Neural Wiskott-Aldrich syndrome protein(N-WASP)promotes distant metastasis in pancreatic ductal adenocarcinoma via activation of LOXL2

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.

Signs and genetics of rare cancer syndromes with gastroenterological features

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.

Updating Genetics Polymorphisms of Non-Syndromic Clefts Lip-Palates

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.

Usher syndrome:Genetic diagnosis and current therapeutic approaches

Usher Syndrome(USH)is the most common deaf-blind syndrome,affecting approximately 1 in 6000 people in the deaf population.This genetic condition is characterized by a combination of hearing loss(HL),retinitis pigmentosa,and,in some cases,vestibular areflexia.Among the subtypes of USH,USH type 1 is considered the most severe form,presenting profound bilateral congenital deafness,vestibular areflexia,and early onset RP.USH type 2 is the most common form,exhibiting congenital moderate to severe HL for low frequencies and severe to profound HL for high frequencies.Conversely,type 3 is the rarest,initially manifesting mild symptoms during childhood that become more prominent in the first decades of life.The dual impact of USH on both visual and auditory senses significantly impairs patients'quality of life,restricting their daily activities and interactions with society.To date,9 genes have been confirmed so far for USH:MYO7A,USH1C,CDH23,PCDH15,USH1G,USH2A,ADGRV1,WHRN and CLRN1.These genes are inherited in an autosomal recessive manner and encode proteins expressed in the inner ear and retina,leading to functional loss.Although non-genetic methods can assist in patient triage and disease extension evaluation,genetic and molecular tests play a pivotal role in providing genetic counseling,enabling appropriate gene therapy,and facilitating timely cochlear implantation(CI).The CRISPR/Cas9 system and viral-based gene replacement therapy have recently emerged as highly promising techniques for treating USH.Regarding drug therapy,PTC-124 and Nb54 have been identified as promising drug interventions for genetic HL in USH.Simultaneously,CI has proven to be critical in the restoration of hearing.This review aims to summarize the genetic and molecular diagnosis of USH and highlight the importance of early diagnosis in Cuzzuol BR et al.Diagnosis and current treatments of USH WJO https://www.wjgnet.com 2 January 19,2024 Volume 11 Issue 1 guiding appropriate treatment strategies and improving patient prognosis.

Obesity and childhood survivors of acute lymphoblastic leukemia: Do genetics play a role?

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.

Advancements in Lynch Syndrome Management: Applying Immunotherapy for Therapeutic Success

Lynch syndrome is the fourth most common cancer in the United States, with an early age of onset and poor prognosis. Here, we present a unique case of a patient with progressive colon cancer due to a late diagnosis of Lynch syndrome showing excellent response to immunotherapy. A 59-year-old male with a history of rectal cancer 30 years ago came to the hospital due to a fever and further found a large necrotic colon mass. Biopsy was positive for colorectal cancer;however, due to the size of the tumor, the patient was deemed not a surgical candidate and offered hospice with palliative chemotherapy. Based on further workup, the patient was diagnosed with Lynch syndrome, with colon cancer determined to be responsive to Immunotherapy. He was started on JEMPERLI (Dosterlimab-gxly), and after three cycles of therapy, imaging and PET scan were repeated, showing decreased activity and extent of the tumor—a tremendous success.

The influence of genetics on epilepsy syndromes in infancy and childhood

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.

Two missense STK11 gene variations impaired LKB1/adenosine monophosphate-activated protein kinase signaling in Peutz-Jeghers syndrome

BACKGROUND Peutz-Jeghers syndrome(PJS)is a rare hereditary neoplastic disorder mainly associated with serine/threonine kinase 11(STK11/LKB1)gene mutations.Preimplantation genetic testing can protect a patient’s offspring from mutated genes;however,some variations in this gene have been interpreted as variants of uncertain significance(VUS),which complicate reproductive decision-making in genetic counseling.AIM To identify the pathogenicity of two missense variants and provide clinical guidance.METHODS Whole exome gene sequencing and Sanger sequencing were performed on the peripheral blood of patients with PJS treated at the Reproductive and Genetic Hospital of Citic-Xiangya.Software was employed to predict the protein structure,conservation,and pathogenicity of the two missense variation sites in patients with PJS.Additionally,plasmids were constructed and transfected into HeLa cells to observe cell growth.The differences in signal pathway expression between the variant group and the wild-type group were compared using western blot and immunohistochemistry.Statistical analysis was performed using one-way analysis of variance.P<0.05 was considered statistically significant.RESULTS We identified two missense STK11 gene VUS[c.889A>G(p.Arg297Gly)and c.733C>T(p.Leu245Phe)]in 9 unrelated PJS families who were seeking reproductive assistance.The two missense VUS were located in the catalytic domain of serine/threonine kinase,which is a key structure of the liver kinase B1(LKB1)protein.In vitro experiments showed that the phosphorylation levels of adenosine monophosphate-activated protein kinase(AMPK)at Thr172 and LKB1 at Ser428 were significantly higher in transfected variation-type cells than in wild-type cells.In addition,the two missense STK11 variants promoted the proliferation of HeLa cells.Subsequent immunohistochemical analysis showed that phosphorylated-AMPK(Thr172)expression was significantly lower in gastric,colonic,and uterine polyps from PJS patients with missense variations than in non-PJS patients.Our findings indicate that these two missense STK11 variants are likely pathogenic and inactivate the STK11 gene,causing it to lose its function of regulating downstream phosphorylated-AMPK(Thr172),which may lead to the development of PJS.The identification of the pathogenic mutations in these two clinically characterized PJS patients has been helpful in guiding them toward the most appropriate mode of pregnancy assistance.CONCLUSION These two missense variants can be interpreted as likely pathogenic variants that mediated the onset of PJS in the two patients.These findings not only offer insights for clinical decision-making,but also serve as a foundation for further research and reanalysis of missense VUS in rare diseases.

