Facing ethical concerns in the age of precise gene therapy:Outlook on inherited arrhythmias

This editorial,comments on the article by Spartalis et al published in the recent issue of the World Journal of Cardiology.We here provide an outlook on potential ethical concerns related to the future application of gene therapy in the field of inherited arrhythmias.As monogenic diseases with no or few therapeutic options available through standard care,inherited arrhythmias are ideal candidates to gene therapy in their treatment.Patients with inherited arrhythmias typically have a poor quality of life,especially young people engaged in agonistic sports.While genome editing for treatment of inherited arrhythmias still has theoretical application,advances in CRISPR/Cas9 technology now allows the generation of knock-in animal models of the disease.However,clinical translation is somehow expected soon and this make consistent discussing about ethical concerns related to gene editing in inherited arrhythmias.Genomic off-target activity is a known technical issue,but its relationship with ethnical and individual genetical diversity raises concerns about an equitable accessibility.Meanwhile,the costeffectiveness may further limit an equal distribution of gene therapies.The economic burden of gene therapies on healthcare systems is is increasingly recognized as a pressing concern.A growing body of studies are reporting uncertainty in payback periods with intuitive short-term effects for insurance-based healthcare systems,but potential concerns for universal healthcare systems in the long term as well.Altogether,those aspects strongly indicate a need of regulatory entities to manage those issues.

Immune remodulation in pediatric inherited metabolic liver diseases

Inherited metabolic liver diseases arise from genetic mutations that lead to dis-ruptions in liver metabolic pathways and are predominantly observed in pedia-tric populations.The spectrum of genetic metabolic liver disorders is diverse,encompassing a range of conditions associated with aberrations in iron,copper,carbohydrate,lipid,protein,and amino acid metabolism.Historically,research in the domain of genetic metabolic liver diseases has predominantly concentrated on hepatic parenchymal cell alterations.Nevertheless,emerging studies suggest that inherited metabolic liver diseases exert significant influences on the immune microenvironment,both within the liver and systemically.This review endeavors to encapsulate the immunological features of genetic metabolic liver diseases,aiming to expand the horizons of researchers in this discipline,and to elucidate the underlying pathophysiological mechanisms pertinent to hereditary metabolic liver diseases and to propose innovative therapeutic approaches.

Genetic variation features of neonatal hyperbilirubinemia caused by inherited diseases

BACKGROUND Genetic factors play an important role in neonatal hyperbilirubinemia(NH)caused by genetic diseases.AIM To explore the characteristics of genetic mutations associated with NH and analyze the correlation with genetic diseases.METHODS This was a retrospective cohort study.One hundred and five newborn patients diagnosed with NH caused by genetic diseases were enrolled in this study between September 2020 and June 2023 at the Second Affiliated Hospital of Xiamen Medical College.A 24-gene panel was used for gene sequencing to analyze gene mutations in patients.The data were analyzed via Statistical Package for the Social Sciences 20.0 software.RESULTS Seventeen frequently mutated genes were found in the 105 patients.Uridine 5'-diphospho-glucuronosyltransferase 1A1(UGT1A1)variants were identified among the 68 cases of neonatal Gilbert syndrome.In patients with sodium taurocholate cotransporting polypeptide deficiency,the primary mutation identified was Na+/taurocholate cotransporting polypeptide Ntcp(SLC10A1).Adenosine triphosphatase 7B(ATP7B)mutations primarily occur in patients with hepatolenticular degeneration(Wilson's disease).In addition,we found that UGT1A1 and glucose-6-phosphate dehydrogenase mutations were more common in the high-risk group than in the low-risk group,whereas mutations in SLC10A1,ATP7B,and heterozygous 851del4 mutation were more common in the low-risk group.CONCLUSION Genetic mutations are associated with NH and significantly increase the risk of disease in affected newborns.

