Exploring the genetic basis of childhood monogenic diabetes

Monogenic diabetes is caused by one or even more genetic variations,which may be uncommon yet have a significant influence and cause diabetes at an early age.Monogenic diabetes affects 1%to 5%of children,and early detection and genetically focused treatment of neonatal diabetes and maturity-onset diabetes of the young can significantly improve long-term health and well-being.The etiology of monogenic diabetes in childhood is primarily attributed to genetic variations affecting the regulatory genes responsible for beta-cell activity.In rare instances,mutations leading to severe insulin resistance can also result in the development of diabetes.Individuals diagnosed with specific types of monogenic diabetes,which are commonly found,can transition from insulin therapy to sulfonylureas,provided they maintain consistent regulation of their blood glucose levels.Scientists have successfully devised materials and methodologies to distinguish individuals with type 1 or 2 diabetes from those more prone to monogenic diabetes.Genetic screening with appropriate findings and interpretations is essential to establish a prognosis and to guide the choice of therapies and management of these interrelated ailments.This review aims to design a comprehensive literature summarizing genetic insights into monogenetic diabetes in children and adolescents as well as summarizing their diagnosis and management.

Monogenic diabetes in children:An underdiagnosed and poorly managed clinical dilemma

Monogenic diabetes,constituting 1%-2%of global diabetes cases,arises from single gene defects with distinctive inheritance patterns.Despite over 50 associated genetic disorders,accurate diagnoses and management of monogenic diabetes remain inadequate,underscoring insufficient clinician awareness.The disease spectrum encompasses maturity-onset diabetes of the young(MODY),characterized by distinct genetic mutations affecting insulin secretion,and neonatal diabetes mellitus(NDM)-a heterogeneous group of severe hyperglycemic disorders in infants.Mitochondrial diabetes,autoimmune monogenic diabetes,genetic insulin resistance and lipodystrophy syndromes further diversify the monogenic diabetes landscape.A tailored approach based on phenotypic and biochemical factors to identify candidates for genetic screening is recommended for suspected cases of MODY.NDM diagnosis warrants immediate molecular genetic testing for infants under six months.Identifying these genetic defects presents a unique opportunity for precision medicine.Ongoing research aimed to develop cost-effective genetic testing methods and gene-based therapy can facilitate appropriate identification and optimize clinical outcomes.Identification and study of new genes offer a valuable opportunity to gain deeper insights into pancreatic cell biology and the pathogenic mechanisms underlying common forms of diabetes.The clinical review published in the recent issue of World Journal of Diabetes is such an attempt to fill-in our knowledge gap about this enigmatic disease.

融合Monogenic幅值和相位的人脸识别方法

针对仅利用图像滤波幅值信息进行识别而忽视相位信息的问题,提出一种融合Monogenic局部相位和幅值的识别方法。该方法先对相位进行量化和异或,并结合方向和尺度信息得到相位编码(MLXP);其次,分别对相位编码和基于幅值的二值编码进行分块,计算直方图特征;然后,采用基于分块的线性判别进行降维,提高特征的判别能力;最后在评分层实行融合。在ORL和CAS-PEAL人脸数据库上,相位方法 MLXP的平均识别率分别为0.97和0.94,融合Monogenic相位和幅值的方法平均识别率分别为0.99和0.979,超越实验中其他所有方法。实验结果表明,相位利用方法 MLXP是有效的,融合Monogenic相位和幅值的方法不但能够避免传统线性判别中的小样本(3S)问题,而且能以较低的时间和空间复杂度,有效地提高身份的正确识别率。

Comprehensive genetic screening reveals wide spectrum of genetic variants in monogenic forms of diabetes among Pakistani population

