BACKGROUND Adenomatous polyposis confers an increased risk of developing colorectal cancer.APC and MUTYH are the major genes investigated in patients suspected of having polyposis.In addition to APC and MUTYH genes,ot...BACKGROUND Adenomatous polyposis confers an increased risk of developing colorectal cancer.APC and MUTYH are the major genes investigated in patients suspected of having polyposis.In addition to APC and MUTYH genes,other genes,such as POLE,POLD1,NTHL1,MBD4,MSH3 and MLH3,have recently been associated with polyposis phenotypes,conferring heterogeneity in terms of the clinical,etiological and heritable aspects of patients with polyposis.AIM To investigate the underlying variant landscape in patients with suspected polyposis who lack variants in the APC and MUTYH genes using whole-exome sequencing.METHODS Twenty-seven participants were included in the study and subjected to germline whole-exome sequencing.In addition,their clinical-pathological,personal,and family history data were collected.RESULTS The mean age at diagnosis was 51 years,and most participants had attenuated forms of polyposis(88.9%),with 63.0%diagnosed with a primary tumor,mostly colorectal cancer(76.5%).Among the variants identified,17 were classified as pathogenic or likely pathogenic(in 12 participants),including variants in genes involved in the Wnt/β-catenin signaling pathway,such as ST7 L,A1CF,and DKK4,and variants in DNA-repair genes,such as NTHL1,PNKP,and PMS2,as well as a variant found at the FRK gene identified in a patient with classic polyposis at age 19 and with a family history of polyps.CONCLUSION This study identified novel genes potentially associated with polyposis in patients lacking germline pathogenic variants in the APC and MUTYH genes.These findings support the use of next-generation sequencing for screening,expanding the scope of polyposis-related variants beyond these two genes.展开更多
Objective To establish and validate a novel diabetic retinopathy(DR)risk-prediction model using a whole-exome sequencing(WES)-based machine learning(ML)method.Methods WES was performed to identify potential single nuc...Objective To establish and validate a novel diabetic retinopathy(DR)risk-prediction model using a whole-exome sequencing(WES)-based machine learning(ML)method.Methods WES was performed to identify potential single nucleotide polymorphism(SNP)or mutation sites in a DR pedigree comprising 10 members.A prediction model was established and validated in a cohort of 420 type 2 diabetic patients based on both genetic and demographic features.The contribution of each feature was assessed using Shapley Additive explanation analysis.The efficacies of the models with and without SNP were compared.Results WES revealed that seven SNPs/mutations(rs116911833 in TRIM7,1997T>C in LRBA,1643T>C in PRMT10,rs117858678 in C9orf152,rs201922794 in CLDN25,rs146694895 in SH3GLB2,and rs201407189 in FANCC)were associated with DR.Notably,the model including rs146694895 and rs201407189 achieved better performance in predicting DR(accuracy:80.2%;sensitivity:83.3%;specificity:76.7%;area under the receiver operating characteristic curve[AUC]:80.0%)than the model without these SNPs(accuracy:79.4%;sensitivity:80.3%;specificity:78.3%;AUC:79.3%).Conclusion Novel SNP sites associated with DR were identified in the DR pedigree.Inclusion of rs146694895 and rs201407189 significantly enhanced the performance of the ML-based DR prediction model.展开更多
BACKGROUND Intracranial epidermoid cyst(IEC)transformation to malignant squamous cell carcinoma(SCC)is extremely rare,and its etiology is yet unknown.Currently,SCC is treated by performing surgery,followed by a combin...BACKGROUND Intracranial epidermoid cyst(IEC)transformation to malignant squamous cell carcinoma(SCC)is extremely rare,and its etiology is yet unknown.Currently,SCC is treated by performing surgery,followed by a combination of radiotherapy and chemotherapy.It is crucial to identify efficient and trustworthy therapeutic targets for SCC to improve its diagnosis,prognosis,and treatment.CASE SUMMARY In this study,we report the case of a 47-year-old female patient with SCC,which progressed from IEC in the left internal capsule region.The patient was sought treatment at our hospital for severe diplopic vision,accompanied with speech disorder and memory loss.Based on the clinical and postoperative pathology,this patient was finally diagnosed with SCC.To identify disease-causing variants,whole exome sequencing(WES)was performed on the proband.WES revealed two pathogenic missense mutations on Gap junction protein beta 2(GJB2)(c.257C>T)and Toll-like receptor 2(TLR2)(c.1039A>G),respectively.CONCLUSION This study provided the first clinical evidence for demonstrating the role of GJB2 and TLR2 in IEC development and treatment.We further confirmed WES as a robust and reliable technique for underlying rare and complex disease-related genetic factor identification.展开更多
