.7235delinsGT(p.Thr2412fs)in SRCAP gene,and the variant was further validated by Sanger sequencing.The mother of the proband was referred to us for prenatal consultation during next pregnancy.We performed prenatal genetic diagnosis for the fetus.The result of Sanger sequencing for c.7235delinsGT(p.Thr2412fs)in SRCAP gene showed that the fetus did not carry the variant,so the fetus has been born successfully.The newborn does not show any similar symptom to the proband till one month.CONCLUSION This case confirms that the c.7235delinsGT(p.Thr2412fs)variant in the SRCAP gene is associated with FHS and expands the spectrum of SRCAP variants.展开更多
Hirschsprung’s disease (HSCR) is a developmental disorder characterized by the absence of ganglion cells in the distal colon, leading to functional obstruction. Bardet-Biedl syndrome (BBS) is a rare ciliopathy associ...Hirschsprung’s disease (HSCR) is a developmental disorder characterized by the absence of ganglion cells in the distal colon, leading to functional obstruction. Bardet-Biedl syndrome (BBS) is a rare ciliopathy associated with various clinical features, including HSCR. This review article aims to explore the underlying causes of HSCR in children with BBS, focusing on the genetic and developmental factors contributing to the pathogenesis of both conditions. We reviewed relevant literature, including peer-reviewed journal articles and case reports, to provide a comprehensive overview of the current understanding of the relationship between HSCR and BBS. Our findings highlight the complex interplay of genetic mutations, signaling pathways, and developmental processes involved in the pathogenesis of HSCR in BBS. Further research is needed to elucidate the precise mechanisms underlying this association and to develop targeted therapeutic strategies for children with HSCR and BBS.展开更多
[Objective] A total of 260 swine samples of dead or sick pigs collected from 7 provinces （municipalities） Jiangsu, Anhui, Shanghai, Shandong, Zhejiang, Fujian and Jiangxi of China during 2008-2010 were detected for ...[Objective] A total of 260 swine samples of dead or sick pigs collected from 7 provinces （municipalities） Jiangsu, Anhui, Shanghai, Shandong, Zhejiang, Fujian and Jiangxi of China during 2008-2010 were detected for porcine reproductive and respiratory syndrome virus （PRRSV）. And the ORF5 genes of some isolates were amplified and sequenced for understanding the molecule epidemiology and the genetic evolution of PRRSV in East China. [Method] Using RT-PCR method, PRRSV was detected by RT-PCR from samples. The complete ORF5 genes of 36 PRRSV positive samples was amplified, sequenced and analyzed with other 15 strains available on GenBank. [Result] PRRSV was detected in 118/260 of the clinical samples, with a positive rate was 45.4%. Sequence analysis showed that the 36 isolates of this study belonged to the North American-type PRRSV strains and were closely related to the highly pathogenic PRRSV （HP-PRRSV） with 94.6%-100% amino acid sequence identities. The sequence analysis combined with the phylogenetic analysis indicated that all these North American-type PRRSV strains in East China were further divided into five subgenotypes, subgenotype Ⅲ showed closer identity with HPPRRSV; almost all subgenotypes were found to be variable in the primary neutralizing epitope; subgenotypes Ⅲ and IV had more glycosylation sites than others. Although these 36 isolates were collected from different provinces in East China, there were no obvious relations between the distribution of PRRSV and the region. [Conclusion] The PRRSV infection was widespread and HP-PRRSV was the popular strain in East China during 2008-2010. However some different genetic characteristics appeared in the genomes, the genetic evolution was relatively stable. There exists a cross-cutting phenomenon on the genetic relationship of PRRSV isolates obtained from different provinces. Subgenotypes IV and V only appeared in some provinces, but the distribution of PRRSV did not show apparent geographical characteristics.展开更多
Kartagener＇s syndrome （KS） is an autosomal recessive genetic disease accounting for approximately 50% of the cases of primary ciliary dyskinesia （PCD）. As it is accompanied by many complications, PCD/KS severely ...Kartagener＇s syndrome （KS） is an autosomal recessive genetic disease accounting for approximately 50% of the cases of primary ciliary dyskinesia （PCD）. As it is accompanied by many complications, PCD/KS severely affects the patient＇s quality of life. Therapeutic approaches for PCD/KS aim to enhance prevention, facilitate rapid definitive diagnosis, avoid misdiagnosis, maintain active treatment, control infection and postpone the development of lesions. In male patients, sperm flagella may show impairment in or complete absence of the ability to swing, which ultimately results in male infertility. Assisted reproductive technology will certainly benefit such patients. For PCD/KS patients with completely immotile sperm, intracytoplasmic sperm injection may be very important and even indispensable. Considering the number of PCD/KS susceptibility genes and mutations that are being identified, more extensive genetic screening is indispensable in patients with these diseases. Moreover, further studies into the potential molecular mechanisms of these diseases are required. In this review, we summarize the available information on various aspects of this disease in order to delineate the therapeutic objectives more clearly, and clarify the efficacy of assisted reproductive technology as a means of treatment for patients with PCD/KS-associated infertility.展开更多
