Genetically modified pigs:Emerging animal models for hereditary hearing loss

Hereditary hearing loss(HHL),a genetic disorder that impairs auditory function,significantly affects quality of life and incurs substantial economic losses for society.To investigate the underlying causes of HHL and evaluate therapeutic outcomes,appropriate animal models are necessary.Pigs have been extensively used as valuable large animal models in biomedical research.In this review,we highlight the advantages of pig models in terms of ear anatomy,inner ear morphology,and electrophysiological characteristics,as well as recent advancements in the development of distinct genetically modified porcine models of hearing loss.Additionally,we discuss the prospects,challenges,and recommendations regarding the use pig models in HHL research.Overall,this review provides insights and perspectives for future studies on HHL using porcine models.

Targeting cholesterol trafficking to mitigate axonal degeneration in hereditary spastic paraplegia

Axonal degeneration underlies many debilitating diseases including hereditary spastic paraplegia(HSP),a genetically and clinically diverse group of disorders characterized by spasticity and weakness of the lower extremities.HSP is one significant cause of chronic neurodisability due to the lack of effective treatments and a wide range of onset ages from early childhood to 70 years.

Dual primary gastric and colorectal cancer:The known hereditary causes and underlying mechanisms

In this editorial,I commented on the paper by Lin et al,published in this issue of the World Journal of Gastrointestinal Oncology.The work aimed at analysing the clinicopathologic characteristics and prognosis of synchronous and metachronous cancers in patients with dual primary gastric and colorectal cancer(CRC).The authors concluded the necessity for regular surveillance for metachronous cancer during postoperative follow-up and reported the prognosis is influenced by the gastric cancer(GC)stage rather than the CRC stage.Although surveillance was recommended in the conclusion,the authors did not explore this area in their study and did not include tests used for such surveillance.This editorial focuses on the most characterized gastrointestinal cancer susceptibility syndromes concerning dual gastric and CRCs.These include hereditary diffuse GC,familial adenomatous polyposis,hereditary nonpolyposis colon cancer,Lynch syndrome,and three major hamartomatous polyposis syndromes associated with CRC and GC,namely Peutz-Jeghers syndrome,juvenile polyposis syndrome,and PTEN hamartoma syndrome.Careful assessment of these syndromes/conditions,including inheritance,risk of gastric and colorectal or other cancer development,genetic mutations and recommended genetic investigations,is crucial for optimum management of these patients.

Complex heterozygous mutations in hereditary spherocytosis:A case report

BACKGROUND The aim of this study was to investigate the complex heterozygous mutations of ANK1 and SPTA1 in the same individual and improve our understanding of hereditary spherocytosis(HS)in children.We also hope to promote the application of gene detection technology in children with HS,with the goals of identifying more related gene mutations,supporting the acquisition of improved molecular genetic information to further reveal the pathogenesis of HS in children,and providing important guidance for the diagnosis,treatment,and prevention of HS in children.CASE SUMMARY A 1-year and 5-month-old patient presented jaundice during the neonatal period,mild anemia 8 months later,splenic enlargement at 1 year and 5 months,and brittle red blood cell permeability.Genetic testing was performed on the patient,their parents,and sister.Swiss Model software was used to predict the protein structure of complex heterozygous mutations in ANK1 and SPTA1.Genetic testing revealed that the patient harbored a new mutation in the ANK1 gene from the father and a mutation in the SPTA1 gene from the mother.Combined with the clinical symptoms of the children,it is suggested that the newly discovered complex heterozygous mutations of ANK1 and SPTA1 may be the cause,providing important guidance for revealing the pathogenesis,diagnosis,treatment,and promotion of gene detection technology in children with HS.CONCLUSION This case involves an unreported complex heterozygous mutation of ANK1 and SPTA1,which provides a reference for exploring HS.

