Magnetic resonance imaging evaluation and nuclear receptor binding SET domain protein 1 mutation in the Sotos syndrome with attention-deficit/hyperactivity disorder

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.

Systemic thrombosis with prothrombin Belgrade mutation in a Chinese patient:A case report

BACKGROUND Thrombophilia contributes to a significant increased risk of venous thromboembolism and can be either inherited or acquired.Hereditary thrombophilia may arise from various gene mutations,some of which have not even been adequately reported or poorly understood.Previous studies reported a rare and novel missense mutation in the prothrombin gene(p.Arg596Gln),known as prothrombin Belgrade.The mechanisms and therapeutic strategies associated with prothrombin Belgrade mutation have not been fully elucidated.CASE SUMMARY We present the case of a 26-year-old woman with recurrent systemic thrombosis induced by prothrombin Belgrade mutation.The patient suffered from cerebral venous sinus thrombosis that rapidly progressed to systemic thrombosis,alongside a family history of cerebral thrombosis,and no traditional risk factors or abnormal coagulation function.Whole-genome sequencing detected a novel and rare heterozygous prothrombin missense mutation,c.1787G>T(p.Arg596Gln),which was responsible for the major etiology of the systemic thrombosis.CONCLUSION This case strengthens our understanding about hereditary basis of thrombophilia and provokes considerations for therapeutic options on prothrombin Belgrade mutation.

Dystrophic epidermolysis bullosa caused by novel frameshift mutation in the COL7A1 gene: A case report

BACKGROUND Dystrophic epidermolysis bullosa is characterized by fragile ulcerations of the skin caused by mutations in specific genes.However,genetic typing of this con-dition is rare.CASE SUMMARY An 11-year-old female suffered from recurrent fever,visible ulcerations of the entire skin,and severe malnutrition.Genetic testing revealed a frameshift mu-tation in the coding region 4047 of the 35th intron region of COL7A1,and she was diagnosed as malnutrition-type epidermolysis bullosa.Drug therapy(immu-noglobulin,fresh frozen plasma),topical therapy(silver ion dressing),fever redu-ction,cough relief,and promotion of gastrointestinal peristalsis are mainly used for respiratory and gastrointestinal complications.The patient’s condition impro-ved after treatment.CONCLUSION Dystrophic epidermolysis bullosa caused by a new framework shift mutation in COL7A1 should be taken seriously.

Combined BRAF G469A mutation and echinoderm microtubule associated protein like-4-anaplastic lymphoma kinase rearrangement with resistance:A case report and review of literature

BACKGROUND Through deeper understanding of targetable driver mutations in non-small-cell lung cancer(NSCLC)over the past years,some patients with driver mutations have benefited from the targeted molecular therapies.Although the anaplastic lymphoma kinase and BRAF mutations are not frequent subtypes in NSCLC,the availability of several targeted-drugs has been confirmed through a series of clinical trials.But little is clear about the proper strategy in rare BRAF G469A mutation,not to mention co-exhibition of anaplastic lymphoma kinase and BRAF G469A mutations,which is extremely rare in NSCLC.CASE SUMMARY We present a patient to stage IVA lung adenocarcinoma with coexisting echinoderm microtubule associated protein like-4 rearrangement and BRAF G469A mutation.She received several targeted drugs with unintended resistance and suffered from unbearable adverse events.CONCLUSION Due to the rarity of co-mutations,the case not only enriches the limited literature on NSCLC harbouring BRAF G469A and echinoderm microtubule associated protein like-4 mutations,but also suggests the efficacy and safety of specific multiple-drug therapy in such patients.