Mitochondrial disorders are phenotypically varied, with serious clinical repercussions. Among them, there is the deficiency of combined oxidative phosphorylation of type 20, which occurs due to a defect in the VARS2 g...Mitochondrial disorders are phenotypically varied, with serious clinical repercussions. Among them, there is the deficiency of combined oxidative phosphorylation of type 20, which occurs due to a defect in the VARS2 gene. This article presents a case of a 2-year-old female with progressive myoclonic epilepsy and psychomotor regression, with refractoriness to multiple anticonvulsants. The diagnosis was only made after the examination was carried out. Therefore, this article highlights the aspects of this rare disease and the importance of the exome for the diagnosis of rare conditions.展开更多
Dilated cardiomyopathy(DCM),a severe heart disease,is the leading cause of heart failure and sudden cardiac death worldwide.DCM is defined by a dilated and deficient systolic left ventricle(LV),and is a major risk fac...Dilated cardiomyopathy(DCM),a severe heart disease,is the leading cause of heart failure and sudden cardiac death worldwide.DCM is defined by a dilated and deficient systolic left ventricle(LV),and is a major risk factor for morbidity and mortality worldwide.DCM progression can be ascribed to genetic and non-genetic factors,including hypertension,infectious agents,toxins,and drugs.Sarcomere genes play crucial roles in myocardial cells’physical structure and physiological function.展开更多
The causes of recurrent spontaneous abortion (RSA) and fetal malformations are multifactorial and unclear in most cases. Environmental, maternal, and genetic factors have been shown to contribute to these defects. Who...The causes of recurrent spontaneous abortion (RSA) and fetal malformations are multifactorial and unclear in most cases. Environmental, maternal, and genetic factors have been shown to contribute to these defects. Whole-exome sequencing (WES) is widely used to detect genetic variations associated with human diseases and has recently been successfully applied to unveil genetic causes of unexplained recurrent spontaneous abortion (URSA) and fetal malformations. Here, we review the current discovery and diagnosis strategies to identify the underlying pathogenic mutations of URSA and fetal malformations using WES technology and propose to further develop WES, both to advance our understanding of these diseases and to eventually lead to targeted therapies for reproductive disorders.展开更多
Short stature is among the most common endocrinological disease phenotypes of childhood and may occur as an isolated finding or in conjunction with other clinical manifestations.Although the diagnostic utility of clin...Short stature is among the most common endocrinological disease phenotypes of childhood and may occur as an isolated finding or in conjunction with other clinical manifestations.Although the diagnostic utility of clinical genetic testing in short stature has been implicated,the genetic architecture and the utility of genomic studies such as exome sequencing(ES)in a sizable cohort of patients with short stature have not been investigated systematically.In this study,we recruited 561 individuals with short stature from two centers in China during a 4-year period.We performed ES for all patients and available parents.All patients were retrospectively divided into two groups:an isolated short stature group(group I,n=257)and an apparently syndromic short stature group(group II,n=304).Causal variants were identified in 135 of 561(24.1%)patients.In group I,29 of 257(11.3%)of the patients were solved by variants in 24 genes.In group II,106 of 304(34.9%)patients were solved by variants in 57 genes.Genes involved in fundamental cellularprocess played an important role in the genetic architecture of syndromic short stature.Distinct genetic architectures and pathophysiological processes underlie isolated and syndromic short stature.展开更多
BACKGROUND Most cases of Apert syndrome(AS)are found after birth.Cases of AS diagnosed by ultrasound combined with magnetic resonance imaging(MRI)and whole exome sequencing(WES)during pregnancy are rare.CASE SUMMARY W...BACKGROUND Most cases of Apert syndrome(AS)are found after birth.Cases of AS diagnosed by ultrasound combined with magnetic resonance imaging(MRI)and whole exome sequencing(WES)during pregnancy are rare.CASE SUMMARY We present the case of a 34-year old female patient(gravida 2,para 1)whose fetus was diagnosed with AS during pregnancy.Fetal ultrasound performed at 30,2/7 wk of pregnancy showed abnormalities.MRI and three-dimensional ultrasound performed at 31,1/7 wk of pregnancy showed the possibility of AS.Chromosome examination and core family WES were conducted at 31,5/7 wk of pregnancy.The results showed that FGFR2 in the fetus had a c.755C>G missense mutation in its nucleotide,and AS was confirmed.CONCLUSION This case highlights the importance of imaging examinations.Prenatal ultrasound combined with MRI can identify fetal morphological abnormalities accurately,which can be confirmed by WES.展开更多
