Newborn screening for genetic disorders:Current status and prospects for the future

Newborn screening(NBS)is a public health service aimed at identifying infants with severe genetic disorders,thus providing effective treatment early enough to prevent or ameliorate the onset of symptoms.Current NBS uses biochemical analysis of dried blood spots,predominately with timeresolved fluorescence immunoassay and tandem mass spectrometry,which produces some false positives and false negatives.The application of enzymatic activity-based testing technology provides a reliable screening method for some disorders.Genetic testing is now commonly used for secondary or confirmatory testing after a positive result in some NBS programs.Recently,next-generation sequencing(NGS)has emerged as a robust tool that enables large panels of genes to be scanned together rapidly.Rapid advances in NGS emphasize the potential for genomic sequencing to improve NBS programs.However,some challenges still remain and require solution before this is applied for population screening.

Notch信号通路——对健康和疾病的机械论观点

The Notch signaling pathway is evolutionarily conserved across metazoan species and plays key roles in many physiological processes.The Notch receptor is activated by two families of canonical ligands(Deltalike and Serrate/Jagged)where both ligands and receptors are single-pass transmembrane proteins usually with large extracellular domains,relative to their intracellular portions.Upon interaction of the core binding regions,presented on opposing cell surfaces,formation of the receptor/ligand complex initiates force-mediated proteolysis,ultimately releasing the transcriptionally-active Notch intracellular domain.This review focuses on structural features of the extracellular receptor/ligand complex,the role of posttranslational modifications in tuning this complex,the contribution of the cell membrane to ligand function,and insights from acquired and genetic diseases.

Prevalence and outcomes of polycystic kidney disease in African populations:A systematic review

BACKGROUND Polycystic kidney disease(PKD)is the most common genetic cause of kidney disease.It is a progressive and irreversible condition that can lead to end-stage renal disease and many other visceral complications.Current comprehensive data on PKD patterns in Africa is lacking.AIM To describe the prevalence and outcomes of PKD in the African population.METHODS A literature search of PubMed,African journal online,and Google Scholar databases between 2000 and 2023 was performed.The Preferred Reporting Items for Systematic Reviews and Meta-Analyses were followed to design the study.Clinical presentations and outcomes of patients were extracted from the included studies.RESULTS Out of 106 articles,we included 13 studies from 7 African countries.Ten of them were retrospective descriptive studies concerning 943 PKD patients with a mean age of 47.9 years.The accurate prevalence and incidence of PKD were not known but it represented the third causal nephropathy among dialysis patients.In majority of patients,the diagnosis of the disease was often delayed.Kidney function impairment,abdominal mass,and hypertension were the leading symptoms at presentation with a pooled prevalence of 72.1%(69.1-75.1),65.8%(62.2-69.4),and 57.4%(54.2-60.6)respectively.Hematuria and infections were the most frequent complications.Genotyping was performed in few studies that revealed a high proportion of new mutations mainly in the PKD1 gene.CONCLUSION The prevalence of PKD in African populations is not clearly defined.Clinical symptoms were almost present with most patients who had kidney function impairment and abdominal mass at the diagnostic.Larger studies including genetic testing are needed to determine the burden of PKD in African populations.

AB090. MOG1, the genetic modifier at 20q13, delays the age-at-onset of glaucoma by 8 to 10 years