Automated Classification of Inherited Retinal Diseases in Optical Coherence Tomography Images Using Few-shot Learning

Objective To develop a few-shot learning(FSL) approach for classifying optical coherence tomography(OCT) images in patients with inherited retinal disorders(IRDs).Methods In this study, an FSL model based on a student–teacher learning framework was designed to classify images. 2,317 images from 189 participants were included. Of these, 1,126 images revealed IRDs, 533 were normal samples, and 658 were control samples.Results The FSL model achieved a total accuracy of 0.974–0.983, total sensitivity of 0.934–0.957, total specificity of 0.984–0.990, and total F1 score of 0.935–0.957, which were superior to the total accuracy of the baseline model of 0.943–0.954, total sensitivity of 0.866–0.886, total specificity of 0.962–0.971,and total F1 score of 0.859–0.885. The performance of most subclassifications also exhibited advantages. Moreover, the FSL model had a higher area under curves(AUC) of the receiver operating characteristic(ROC) curves in most subclassifications.Conclusion This study demonstrates the effective use of the FSL model for the classification of OCT images from patients with IRDs, normal, and control participants with a smaller volume of data. The general principle and similar network architectures can also be applied to other retinal diseases with a low prevalence.

SEMI INHERITED BIVARIATE INTERPOLATION

The bivariate interpolation in two dimensional space R2 is more complicated than that in one dimensional space R, because there is no Haar space of continuous functions in R2. Therefore, the bivariate interpolation has not a unique solution for a set of arbitrary distinct pairwise points. In this work, we suggest a type of basis which depends on the points such that the bivariate interpolation has the unique solution for any set of distinct pairwise points. In this case, the matrix of bivariate interpolation has the semi inherited factorization.

Current and future therapies for inherited cholestatic liver diseases

Familial intrahepatic cholestasis(FIC) comprises a group of rare cholestatic liver diseases associated with canalicular transport defects resulting predominantly from mutations in ATP8B1, ABCB11 and ABCB4. Phe-notypes range from benign recurrent intrahepatic cholestasis(BRIC), associated with recurrent cholestatic attacks, to progressive FIC(PFIC). Patients often suffer from severe pruritus and eventually progressive cholestasis results in liver failure. Currently, first-line treatment includes ursodeoxycholic acid in patients with ABCB4 deficiency(PFIC3) and partial biliary diversion in patients with ATP8B1 or ABCB11 deficiency(PFIC1 and PFIC2). When treatment fails, liver transplantation is needed which is associated with complications like rejection, post-transplant hepatic steatosis and recurrence of disease. Therefore, the need for more and better therapies for this group of chronic diseases remains. Here, we discuss new symptomatic treatment options like total biliary diversion, pharmacological diversion of bile acids and hepatocyte transplantation. Furthermore, we focus on emerging mutation-targeted therapeutic strategies, providing an outlook for future personalized treatment for inherited cholestatic liver diseases.

HUMAN MITOCHONDRIAL tRNA MUTATIONS IN MATERNALLY INHERITED DEAFNESS

Mutations in mitochondrial tRNA genes have been shown to be associated with maternally inherited syn-dromic and non-syndromic deafness. Among those, mutations such as tRNALeu(UUR) 3243A>G associated with syndromic deafness are often present in heteroplasmy, and the non-syndromic deafness-associated tRNA mu-tations including tRNASer(UCN) 7445A>G are often in homoplasmy or in high levels of heteroplasmy. These tRNA mutations are the primary factors underlying the development of hearing loss. However, other tRNA mutations such as tRNAThr 15927G>A and tRNASer(UCN) 7444G>A are insufficient to produce a deafness phe-notype, but always act in synergy with the primary mitochondrial DNA mutations, and can modulate their phenotypic manifestation. These tRNA mutations may alter the structure and function of the corresponding mitochondrial tRNAs and cause failures in tRNAs metabolism. Thereby, the impairment of mitochondrial protein synthesis and subsequent defects in respiration caused by these tRNA mutations, results in mitochon-drial dysfunctions and eventually leads to the development of hearing loss. Here, we summarized the deaf-ness-associated mitochondrial tRNA mutations and discussed the pathophysiology of these mitochondrial tRNA mutations, and we hope these data will provide a foundation for the early diagnosis, management, and treatment of maternally inherited deafness.