AIM： To identify the potentially pathogenic gene variants that contributes to the etiology of strabismus. METHODS： A Chinese pedigree with strabismus was collected and the exomes of two affected individuals were se...AIM： To identify the potentially pathogenic gene variants that contributes to the etiology of strabismus. METHODS： A Chinese pedigree with strabismus was collected and the exomes of two affected individuals were sequenced using the next-generation sequencing technology. The resulting variants from exome sequencing were filtered by subsequent bioinformatics methods and the candidate mutation was verified as heterozygous in the affected proposita and her mother by sanger sequencing. RESULTS： Whole exome sequencing and filtering identified a nonsynonymous mutation Co434G-T transition in paired box 3 （PAX3） in the two affected individuals, which were predicted to be deleterious by more than 4 bioinformatics programs. This altered amino acid residue was located in the conserved PAX domain of PAX3. This gene encodes a member of the PAX family of transcription factors, which play critical roles during fetal development. Mutations in PAX3 were associated with Waardenburg syndrome with strabismus. CONCLUSION： Our results report that the c.434G-T mutation （p.R145L） in PAX3 may contribute to strabismus, expanding our understanding of the causally relevant genes for this disorder.展开更多
Tooth development is a complex process that involves precise and time-dependent orchestration of multiple genetic, molecular,and cellular interactions. Ameloblastin(AMBN, also named "amelin" or "sheathl...Tooth development is a complex process that involves precise and time-dependent orchestration of multiple genetic, molecular,and cellular interactions. Ameloblastin(AMBN, also named "amelin" or "sheathlin") is the second most abundant enamel matrix protein known to have a key role in amelogenesis. Amelogenesis imperfecta(AI [MIM: 104500]) refers to a genetically and phenotypically heterogeneous group of conditions characterized by inherited developmental enamel defects. The hereditary dentin disorders comprise a variety of autosomal-dominant genetic symptoms characterized by abnormal dentin structure affecting either the primary or both the primary and secondary teeth. The vital role of Ambn in amelogenesis has been confirmed experimentally using mouse models. Only two cases have been reported of mutations of AMBN associated with non-syndromic human AI. However, no AMBN missense mutations have been reported to be associated with both human AI and dentin disorders.We recruited one kindred with autosomal-dominant amelogenesis imperfecta(ADAI) and dentinogenesis imperfecta/dysplasia characterized by generalized severe enamel and dentin defects. Whole exome sequencing of the proband identified a novel heterozygous C-T point mutation at nucleotide position 1069 of the AMBN gene, causing a Pro to Ser mutation at the conserved amino acid position 357 of the protein. Exfoliated third molar teeth from the affected family members were found to have enamel and dentin of lower mineral density than control teeth, with thinner and easily fractured enamel, short and thick roots, and pulp obliteration. This study demonstrates, for the first time, that an AMBN missense mutation causes non-syndromic human AI and dentin disorders.展开更多
BACKGROUND Cronkhite-Canada syndrome(CCS)is a rare,non-genetic disorder characterized by multiple gastrointestinal polyps,and ectodermal lesions such as alopecia,fingernail atrophy,and skin mucosal pigmentation.Unfort...BACKGROUND Cronkhite-Canada syndrome(CCS)is a rare,non-genetic disorder characterized by multiple gastrointestinal polyps,and ectodermal lesions such as alopecia,fingernail atrophy,and skin mucosal pigmentation.Unfortunately,the pathogenesis of CCS is currently unknown.CASE SUMMARY Here,we describe the case of an elderly female with diarrhea,fatigue,and hair loss,who experienced abdominal pain for over half a year and was found to have multiple gastrointestinal polyps.She was diagnosed with CCS and was treated with albumin supplementation and prednisone,and her electrolyte imbalance was corrected.Following treatment,her symptoms significantly improved.To elucidate the role of potential genetic events in the pathogenesis of CCS,we performed exome sequencing using an extract of her colorectal adenoma.CONCLUSION Our data revealed multiple somatic mutations and copy number variations.Our findings provide a novel insight into the potential mechanisms of CCS etiology.展开更多