BACKGROUND Monogenic forms of diabetes(MFD)are single gene disorders.Their diagnosis is challenging,and symptoms overlap with type 1 and type 2 diabetes.AIM To identify the genetic variants responsible for MFD in the Pakistani population and their frequencies.METHODS A total of 184 patients suspected of having MFD were enrolled.The inclusion criterion was diabetes with onset below 25 years of age.Brief demographic and clinical information were taken from the participants.The maturity-onset diabetes of the young(MODY)probability score was calculated,and glutamate decarboxylase ELISA was performed.Antibody negative patients and features resembling MODY were selected(n=28)for exome sequencing to identify the pathogenic variants.RESULTS A total of eight missense novel or very low-frequency variants were identified in 7 patients.Three variants were found in genes for MODY,i.e.HNF1A(c.169C>A,p.Leu57Met),KLF11(c.401G>C,p.Gly134Ala),and HNF1B(c.1058C>T,p.Ser353Leu).Five variants were found in genes other than the 14 known MODY genes,i.e.RFX6(c.919G>A,p.Glu307Lys),WFS1(c.478G>A,p.Glu160Lys)and WFS1(c.517G>A,p.Glu173Lys),RFX6(c.1212T>A,p.His404Gln)and ZBTB20(c.1049G>A,p.Arg350His).CONCLUSION The study showed wide spectrum of genetic variants potentially causing MFD in the Pakistani population.The MODY genes prevalent in European population(GCK,HNF1A,and HNF4a)were not found to be common in our population.Identification of novel variants will further help to understand the role of different genes causing the pathogenicity in MODY patient and their proper management and diagnosis.

Genetic perspectives on childhood monogenic diabetes:Diagnosis,management,and future directions

Monogenic diabetes is caused by one or even more genetic variations, which maybe uncommon yet have a significant influence and cause diabetes at an early age.Monogenic diabetes affects 1 to 5% of children, and early detection and geneticallyfocused treatment of neonatal diabetes and maturity-onset diabetes of theyoung can significantly improve long-term health and well-being. The etiology ofmonogenic diabetes in childhood is primarily attributed to genetic variationsaffecting the regulatory genes responsible for beta-cell activity. In rare instances,mutations leading to severe insulin resistance can also result in the developmentof diabetes. Individuals diagnosed with specific types of monogenic diabetes,which are commonly found, can transition from insulin therapy to sulfonylureas,provided they maintain consistent regulation of their blood glucose levels.Scientists have successfully devised materials and methodologies to distinguishindividuals with type 1 or 2 diabetes from those more prone to monogenicdiabetes. Genetic screening with appropriate findings and interpretations isessential to establish a prognosis and to guide the choice of therapies andmanagement of these interrelated ailments. This review aims to design a comprehensiveliterature summarizing genetic insights into monogenetic diabetes inchildren and adolescents as well as summarizing their diagnosis and management.

Human induced pluripotent stem cells for monogenic disease modelling and therapy

Recent and advanced protocols are now available to derive human induced pluripotent stem cells (hiPSCs) from patients affected by genetic diseases. No curative treatments are available for many of these diseases; thus, hiPSCs represent a major impact on patient’ health. hiPSCs represent a valid model for the in vitro study of monogenic diseases, together with a better comprehension of the pathogenic mechanisms of the pathology, for both cell and gene therapy protocol applications. Moreover, these pluripotent cells represent a good opportunity to test innovative pharmacological treatments focused on evaluating the efficacy and toxicity of novel drugs. Today, innovative gene therapy protocols, especially gene editing-based, are being developed, allowing the use of these cells not only as in vitro disease models but also as an unlimited source of cells useful for tissue regeneration and regenerative medicine, eluding ethical and immune rejection problems. In this review, we will provide an up-to-date of modelling monogenic disease by using hiPSCs and the ultimate applications of these in vitro models for cell therapy. We consider and summarize some peculiar aspects such as the type of parental cells used for reprogramming, the methods currently used to induce the transcription of the reprogramming factors, and the type of iPSC-derived differentiated cells, relating them to the genetic basis of diseases and to their inheritance model.