Irritable bowel syndrome (IBS) is a complex symptom-based disorder without established biomarkers or putative pathophysiology. IBS is a common functional gastrointestinal disorder which is defined as recurrent abdomin...Irritable bowel syndrome (IBS) is a complex symptom-based disorder without established biomarkers or putative pathophysiology. IBS is a common functional gastrointestinal disorder which is defined as recurrent abdominal pain or discomfort that has at least two of the following symptoms for 3 d per month in the past 3 mo according to ROME III: relief by defecation, onset associated with a change in stool frequency or onset with change in appearance or form of stool. Recent discoveries revealed genetic polymorphisms in specific cytokines and neuropeptides may possibly influence the frequencies and severity of symptoms, as well as the therapeutic responses in treating IBS patients. This review gives new insights on how genetic determinations influence in clinical manifestations, treatment responses and potential biomarkers of IBS.展开更多
Genetic polymorphism is associated with irritable bowel syndrome(IBS)in terms of susceptibility and clinical manifestations.Previous studies have shown that genetic polymorphism might play a key role in the onset and ...Genetic polymorphism is associated with irritable bowel syndrome(IBS)in terms of susceptibility and clinical manifestations.Previous studies have shown that genetic polymorphism might play a key role in the onset and progression of IBS by modulating components of its pathogenesis such as the gut-brain axis,gastrointestinal motility,inflammatory activity,and immune status.Although underlying pathophysiological mechanisms have not been fully clarified,the potential ethnic differences that are present in worldwide genetic studies of IBS deserve attention.This review surveyed numerous studies focusing on IBSassociated single nucleotide polymorphisms,and investigated the ethnic disparities revealed by them.The results demonstrate the need for more attention on ethnic factors in IBS-related genetic studies.Taking ethnic backgrounds into accounts and placing emphasis on disparities potentially ascribed to ethnicity could help lay a solid and generalized foundation for transcultural,multi-ethnic,or secondary analyses in IBS,for example,a meta-analysis.Broader genetic studies considering ethnic factors are greatly needed to obtain a better understanding of the pathophysiological mechanisms of IBS and to improve the prevention,intervention,and treatment of this disease.展开更多
Irritable bowel syndrome （IBS） is a common functional gastrointestinal disorder. According to the Rome m criteria, IBS is defined as recurrent abdominal pain or discomfort for at least 3 d per month during the previ...Irritable bowel syndrome （IBS） is a common functional gastrointestinal disorder. According to the Rome m criteria, IBS is defined as recurrent abdominal pain or discomfort for at least 3 d per month during the previous 3 mo associated with two or more of the following symptoms： improvement with defecation, onset associated with a change in the frequency of stool and/or onset associated with a change in form or appearance of stool. There is growing evidence regarding the genetic contribution in IBS, however the precise etiology of IBS is still unknown. The evaluation of the genetic influence is based on twin studies, familial aggregation and genetic epidemiological investigations. Most studies showed a concordance for IBS significantly greater in monozygotic than in dizygotic twins. The majority of the studies have shown that familial aggregation may represent exposures to a similar environment, as well as the influence of genetic factors. Whereas no specific gene has been identified in association with IBS, recent studies have noticed the importance of polymorphisms in the promoter region of the serotonin reuptake transporter gene, G-protein beta 3 subunit gene （C825T）, cholecystokinin receptor （CCKAR gene 779T〉C）, and high-producer tumor necrosis factor genotype. Further studies are necessary to determine how genetic factors influence the clinical manifestations and therapeutical response in IBS patients.展开更多