Hereditary polyposis syndromes remain a challenging disease entity:Old dilemmas and new insights

In this editorial we present an overview and insights of the management of hereditary polyposis syndromes.The primary focus was on familial adenomatous polyposis,juvenile polyposis syndrome and Peutz-Jegher syndrome.Genetic testing has become increasingly available and is easier than ever to integrate into clinical practice.Furthermore,several genes have been added to the expanding list of genes associated with hereditary polyposis syndromes,allowing for precise diagnostics and tailored follow-up.Endoscopic evaluation of patients with hereditary polyposis syndromes is paramount in the surveillance strategies.Current endoscopic procedures include both diagnostic procedures and surveillance as well as therapeutic interventions.Recommendations for endoscopic procedures in the upper and lower gastrointestinal canal were described.Surgery is still a key component in the management of patients with hereditary polyposis syndromes.The increased cancer risk in these patients often render prophylactic procedures or intended curative procedures in the case of cancer development.Surgical interventions in the upper and lower gastrointestinal canal were described with relevant considerations.Development of chemopreventive medications is ongoing.Few drugs have been investigated,including nonsteroidal anti-inflammatory drugs.It has been demonstrated that cyclooxygenase-2 inhibitors may lower the number of polyps.Other medications are currently under investigation,but none have,to date,consistently been able to prevent development of disease.

Double heterozygous pathogenic mutations in KIF3C and ZNF513 cause hereditary gingival fibromatosis

Hereditary gingival fibromatosis(HGF)is a rare inherited condition with fibromatoid hyperplasia of the gingival tissue that exhibits great genetic heterogeneity.Five distinct loci related to non-syndromic HGF have been identified;however,only two diseasecausing genes,SOS1 and REST,inducing HGF have been identified at two loci,GINGF1 and GINGF5,respectively.Here,based on a family pedigree with 26 members,including nine patients with HGF,we identified double heterozygous pathogenic mutations in the ZNF513(c.C748T,p.R250W)and KIF3C(c.G1229A,p.R410H)genes within the GINGF3 locus related to HGF.Functional studies demonstrated that the ZNF513 p.R250W and KIF3C p.R410H variants significantly increased the expression of ZNF513 and KIF3C in vitro and in vivo.ZNF513,a transcription factor,binds to KIF3C exon 1 and participates in the positive regulation of KIF3C expression in gingival fibroblasts.Furthermore,a knock-in mouse model confirmed that heterozygous or homozygous mutations within Zfp513(p.R250W)or Kif3c(p.R412H)alone do not led to clear phenotypes with gingival fibromatosis,whereas the double mutations led to gingival hyperplasia phenotypes.In addition,we found that ZNF513 binds to the SOS1 promoter and plays an important positive role in regulating the expression of SOS1.Moreover,the KIF3C p.R410H mutation could activate the PI3K and KCNQ1 potassium channels.ZNF513 combined with KIF3C regulates gingival fibroblast proliferation,migration,and fibrosis response via the PI3K/AKT/mTOR and Ras/Raf/MEK/ERK pathways.In summary,these results demonstrate ZNF513+KIF3C as an important genetic combination in HGF manifestation and suggest that ZNF513 mutation may be a major risk factor for HGF.

Decoding hereditary spastic paraplegia pathogenicity through transcriptomic profiling

Hereditary spastic paraplegia(HSP)is a group of genetic motor neuron diseases resulting from length-dependent axonal degeneration of the corticospinal upper motor neurons.Due to the advancement of next-generation sequencing,more than 70 novel HSP disease-causing genes have been identified in the past decade.Despite this,our understanding of HSP physiopathology and the development of efficient management and treatment strategies remain poor.One major challenge in studying HSP pathogenicity is selective neuronal vulnerability,characterized by the manifestation of clinical symptoms that are restricted to specific neuronal populations,despite the presence of germline disease-causing variants in every cell of the patient.Furthermore,disease genes may exhibit ubiquitous expression patterns and involve a myriad of different pathways to cause motor neuron degeneration.In the current review,we explore the correlation between transcriptomic data and clinical manifestations,as well as the importance of interspecies models by comparing tissue-specific transcriptomic profiles of humans and mice,expression patterns of different genes in the brain during development,and single-cell transcriptomic data from related tissues.Furthermore,we discuss the potential of emerging single-cell RNA sequencing technologies to resolve unanswered questions related to HSP pathogenicity.