POINTWISE CONVERGENCE FOR EXPANSIONS IN SPHERICAL MONOGENICS

We offer a new approach to deal with the pointwise convergence of FourierLaplace series on the unit sphere of even-dimensional Euclidean spaces. By using spherical monogenics defined through the generalized Cauchy-Riemann operator, we obtain the spherical monogenic expansions of square integrable functions on the unit sphere. Based on the generalization of Fueter＇s theorem inducing monogenic functions from holomorphic functions in the complex plane and the classical Carleson＇s theorem, a pointwise convergence theorem on the new expansion is proved. The result is a generalization of Carleson＇s theorem to the higher dimensional Euclidean spaces. The approach is simpler than those by using special functions, which may have the advantage to induce the singular integral approach for pointwise convergence problems on the spheres.

Knowledge explosion for monogenic skin diseases

During the past few decades, the investigative technologies of molecular biology- especially sequencing-underwent huge advances, leading to the sequencing of the entire human genome, as well as the identification of several candidate genes and the causative geneticvariations that are responsible for monogenic skin diseases. These advances provided a solid basis for subsequent studies elucidating mechanisms of monogenic skin diseases and improving our understanding of common skin diseases. Furthermore, these discoveries also contributed to the development of novel therapeutic modalities for monogenic skin diseases. In this review, we have used the disease spectrum caused by mutations in the CYLD gene- Brooke-Spiegler syndrome, familial cylindromatosis and multiple familial trichoepithelioma type 1- as a model for demonstrating the knowledge explosion for this group of diseases.

Face Recognition Algorithm Fusing Monogenic Binary Coding and Collaborative Representation

Monogenic binary coding （MBC） have been known to be effective for local feature extraction, while sparse or collaborative representation based classification （CRC） has shown interesting results in robust face recognition. In this paper, a novel face recognition algorithm of fusing MBC and CRC named M-CRC is proposed; in which the dimensionality problem is resolved by projection matrix. The proposed algorithm is evaluated on benchmark face databases, including AR, PolyU-NIR and CAS-PEAL. The results indicate a significant increase in the performance when compared with state-of-the-art face recognition methods.

Gene therapy for monogenic disorders: challenges, strategies, and perspectives

Monogenic disorders refer to a group of human diseases caused by mutations in single genes. While disease-modifying therapies have offered some relief from symptoms and delayed progression for some monogenic diseases, most of these diseases still lack effective treatments. In recent decades, gene therapy has emerged as a promising therapeutic strategy for genetic disorders. Researchers have developed various gene manipulation tools and gene delivery systems to treat monogenic diseases. Despite this progress, concerns about inefficient delivery, persistent expression, immunogenicity, toxicity, capacity limitation, genomic integration, and limited tissue specificity still need to be addressed. This review gives an overview of commonly used gene therapy and delivery tools, along with the challenges they face and potential strategies to counter them.

LASSO-derived nomogram for early identification of pediatric monogenic lupus

Background Monogenic lupus is defined as systemic lupus erythematosus(SLE)/SLE-like patients with either dominantly or recessively inherited pathogenic variants in a single gene with high penetrance.However,because the clinical phenotype of monogenic SLE is extensive and overlaps with that of classical SLE,it causes a delay in diagnosis and treatment.Currently,there is a lack of early identification models for clinical practitioners to provide early clues for recognition.Our goal was to create a clinical model for the early identification of pediatric monogenic lupus,thereby facilitating early and precise diagnosis and treatment for patients.Methods This retrospective cohort study consisted of 41 cases of monogenic lupus treated at the Department of Pediatrics at Peking Union Medical College Hospital from June 2012 to December 2022.The control group consisted of classical SLE patients recruited at a 1:2 ratio.Patients were randomly divided into a training group and a validation group at a 7:3 ratio.A logistic regression model was established based on the least absolute shrinkage and selection operator to generate the coefficient plot.The predictive ability of the model was evaluated using receiver operator characteristic curves and the area under the curve(AUC)index.Results A total of 41 cases of monogenic lupus patients and 82 cases of classical SLE patients were included.Among the monogenic lupus cases(with a male-to-female ratio of 1:1.05 and ages of onset ranging from birth to 15 years),a total of 18 gene mutations were identified.The variables included in the coefficient plot were age of onset,recurrent infections,intracranial calcifications,growth and developmental delay,abnormal muscle tone,lymphadenopathy/hepatosplenomegaly,and chilblain-like skin rash.Our model demonstrated satisfactory diagnostic performance through internal validation,with an AUC value of 0.97(95% confidence interval=0.92–0.97).Conclusions We summarized and analyzed the clinical characteristics of pediatric monogenic lupus and developed a predictive model for early identification by clinicians.Clinicians should exercise high vigilance for monogenic lupus when the score exceeds -9.032299.