Review:Mechanisms of inherited cancer susceptibility

A small proportion of many cancers are due to inherited mutations in genes,which result in a high risk to the indi-vidual of developing specific cancers. There are several classes of genes that may be involved: tumour suppressor genes,onco-genes,genes encoding proteins involved in DNA repair and cell cycle control,and genes involved in stimulating the angiogenic pathway. Alterations in susceptibility to cancer may also be due to variations in genes involved in carcinogen metabolism. This review discusses examples of some of these genes and the associated clinical conditions caused by the inheritance of mutations in such genes.

Secret sharing scheme with inherited characteristic

To assure the shareholders can look for their ＂legal＂ attorneys to renew the secret, once the secret sharing scheme is initialized, a secret sharing scheme with inherited characteristic is constructed. In this scheme, each shareholder can produce a new share by his algorithm, which is equivalent to the primary one. Together with other shares, the primary secret can be renewed. Since this scheme is constructed not by replacing the primary share with a new share produced by the dealer in his primitive secret sharing scheme, so no matter how much shares the shareholder produces, these shares can not be gathered together to renew the secret in this scheme. Compared with the existing secret sharing schemes, this scheme provides more agility for the shareholders by investing each of them a function but not affect its security.

Impact of next-generation sequencing on molecular diagnosis of inherited non-syndromic hearing loss

Hearing loss is one of the most common birth defects,with inherited genetic defects play an important role,contributing to about 60%of deafness occurring in infants.However,hearing impairment is genetically heterogeneous,with both common and rare forms occurring due to mutations in estimated 500 genes.Due to the large number and presumably low mutation frequencies of those genes,it would be highly expensive and time-consuming to address this issue by conventional gene-by-gene Sanger sequencing.Next-generation sequencing is a revolutionary technology that allows the simultaneous screening of mutations in a large number of genes.It is cost effective compared to classical strategies of linkage analysis and direct sequencing when the number or size of genes is large,and thus has become a highly efficient strategy for identifying novel causative genes and mutations involved in heritable disease.In this review, we describe major NGS methodologies currently used for genetic disorders and highlight applications of these technologies in studies of molecular diagnosis and the discovery of genes implicated in non-syndromic hearing loss.

Liver transplantation for pediatric inherited metabolic liver diseases

Liver transplantation(LT)remains the gold standard treatment for end stage liver disease in the pediatric population.For liver based metabolic disorders(LBMDs),the decision for LT is predicated on a different set of paradigms.With improved outcomes post-transplantation,LT is no longer merely life saving,but has the potential to also significantly improve quality of life.This review summarizes the clinical presentation,medical treatment and indications for LT for some of the common LBMDs.We also provide a practical update on the dilemmas and controversies surrounding the indications for transplantation,surgical considerations and prognosis and long terms outcomes for pediatric LT in LBMDs.Important progress has been made in understanding these diseases in recent years and with that we outline some of the new therapies that have emerged.

Inherited susceptibility for aggressive prostate cancer

Whether or not there is inherited basis for prostate cancer aggressiveness is not clear, but advances in DNA analysis should provide an answer to this question in the very near future.