Background:Primary open-angle glaucoma(POAG)is a genetically complex disorder caused primarily by gene-gene interactions.To identify these interactions,we studied the CA family,a large French-Canadian pedigree in which the myocilin K423E mutation(MYOCK423E)causes autosomal dominant glaucoma with diagnoses ranging from juvenile-onset OAG(JOAG)to late adult-onset POAG in the heterozygotes(HTZ).To explain this extreme variability,we hypothesized that a second gene,called a modifier,was interacting with MYOC,the primary disease gene.Our goals were(I)to map the modifier on the human genome and;(II)to characterize the symptoms affected genetically by the modifier.These symptoms are called endophenotypes.Methods:Three hundred seventy-five CA members were studied using four quantitative endophenotypes:age of maximal intra-ocular pressures(IOPmax),IOPs progression,progression of cup to disk ratios and age-at-onset(AAO)defined as age at which ocular hypertension(OHT)was first detected with IOP≥22 mmHg.Genome-wide linkage analysis was performed by genotyping 408 genetic markers in 184 CA members.An unbiased pedigree-based algorithm was designed to identify the individuals who were double-mutants,i.e.,these individuals carried one MYOCK423E mutation(i.e.,they were HTZ,affected or not)and they also carry simultaneously a DNA mutation within the modifier.Results:Out of the 375 CA family members investigated,156 were HTZ for the MYOCK423E mutation.120 HTZ were affected with OAG or OHT with treatment while the remaining 36 HTZ were asymptomatic.AAO ranged from 7 to 63 years old;4 individuals over 50 years old were still asymptomatic.OHT preceded optic nerve damage in>98%of the HTZ carriers,confirming that AAO reflected the true severity of the disorder.The modifier showed strong inherited effects on 2 of the 4 endophenotypes:AAO and IOPmax.We next mapped with very high confidence the modifier locus for AAO at chromosome 20q13.Saturation genotyping with additional markers refined the locus to a 9 to 10 centimorgan interval,or about 10 million DNA nucleotides,between D20S857 and D20S832.The locus was named modifier of glaucoma 1(MOG1).When comparing the AAOs of the double mutants versus the median of the AAOs of the MYOCK423E HTZ who carried a wild-type(normal)MOG1 gene and were 1st cousins or closer with the double mutant under investigation,we observed that MOG1 delayed the ages at onset by an average of 8 to 10 years in the double mutants.Conclusions:The MOG1 locus encodes a DNA element that delays the onset of glaucoma by an average of 8-10 years by hampering the first manifestations of OHT.This research will lead to the development of new therapeutic targets for glaucoma.These treatments should prevent optic nerve damage by maintaining IOPs within the normal range.

Measuring the Awareness of Thalassemia in Saudi Arabia

Introduction: Thalassemia disorder is a genetic disease that causes the blood to have less hemoglobin than normal, the main requirement to control thalassemia’s propagation is to educate the entire society. Methodology: A descriptive survey was taken to evaluate the awareness of thalassemia among Saudi Arabia’s society, with a sample size of 384. Results: The results were written in frequencies, and it shows that most of the participants were unaware and lacking information on thalassemia syndrome. Discussion: The results of this study provide valuable insights into the awareness of thalassemia in Saudi Arabia and highlight the need to raise awareness of this disease. Conclusion: This study is not comprehensive because the survey was not disrupted evenly, but it can give us an overview of the awareness of thalassemia in Saudi Arabia, and it shows that most of the participants were unaware and lacked information on thalassemia.

Screening for the familial defective apolipoprotein B-100 R3500W by mutagenic primers PCR

Objective A method combining the mutagenic primers PCR and restriction enzyme digestion was designed to facilitate the detection of gene mutation in familial defective apolipoprotein B 100 R3500W. Methods A pair of primer was designed and a mismatch nucleotide was introduced in its upstream primer. A segment of target DNA including the possibly mutated nucleotide was amplified by PCR and the products were digested by restriction enzyme Nco l. To overcome the potential false negative results due to improper digestion conditions, a segment of DNA with Nco1 cut size was added as reference. Results The target sequence was successfully amplified by PCR, producing a 144 bp DNA fragment as expected. When incubated with Nco1, the enzyme could digest the DNA, producing a 114 bp segment, only if it was amplified from the mutated gene, but not from the normal allele. This difference in length of DNA could be separated by electrophoresis on a 2%agarose gel. Thus we successfully detected two carriers of heterozygous FDB R3500W in 162 hypercholesterolemic patients. Conclusions Mutagenic primers PCR can be used to detect the gene mutation of apo B 100 R3500W, two cases were detected among 162 patients with hypercholesterolemia. It suggests that this mutation is not rare in China's Mainland.

Single and Mitochondrial Gene Inheritance Disorder Prediction Using Machine Learning

One of the most difficult jobs in the post-genomic age is identifying a genetic disease from a massive amount of genetic data.Furthermore,the complicated genetic disease has a very diverse genotype,making it challenging to find genetic markers.This is a challenging process since it must be completed effectively and efficiently.This research article focuses largely on which patients are more likely to have a genetic disorder based on numerous medical parameters.Using the patient’s medical history,we used a genetic disease prediction algorithm that predicts if the patient is likely to be diagnosed with a genetic disorder.To predict and categorize the patient with a genetic disease,we utilize several deep and machine learning techniques such as Artificial neural network(ANN),K-nearest neighbors(KNN),and Support vector machine(SVM).To enhance the accuracy of predicting the genetic disease in any patient,a highly efficient approach was utilized to control how the model can be used.To predict genetic disease,deep and machine learning approaches are performed.The most productive tool model provides more precise efficiency.The simulation results demonstrate that by using the proposed model with the ANN,we achieve the highest model performance of 85.7%,84.9%,84.3%accuracy of training,testing and validation respectively.This approach will undoubtedly transform genetic disorder prediction and give a real competitive strategy to save patients’lives.