A multicenter prospective study of next-generation sequencing-based newborn screening for monogenic genetic diseases in China

Background Newborn screening(NBS)is an important and successful public health program that helps improve the long-term clinical outcomes of newborns by providing early diagnosis and treatment of certain inborn diseases.The develop-ment of next-generation sequencing(NGS)technology provides new opportunities to expand current newborn screening methodologies.Methods We designed a a newborn genetic screening(NBGS)panel targeting 135 genes associated with 75 inborn disorders by multiplex PCR combined with NGS.With this panel,a large-scale,multicenter,prospective multidisease analysis was conducted on dried blood spot(DBS)profiles from 21,442 neonates nationwide.Results We presented the positive detection rate and carrier frequency of diseases and related variants in different regions;and 168(0.78%)positive cases were detected.Glucose-6-Phosphate Dehydrogenase deficiency(G6PDD)and phenylketonuria(PKU)had higher prevalence rates,which were significantly different in different regions.The positive detection of G6PD variants was quite common in south China,whereas PAH variants were most commonly identified in north China.In addi-tion,NBGS identified 3 cases with DUOX2 variants and one with SLC25A13 variants,which were normal in conventional NBS,but were confirmed later as abnormal in repeated biochemical testing after recall.Eighty percent of high-frequency gene carriers and 60%of high-frequency variant carriers had obvious regional differences.On the premise that there was no significant difference in birth weight and gestational age,the biochemical indicators of SLC22A5 c.1400C>G and ACADSB c.1165A>G carriers were significantly different from those of non-carriers.Conclusions We demonstrated that NBGS is an effective strategy to identify neonates affected with treatable diseases as a supplement to current NBS methods.Our data also showed that the prevalence of diseases has significant regional charac-teristics,which provides a theoretical basis for screening diseases in different regions.

Approximation of monogenic functions by higher order Szego kernels on the unit ball and half space

We study the adaptive decomposition of functions in the monogenic Hardy spaces H2by higher order Szeg kernels under the framework of Clifford algebra and Clifford analysis,in the context of unit ball and half space.This is a sequel and a higher-dimensional generalization of our recent study on the complex Hardy spaces.

Multi-vector Spherical Monogenics,Spherical Means and Distributions in Clifford Analysis

New higher-dimensional distributions have been introduced in the framework of Clifford analysis in previous papers by Brackx, Delanghe and Sommen. Those distributions were defined using spherical co-ordinates, the ＂finite part＂ distribution Fp x＋^μ on the real line and the generalized spherical means involving vector-valued spherical monogenics. In this paper, we make a second generalization, leading to new families of distributions, based on the generalized spherical means involving a multivector-valued spherical monogenic. At the same time, as a result of our attempt at keeping the paper self-contained, it offers an overview of the results found so far.