Appropriate Combination of Crossover Operator and Mutation Operator in Genetic Algorithms for the Travelling Salesman Problem

Genetic algorithms(GAs)are very good metaheuristic algorithms that are suitable for solving NP-hard combinatorial optimization problems.AsimpleGAbeginswith a set of solutions represented by a population of chromosomes and then uses the idea of survival of the fittest in the selection process to select some fitter chromosomes.It uses a crossover operator to create better offspring chromosomes and thus,converges the population.Also,it uses a mutation operator to explore the unexplored areas by the crossover operator,and thus,diversifies the GA search space.A combination of crossover and mutation operators makes the GA search strong enough to reach the optimal solution.However,appropriate selection and combination of crossover operator and mutation operator can lead to a very good GA for solving an optimization problem.In this present paper,we aim to study the benchmark traveling salesman problem(TSP).We developed several genetic algorithms using seven crossover operators and six mutation operators for the TSP and then compared them to some benchmark TSPLIB instances.The experimental studies show the effectiveness of the combination of a comprehensive sequential constructive crossover operator and insertion mutation operator for the problem.The GA using the comprehensive sequential constructive crossover with insertion mutation could find average solutions whose average percentage of excesses from the best-known solutions are between 0.22 and 14.94 for our experimented problem instances.

The evolutionarily diverged single-stranded DNA-binding proteins SSB1/SSB2 differentially affect the replication,recombination and mutation of organellar genomes in Arabidopsis thaliana

Single-stranded DNA-binding proteins(SSBs)play essential roles in the replication,recombination and repair processes of organellar DNA molecules.In Arabidopsis thaliana,SSBs are encoded by a small family of two genes(SSB1 and SSB2).However,the functional divergence of these two SSB copies in plants remains largely unknown,and detailed studies regarding their roles in the replication and recombination of organellar genomes are still incomplete.In this study,phylogenetic,gene structure and protein motif analyses all suggested that SSB1 and SSB2 probably diverged during the early evolution of seed plants.Based on accurate long-read sequencing results,ssb1 and ssb2 mutants had decreased copy numbers for both mitochondrial DNA(mtDNA)and plastid DNA(ptDNA),accompanied by a slight increase in structural rearrangements mediated by intermediate-sized repeats in mt genome and small-scale variants in both genomes.Our findings provide an important foundation for further investigating the effects of DNA dosage in the regulation of mutation frequencies in plant organellar genomes.

Drosophila models used to simulate human ATP1A1 gene mutations that cause Charcot-Marie-Tooth type 2 disease and refractory seizures

Certain amino acids changes in the human Na^(+)/K^(+)-ATPase pump,ATPase Na^(+)/K^(+)transporting subunit alpha 1(ATP1A1),cause Charcot-Marie-Tooth disease type 2(CMT2)disease and refractory seizures.To develop in vivo models to study the role of Na^(+)/K^(+)-ATPase in these diseases,we modified the Drosophila gene homolog,Atpα,to mimic the human ATP1A1 gene mutations that cause CMT2.Mutations located within the helical linker region of human ATP1A1(I592T,A597T,P600T,and D601F)were simultaneously introduced into endogenous Drosophila Atpαby CRISPR/Cas9-mediated genome editing,generating the Atpα^(TTTF)model.In addition,the same strategy was used to generate the corresponding single point mutations in flies(Atpα^(I571T),Atpα^(A576T),Atpα^(P579T),and Atpα^(D580F)).Moreover,a deletion mutation(Atpα^(mut))that causes premature termination of translation was generated as a positive control.Of these alleles,we found two that could be maintained as homozygotes(Atpα^(I571T)and Atpα^(P579T)).Three alleles(Atpα^(A576T),Atpα^(P579)and Atpα^(D580F))can form heterozygotes with the Atpαmut allele.We found that the Atpαallele carrying these CMT2-associated mutations showed differential phenotypes in Drosophila.Flies heterozygous for Atpα^(TTTF)mutations have motor performance defects,a reduced lifespan,seizures,and an abnormal neuronal morphology.These Drosophila models will provide a new platform for studying the function and regulation of the sodium-potassium pump.