Kabuki-Syndrome and Congenital Heart Disease-A Twenty-Year Institutional Experience

Background:Patients with genetic syndromes who undergo surgery to correct congenital heart defects can be at risk for increased morbidity or mortality.Surgical outcomes and postoperative courses following congenital heart surgery in patients with Kabuki-Syndrome(KS)have not been well studied.Objectives:The purpose of this study was to describe the postoperative courses and associated outcomes in the largest set of KS patients undergoing congenital heart surgery to date.Methods:Patients with a confirmed molecular diagnosis of KS and a diagnosis of a CHD admitted to Texas Children’s Hospital between January 1,2000 and January 1,2020 were included(n=20).Demographics and medical histories were collected from the hospitals’electronic health records.Results:Of 20 patients identified with KS and a CHD,15 required surgical correction of their congenital cardiac malformation.Median age and weight at the time of surgery was 2 months and 4.1 kg,respectively.Median duration of hospital stay was 49 days for all surgeries and 151 days for the Norwood procedure.Postoperative infections and pleural effusions were detected and treated in 45.8%and 50%of patients,respectively.There was no in-hospital mortality for any surgery.Median follow up time was 5.6 years;survival at 6 years was 94%.Conclusions:Although KS patients seem to be at increased risk for a more complicated,prolonged postoperative course than that of patients without a genetic syndrome,patients with a diagnosis of a CHD and KS do not appear to be at increased risk of mortality following congenital heart surgery.

Oral Manifestations of Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF-1) is a common genetic disorder with a highly variable phenotype. The disease affects both proliferation and differentiation of cells of neurectodermal origin. The presence of tumors is very common like benign nodular neurofibromas. Tumors with unclear prognosis may be present like plexiform neurofibromas whose prognosis is more uncertain. While many organs exhibit pathologies, most commonly affected are the nervous system, skin, gastrointestinal tract and heart. Oral abnormalities are also very common: 72% of NF-1 patients exhibit pathologies in oral mucosa, gums, maxillary and temporomandibular joints, and teeth. The incidence of NF-1 and its relationship to the prevalence of caries have been discussed in other researches. It is known that poor oral hygiene plays a key role in the development of periodontal disease and caries. Here we review the oral manifestations of neurofibromatosis type 1 that we illustrate by a patient followed in the center of rare diseases of the hospital Henri Mondor, clinical service in which we work.

The current landscape for the treatment of mitochondrial disorders

The mitochondrial organelle is crucial to the energy metabolism of the eukaryotic cell. Defects in mitochondrial function lie at the core of a wide range of disorders, including both rare primary mitochondrial disorders and more common conditions such as Parkinson＇s disease and diabetes. Inherited defects in mitochondrial function can be found in both the nuclear genome and the mitochondrial genome, with the latter creating unique challenges in the treatment and understanding of disease passed on through the mitochondrial genome. In this review, we will describe the limited treatment regimens currently used to alleviate primary mitochondrial disorders, as well as the potential for emerging technologies（in particular, those involving direct manipulation of the mitochondrial genome） to more decisively treat this class of disease. We will also emphasize the critical parallels between primary mitochondrial disorders and more common ailments such as cancer and diabetes.

Prenatal risk factors and genetic causes of ADHD in children

Background Attention deficit/hyperactivity disorder(ADHD)is a common disease among children;it affected 5-7% of the population in 2015.ADHD is a multifactorial disease,and its etiology is still not clearly understood.Data Sources This narrative review has been done by searching the PubMed and Embase databases using attention deficit/hyperactivity disorder,ADHD,risk factors;genetics;pediatrics;psychiatrics as keywords.Results ADHD is considered to be a hereditary disorder in which genes play the fundamental role in the pathogenesis;however,findings from genetic-environmental studies support the hypothesis that genetic factors can exert effects on an indi-viduaFs condition by determining his/her responses to environmental exposures,especially those during the prenatal stage.Conclusion ADHD is considered as a hereditary disorder in which genes and prenatal risk factors play fundamental roles in the pathogenesis.

How genetic errors in GPCRs affect their function:Possible therapeutic strategies

Activating and inactivating mutations in numerous human G protein-coupled receptors(GPCRs)are associated with a wide range of disease phenotypes.Here we use several class A GPCRs with a particularly large set of identified disease-associated mutations,many of which were biochemically characterized,along with known GPCR structures and current models of GPCR activation,to understand the molecular mechanisms yielding pathological phenotypes.Based on this mechanistic understanding we also propose different therapeutic approaches,both conventional,using small molecule ligands,and novel,involving gene therapy.