Hereditary Multiple Exostoses (HME) with Peroneal Nerve Compresion: A Case Report

Introduction: Hereditary multiple exostosis (HME) is a hereditary disorder characterized by multiple osteochondromas. Clinical symptoms can result from compression of adjacent structures such as peripheral nerves. In Indonesia, HME with nerve compression cases have rarely reported. Presentation of Case: An eleven-year-old female with complaining of left knee joint pain and progressive masses in left lower leg since 6 years ago. This complains followed by numbness and difficulty to dorso flexion motion on left ankle joint since four months ago. Physical examination showed of the bony masses was detected at the left lateral upper third lower leg with measuring about six into eight centimeters. Range of motion of left ankle joint patient had difficult to dorso flexion. X-ray imaging viewed demonstrates multiple exostosis appearance involving distal femoral, proximal fibula, proximal tibia and distal fibula bone. MR Imaging revealed cartilage cap of head fibula is thin less 1.5 cm and the axially specimen showed peroneal nerve compression. The patient underwent left head fibula wide resection. Intraoperative findings peripheral nerve peroneal compression and was decompression. Medical rehabilitation for physiotherapy was advised. The results of the follow-up after 2 years, no pain feels and the patient was able to dorso flexion of left ankle joint and no additional bumps in other areas of the body. These lesions may arise from any bone which was pre-formed in the cartilage. Nerve compression syndromes are the neurological complex symptom caused by the mechanical or dynamic compression of a specific single segment. MRI was excellent demonstration of blood vessels compromise and represents choices with peripheral nerves structures and to measuring cartilage cap thickness for criterion of osteochondromas differentiation and exostotic grade. Complete resection was importance of the cartilaginous cap to prevent recurrence. The decompressing the peroneal nerve that pressured by the masses and vascular problems occured. Conclusion: Hereditary multiple exostosis is an inherited disorder characterized by multiple osteochondromas. It is important to monitor all cases of HME especially if the patient complains of pain or growth of an osteochondroma. The surgical excision, with complete resection of the cartilaginous cap of the tumor, is important in preventing recurrence.

Clinical manifestations of adult hereditary spherocytosis with novel SPTB gene mutations and hyperjaundice:A case report

BACKGROUND The aim of the present study was to enhance understanding of the diagnosis and treatment of atypical hereditary spherocytosis(HS),and to broaden the diagnostic thoughts of physicians for patients with jaundice.CASE SUMMARY A 28-year-old male presented with jaundice,bile duct stone,and splenomegaly,but without anemia.Other causes of jaundice were excluded,and gene se-quencing revealed a novel heterozygous variant of c.1801C>T(p.Q601X)in exon 14 of the SPTB(NM_01355436)gene on chromosome 14(chr14:65260580)in the patient’s blood;the biological parents and child of the patient did not have similar variants.A splenectomy was performed on the patient and his bilirubin levels returned to normal after surgery.Thus,a novel gene variant causing HS was identified.This variant may result in the truncation ofβ-hemoglobin in the erythrocyte membrane,leading to loss of normal function,jaundice,and hemolytic anemia.The clinical manifestations of the patient were hyperjaundice and an absence of typical hemolysis during the course of the disease,which caused challenges for diagnosis by the clinicians.CONCLUSION Following a definitive diagnosis,genetic testing and response to treatment identified a gene variant site for a novel hemolytic anemia.

Photoreceptor changes in Leber hereditary optic neuropathy with m.G11778A mutation

·AIM:To evaluate the functional and structural changes of photoreceptors in patients and asymptomatic carriers with Leber hereditary optic neuropathy(LHON)using fullfield electroretinography(FERG)and optical coherence tomography(OCT).·METHODS:Individuals diagnosed with LHON at the Renmin Hospital of Wuhan University and their family members were included in this cross-sectional observational study.The FERG a-wave amplitude of affected patients and asymptomatic carriers was analyzed.The thickness of the outer nuclear layer(ONL),inner and outer segment(IS/OS)and total photoreceptors in the macular fovea and parafovea were measured.·RESULTS:This study included 14 LHON patients(mean age:20.00±9.37y),12 asymptomatic carriers(mean age:39.83±6.48y),and 14 normal subjects(mean age:24.20±1.52y).The FERG results showed that the darkadapted 3.0 electroretinography and light-adapted 3.0 electroretinography a-wave amplitudes of patients and carriers were significantly decreased(P<0.001).The ONL and photoreceptors layers were slightly thicker in patients than in normal subjects(P<0.05),whereas they were thinner in carriers(P<0.05).There were no differences in IS/OS thickness among the groups(P>0.05).·CONCLUSION:Photoreceptors function is significantly impaired in LHON-affected patients and asymptomatic carriers.Meanwhile,photoreceptors morphology is slightly altered,mainly manifesting as a change in ONL thickness.