Genetic mutation of Tas2r104/Tas2r105/Tas2r114 cluster leads to a loss of taste perception to denatonium benzoate and cucurbitacin B

Background:Bitter taste receptors(Tas2rs)are generally considered to sense various bitter compounds to escape the intake of toxic substances.Bitter taste receptors have been found to widely express in extraoral tissues and have important physiological functions outside the gustatory system in vivo.Methods:To investigate the physiological functions of the bitter taste receptor cluster Tas2r106/Tas2r104/Tas2r105/Tas2r114 in lingual and extraoral tissues,multiple Tas2rs mutant mice and Gnat3 were produced using CRISPR/Cas9 gene-editing technique.A mixture containing Cas9 and sgRNA mRNAs for Tas2rs and Gnat3 gene was microinjected into the cytoplasm of the zygotes.Then,T7EN1 assays and sequencing were used to screen genetic mutation at the target sites in founder mice.Quantitative real-time polymerase chain reaction(qRT-PCR)and immunostaining were used to study the expression level of taste signaling cascade and bitter taste receptor in taste buds.Perception to taste substance was also studied using twobottle preference tests.Results:We successfully produced several Tas2rs and Gnat3 mutant mice using the CRISPR/Cas9 technique.Immunostaining results showed that the expression of GNAT3 and PLCB2 was not altered in Tas2rs mutant mice.But qRT-PCR results revealed the changed expression profile of m Tas2rs gene in taste buds of these mutant mice.With two-bottle preference tests,these mutant mice eliminate responses to cycloheximide due to genetic mutation of Tas2r105.In addition,these mutant mice showed a loss of taste perception to quinine dihydrochloride,denatonium benzoate,and cucurbitacin B(CuB).Gnat3-mediated taste receptor and its signal pathway contribute to CuB perception.Conclusions:These findings implied that these mutant mice would be a valuable means to understand the biological functions of TAS2Rs in extraoral tissues and investigate bitter compound-induced responses mediated by these TAS2Rs in many extraoral tissues.

The genetics of pediatric inflammatory bowel disease:Towards precision medicine

Pediatric inflammatory bowel disease(IBD)is a chronic and heterogeneous disease.IBD is commonly classified into Crohn’s disease and ulcerative colitis.It is linked to serious symptoms and complications.The onset of IBD commonly occurs during adolescence.Despite the significant number of cases globally(~5 million),the causes of pediatric IBD,which constitutes 25%of IBD patients,are not yet fully understood.Apart from environmental factors,genetic factors contribute to a higher risk of developing IBD.The predisposition risk of IBD can be investigated using genetic testing.Genetic mechanisms of pediatric IBD are highly complex which resulted in difficulty in selecting effective treatment or patient management.Genetic variation of IBD would serve as a basis for precision medicine and allow for the discovery of more robust treatment avenues for this condition in pediatric patients.This review aims to discuss the genetics of pediatric IBD,and current development in the screening,diagnosis,and treatment based on genetic profiling of pediatric IBD subjects toward more personalized management of this disease.

MYH7 mutation in a pedigree with familial dilated hypertrophic cardiomyopathy:A case report and review of literature

BACKGROUND Hypertrophic cardiomyopathy(HCM)is one of the most prevalent inherited myocardial disorders and is charac-terized by considerable genetic and phenotypic heterogeneity.A subset of patients with HCM progress to a dilated phase of HCM(DPHCM),which is associated with a poor prognosis;however,the underlying pathogenesis remains inadequately understood.CASE SUMMARY In this study,we present a case involving a pedigree with familial DPHCM and conduct a retrospective review of patients with DPHCM with identified gene mutations.Through panel sequencing targeting the coding regions of 312 genes associated with inherited cardiomyopathy,a heterozygous missense mutation(c.746G>A,p.Arg249Glu)in the MYH7 gene was identified in the proband(III-5).Sanger sequencing subsequently confirmed this pathogenic mutation in three additional family members(II-4,III-4,and IV-3).A total of 26 well-documented patients with DPHCM were identified in the literature.Patients with DPHCM are commonly middle-aged and male.The mean age of patients with DPHCM was 53.43±12.79 years.Heart failure,dyspnoea,and atrial fibrillation were the most prevalent symptoms observed,accompanied by an average left ventricular end-diastolic size of 58.62 mm.CONCLUSION Our findings corroborate the pathogenicity of the MYH7(c.746G>A,p.Arg249Glu)mutation for DPHCM and suggest that the Arg249Gln mutation may be responsible for high mortality.