Identification of the Genetic Cause for Childhood Disintegrative Disorder by Whole-Exome Sequencing

Dear Editor,Childhood Disintegrative Disorder（CDD）,also known as Heller’s syndrome and disintegrative psychosis,is a rare progressive neurological disorder,characterized by a late onset（[2 years of age）and regression of language,social

Intestinal stem cells and intestinal organoids

The intestinal epithelium is one of the most rapidly renewing tissues,which is fueled by stem cells at the base of the crypts.Strategies of genetic lineage tracing and organoids,which capture major features of original tissues,are powerful avenues for exploring the biology of intestinal stem cells in vivo and in vitro,respectively.The combination of intestinal organoideculturing system and genetic modification approaches provides an attractive platform to uncover the mechanism of colorectal cancer and genetic disorders in the human minigut.Here,we will provide a comprehensive overview of studies on intestinal epithelium and intestinal stem cells.We will also review the applications of organoids and genetic markers in intestinal research studies.Furthermore,we will discuss the advantages and drawbacks of organoids as disease models compared with mice models and cell lines.

Precision medicine via the integration of phenotype-genotype information in neonatal genome project

The explosion of next-generation sequencing(NGS)has enabled the widespread use of genomic data in precision medicine.Currently,several neonatal genome projects have emerged to explore the advantages of NGS to diagnose or screen for rare genetic disorders.These projects have made remarkable achievements,but still the genome data could be further explored with the assistance of phenotype collection.In contrast,longitudinal birth cohorts are great examples to record and apply phenotypic information in clinical studies starting at the neonatal period,especially the trajectory analyses for health development or disease progression.It is obvious that efficient integration of genotype and phenotype benefits not only the clinical management of rare genetic disorders but also the risk assessment of complex diseases.Here,we first summarize the recent neonatal genome projects as well as some longitudinal birth cohorts.Then,we propose two simplified strategies by integrating genotypic and phenotypic information in precision medicine based on current studies.Finally,research collaborations,sociological issues,and future perspectives are discussed.How to maximize neonatal genomic information to benefit the pediatric population remains an area in need of more research and effort.

Long-term amelioration of an early-onset familial atrial fibrillation model with AAV-mediated in vivo gene therapy

Atrial fibrillation(AF)is a common cardiac disease with high prevalence in the general population.Despite a mild manifestation at the onset stage,it causes serious consequences,including sudden death,when the disease progresses to the late stage.Most available treatments of AF focus on symptom management or alleviation,due to a lack of fundamental knowledge and the fact that considerable variations of AF exist.With the popularisation of the next-generation sequencing technology,several causal genetic factors,including MYL4,have been discovered to contribute to AF,giving hope to developing its gene therapies.In this study,we attempted to treat a previously established rat AF model,which carried Myl4E11K/E11K loss of function mutation,via overexpression of exogenous wild-type Myl4 by AAV9 vectors.Our results showed that delivery of Myl4 expressing AAV9 to postnatal rat models rescued the symptoms of AF,indicating the therapeutic potential that early gene therapy intervention can achieve long-term effects in treating cardiac arrhythmias caused by gene mutations.

Identification of a novel nonsense mutation in kyphoscoliosis peptidase gene in an Iranian patient with myofibrillar myopathy

Myofibrillar myopathies(MFMs)are rare genetic and slowly progressive neuromuscular disorders.Several pathogenic mutations have been reported in MFM-related genes including DES,CRYAB,MYOT,LDB3 or ZASP,FLNC,BAG3,FHL1 and DNAJB6.Although MFMs is commonly inherited in an autosomal dominant manner,the inheritance pattern and novel mutated genes are not thoroughly elucidated in some cases.Here,we report discovery of a novel nonsense mutation in a 29-year-old Iranian male patient with motor disorders and deformity in his lower limbs.His parents are second cousins.Hereditary Motor Sensory Neuropathy as initial genetic diagnosis was ruled out.Whole exome sequencing using NGS on Illumina Hi-Seq4000 platform was performed to identify the disease and possible mutated gene(s).Our data analysis identified a homozygous nonsense unreported c.C415T(p.R139X)variant on kyphoscoliosis peptidase(KY)gene(NM_178554:exon4).Sanger sequencing of this mutation has been performed for his other related family members.Sequencing and segregation analysis was confirmed the NGS results and autosomal recessive inheritance pattern of the disease.