Circulating tumour cells(CTCs)were enriched in the peripheral blood of four patients with Stage I non-small cell lung cancer(NSCLC).Octamer-binding transcription factor-4 positive(OCT4+)and negative(OCT4−)CTCs were id...Circulating tumour cells(CTCs)were enriched in the peripheral blood of four patients with Stage I non-small cell lung cancer(NSCLC).Octamer-binding transcription factor-4 positive(OCT4+)and negative(OCT4−)CTCs were identified and captured by interphase fluorescence in situ hybridisation(iFISH).Single cell whole exome sequencing(WES)was performed and the corresponding bioinformatics data were analysed.OCT4+cells were successfully detected in peripheral blood collected from all four Stage I lung cancer patients.Moreover,the tumour mutational burden(TMB)values observed for OCT4+samples from the same patients were slightly smaller than those of the OCT4−samples;the difference was not statistically significant(P>0.05).Thirteen and six characteristic mutations were found in negative samples and positive samples,respectively.The findings indicate that this methodology provides a potential diagnostic index for the early detection of NSCLC.展开更多
Background: Androgen insensitivity syndrome(AIS), a disorder of sexual development in 46, XY individuals, is caused by loss-of-function mutations in the androgen receptor(AR) gene. A variety of tumors have been report...Background: Androgen insensitivity syndrome(AIS), a disorder of sexual development in 46, XY individuals, is caused by loss-of-function mutations in the androgen receptor(AR) gene. A variety of tumors have been reported in association with AIS, but no cases with colorectal cancer(CRC) have been described.Case presentation: Here, we present a male patient with AIS who developed multiple early-onset CRCs and his pedigree. His first cousin was diagnosed with AIS and harbored the same AR gene mutation, but with no signs of CRC. The difference in clinical management for the two patients was that testosterone treatment was given to the proband for a much longer time compared with the cousin. The CRC family history was negative, and no germline mutations in well-known CRC-related genes were identified. A single nucleotide polymorphism array revealed a microduplication on chromosome 22q11.22 that encompassed a micro RNA potentially related to CRC pathogenesis. In the proband, whole exome sequencing identified a polymorphism in an oncogene and 13 rare loss-of-function variants, of which two were in CRC-related genes and four were in genes associated with other human cancers.Conclusions: By pathway analysis, all inherited germline genetic events were connected in a unique network whose alteration in the proband, together with continuous testosterone stimulation, may have played a role in CRC pathogenesis.展开更多
Approaches to understanding the genetic contribution to inflammatory bowel disease(IBD)have continuously evolved from family-and population-based epidemiology,to linkage analysis,and most recently,to genome-wide assoc...Approaches to understanding the genetic contribution to inflammatory bowel disease(IBD)have continuously evolved from family-and population-based epidemiology,to linkage analysis,and most recently,to genome-wide association studies(GWAS).The next stage in this evolution seems to be the sequencing of the exome,that is,the regions of the human genome which encode proteins.The GWAS approach has been very fruitful in identifying at least 163 loci as being associated with IBD,and now,exome sequencing promises to take our genetic understanding to the next level.In this review we will discuss the possible contributions that can be made by an exome sequencing approach both at the individual patient level to aid with disease diagnosis and future therapies,as well as in advancing knowledge of the pathogenesis of IBD.展开更多
Dozens of genes are associated with idiopathic hypogonadotropic hypogonadism(IHH)and an oligogenic etiology has been suggested.However,the associated genes may account for only approximately 50%cases.In addition,a gen...Dozens of genes are associated with idiopathic hypogonadotropic hypogonadism(IHH)and an oligogenic etiology has been suggested.However,the associated genes may account for only approximately 50%cases.In addition,a genomic systematic pedigree analysis is still lacking.Here,we conducted whole exome sequencing(WES)on 18 unrelated men affected by IHH and their corresponding parents.Notably,one reported and 10 novel variants in eight known IHH causative genes(AXL,CCDC141,CHD7,DMXL2,FGFR1,PNPLA6,POLR3A,and PR0KR2),nine variants in nine recently reported candidate genes(DCAF17,DCC,EGF,IGSF10,NOTCH1,PDE3A,RELN,SLIT2,and TRAPPC9),and four variants in four novel candidate genes for IHH(CCDC88C,CDON,GADL1,and SPRED3)were identified in 77.8%(14/18)of IHH cases.Among them,eight(8/18,44.4%)cases carried more than one variant in IHH-related genes,supporting the oligogenic model.Interestingly,we found that those variants tended to be maternally inherited(maternal with n=17 vs paternal with n=7;P=0.028).Our further retrospective investigation of published reports replicated the maternal bias(maternal with n=46 i^s paternal with n=28;P=0.024).Our study extended a variant spectrum for IHH and provided the first evidence that women are probably more tolerant to variants of IHH-related genes than men.展开更多