Simultaneous expression of two pathogenic genes in four Chinese patients affected with inherited retinal dystrophy

●AIM:To describe the complex,overlapping phenotype of four Chinese patients with inherited retinal dystrophies(IRDs)who harbored two pathogenic genes simultaneously.●METHODS:This retrospective study included 4 patients affected with IRDs.Medical and ophthalmic histories were obtained,and clinical examinations were performed.A specific Hereditary Eye Disease Enrichment Panel(HEDEP)based on exome capture technology was used for genetic screening.●RESULTS:Four patients were identified to harbor disease-causing variants in two different genes.Patient retinitis pigmentosa(RP)01-II:1 exhibited both classical ABCA4-induced Stargardt disease(STGD)1 and USH2 Aassociated RP,patient RP02-III:2 exhibited both classical ABCA4-induced STGD1 and CDH23-associated RP,patient RP03-II:1 exhibited both USH2 A-induced autosomal recessive retinitis pigmentosa(arRP)syndrome and SNRNP200-induced autosomal dominant retinitis pigmentosa(adRP),and patient RP04-II:2 exhibited USH2 Ainduced arRP syndrome and EYS-induced arRP at the same time.●CONCLUSION:Our study demonstrates that genotype–phenotype correlations and comprehensive genetic screening is crucial for diagnosing IRDs and helping family planning for patients suffering from the disease.

Cellular reprogramming and inherited peripheral neuropathies: perspectives and challenges

Inherited peripheral neuropathies （or Charcot-Marie-Tooth disease, CMT） are a phenotypically and genetically heterogeneous group of disorders, which are currently untreatable. They are the most common inherited neuromuscular disorder, affecting around 1 in every 2,500 people （over 120,000 people in the US）. Based on clinical neurophysiological and histopathological features, inherited neuropathies can be divided into two major forms： demyelinating （type 1） and axonal （type 2） CMT （Saporta, 2014）.

Coenzyme Q10 as a therapeutic candidate for treating inherited photoreceptor degeneration

Inherited photoreceptor degeneration（IPD）：The human retina is a highly specialised tissue that enables the perception of light across a range of intensities and colours.It covers about65%of the inner surface of the eye and contains three layers of cells：the outer nuclear layer（ONL）containing the cell bodies and nuclei of the light-sensitive rod and cone photoreceptorswhose photopigment-containing outer segments form the photoreceptor layer; the inner nuclear layer （INL） containing bipolar, horizontal and amacrine cells; and the ganglion cell layer （GCL） from which the optic nerve arises. There are two layers of synaptic connections between these three layers： the photoreceptors synapse with second order neurons, mainly bi- polar cells, in the outer plexiform layer （OPL）, while in turn the bipolar cells form connections in the inner plexiform layer （IPL） with ganglion cells. The retinal pigment epithelium （RPE） lies directly behind the photoreceptor layer, is heavily pigmented to reduce scattering of light, and is essential for the nourishment, maintenance and metabolism of photoreceptors.

Genetic modifier genes for inherited heart and muscle disease

Genetic mutations in single genes lead to inherited forms of cardiac and muscle disease. Cardiomyopathy from genetic mutations may develop in early or later life and may be associated with heart failure or be asymptomatic.The range of clinical outcome with inherited cardiomyopathy within families where there is a single genetic defect is,in part,determined by other genetic variants.We hypothesized that the interaction of single gene mutations with common genetic variants was responsible for cardiac and muscle disease.In a mouse model, we used a whole genome approach to identify genes that cause more severe heart and muscle disease. We identified a genetic locus on chromosome 7 that was significantly associated with severe disease.We identified the causative gene as Ltbp4,a gene that encodes the latent TGFbeta binding protein.We found that increased TGFbeta signaling was seen in the severely affected heart and muscle compared to the mildly affected strain.We found that increased proteolytic cleavage of LTBP4 protein was associated with increased SMAD signaling.These data support a model where increased proteolytic cleavage of LTBP4 results in increased TGFbeta release and signaling.We also identified other genetic regions that influence the severity of cardiomyopathy in this model.A genetic region on chromosome 9 was specifically associated with increased cardiac fibrosis in cardiomyopathy.Identifying modifier genes helps explain pathways important for modulating heart and muscle disease and may point to pathways that can be used therapeutically.(Supported by NIH,the Muscular Dystrophy Association and the Doris Duke Charitable Foundation.)