Severe fever with thrombocytopenia syndrome virus(SFTSV)is an emerging tick-borne bunyavirus that causes hemorrhagic fever-like disease(SFTS)in humans with a case fatality rate up to 30%.To date,the molecular biology ...Severe fever with thrombocytopenia syndrome virus(SFTSV)is an emerging tick-borne bunyavirus that causes hemorrhagic fever-like disease(SFTS)in humans with a case fatality rate up to 30%.To date,the molecular biology involved in SFTSV infection remains obscure.There are seven major genotypes of SFTSV(C1-C4 and J1-J3)and previously a reverse genetic system was established on a C3 strain of SFTSV.Here,we reported successfully establishment of a reverse genetics system based on a SFTSV C4 strain.First,we obtained the 5’-and 3’-terminal untranslated region(UTR)sequences of the Large(L),Medium(M)and Small(S)segments of a laboratory-adapted SFTSV C4 strain through rapid amplification of cDNA ends analysis,and developed functional T7 polymerase-based L-,M-and S-segment minigenome assays.Then,fulllength cDNA clones were constructed and infectious SFTSV were recovered from co-transfected cells.Viral infectivity,growth kinetics,and viral protein expression profile of the rescued virus were compared with the laboratory-adapted virus.Focus formation assay showed that the size and morphology of the foci formed by the rescued SFTSV were indistinguishable with the laboratory-adapted virus.However,one-step growth curve and nucleoprotein expression analyses revealed the rescued virus replicated less efficiently than the laboratory-adapted virus.Sequence analysis indicated that the difference may be due to the mutations in the laboratory-adapted strain which are more prone to cell culture.The results help us to understand the molecular biology of SFTSV,and provide a useful tool for developing vaccines and antivirals against SFTS.展开更多
Acephalic spermatozoa syndrome(ASS)is one of the most severe spermatogenic failures of all infertility in men.The cognition of ASS has experienced a tortuous process.Over the past years,with the in-depth understanding...Acephalic spermatozoa syndrome(ASS)is one of the most severe spermatogenic failures of all infertility in men.The cognition of ASS has experienced a tortuous process.Over the past years,with the in-depth understanding of spermatogenesis and the emergence of new genetic research technologies,the unraveling of the genetic causes of spermatogenic failure has become highly active.From these advances,we established a genetic background and made significant progress in the discovery of the genetic causes of ASS.It is important to identify pathogenic genes and mutations in ASS to determine the biological reasons for the occurrence of the disease as well as provide genetic diagnosis and treatment strategies for patients with this syndrome.In this review,we enumerate various technological developments,which have made a positive contribution to the discovery of candidate genes for ASS from the past to the present.Simultaneously,we summarize the known genetic etiology of this phenotype and the clinical outcomes of treatments in the present.Furthermore,we propose perspectives for further study and application of genetic diagnosis and assisted reproductive treatment in the future.展开更多
Sotos syndrome is characterized by overgrowth features and is caused by alterations in the nuclear receptor binding SET domain protein 1 gene.Attentiondeficit/hyperactivity disorder(ADHD)is considered a neurodevelopme...Sotos syndrome is characterized by overgrowth features and is caused by alterations in the nuclear receptor binding SET domain protein 1 gene.Attentiondeficit/hyperactivity disorder(ADHD)is considered a neurodevelopment and psychiatric disorder in childhood.Genetic characteristics and clinical presentation could play an important role in the diagnosis of Sotos syndrome and ADHD.Magnetic resonance imaging(MRI)has been used to assess medical images in Sotos syndrome and ADHD.The images process is considered to display in MRI while wavelet fusion has been used to integrate distinct images for achieving more complete information in single image in this editorial.In the future,genetic mechanisms and artificial intelligence related to medical images could be used in the clinical diagnosis of Sotos syndrome and ADHD.展开更多
文摘Lynch syndrome(LS),also known as hereditary non-polyposis colorectal cancer(HNPCC),is an inherited condition associated with a higher risk of colorectal cancer(CRC)and other cancers.It is caused by germline mutations in DNA mismatch repair(MMR)genes,including MLH1,MSH2,MSH6 and PMS2.These mutations lead to microsatellite instability(MSI)and defective DNA repair mechanisms,resulting in increased cancer risk.Early detection of LS is crucial for effective management and cancer prevention.Endoscopic surveillance,particularly regular colonoscopy,is recommended for individuals with LS to detect CRC at early stages.Additionally,universal screening of CRC for MMR deficiency can help identify at-risk individuals.Genetic counseling plays a valuable role in LS by guiding patients and their families in understanding the genetic basis,making informed decisions regarding surveillance and prevention,and offering reproductive options to reduce the transmission of pathogenic variants of the offspring.The aim of this review is to outline current strategies for the diagnosis,surveillance,and management of LS,with a focus on the role of genetic counseling,endoscopic screening,and emerging therapeutic approaches to mitigate cancer risk in affected individuals.