Objective： Nance-Horan syndrome （NHS） is a rare X-linked disorder characterized by congenital nuclear cataracts, dental anomalies, and craniofacial dysmorphisms. Mental retardation was present in about 30% of the r...Objective： Nance-Horan syndrome （NHS） is a rare X-linked disorder characterized by congenital nuclear cataracts, dental anomalies, and craniofacial dysmorphisms. Mental retardation was present in about 30% of the reported cases. The purpose of this study was to investigate the genetic and clinical features of NHS in a Chinese family. Methods： Whole exome sequencing analysis was performed on DNA from an affected male to scan for can- didate mutations on the X-chromosome. Sanger sequencing was used to verify these candidate mutations in the whole family. Clinical and ophthalmological examinations were performed on all members of the family. Results： A combi- nation of exome sequencing and Sanger sequencing revealed a nonsense mutation c.322G〉T （E108X）in exon 1 of NHS gene, co-segregating with the disease in the family. The nonsense mutation led to the conversion of glutamic acid to a stop codon （E108X）, resulting in truncation of the NHS protein. Multiple sequence alignments showed that codon 108, where the mutation （c.322G〉T） occurred, was located within a phylogenetically conserved region. The clinical features in all affected males and female carriers are described in detail. Conclusions： We report a nonsense mutation c.322G〉T （E108X） in a Chinese family with NHS. Our findings broaden the spectrum of NHS mutations and provide molecular insight into future NHS clinical genetic diagnosis.展开更多
Purpose The present study aimed to evaluate the genetic diagnostic yield and accuracy of exome sequencing in Chinese patients with split hand–foot malformation(SHFM),a severe heterogeneous congenital anomaly characte...Purpose The present study aimed to evaluate the genetic diagnostic yield and accuracy of exome sequencing in Chinese patients with split hand–foot malformation(SHFM),a severe heterogeneous congenital anomaly characterized by hypodevelopment of the central ray of the hands and feet.Methods A cohort of seven families and five sporadic patients with SHFM was investigated.Genomic DNA was prepared from the peripheral blood of affected as well as unaffected individuals.Whole exome sequencing(WES)was performed to identify the pathogenic mutations.Array-based comparative genomic hybridization(aCGH),CytoScan,quantitative polymerase chain reaction(qPCR),and Sanger sequencing were performed to validate the findings of WES.WES data of an additional cohort of 24 patients with non-SHFM congenital hand anomalies were analyzed as the control.Results Pathogenic variants of TP63,c.G956A p.R319H,and c.T602A:p.L201H,were identified in two families by WES.In the remaining patients,copy number analysis of the WES data by XHMM software identified pathogenic 10q 24 duplication in five individuals from three families,which was further validated via CytoScan and qPCR;however,WES could not detect duplication in 10q24 in an additional cohort of 24 individuals with non-SHFM congenital hand anomaly.Importantly,qPCR analysis of the 10q24 region copy number revealed a definite consistency with WES data in all individuals.Genotype–phenotype analysis did not present any unique feature that could differentiate between the families with TP63 mutation and 10q24 duplication.Conclusions Our study demonstrated that WES is an accurate and sensitive method to detect the pathogenic 10q24 duplication.Collectively,with TP63 mutation,a single WES testing could yield a diagnosis rate of about 40%(5/12)for the SHFM patients,at least in our cohort.As the genotype–phenotype correlation remains unclear,WES could be used as a cost-effective method for the genetic diagnosis of SHFM.展开更多