Genetically modified pigs with CD163 point mutation are resistant to HP-PRRSV infection

Porcine reproductive and respiratory syndrome(PRRS)is a globally prevalent contagious disease caused by the positive-strand RNA PRRS virus(PRRSV),resulting in substantial economic losses in the swine industry.Modifying the CD163 SRCR5 domain,either through deletion or substitution,can eff1ectively confer resistance to PRRSV infection in pigs.However,large fragment modifications in pigs inevitably raise concerns about potential adverse effects on growth performance.Reducing the impact of genetic modifications on normal physiological functions is a promising direction for developing PRRSV-resistant pigs.In the current study,we identified a specific functional amino acid in CD163 that influences PRRSV proliferation.Viral infection experiments conducted on Marc145 and PK-15CD163 cells illustrated that the mE535G or corresponding pE529G mutations markedly inhibited highly pathogenic PRRSV(HP-PRRSV)proliferation by preventing viral binding and entry.Furthermore,individual viral challenge tests revealed that pigs with the E529G mutation had viral loads two orders of magnitude lower than wild-type(WT)pigs,confirming effective resistance to HP-PRRSV.Examination of the physiological indicators and scavenger function of CD163 verified no significant differences between the WT and E529G pigs.These findings suggest that E529G pigs can be used for breeding PRRSV-resistant pigs,providing novel insights into controlling future PRRSV outbreaks.

Discrete Evolutionary Genetics: Multiplicative Fitnesses and the Mutation-Fitness Balance

We revisit the multi-allelic mutation-fitness balance problem especially when fitnesses are multiplicative. Using ideas arising from quasi-stationary distributions, we analyze the qualitative differences between the fitness-first and mutation-first models, under various schemes of the mutation pattern. We give some stochastic domination relations between the equilibrium states resulting from these models.

Mass genetics study of rhodopsin point mutations in retinitis pigmentosa

Objective: To evaluate the incidence and pattern of rhodopsin (RHO) mutations in Chinese patients with retinitis pigmentosa (RP). Methods: Conformation sensitive gel electrophoresis (CSGE) and direct DNA sequencing were applied to detect point mutations that occurred in the five coding exons and splice sites of RHO gene in 98 index patients with RP. Results: Four patients of one ADRP family were found to have a missense mutation at codon 347, Pro347Leu. One late-onset RP patient and her daughter, without clinical expression at present, were discovered to have a novel frameshift mutation at codon 327, Pro327 (1-bp del) . Neither of the two mutations was found in 100 normal controls. Ala299Ser was found in one RP patient. Two control subjects also had Ala299Ser, suggesting its nonpathogenicity and just single nucleotide polymorphism (SNP). Conclusion: Two RP patients had rhodopsin mutations, thus the expected frequency of RHO mutations in RP is about 2.0% (95% confidence interval: 0.3%-4.4%). A highly conserved C-terminal sequence QVS(A) PA was altered due to Pro347Leu and thereby misdirecting rhodopsin to incorrect subcellular location. Loss of all phosphory-lation sites at the C-terminus and a highly conserved sequence QVS(A)PA may occur because of Pro327(1-bp del) . To elucidate the predominant biochemical defects in such mutant, transgenic mice and transfected culture cells carrying Pro327(1-bp del) would be of great value.