基金Supported by Grants from the Italian Ministry of Health,5 per 1000,AIRC 15460 and Genoa Atheneum 2014(to Ghiorzo P)
文摘Although the genetic bases of most hereditary cancer syndromes are known,and genetic tests are available for them,the incidence of the most rare of these syndromes is likely underestimated,partially because the clinical expression is neither fully understood nor easily diagnosed due to the variable and complex expressivity. The clinical features of a small pool of rare cancer syndromes include gastroenterological signs,though not necessarily tumors,that could require the intervention of a gastroenterologist during any of the phases of the clinical management. Herein we will attempt to spread the knowledge on these rare syndromes by summarizing the phenotype and genetic basis,and revising the peculiar gastroenterological signs whose underlying role in these rare hereditary cancer syndromes is often neglected. Close collaboration between geneticists and gastroenterologists could facilitate both the early identification of patients or relatives at-risk and the planning of multidisciplinary and tailored management of these subjects.
基金supported by a National Research Foundation of Korea(NRF)grant funded by the Korean Government,Ministry of Science and ICT(MSIT)(2016R1C1B102207,2022R1A2C1004141 and 2022R1A2C-1091712)the National R&D Program for Cancer Control through the National Cancer Center(NCC)funded by the Ministry of Health&Welfare,Republic of Korea(HA22C0053000022).
文摘Pancreatic ductal adenocarcinoma(PDAC)is one of the most aggressive solid malignancies.A specific mechanism of its metastasis has not been established.In this study,we investigated whether Neural Wiskott-Aldrich syndrome protein(N-WASP)plays a role in distant metastasis of PDAC.We found that N-WASP is markedly expressed in clinical patients with PDAC.Clinical analysis showed a notably more distant metastatic pattern in the N-WASP-high group compared to the N-WASP-low group.N-WASP was noted to be a novel mediator of epithelialmesenchymal transition(EMT)via gene expression profile studies.Knockdown of N-WASP in pancreatic cancer cells significantly inhibited cell invasion,migration,and EMT.We also observed positive association of lysyl oxidase-like 2(LOXL2)and focal adhesion kinase(FAK)with the N-WASP-mediated response,wherein EMT and invadopodia function were modulated.Both N-WASP and LOXL2 depletion significantly reduced the incidence of liver and lung metastatic lesions in orthotopic mouse models of pancreatic cancer.These results elucidate a novel role for N-WASP signaling associated with LOXL2 in EMT and invadopodia function,with respect to regulation of intercellular communication in tumor cells for promoting pancreatic cancer metastasis.These findings may aid in the development of therapeutic strategies against pancreatic cancer.
文摘Introduction: Non-Syndromic Clefts Lip-Palates (NSCLP/CP) are most common congenital malformation in the world, with very important psychic and social impact. Formation of NSCLP/CP arises from the interaction of environmental and genetic factors. This paper provides a review of recent progress in defining the genetic causes of NSCLP. Methods: A literature review was conducted on the Medline data by searching for the following keywords: genes, non-syndromic cleft lip-palate, and genetics of clefts lip-palates, until January 2018. Results: Various genes are identified in different population and country, with the study using case parent’s trio. The aim of this study contributes to review relative gene which has been identify in non-syndromic cleft lip and palate, and to help to have a better understanding of the inheritance pattern of this pathology and the prevention of genetic disease. Conclusion: Although three major genes have been confirmed, the genetic research is necessary to provide an understanding of the pathophysiology of the clefts lip-palates.
基金Supported by the Research Grants of the National Research,Development and Innovation Office,No.K125377,No.K134863 and No.K143549New National Excellence Program of the Ministry of Human Capacities,No.UNKP-20-5-SZTE-161,No.UNKP-22-3-SZTE-233,No.UNKP-23-5-SZTE-719,No.UNKP-22-4-SZTE-296 and No.UNKP-22-3-SZTE-278+1 种基金Janos Bolyai Research Grant,No.BO/00723/22the Géza Hetényi Research Grant by Albert Szent-Györgyi Medical School,University of Szeged.
文摘BACKGROUND Familial adenomatous polyposis(FAP)is a disorder of autosomal dominant inheritance that is responsible for around 1%of colorectal cancer(CRC)cases.AIM To determine the mutation profile of FAP-specific to the Hungarian population.METHODS This prospective single-center study enrolled patients with clinically suspected FAP or attenuated FAP(aFAP).Whole-exome next-generation sequencing was performed to detect variants of 50 FAP priority genes and 173 CRC predisposing genes or other CRC disease-associated genes.To identify larger deletions and insertions,a multiplex amplifiable probe hybridization technique was used.The identified genes were then classified according to the American College of Medical Genetics and Genomics guidelines.RESULTS A total of 26 index patients with clinically suspected FAP(n=21)and aFAP(n=5)were enrolled.APC gene alterations were confirmed in 92.31%of the cases(region 1B deletion,n=2;whole-gene deletion,n=4;frameshift mutation,n=2;nonsense mutation,n=5,and splice mutation,n=1),with the remaining two cases having CHEK2 and MSH3 gene alterations.According to pathogenicity,21 cases had pathogenic mutations,6 cases had likely pathogenic mutations,and 16 cases had variants of unknown significance(VUS).The most frequent of the latter were the POLE(n=5)and PIEZO1(n=4)gene variants.CONCLUSION Germline mutations in the APC gene were confirmed in more than 90%of Hungarian patients with clinically suspected FAP.Although the role of VUS genes is unclear,they are highly likely to play a role in the development of CRC.