Hereditary cancer syndromes

Hereditary cancer syndromes(HCSs)are arguably the most frequent category of Mendelian genetic diseases,as at least 2%of presumably healthy subjects carry highly-penetrant tumor-predisposing pathogenic variants(PVs).Hereditary breast-ovarian cancer and Lynch syndrome make the highest contribution to cancer morbidity;in addition,there are several dozen less frequent types of familial tumors.The development of the majority albeit not all hereditary malignancies involves two-hit mechanism,i.e.the somatic inactivation of the remaining copy of the affected gene.Earlier studies on cancer families suggested nearly fatal penetrance for the majority of HCS genes;however,population-based investigations and especially large-scale next-generation sequencing data sets demonstrate that the presence of some highly-penetrant PVs is often compatible with healthy status.Hereditary cancer research initially focused mainly on cancer detection and prevention.Recent studies identified multiple HCS-specific drug vulnerabilities,which translated into the development of highly efficient therapeutic options.

Multi-organ hereditary hemorrhagic telangiectasia:A case report

BACKGROUND Type 2 hereditary hemorrhagic telangiectasia(HHT)is a rare autosomal dominant disease and is associated with ALK1 gene mutations.Type 2 HHT patients primarily suffer from recurrent bleeding.There is currently no promising treatment.CASE SUMMARY A 5-year-old Chinese patient(III23)was admitted to Zhongshan Hospital for recurrent melena occurring over 2 mo.She had been experiencing epistaxis for years and had been diagnosed with idiopathic pulmonary hypertension 4 mo before presentation.Abdominal computed tomography examination showed hepatic arteriovenous malformation.Gene testing revealed a c.1121G>A mutation on the ALK1 gene.According to the international diagnostic criteria,this patient was diagnosed with HHT.In addition,8 more family members exhibited HHT symptoms to varying degrees.Gene testing in 5 family members(2 with HHT symptoms and 3 without HHT symptoms)revealed the ALK1 c.1121G>A mutation in the 2 family members with HHT symptoms.This missense mutation results in the substitution of arginine for glutamine at amino acid position 374(R374Q)in the conserved functional kinase domain of ALK1.Biological studies revealed that this mutation decreased the kinase activity of ALK1 and impeded the phosphorylation of its substrate Smad1.Moreover,the R374Q mutant downregulated the protein level of collagen-1,a fibrogenic factor,indicating abnormal fiber generation during vascular formation.CONCLUSION The R374Q mutant of ALK1 and its subsequent influence on fiber generation highly indicated its pathogenic role in this family with type 2 HHT.Detection of this gene mutation will facilitate early diagnosis of suspected type 2 HHT patients,and mechanistic studies will provide insights for future therapy.

Hereditary hemorrhagic telangiectasia involving portal venous system:A case report and review of the literature

BACKGROUND Hereditary hemorrhagic telangiectasia(HHT)is an autosomal dominant genetic disorder with an incidence of approximately 1 in 5000 in the general population.It is characterized by vasodilation,which affects specific organs,such as the skin,mucous membranes,brain,lungs,gastrointestinal tract,liver,and others.However,HHT rarely involves the portal venous system to cause serious clinical compli-cations.CASE SUMMARY A 68-year-old woman was admitted to the emergency department due to four consecutive days of abdominal pain and bloody stool and was subsequently diagnosed with HHT.Computed tomography angiography confirmed the presence of an arteriovenous fistula(AVFs).Considering this specific manifestation,whole exome sequencing was performed.After a comprehensive evaluation,a selective superior mesenteric artery embolization was prioritized to avoid intestinal ischemia.The postoperative symptoms of the patient were quickly relieved.Unfortunately,two months post-procedure the patient died from intestinal necrosis and abdominal infection related to remaining AVFs.CONCLUSION For patients with diffuse superior mesenteric AVFs,selective mesenteric arterial embolization may lead to positive short-term outcomes.