Monogenic diseases in respiratory medicine:Clinical perspectives

With the increasing awareness of genetics in respiratory medicine and improvements in molecular diagnostic techniques,many complicated and rare diseases in respiratory medicine can be diagnosed.Most respiratory diseases have no specific phenotype.However,the clinical spectrum of monogenic diseases in respiratory medicine varies,from pulmonary disease to other inherited disorders that involve the lung.The genes that mediate some of these diseases have been identified.Certain monogenic diseases remain poorly characterized clinically.Because of the specificity of the phenotype of respiratory disease,a future challenge will be to correlate the phenotype and genotype and understand its phenotypic variability.With the development of precision medicine,research on monogenic disorders has been intensive and vigorous.In this article,we provide a brief clinical introduction to monogenic diseases in pediatrics.

Phenotypic and genotypic characterization of inflammatory bowel disease in children under six years of age in China

AIM To analyze clinical differences between monogenic and nonmonogenic very-early-onset inflammatory bowel disease(VEO-IBD) and to characterize monogenic IBD phenotypically and genotypically via genetic testing. METHODS A retrospective analysis of children aged 0 to 6 years diagnosed with VEO-IBD in a tertiary hospital in southern China from 2005 to 2017 was performed. Clinical data for VEO-IBD patients were collected, and genetic characteristics were analyzed using whole exome sequencing or target gene panel sequencing. RESULTS A total of 54 VEO-IBD patients were included in this study. A diagnosis of Crohn's disease(CD) or CDlike intestinal manifestations accounted for 72.2% of the VEO-IBD cases. Nine patients(16.7%) were identified by genetic testing as having monogenic IBD. The median age of diagnosis in the monogenic group was younger than that of the nonmonogenic IBD group, at 18 mo(interquartile range(IQR): 4 to 78) and 43.5 mo(IQR: 3 to 173), respectively; the P-value was 0.021. The incidence of perianal disease in the monogenic group was higher than that in the nonmonogenic group(P = 0.001). However, there were no significant differences between weight-forage and height-for-age Z-scores between the two groups, and similar laboratory results were obtained for the two groups. Five patients were found to have IL10 receptor mutation, two patients had chronic granulomatous disease, one patient had common variable immunodeficiency disease, and one patient had X-linked inhibitor of apoptosis protein deficiency. CONCLUSION A high proportion of monogenic IBD was observed in the VEO-IBD group, especially with disease onset before the age of 6 mo. Monogenic IBD and nonmonogenic IBD exhibited similar clinical features. Furthermore, next-generation sequencing played an important role in the diagnosis of monogenic IBD, and IL10 receptor mutation was predominant in this cohort.

MATCHING PURSUITS AMONG SHIFTED CAUCHY KERNELS IN HIGHER-DIMENSIONAL SPACES

Appealing to the Clifford analysis and matching pursuits, we study the adaptive decompositions of functions of several variables of finite energy under the dictionaries consisting of shifted Cauchy kernels. This is a realization of matching pursuits among shifted Cauchy kernels in higher-dimensional spaces. It offers a method to process signals in arbitrary dimensions.

Conventional Breeding and Molecular Markers for Blast Disease Resistance in Rice (Oryza sativa L.)