Global developmental delay/intellectual disability(GDD/ID)with a prevalence of 1%e3%represents one of the biggest medical and social challenges in our society.^(1)Genetic factors are the main causes of GDD/ID and earl...Global developmental delay/intellectual disability(GDD/ID)with a prevalence of 1%e3%represents one of the biggest medical and social challenges in our society.^(1)Genetic factors are the main causes of GDD/ID and early diagnosis is crucial to improving the prognosis of GDD/ID children.^(2)Chromosomal microarray analysis,as a first-tier clinical test,^(3)remains limited because of the insufficient to detect small variations while whole exome sequencing(WES)can detect both single-nucleotide variants(SNVs)and copy-number variants(CNVs),effectively improving the diagnostic yield of GDD/ID.展开更多
Dear Editor,It was our pleasure to read this letter,which responded with positive comments to our research article entitled“Brain iron deposition and whole-exome sequencing of non-Wilson's disease hypoceruloplasm...Dear Editor,It was our pleasure to read this letter,which responded with positive comments to our research article entitled“Brain iron deposition and whole-exome sequencing of non-Wilson's disease hypoceruloplasminemia in a family”.1 Hepatolenticular degeneration,also known as Wilson's disease(WD),was first described in 1912 by Samuel Alexander Kinnier Wilson,a neurologist from the Queen Square Institute of Neurology,in his doctoral dissertation.WD is caused by mutations in the ATPase copper transporting beta(ATP7B)gene,located on chromosome 13q,which result in the defective biliary excretion of copper.The subsequent excessive copper accumulation in multiple organs,such as the brain and liver,causes symptoms that include movement disorders,cognitive/psychiatric symptoms,and liver disease.展开更多
AIM:To identify the genetic factors underlying anophthalmia and microphthalmia(A/M),and to perform computational analysis to verify the pathophysiological mechanisms of the disease.METHODS:This study investigated a co...AIM:To identify the genetic factors underlying anophthalmia and microphthalmia(A/M),and to perform computational analysis to verify the pathophysiological mechanisms of the disease.METHODS:This study investigated a consanguineous Pakistani family with multiple affected individuals.Clinical evaluations were conducted using A-Scan and ophthalmic B-Scan ultrasonography(B-Scan).To identify the diseasecausing variant,whole exome sequencing(WES)and Sanger sequencing were performed.In silico functional analyses were carried out using AlphaFold(for protein modeling)and ClusPro(for protein docking analysis)tools,and the hydrodynamic properties of the protein were determined via molecular dynamics simulations.RESULTS:Clinical analysis of the five patients revealed severe phenotypes of bilateral anophthalmia.Ocular B-Scan did not detect ocular tissue or intraocular fluid,thus confirming the diagnosis of anophthalmia in all patients.Due to these structural defects,all patients exhibited complete blindness and absence of light perception;additionally,two patients had mild to moderate intellectual disability.Genetic analysis identified a splice site variant[NM_000693.2:c.884-2_885dup;p.(Asp296SerfsTer35)]in the 9^(th)exon of the ALDH1A3 gene.CONCLUSION:The present study expands the genetic spectrum of ALDH1A3 and contributes to establishing the genotype-phenotype correlation for this gene.展开更多
基金Supported by the National Oncology Care Support Program,No.25000.056766/2015-64.
文摘BACKGROUND Adenomatous polyposis confers an increased risk of developing colorectal cancer.APC and MUTYH are the major genes investigated in patients suspected of having polyposis.In addition to APC and MUTYH genes,other genes,such as POLE,POLD1,NTHL1,MBD4,MSH3 and MLH3,have recently been associated with polyposis phenotypes,conferring heterogeneity in terms of the clinical,etiological and heritable aspects of patients with polyposis.AIM To investigate the underlying variant landscape in patients with suspected polyposis who lack variants in the APC and MUTYH genes using whole-exome sequencing.METHODS Twenty-seven participants were included in the study and subjected to germline whole-exome sequencing.In addition,their clinical-pathological,personal,and family history data were collected.RESULTS The mean age at diagnosis was 51 years,and most participants had attenuated forms of polyposis(88.9%),with 63.0%diagnosed with a primary tumor,mostly colorectal cancer(76.5%).Among the variants identified,17 were classified as pathogenic or likely pathogenic(in 12 participants),including variants in genes involved in the Wnt/β-catenin signaling pathway,such as ST7 L,A1CF,and DKK4,and variants in DNA-repair genes,such as NTHL1,PNKP,and PMS2,as well as a variant found at the FRK gene identified in a patient with classic polyposis at age 19 and with a family history of polyps.CONCLUSION This study identified novel genes potentially associated with polyposis in patients lacking germline pathogenic variants in the APC and MUTYH genes.These findings support the use of next-generation sequencing for screening,expanding the scope of polyposis-related variants beyond these two genes.