Chest wall osteochondroma resection with biologic acellular bovine dermal mesh reconstruction in pediatric hereditary multiple exostoses:A case report and review of literature

BACKGROUND Hereditary multiple exostoses is a rare genetic disorder characterized by the growth of multiple osteochondromas affecting primarily long bones.Chest wall lesions may represent a challenge,particularly in pediatric patients.Pain is a common manifestation.However,life-threatening complications can result from direct involvement of adjacent structures.Surgical resection with appropriate reconstruction is often required.CASE SUMMARY A 5-year-old male who was diagnosed with hereditary multiple exostoses presented with significant pain from a large growing chest wall exostosis lesion.After appropriate preoperative investigations,he underwent surgical resection with reconstruction of his chest wall using a biologic bovine dermal matrix mesh.CONCLUSION Resection of chest wall lesions in children represents a challenge.Preoperative planning to determine the appropriate reconstruction strategy is essential.

Novel mutation of SPG4 gene in a Chinese family with hereditary spastic paraplegia:A case report

BACKGROUND Hereditary spastic paraplegia(HSP)is a group of neurogenetic diseases of the corticospinal tract,accompanied by distinct spasticity and weakness of the lower extremities.Mutations in the spastic paraplegia type 4(SPG4)gene,encoding the spastin protein,are the major cause of the disease.This study reported a Chinese family with HSP caused by a novel mutation of the SPG4 gene.CASE SUMMARY A 44-year-old male was admitted to our hospital for long-term right lower limb weakness,leg stiffness,and unstable walking.His symptoms gradually worsened,while no obvious muscle atrophy in the lower limbs was found.Neurological examinations revealed that the muscle strength of the lower limbs was normal,and knee reflex hyperreflexia and bilateral positive Babinski signs were detected.Members of his family also had the same symptoms.Using mutation analysis,a novel heterozygous duplication mutation,c.1053dupA,p.(Gln352Thrfs*15),was identified in the SPG4 gene in this family.CONCLUSION A Chinese family with HSP had a novel mutation of the SPG4 gene,which is autosomal dominant and inherited as pure HSP.The age of onset,sex distribution,and clinical manifestations of all existing living patients in this family were analyzed.The findings may extend the current knowledge on the existing mutations in the SPG4 gene.

北海地区遗传性乳腺癌和健康遗传高危人群BRCA1和BRCA2基因突变研究

目的:探讨北海地区遗传性乳腺癌和健康遗传高危人群乳腺癌易感基因(BRCA)1和BRCA2基因突变特征。方法:选取北海市人民医院普通外科收治的50例遗传性乳腺癌患者及150例健康遗传性高危人群,PCR-DNA直接测序法检测BRCA1、BRCA2的全编码外显子基因序列。结果:50例遗传性乳腺癌患者中共有8例BRCA1/2基因突变,总突变率为16%;其中BRCA1突变占12.0%,BRCA2突变占4.0%。三阴性乳腺癌患者BRCA1/2基因突变率为57.1%(4/7),高于非三阴性乳腺癌患者的9.3%(4/43),差异有统计学意义(P<0.05)。150例健康遗传性高危人群存在2例致病性突变,均位于BRCA1的11外显子,突变率为1.3%(2/150)。结论:北海地区女性遗传性乳腺癌存在BRCA1和BRCA2基因突变,与三阴乳腺癌有关,突变类型以碱基置换突变为主;健康遗传高危人群也存在BRCA1突变。