Clinical applications of high-throughput genetic diagnosis in inherited retinal dystrophies: Present challenges and future directions

The advent of next generation sequencing(NGS) tech-niques has greatly simplified the molecular diagnosis and gene identification in very rare and highly heterogeneous Mendelian disorders. Over the last two years, these approaches, especially whole exome sequencing(WES), alone or combined with homozygosity mapping and linkage analysis, have proved to be successful in the identification of more than 25 new causative retinal dystrophy genes. NGS-approaches have also identified a wealth of new mutations in previously reported genes and have provided more comprehensive information concerning the landscape of genotype-phenotype correlations and the genetic complexity/diversity of human control populations. Although whole genome sequencing is far more informative than WES, the functional meaning of the genetic variants identified by the latter can be more easily interpreted, and final diagnosis of inherited retinal dystrophies is extremely successful, reaching 80%, particularly for recessive cases. Even considering the present limitations of WES, the reductions in costs and time, the continual technical improvements, the implementation of refined bioinformatic tools and the unbiased comprehensive genetic information it provides, make WES a very promising diagnostic tool for routine clinical and genetic diagnosis in the future.

Retinal imaging in inherited retinal diseases

Inherited retinal diseases(IRD)are a leading cause of blindness in the working age population.The advances in ocular genetics,retinal imaging and molecular biology,have conspired to create the ideal environment for establishing treatments for IRD,with the first approved gene therapy and the commencement of multiple therapy trials.The scope of this review is to familiarize clinicians and scientists with the current landscape of retinal imaging in IRD.Herein we present in a comprehensive and concise manner the imaging findings of:(I)macular dystrophies(MD)[Stargardt disease(ABCA4),X-linked retinoschisis(RS1),Best disease(BEST1),pattern dystrophy(PRPH2),Sorsby fundus dystrophy(TIMP3),and autosomal dominant drusen(EFEMP1)],(II)cone and cone-rod dystrophies(GUCA1A,PRPH2,ABCA4 and RPGR),(III)cone dysfunction syndromes[achromatopsia(CNGA3,CNGB3,PDE6C,PDE6H,GNAT2,ATF6],blue-cone monochromatism(OPN1LW/OPN1MW array),oligocone trichromacy,bradyopsia(RGS9/R9AP)and Bornholm eye disease(OPN1LW/OPN1MW),(IV)Leber congenital amaurosis(GUCY2D,CEP290,CRB1,RDH12,RPE65,TULP1,AIPL1 and NMNAT1),(V)rod-cone dystrophies[retinitis pigmentosa,enhanced S-Cone syndrome(NR2E3),Bietti crystalline corneoretinal dystrophy(CYP4V2)],(VI)rod dysfunction syndromes(congenital stationary night blindness,fundus albipunctatus(RDH5),Oguchi disease(SAG,GRK1),and(VII)chorioretinal dystrophies[choroideremia(CHM),gyrate atrophy(OAT)].

Ultrafast laser processing of camouflaged metals by topography inherited multistep removal for information encryption

Surfaces with micro-nanoscale structures show different optical responses,including infrared reflection,thermal radiation,and protective coloration.Direct realization of structure camouflage is important for material functionalities.However,external cloaks or coatings are necessary in structure camouflage,which limits the surface functionality.Here,we propose a novel strategy for the direct structure camouflage through topography inherited removal(TIR)with ultrafast laser,featuring pristine topography preservation and scattering surface fabrication.After multistep TIR,pristine topographies are partially and uniformly removed to preserve the original designed structures.Optical response changes show the suppression of specular reflection by uniformizing reflected light intensity to a low level on the inherited surface.We produce various structure camouflages on large scaled substrates,and demonstrate applications of information encryption in code extraction and word recognition through structure camouflage.The proposed strategy opens opportunities for infrared camouflage and other technologies,such as thermal management,device security,and information encryption.