基金supported by the National Natural Science Foundation of China[Grant No.62206185]。
文摘Objective To establish and validate a novel diabetic retinopathy(DR)risk-prediction model using a whole-exome sequencing(WES)-based machine learning(ML)method.Methods WES was performed to identify potential single nucleotide polymorphism(SNP)or mutation sites in a DR pedigree comprising 10 members.A prediction model was established and validated in a cohort of 420 type 2 diabetic patients based on both genetic and demographic features.The contribution of each feature was assessed using Shapley Additive explanation analysis.The efficacies of the models with and without SNP were compared.Results WES revealed that seven SNPs/mutations(rs116911833 in TRIM7,1997T>C in LRBA,1643T>C in PRMT10,rs117858678 in C9orf152,rs201922794 in CLDN25,rs146694895 in SH3GLB2,and rs201407189 in FANCC)were associated with DR.Notably,the model including rs146694895 and rs201407189 achieved better performance in predicting DR(accuracy:80.2%;sensitivity:83.3%;specificity:76.7%;area under the receiver operating characteristic curve[AUC]:80.0%)than the model without these SNPs(accuracy:79.4%;sensitivity:80.3%;specificity:78.3%;AUC:79.3%).Conclusion Novel SNP sites associated with DR were identified in the DR pedigree.Inclusion of rs146694895 and rs201407189 significantly enhanced the performance of the ML-based DR prediction model.
文摘BACKGROUND Intracranial epidermoid cyst(IEC)transformation to malignant squamous cell carcinoma(SCC)is extremely rare,and its etiology is yet unknown.Currently,SCC is treated by performing surgery,followed by a combination of radiotherapy and chemotherapy.It is crucial to identify efficient and trustworthy therapeutic targets for SCC to improve its diagnosis,prognosis,and treatment.CASE SUMMARY In this study,we report the case of a 47-year-old female patient with SCC,which progressed from IEC in the left internal capsule region.The patient was sought treatment at our hospital for severe diplopic vision,accompanied with speech disorder and memory loss.Based on the clinical and postoperative pathology,this patient was finally diagnosed with SCC.To identify disease-causing variants,whole exome sequencing(WES)was performed on the proband.WES revealed two pathogenic missense mutations on Gap junction protein beta 2(GJB2)(c.257C>T)and Toll-like receptor 2(TLR2)(c.1039A>G),respectively.CONCLUSION This study provided the first clinical evidence for demonstrating the role of GJB2 and TLR2 in IEC development and treatment.We further confirmed WES as a robust and reliable technique for underlying rare and complex disease-related genetic factor identification.
文摘Mitochondrial disorders are phenotypically varied, with serious clinical repercussions. Among them, there is the deficiency of combined oxidative phosphorylation of type 20, which occurs due to a defect in the VARS2 gene. This article presents a case of a 2-year-old female with progressive myoclonic epilepsy and psychomotor regression, with refractoriness to multiple anticonvulsants. The diagnosis was only made after the examination was carried out. Therefore, this article highlights the aspects of this rare disease and the importance of the exome for the diagnosis of rare conditions.
文摘Dilated cardiomyopathy(DCM),a severe heart disease,is the leading cause of heart failure and sudden cardiac death worldwide.DCM is defined by a dilated and deficient systolic left ventricle(LV),and is a major risk factor for morbidity and mortality worldwide.DCM progression can be ascribed to genetic and non-genetic factors,including hypertension,infectious agents,toxins,and drugs.Sarcomere genes play crucial roles in myocardial cells’physical structure and physiological function.
基金supported by the National Natural Science Foundation of China (Nos. 31522034 and 81730038)the National High Technology Research and Development Program Grant (2015AA020407)
文摘The causes of recurrent spontaneous abortion (RSA) and fetal malformations are multifactorial and unclear in most cases. Environmental, maternal, and genetic factors have been shown to contribute to these defects. Whole-exome sequencing (WES) is widely used to detect genetic variations associated with human diseases and has recently been successfully applied to unveil genetic causes of unexplained recurrent spontaneous abortion (URSA) and fetal malformations. Here, we review the current discovery and diagnosis strategies to identify the underlying pathogenic mutations of URSA and fetal malformations using WES technology and propose to further develop WES, both to advance our understanding of these diseases and to eventually lead to targeted therapies for reproductive disorders.