文摘Childhood survivors of acute lymphoblastic leukemia (ALL) are increased risk of several chronic complications, such as second cancers, pulmonary, metabolic complications and cardiovascular disease. Obesity and metabolic syndrome is one of the most common treatment related complication in children surviving cancer, which concurs with our nations childhood epidemic [1-3] Recent research has identified the role of genetics in the development of obesity and metabolic syndrome in childhood survivors of ALL. Growth hormone deficiency, Leptin regulation, fat mass obesity (FTO) gene and the insulin resistant ENPP1 variants disorders has been associated adverse effects of chemotherapeutic treatment and the cause of clinical manifestations of metabolic syndrome [4-8]. The illumination of the role of genetic variants can shed insights into obesity within high risk population, as well as, a target to prevent disease.
文摘AIM:To investigate the genetic basis of Weill-Marchesani syndrome(WMS)in a Chinese family and clarify the pathogenic mechanism of novel ADAMTS17 mutations.METHODS:Comprehensive clinical assessments and genetic analyses were performed on a Chinese family with two affected siblings.Whole-exome sequencing(WES)was conducted for the proband and other family members.Bioinformatics tools were used to evaluate the conservation,predicted pathogenicity,and structural effects of the identified ADAMTS17 variants.In addition,protein structure modeling was applied to assess the functional impacts of the mutations.RESULTS:The proband(a 32-year-old male)and his elder sister(42y)presented typical clinical features of WMS,including short stature,brachydactyly,high myopia,ectopia lentis,and secondary glaucoma.WES identified a novel compound heterozygous mutation in ADAMTS17:a splicing mutation(c.451-2A>G)inherited from the father and a missense mutation(c.1043G>A;p.C348Y)inherited from the mother.The splicing mutation disrupted normal mRNA splicing and processing,leading to premature translation termination.The missense mutation,which is located in the metalloprotease catalytic domain,was predicted to abolish a critical disulfide bond,thereby impairing protein stability.Both mutations exhibited high evolutionary conservation and were predicted to be pathogenic by multiple bioinformatics algorithms.CONCLUSION:A novel compound heterozygous mutation in ADAMTS17 is identified in this WMS-affected Chinese family,and its pathogenicity is verified via bioinformatics analysis and protein structural modeling.These findings are expected to facilitate the genetic diagnosis of WMS and deepen the understanding of its molecular pathogenesis.
文摘Genetics is rapidly evolving and is actively playing a role in how we diagnose and manage epilepsy.The definition of an epilepsy syndrome has changed throughout the years.The International League Against Epilepsy(ILAE)has developed a classification of the epilepsies and has recently described specific epilepsy syndromes taking into account emerging genetic information which is rapidly evolving as well as etiology-specific syndromes.Understanding genetics can help clarify the syndrome and its treatment.This review provides a history of the definition of a syndrome,and the evolving contribution of genetic information that is part of the syndromic classification.We provide few examples of several phenotypes/genotypes of epilepsy syndromes in infancy and childhood and treatment issues that may arise from the available genetic information.Epilepsy syndromes and their genetics have been rapidly changing as new gene technologies are being developed.Understanding genetics can help clarify the syndrome,its treatment,and will help change the field of epilepsy to improve patients qualify of life by creating new means of preventing,controlling,and curing epilepsy.
基金This work was supported by the China National Basic Research Program(973 program)(No.2007CB512002)a grant from the National Natural Science Foundation of China(Grant No.30700455)a Wuhan City Academic Leadership award,and the Hubei Natural Science Key Program.