Genetic Screening of the Lipoprotein Lipase Gene for Mutations in Chinese Subjects with or without Hypertriglyceridemia

Objective： To investigate the association between the mutations in lipoprotein lipase gene and hypertriglyceridemia （HTG）. Methods： The lipoprotein lipase （LPL） gene was screened for mutations in 386 Chinese subjects with （108 cases in the HTG group） or without HTG （278 cases in the control group）, by single-strand conformation polymorphism （SSCP） analysis and DNA sequencing. Results： One novel silent mutation L103L, one missense mutation P207L, three splicing mutations Int3/3＇ -ass/C（-6）→T, and the common S447X polymorphism has been identified in the whole coding region and exon-intron junctions of the LPL gene were examined. Heterozygous P207L found in the HTG group was the first case reported in Asia and subsequently another P207L heterozygote was found in the proband＇s family, all of which suggested that P207L was one of the causes of familial combined hyperlipidemia, but was not so prevalent as that in French Canadian. Int3/3＇-ass/C（-6）→T was found in both groups in the present study although it was regarded as a pathogenic variant to HTG earlier on. Moreover about the beneficial polymorphism S447X, there was also some supportive evidence that the levels of triglycerides （TG） in S447X carriers were significantly lower than noncarders in the subjects without HTG. Conclusions： The association between the LPL variants and HTG is quite complicated and versatile, genotyping of LPL in a larger-scale screening should be necessary and justifiable.

Mutation Classification and Genetic Diversity Analysis of Triticum aestivum ssp. yunnanense King Based on Agronomic Traits

[Objective] The present study was conducted to provide basis for researches on breeding new wheat varieties and conserving rare species in Yunnan Province.[Method] 29 materials of Triticum aestivum ssp.yunnanense King（Yunnan Hulled Wheat）were taken for the research on classification and genetic diversity analysis based on 14 agronomic traits.[Result] Yunnan hulled wheat A14 could be an unnamed white seed variety,and other 28 materials were divided into 10 named mutation types;Yunnan hulled wheat was rich in variability of agronomic traits,in which the coefficient of variance（CV）of sterile spikelet number was the largest（22.59%）,while the CV of earing period was the lowest（3.71%）;the diversity indexes of seven qualitative characters ranged from 1.55-2.04.Moreover,the 29 Yunnan hulled wheat could be divided into 3 clusters by the UPGMA analysis.However,Yunnan hulled wheat varieties originating from similar mutation types did not completely cluster together.The genetic relationship was relatively close among A13（YT-35）,A14（YT-36）and A21（YT-37）,but the faster genetic relationship was observed between them and other Yunnan hulled wheat varieties.[Conclusion] Yunnan hulled wheat had an extensive genetic diversity in agronomic traits.

A new era of mutation rate analyses: Concepts and methods

The mutation rate is a pivotal biological characteristic,intricately governed by natural selection and historically garnering considerable attention.Recent advances in high-throughput sequencing and analytical methodologies have profoundly transformed our understanding in this domain,ushering in an unprecedented era of mutation rate research.This paper aims to provide a comprehensive overview of the key concepts and methodologies frequently employed in the study of mutation rates.It examines various types of mutations,explores the evolutionary dynamics and associated theories,and synthesizes both classical and contemporary hypotheses.Furthermore,this review comprehensively explores recent advances in understanding germline and somatic mutations in animals and offers an overview of experimental methodologies,mutational patterns,molecular mechanisms,and driving forces influencing variations in mutation rates across species and tissues.Finally,it proposes several potential research directions and pressing questions for future investigations.

A rare missense PAX6 mutation causes atypical aniridia in a three-generation Chinese family

●AIM:To investigate the molecular diagnosis of a threegeneration Chinese family affected with aniridia,and further to identify clinically a PAX6 missense mutation in members with atypical aniridia.●METHODS:Eleven family members with and without atypical aniridia were recruited.All family members underwent comprehensive ophthalmic examinations.A combination of whole exome sequencing(WES)and direct Sanger sequencing were performed to uncover the causative mutation.●RESULTS:Among the 11 family members,8 were clinically diagnosed with congenital aniridia(atypical aniridia phenotype).A rare heterozygous mutation c.622C>T(p.Arg208Trp)in exon 8 of PAX6 was identified in all affected family members but not in the unaffected members or in healthy control subjects.●CONCLUSION:A rare missense mutation in the PAX6 gene is found in members of a three-generation Chinese family with congenital atypical aniridia.This result contributes to an increase in the phenotypic spectrum caused by PAX6 missense heterozygous variants and provides useful information for the clinical diagnosis of atypical aniridia,which may also contribute to genetic counselling and family planning.