Monogenic lines,which carried 23 genes for blast resistance were tested and used donors to transfer resistance genes by crossing method.The results under blast nursery revealed that 9 genes from 23 genes were susceptible to highly susceptible under the three locations(Sakha,Gemmeza,and Zarzoura in Egypt);Pia,Pik,Pik-p,Piz-t,Pita,Pi b,Pi,Pi 19 and Pi 20.While,the genes Pii,Pik-s,Pik-h,Pi z,Piz-5,Pi sh,Pi 3,Pi 1,Pi 5,Pi 7,Pi 9,Pi 12,Pikm and Pita-2 were highly resistant at the same locations.Clustering analysis confirmed the results,which divided into two groups;the first one included all the susceptible genes,while the second one included the resistance genes.In the greenhouse test,the reaction pattern of five races produced 100%resistance under artificial inoculation with eight genes showing complete resistance to all isolates.The completely resistant genes:Pii,Pik-s,Piz,Piz-5(=bi2)(t),Pita(=Pi4)(t),Pita,Pi b and Pi1 as well as clustering analysis confirmed the results.In the F1 crosses,the results showed all the 25 crosses were resistant for leaf blast disease under field conditions.While,the results in F2 population showed seven crosses with segregation ratio of 15(R):1(S),two cross gave segregated ratio of 3 R:1 S and one gave 13:3.For the identification of blast resistance genes in the parental lines,the marker K3959,linked to Pik-s gene and the variety IRBLKS-F5 carry this gene,which was from the monogenic line.The results showed that four genotypes;Sakha 105,Sakha 103,Sakha 106 and IRBLKS-F5 were carrying Pik-s gene,while was absent in the Sakha 101,Sakha 104,IRBL5-M,IRBL9-W,IRBLTACP1 and IRBL9-W(R)genotypes.As for Pi 5 gene,the results showed that it was present in Sakha 103 and Sakha 104 varieties and absent in the rest of the genotypes.In addition,Pita-Pita-2 gene was found in the three Egyptian genotypes(Sakha 105,Sakha 101 and Sakha 104)plus IRBLTACP1 monogenetic.In F2 generation,six populations were used to study the inheritance of blast resistance and specific primers to confirm the ratio and identify the resistance genes.However,the ratios in molecular markers were the same of the ratio under field evaluation in the most population studies.These findings would facilitate in breeding programs for gene pyramiding and gene accumulation to produce durable resistance for blast using those genotypes.

The EPSPS Pro106Ser substitution solely accounts for glyphosate resistance in a goosegrass(Eleusine indica) population from Tennessee, United States

Previous studies have documented the occurrence of glyphosate-resistant （GR） goosegrass （Eleusine indica （L.） Gaertn.） and, in at least some cases, resistance is due to an altered target site. Research was performed to determine if an altered target site was responsible for GR in a Tennessee, United States goosegrass population （TennGR）. DNA sequencing revealed a mutation in TennGR plants conferring the Prol06Ser 5-enolpyruvylshikimate-3-phosphate synthase （EPSPS） substitution previously identified in other GR populations. F2 populations were derived from TennGR plants crossed with plants from a glyphosate-susceptible population （TennGS） and analyzed for their response to glyphosate and genotyped at the EPSPS locus. Plants from the F2 populations segregated 1：2：1 sensitive：intermediate：resistant in response to a selec- tive dose of glyphosate, and these responses co-segregated with the EPSPS genotypes （PP106, PS106, and SS106）. To separately investigate the effect of the Prol06Ser substitution on GR, glyphosate dose-response curves and 50% effective dose （EDso） values were compared among the three genotypes and the two parental populations. The SS106 genotype was 3.4-fold resistant relative to the PP106 genotype, identical to the resistance level obtained when comparing the resistant and susceptible parental populations. We conclude that the mutation conferring a Prol06Ser EPSPS mutation is solely responsible for GR in the TennGR goosegrass population.

Parametric Methods for the Regional Assessment of Cardiac Wall Motion Abnormalities: Comparison Study

Left ventricular(LV)dysfunction is mainly assessed by global contractile indices such as ejection fraction and LV Volumes in cardiac MRI.While these indices give information about the presence or not of LV alteration,they are not able to identify the location and the size of such alteration.The aim of this study is to compare the performance of three parametric imaging techniques used in cardiac MRI for the regional quantification of cardiac dysfunction.The proposed approaches were evaluated on 20 patients with myocardial infarction and 20 subjects with normal function.Three parametric images approaches:covariance analysis,parametric images based on Hilbert transform and those based on the monogenic signal were evaluated using cine-MRI frames acquired in three planes of views.The results show that parametric images generated from the monogenic signal were superior in term of sensitivity(89.69%),specificity(86.51%)and accuracy(89.06%)to those based on covariance analysis and Hilbert transform in the detection of contractile dysfunction related to myocardial infarction.Therefore,the parametric image based on the monogenic signal is likely to provide additional regional indices about LV dysfunction and it may be used in clinical practice as a tool for the analysis of the myocardial alterations.