文摘Brugada syndrome(BrS)is a life-threatening cardiac rhythm disorder characterized by persistent STsegment elevation in leads V1–V3 and right bundle branch block on electrocardiograms(ECG),and by syncope and sudden death from ventricular tachycardia(VT)and ventricular fibrillation(VF).BrS is responsible for nearly 4%of sudden cardiac deaths and considered to be the most common cause of natural death in males younger than 50 years in some Asian countries.Since the first diseasecausing gene for BrS(the cardiac sodium channel gene SCN5A)was identified in 1998,extensive investigations on both clinical and basic aspects of BrS have occurred rapidly.SCN5A mutations remain the most common cause of BrS;nearly 300 SCN5A mutations have been identified and are responsible for 20%–30%of BrS cases.Commercial genetic testing is available for SCN5A.Recently,seven other disease-causing genes for BrS have been identified and include GPD1L(BrS2),CACNA1C(Cav1.2,BrS3),CACNB2(Cavβ2,BrS4),SCN1B(Navβ1,BrS5),KCNE3(MiRP2,BrS6),SCN3B(Navβ3,BrS7),and HCN4(BrS8).This article will briefly review the progress made over the past decade in our understanding of the clinical,genetic and molecular aspects of BrS.
文摘BACKGROUND Birt-Hogg-Dubé(BHD)syndrome is a rare genetic disorder associated with mutations in the BHD gene,which can manifest symptoms at any age,including dermatological and pulmonary complications,as well as renal tumors.This study presents a case of a BHD patient who experienced spontaneous pneumothorax,aiming to enhance the understanding of this syndrome.CASE SUMMARY A 42-year-old female patient presented with left-sided chest pain and tightness lasting three days.Chest computed tomography scans revealed left-sided pneumothorax and multiple pulmonary bullae.Physical examination indicated decreased vocal fremitus and tympanic percussion on the left side.A thorough family history revealed a pattern of pulmonary disorders,including emphysema,spontaneous pneumothorax,and lung cancer among relatives.Genetic testing identified a heterozygous frameshift mutation in the FLCN gene at the 17p11.2 locus.Based on the clinical presentation,imaging findings,family history,and genetic results,the patient was suspected to have BHD syndrome.CONCLUSION We present a case of a heterozygous mutation in the FLCN gene in a patient with BHD syndrome,aiming to review the associated clinical characteristics and genetic mechanisms of this condition.This case serves as a reference point to offer insights into the diagnosis of multiple pulmonary cysts and spontaneous pneumo-thorax of unknown etiology in clinical practice.
基金Supported by National Key Research and Development Program of China,No.2022YFC2703302.
文摘BACKGROUND Floating-harbor syndrome(FHS)is a rare genetic disorder caused by pathogenic variants in the SRCAP gene.Most individuals with FHS have short stature,delayed speech and language development,and dysmorphic facial features.However,the patients with FHS are not easy to diagnose due to the overlap of clinical phenotypes with other disorders.CASE SUMMARY We reported a 10-year-old boy who presented with severe short stature,developmental delay and distinctive facial features.Exome sequencing was provided for the proband and his parents.We identified a novel frameshift variant c.7235delinsGT(p.Thr2412fs)in SRCAP gene,and the variant was further validated by Sanger sequencing.The mother of the proband was referred to us for prenatal consultation during next pregnancy.We performed prenatal genetic diagnosis for the fetus.The result of Sanger sequencing for c.7235delinsGT(p.Thr2412fs)in SRCAP gene showed that the fetus did not carry the variant,so the fetus has been born successfully.The newborn does not show any similar symptom to the proband till one month.CONCLUSION This case confirms that the c.7235delinsGT(p.Thr2412fs)variant in the SRCAP gene is associated with FHS and expands the spectrum of SRCAP variants.
文摘Hirschsprung’s disease (HSCR) is a developmental disorder characterized by the absence of ganglion cells in the distal colon, leading to functional obstruction. Bardet-Biedl syndrome (BBS) is a rare ciliopathy associated with various clinical features, including HSCR. This review article aims to explore the underlying causes of HSCR in children with BBS, focusing on the genetic and developmental factors contributing to the pathogenesis of both conditions. We reviewed relevant literature, including peer-reviewed journal articles and case reports, to provide a comprehensive overview of the current understanding of the relationship between HSCR and BBS. Our findings highlight the complex interplay of genetic mutations, signaling pathways, and developmental processes involved in the pathogenesis of HSCR in BBS. Further research is needed to elucidate the precise mechanisms underlying this association and to develop targeted therapeutic strategies for children with HSCR and BBS.