产前序贯性筛查遗传性耳聋基因携带者的临床意义分析

目的分析产前序贯性筛查遗传性耳聋基因携带者的临床意义。方法选择2022年5月至12月于首都医科大学附属北京妇产医院进行遗传性耳聋基因突变位点筛查的孕妇9391例,采用微流控芯片法检测遗传性耳聋基因,分析其在孕妇人群中的携带率。对检出GJB2基因和SLC26A4基因变异的孕妇配偶采用靶向高通量测序进行相同致病基因筛查,当夫妻双方均检出同一基因致病变异时建议对胎儿进行致病基因的产前诊断。对于检出GJB3基因变异孕妇,建议其进行听力学评估和遗传咨询及随访。对检出线粒体12S rRNA基因变异孕妇进行遗传咨询及用药指导。结果9391例孕妇中检出遗传性耳聋基因突变携带者1002例,携带率为10.67%;GJB2、SLC26A4、GJB3及线粒体12S rRNA突变的携带率分别为7.93%、1.99%、0.28%和0.15%。突变经Sanger测序验证,符合率达99.80%。293例GJB2基因或SLC26A4基因突变携带者的配偶进行了序贯性筛查,其中4对夫妇双方检出携带相同基因上的致病突变位点,经羊水细胞测序,1例为GJB2 c.235 del C纯合突变,1例为SLC26A4 c.919-2 A>G纯合突变,其余2例均为杂合突变。结论产前序贯性筛查耳聋基因携带者不仅可以筛查遗传性耳聋基因突变的携带者,还可以发现药物性耳聋敏感性个体,从而实现耳聋胎儿早期诊断、早期干预和及时预警。

影像学检查在遗传性出血性毛细血管扩张症中的诊断价值探讨

目的探讨影像学检查在遗传性出血性毛细血管扩张症(HHT)中的诊断价值。方法回顾性分析2019年10月至2024年3月在首都医科大学附属北京安贞医院经临床明确诊断的累及肝脏的7例HHT患者的临床资料。收集患者的临床表现、影像学检查结果[包括超声、CT血管造影(CTA)及右心导管],并总结HHT在不同影像学方法中的诊断特征。结果7例HHT患者中鼻出血6例、贫血5例、皮肤和黏膜的毛细血管扩张3例、咯血和消化道出血各2例,下肢水肿5例、盆腔积液和腹胀各2例。7例患者均有肺动脉高压表现,3例患者合并心房颤动,3例出现肝功能异常,2例患者合并右心衰竭,1例患者合并结缔组织病。所有患者均接受腹部彩色多普勒超声检查,均呈肝脏受累表现,7例患者均探及肝内外动脉明显迂曲扩张,血流速度明显增快;其中4例患者肝内见异常迂曲血管环;4例多发分支血管团;5例患者有肝脏动静脉畸形。经肺血管CTA检查提示合并肺动静脉瘘5例,3例患者呈多发肺动静脉瘘表现;所有患者均接受右心导管检查并呈现不同程度的肺动脉高压。6例患者接受肺动脉高压靶向治疗,2例患者接受基因检测呈阳性。结论HHT女性患者多见,HHT累及肝脏的超声表现具有特异性,CTA和右心导管检查可以及时评估患者肺血管受累情况及肺动脉压力,为靶向治疗的开展提供有效证据。

以急性血管内溶血为首发表现的青少年遗传性球形红细胞增多症

目的 提高临床医生对表现不典型、缺乏明确的家族遗传史HS患者的认识。方法 回顾一例以急性血管内溶血为首发表现的青少年HS患儿的临床资料并进行分析。结果 患儿,男,13岁3月,以急性血管内溶血为首发表现,早期诊断不明确,后经基因检测最终确诊为球形红细胞增多症2型。结论 部分HS表现不典型、缺乏明确的家族遗传史,在诊断不确定或疑似HS的情况下,需进行基因检测。

遗传性血管性水肿急诊科诊疗路径

遗传性血管性水肿(hereditary angioedema,HAE)是一种常染色体显性遗传病,以反复发作的皮肤和黏膜水肿为特征。水肿可出现在任何部位,最致命的为喉水肿,引发窒息,危及生命。若水肿累及消化道黏膜,可引起腹痛、呕吐等症状,易误诊为急腹症。颜面、躯干及四肢等皮肤水肿也严重影响患者生活质量。为提高急诊科医生的识别及处理能力,本专业组特编写此诊疗路径。路径除对HAE的发病机制、临床表现等进行介绍外,还汇总了既往在中国已经发表的急诊科病例,以便广大医生更好的理解疾病,并绘制诊疗路径图,为临床实践提供参考依据。