Mutation in the Agrobacterium his I gene enhances transient expression in pepper

Agrobacterium-mediated plant transformation is widely used in plant genetic engineering.However,its efficiency is limited by plant immunity against Agrobacterium.Chili pepper(Capsicum annuum L.)is an important vegetable that is recalcitrant to Agrobacterium-mediated transformation.In this work,Agrobacterium was found to induce a strong immune response in pepper,which might be the reason for T-DNA being difficult to express in pepper.An Agrobacterium mutant screen was conducted and a point mutation in the hisI gene was identified due to a weak immune response and enhanced transient expression mediated by this Agrobacterium mutant in pepper leaves.Further genetic analysis revealed that histidine biosynthesis deficiency caused by mutations in many genes of this pathway led to reduced pepper cell death,presumably due to reduced bacterial growth.However,mutation analysis of threonine and tryptophan biosynthesis genes showed that the biosynthesis of different amino acids may play different roles in Agrobacterium growth and stimulating the pepper immune response.The possible application of Agrobacterium amino acid biosynthesis mutations in plant biology was discussed.

Mutational landscape of TP53 and CDH1 in gastric cancer

In this editorial we comment on an article published in a recent issue of the World J Gastrointest Surg.A common gene mutation in gastric cancer(GC)is the TP53 mutation.As a tumor suppressor gene,TP53 is implicated in more than half of all tumor occurrences.TP53 gene mutations in GC tissue may be related with clinical pathological aspects.The TP53 mutation arose late in the progression of GC and aided in the final switch to malignancy.CDH1 encodes E-cadherin,which is involved in cell-to-cell adhesion,epithelial structure maintenance,cell polarity,differentiation,and intracellular signaling pathway modulation.CDH1 mutations and functional loss can result in diffuse GC,and CDH1 mutations can serve as independent prognostic indicators for poor prognosis.GC patients can benefit from genetic counseling and testing for CDH1 mutations.Demethylation therapy may assist to postpone the onset and progression of GC.The investigation of TP53 and CDH1 gene mutations in GC allows for the investigation of the relationship between these two gene mutations,as well as providing some basis for evaluating the prognosis of GC patients.

Mental retardation,seizures and language delay caused by new SETD1B mutations:Three case reports

BACKGROUND The SETD1B gene is instrumental in human intelligence and nerve development.Mutations in the SETD1B gene have been linked in recent studies to neurodevelopmental disorders,seizures,and language delay.CASE SUMMARY This study aimed to analyze the clinical manifestations and treatment of three patients suffering from mental retardation,epilepsy,and language delay resulting from a new mutation in the SETD1B gene.Three individuals with these symptoms were selected,and their clinical symptoms,gene test results,and treatment were analyzed.This article discusses the impact of the SETD1B gene mutation on patients and outlines the treatment approach.Among the three patients(two females and one male,aged 8,4,and 1,respectively),all exhibited psychomotor retardation,attention deficit,and hyperactivity disorder,and two had epilepsy.Antiepileptic treatment with sodium tripolyvalproate halted the seizures in the affected child,although mental development remained somewhat delayed.Whole exome sequencing revealed new mutations in the SETD1B gene for all patients,specifically with c.5473C>T(p.Arg1825trp),c.4120C>T(p.Gln1374*,593),c.14_15insC(p.His5Hisfs*33).CONCLUSION Possessing the SETD1B gene mutation may cause mental retardation accompanied by seizures and language delay.Although the exact mechanism is not fully understood,interventions such as drug therapy,rehabilitation training,and family support can assist patients in managing their symptoms and enhancing their quality of life.Furthermore,genetic testing supplies healthcare providers with more precise diagnostic and therapeutic guidance,informs families about genetic disease risks,and contributes to understanding disease pathogenesis and drug research and development.