基金Supported by Funds for Agricultural Science and Technology Innovation in Jiangsu Province (cx(10)424)~~
文摘[Objective] A total of 260 swine samples of dead or sick pigs collected from 7 provinces （municipalities） Jiangsu, Anhui, Shanghai, Shandong, Zhejiang, Fujian and Jiangxi of China during 2008-2010 were detected for porcine reproductive and respiratory syndrome virus （PRRSV）. And the ORF5 genes of some isolates were amplified and sequenced for understanding the molecule epidemiology and the genetic evolution of PRRSV in East China. [Method] Using RT-PCR method, PRRSV was detected by RT-PCR from samples. The complete ORF5 genes of 36 PRRSV positive samples was amplified, sequenced and analyzed with other 15 strains available on GenBank. [Result] PRRSV was detected in 118/260 of the clinical samples, with a positive rate was 45.4%. Sequence analysis showed that the 36 isolates of this study belonged to the North American-type PRRSV strains and were closely related to the highly pathogenic PRRSV （HP-PRRSV） with 94.6%-100% amino acid sequence identities. The sequence analysis combined with the phylogenetic analysis indicated that all these North American-type PRRSV strains in East China were further divided into five subgenotypes, subgenotype Ⅲ showed closer identity with HPPRRSV; almost all subgenotypes were found to be variable in the primary neutralizing epitope; subgenotypes Ⅲ and IV had more glycosylation sites than others. Although these 36 isolates were collected from different provinces in East China, there were no obvious relations between the distribution of PRRSV and the region. [Conclusion] The PRRSV infection was widespread and HP-PRRSV was the popular strain in East China during 2008-2010. However some different genetic characteristics appeared in the genomes, the genetic evolution was relatively stable. There exists a cross-cutting phenomenon on the genetic relationship of PRRSV isolates obtained from different provinces. Subgenotypes IV and V only appeared in some provinces, but the distribution of PRRSV did not show apparent geographical characteristics.
文摘Kartagener＇s syndrome （KS） is an autosomal recessive genetic disease accounting for approximately 50% of the cases of primary ciliary dyskinesia （PCD）. As it is accompanied by many complications, PCD/KS severely affects the patient＇s quality of life. Therapeutic approaches for PCD/KS aim to enhance prevention, facilitate rapid definitive diagnosis, avoid misdiagnosis, maintain active treatment, control infection and postpone the development of lesions. In male patients, sperm flagella may show impairment in or complete absence of the ability to swing, which ultimately results in male infertility. Assisted reproductive technology will certainly benefit such patients. For PCD/KS patients with completely immotile sperm, intracytoplasmic sperm injection may be very important and even indispensable. Considering the number of PCD/KS susceptibility genes and mutations that are being identified, more extensive genetic screening is indispensable in patients with these diseases. Moreover, further studies into the potential molecular mechanisms of these diseases are required. In this review, we summarize the available information on various aspects of this disease in order to delineate the therapeutic objectives more clearly, and clarify the efficacy of assisted reproductive technology as a means of treatment for patients with PCD/KS-associated infertility.
文摘Irritable bowel syndrome (IBS) is a complex symptom-based disorder without established biomarkers or putative pathophysiology. IBS is a common functional gastrointestinal disorder which is defined as recurrent abdominal pain or discomfort that has at least two of the following symptoms for 3 d per month in the past 3 mo according to ROME III: relief by defecation, onset associated with a change in stool frequency or onset with change in appearance or form of stool. Recent discoveries revealed genetic polymorphisms in specific cytokines and neuropeptides may possibly influence the frequencies and severity of symptoms, as well as the therapeutic responses in treating IBS patients. This review gives new insights on how genetic determinations influence in clinical manifestations, treatment responses and potential biomarkers of IBS.
基金Supported by the Program of International S&T Cooperation,No.2014DFA31850National Natural Science Foundation of China,No.81870379.
文摘Genetic polymorphism is associated with irritable bowel syndrome(IBS)in terms of susceptibility and clinical manifestations.Previous studies have shown that genetic polymorphism might play a key role in the onset and progression of IBS by modulating components of its pathogenesis such as the gut-brain axis,gastrointestinal motility,inflammatory activity,and immune status.Although underlying pathophysiological mechanisms have not been fully clarified,the potential ethnic differences that are present in worldwide genetic studies of IBS deserve attention.This review surveyed numerous studies focusing on IBSassociated single nucleotide polymorphisms,and investigated the ethnic disparities revealed by them.The results demonstrate the need for more attention on ethnic factors in IBS-related genetic studies.Taking ethnic backgrounds into accounts and placing emphasis on disparities potentially ascribed to ethnicity could help lay a solid and generalized foundation for transcultural,multi-ethnic,or secondary analyses in IBS,for example,a meta-analysis.Broader genetic studies considering ethnic factors are greatly needed to obtain a better understanding of the pathophysiological mechanisms of IBS and to improve the prevention,intervention,and treatment of this disease.