Molecular genetics of Brugada syndrome

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.

Peters-Plus Syndrome: What Outcome in the Absence of Genetic Confirmation? A Case Report

Anterior segment dysgenesis is a group of non-acquired ocular anomalies whose cause is multifactorial;many genes are involved. It is characterized by developmental anomalies of the tissues of the anterior segment, of which Peters-Plus syndrome is included. Our aim is to describe the different ophthalmological and systemic aspects of Peters-Plus syndrome in order to improve the quality of diagnosis of this syndrome even in the absence of genetic confirmation, especially in low-income countries or when genetic studies are not available. In this observation, we report the case of a newborn with Peters-Plus syndrome admitted to the neonatology unit. The diagnosis was made on the basis of clinical-radiological criteria, and treatment consisted of caring for the baby and the parents, given the particular psychological context often associated with the birth of a baby with polymalformative syndrome. From this study, Peters-Plus syndrome should be borne in mind in a fetus with typical ocular anomalies, unusual facial appearance and long tubular bone insufficiency, especially in the presence of a positive family history. In such cases, prenatal diagnosis could be an option for the couples. A genetic study should be undertaken to confirm the clinical diagnosis and provide appropriate genetic counseling and prenatal diagnostic options.

Novel homozygous ADAMTS17 missense variant in Weill-Marchesani syndrome

AIM: To explore the phenotype and genotype of WeillMarchesani syndrome(WMS) in a Chinese family and review related literature.METHODS: Three WMS patients and other unaffected individuals in this family with a history of consanguineous marriage were included in this study. Medical history, comprehensive ophthalmic examinations, and systemic evaluation, as well as whole exome and Sanger sequencing of specific genomic regions, were performed. RESULTS: The three affected siblings presented with short stature, brachydactyly and ocular disorders, including very shallow anterior chamber, high myopia, microspherophakia lens subluxation with stretched zonules and glaucoma. Genetic analysis verified a homozygous missense mutation(c.2983C>T: p. Arg995Trp) in ADAMTS17,which was correlated with the diseases in this family, indicating an autosomal recessive inherited manner of WMS. This review aims to summarize the mutation sites of WMS genes, so as to prevent the disease and better guide clinical diagnosis and treatment.CONCLUSION: A novel homozygous missense variant of ADAMTS17 is identified in a WMS family with a history of consanguineous marriage. Our study expands the range of mutations associated with WMS and deepens our understanding of pathology in disease associated with ADAMTS17 variants.

Management of primary ciliary dyskinesia/Kartagener＇s syndrome in infertile male patients and current progress in defining the underlying genetic mechanism

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.

Genetic polymorphism in pathogenesis of irritable bowel syndrome

Irritable bowel syndrome(IBS)is a complex symptombased 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 3mo according to ROMEⅢ: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.

Ethnic differences in genetic polymorphism associated with irritable bowel syndrome

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.

Inherited CHEK2 p.H371Y mutation in solitary rectal ulcer syndrome among familial patients:A case report

BACKGROUND Solitary rectal ulcer syndrome(SRUS)is a rare rectal disease with unknown etiology.Data on the genetic background in SRUS is lacking.CASE SUMMARY Here,we report the first case of SRUS in a mother-son relationship.Gene sequencing was conducted on the whole family,which revealed an inherited CHEK2 p.H371Y mutation.The experiment preliminarily revealed that the CHEK2 mutation did not affect the expression of CHEK2 protein,but affected the function of CHEK2,resulting in the expression level changes of downstream genes such as CDC25A.CONCLUSION SRUS is a genetic susceptibility disease where CHEK2 p.H371Y mutation may play a crucial role in the development and prognosis of SRUS.