文摘Irritable bowel syndrome （IBS） is a common functional gastrointestinal disorder. According to the Rome m criteria, IBS is defined as recurrent abdominal pain or discomfort for at least 3 d per month during the previous 3 mo associated with two or more of the following symptoms： improvement with defecation, onset associated with a change in the frequency of stool and/or onset associated with a change in form or appearance of stool. There is growing evidence regarding the genetic contribution in IBS, however the precise etiology of IBS is still unknown. The evaluation of the genetic influence is based on twin studies, familial aggregation and genetic epidemiological investigations. Most studies showed a concordance for IBS significantly greater in monozygotic than in dizygotic twins. The majority of the studies have shown that familial aggregation may represent exposures to a similar environment, as well as the influence of genetic factors. Whereas no specific gene has been identified in association with IBS, recent studies have noticed the importance of polymorphisms in the promoter region of the serotonin reuptake transporter gene, G-protein beta 3 subunit gene （C825T）, cholecystokinin receptor （CCKAR gene 779T〉C）, and high-producer tumor necrosis factor genotype. Further studies are necessary to determine how genetic factors influence the clinical manifestations and therapeutical response in IBS patients.
基金supported by grants from the National Natural Science Foundation of China(No.31900146Open Research Fund Program of the State Key Laboratory of Virology of China(No.2020IOV003)Team project of Health Commission of Hubei Province(WJ2019C003)。
文摘Severe fever with thrombocytopenia syndrome virus(SFTSV)is an emerging tick-borne bunyavirus that causes hemorrhagic fever-like disease(SFTS)in humans with a case fatality rate up to 30%.To date,the molecular biology involved in SFTSV infection remains obscure.There are seven major genotypes of SFTSV(C1-C4 and J1-J3)and previously a reverse genetic system was established on a C3 strain of SFTSV.Here,we reported successfully establishment of a reverse genetics system based on a SFTSV C4 strain.First,we obtained the 5’-and 3’-terminal untranslated region(UTR)sequences of the Large(L),Medium(M)and Small(S)segments of a laboratory-adapted SFTSV C4 strain through rapid amplification of cDNA ends analysis,and developed functional T7 polymerase-based L-,M-and S-segment minigenome assays.Then,fulllength cDNA clones were constructed and infectious SFTSV were recovered from co-transfected cells.Viral infectivity,growth kinetics,and viral protein expression profile of the rescued virus were compared with the laboratory-adapted virus.Focus formation assay showed that the size and morphology of the foci formed by the rescued SFTSV were indistinguishable with the laboratory-adapted virus.However,one-step growth curve and nucleoprotein expression analyses revealed the rescued virus replicated less efficiently than the laboratory-adapted virus.Sequence analysis indicated that the difference may be due to the mutations in the laboratory-adapted strain which are more prone to cell culture.The results help us to understand the molecular biology of SFTSV,and provide a useful tool for developing vaccines and antivirals against SFTS.
文摘Acephalic spermatozoa syndrome(ASS)is one of the most severe spermatogenic failures of all infertility in men.The cognition of ASS has experienced a tortuous process.Over the past years,with the in-depth understanding of spermatogenesis and the emergence of new genetic research technologies,the unraveling of the genetic causes of spermatogenic failure has become highly active.From these advances,we established a genetic background and made significant progress in the discovery of the genetic causes of ASS.It is important to identify pathogenic genes and mutations in ASS to determine the biological reasons for the occurrence of the disease as well as provide genetic diagnosis and treatment strategies for patients with this syndrome.In this review,we enumerate various technological developments,which have made a positive contribution to the discovery of candidate genes for ASS from the past to the present.Simultaneously,we summarize the known genetic etiology of this phenotype and the clinical outcomes of treatments in the present.Furthermore,we propose perspectives for further study and application of genetic diagnosis and assisted reproductive treatment in the future.
基金Supported by Natural Science Foundation of Shanghai,No.17ZR1431400National Key R and D Program of China,No.2017YFA0103902.
文摘Sotos syndrome is characterized by overgrowth features and is caused by alterations in the nuclear receptor binding SET domain protein 1 gene.Attentiondeficit/hyperactivity disorder(ADHD)is considered a neurodevelopment and psychiatric disorder in childhood.Genetic characteristics and clinical presentation could play an important role in the diagnosis of Sotos syndrome and ADHD.Magnetic resonance imaging(MRI)has been used to assess medical images in Sotos syndrome and ADHD.The images process is considered to display in MRI while wavelet fusion has been used to integrate distinct images for achieving more complete information in single image in this editorial.In the future,genetic mechanisms and artificial intelligence related to medical images could be used in the clinical diagnosis of Sotos syndrome and ADHD.