Realizing the potential of exploiting human IPSCs and their derivatives in research of Down syndrome

Down syndrome(DS)is a genetic condition characterized by intellectual disability,delayed brain development,and early onset Alzheimer’s disease.The use of primary neural cells and tissues is important for understanding this disease,but there are ethical and practical issues,including availability from patients and experimental manipulability.Moreover,there are significant genetic and physiological differences between animal models and humans,which limits the translation of the findings in animal studies to humans.Advancements in induced pluripotent stem cells(iPSC)technology have revolutionized DS research by providing a valuable tool for studying the cellular and molecular pathologies associated with DS.Induced pluripotent stem cells derived from cells obtained from DS patients contain the patient’s entire genome including trisomy 21.Trisomic iPSCs as well as their derived cells or organoids can be useful for disease modeling,investigating the molecular mechanisms,and developing potential strategies for treating or alleviating DS.In this review,we focus on the use of iPSCs and their derivatives obtained from DS individuals and healthy humans for DS research.We summarize the findings from the past decade of DS studies using iPSCs and their derivatives.We also discuss studies using iPSC technology to investigate DS-associated genes(e.g.,APP,OLIG1,OLIG2,RUNX1,and DYRK1A)and abnormal phenotypes(e.g.,dysregulated mitochondria and leukemia risk).Lastly,we review the different strategies for mitigating the limitations of iPSCs and their derivatives,for alleviating the phenotypes,and for developing therapies.

Diagnosis and treatment of McCune-Albright syndrome:A case report

BACKGROUND McCune-Albright syndrome(MAS)is extremely rare clinically.We here report a case of MAS with severe symptoms that have not been reported previously.CASE SUMMARY A 10-year-old boy attended our outpatient clinic due to craniofacial malformations found two years ago.He underwent temporal bone computed tomography and digital radiography photography.Based on a literature review combined with the patient's medical history and imaging examination findings,he was diagnosed with multiple fibrous dysplasia of bone.As the clinical symptoms related to MAS in this patient were not obvious,he was only followed up and not given any special treatment.CONCLUSION The unique clinical manifestations in this MAS patient may be related to mutations in the GNAS gene.

Genetic analysis of reproductive performance in sows during porcine reproductive and respiratory syndrome(PRRS)and porcine epidemic diarrhea(PED)outbreaks

Background: Porcine reproductive and respiratory syndrome(PRRS) is one of the most infectious swine diseases in the world, resulting in over 600 million dollars of economic loss in the USA alone. More recently, the USA swine industry has been having additional major economic losses due to the spread of porcine epidemic diarrhea(PED).However, information regarding the amount of genetic variation for response to diseases in reproductive sows is still very limited. The objectives of this study were to identify periods of infection with of PRRS virus(PRRSV) and/or PED virus(PEDV), and to estimate the impact their impact on the phenotypic and genetic reproductive performance of commercial sows.Results: Disease(PRRS or PED) was significant(P < 0.05) for all traits analyzed except for total piglets born.Heritability estimates for traits during Clean(without any disease), PRRS, and PED ranged from 0.01(number of mummies;Clean and PED) to 0.41(abortion;PED). Genetic correlations between traits within disease statuses ranged from-0.99(proportion born dead with number weaned;PRRS) to 0.99(number born dead with born alive;Clean). Within trait, between disease statuses, estimates ranged from-0.17(number weaned between PRRS and PED) to 0.99(abortion between Clean and PRRS).Conclusion: Results indicate that selection for improved performance during PRRS and PED in commercial sows is possible and would not negatively impact performance in Clean environments.

Genetic determination of irritable bowel syndrome

急躁的肠症候群(IBS ) 是普通功能的胃肠的混乱。根据罗马 III 标准， IBS 在下列症状的与二联系的以前的 3 瞬间或更多期间每月为至少 3 d 被定义为周期性的腹的疼痛或不快：有澄清，在凳子的频率与一个变化联系的发作或与一个变化联系处于良好的竟技状态的发作或凳子的外观的改进。在 IBS 关于基因贡献正在种证据，然而， IBS 的精确病原学仍然是未知的。基因影响的评估基于成双的研究，家庭聚集和基因流行病学调查。大多数研究比在 dizygotic 为在单合子显著地更大的 IBS 显示出一个词语索引。研究的多数证明了家庭聚集可以代表暴露到基因因素的类似的环境，以及影响。而没有特定的基因与 IBS 联合被识别了，最近的研究在血清素的倡导者区域注意了多型性的重要性再入伍拿 transporter 基因，G蛋白质贝它 3 子单元基因( C825T )，缩胆囊素受体( CCKAR 基因 779T 】C )，并且高制片人的肿瘤坏死因素遗传型。进一步的研究是必要的决定基因因素怎么在 IBS 病人影响临床的表明和 therapeutical 反应。

Preimplantation genetic diagnosis for Down syndrome pregnancy

Objective: To evaluate the effect of preimplantation genetic diagnosis (PGD) conducted for women who had Down syndrome pregnancy previously. Methods: Trisomy 21 was diagnosed by using fluorescence in site hybridization (FISH) before embryo transfer in two women who had Down syndrome pregnancies. Each received one or two PGD cycles respectively. Results: Case 1: one PGD cycle was conducted, two oocytes were fertilized and biopsied. One embryo is of trisomy 21 and the other of monosomy 21. No embryo was transferred. Case 2: two PGD cycles were conducted, in total, sixteen oocytes were fertilized and biopsied. Four embryos were tested to be normal, six of trisomy 21, and one of monosomy 21. Five had no signal. Four normal embryos were transferred but no pregnancy resulted. Conclusion: For couples who had pregnancies with Down syndrome pre-viously, PGD can be considered, and has been shown to be an effective strategy.