基金funded in part by the Beijing Natural Science Foundation(JQ20032 to N.W.and to 7191007 to Z.W.)National Natural Science Foundation of China(81822030 and 82072391 to N.W.,81772299and 81930068 to Z.W.,81772301 and 81972132 to G.Q.,81672123and 81972037 to J.Z.)+7 种基金Capital's Funds for Health Improvement and Research(2020-4-40114 to N.W.)Tsinghua University-Peking Union Medical College Hospital Initiative Scientific Research ProgramNational Key Research and Development Program of China(2018YFC0910500 to N.W.and Z.W.,2016YFC0901501 to S.Z.)the PUMC Youth Fund and the Fundamental Research Funds for the Central Universities(3332019052 to Y.M.)the CAMS Initiative Fund for Medical Sciences(2016-I2M-3-003 to G.Q.and N.W.,2016-I2M-2-006 and 2017-I2M-2-001 to Z.W.)the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2019PT320025 to N.W.)sponsored by GeneScience Pharmaceuticals Co.,Ltd.(Changchun,China)funded by the United States National Institutes of Health(UM1HG006542 and K08 HG008986)。
文摘Short stature is among the most common endocrinological disease phenotypes of childhood and may occur as an isolated finding or in conjunction with other clinical manifestations.Although the diagnostic utility of clinical genetic testing in short stature has been implicated,the genetic architecture and the utility of genomic studies such as exome sequencing(ES)in a sizable cohort of patients with short stature have not been investigated systematically.In this study,we recruited 561 individuals with short stature from two centers in China during a 4-year period.We performed ES for all patients and available parents.All patients were retrospectively divided into two groups:an isolated short stature group(group I,n=257)and an apparently syndromic short stature group(group II,n=304).Causal variants were identified in 135 of 561(24.1%)patients.In group I,29 of 257(11.3%)of the patients were solved by variants in 24 genes.In group II,106 of 304(34.9%)patients were solved by variants in 57 genes.Genes involved in fundamental cellularprocess played an important role in the genetic architecture of syndromic short stature.Distinct genetic architectures and pathophysiological processes underlie isolated and syndromic short stature.
文摘BACKGROUND Most cases of Apert syndrome(AS)are found after birth.Cases of AS diagnosed by ultrasound combined with magnetic resonance imaging(MRI)and whole exome sequencing(WES)during pregnancy are rare.CASE SUMMARY We present the case of a 34-year old female patient(gravida 2,para 1)whose fetus was diagnosed with AS during pregnancy.Fetal ultrasound performed at 30,2/7 wk of pregnancy showed abnormalities.MRI and three-dimensional ultrasound performed at 31,1/7 wk of pregnancy showed the possibility of AS.Chromosome examination and core family WES were conducted at 31,5/7 wk of pregnancy.The results showed that FGFR2 in the fetus had a c.755C>G missense mutation in its nucleotide,and AS was confirmed.CONCLUSION This case highlights the importance of imaging examinations.Prenatal ultrasound combined with MRI can identify fetal morphological abnormalities accurately,which can be confirmed by WES.
文摘AIM： To identify the potentially pathogenic gene variants that contributes to the etiology of strabismus. METHODS： A Chinese pedigree with strabismus was collected and the exomes of two affected individuals were sequenced using the next-generation sequencing technology. The resulting variants from exome sequencing were filtered by subsequent bioinformatics methods and the candidate mutation was verified as heterozygous in the affected proposita and her mother by sanger sequencing. RESULTS： Whole exome sequencing and filtering identified a nonsynonymous mutation Co434G-T transition in paired box 3 （PAX3） in the two affected individuals, which were predicted to be deleterious by more than 4 bioinformatics programs. This altered amino acid residue was located in the conserved PAX domain of PAX3. This gene encodes a member of the PAX family of transcription factors, which play critical roles during fetal development. Mutations in PAX3 were associated with Waardenburg syndrome with strabismus. CONCLUSION： Our results report that the c.434G-T mutation （p.R145L） in PAX3 may contribute to strabismus, expanding our understanding of the causally relevant genes for this disorder.
基金partially supported by a grant from the National Natural Science Foundation of China 31371279 (to Fu Xiong)the National Natural Science Foundation of China 81371137 (to Bu-Ling Wu)the Science and Technology Program of Guangzhou 201707010301 (to Fu Xiong)
文摘Tooth development is a complex process that involves precise and time-dependent orchestration of multiple genetic, molecular,and cellular interactions. Ameloblastin(AMBN, also named "amelin" or "sheathlin") is the second most abundant enamel matrix protein known to have a key role in amelogenesis. Amelogenesis imperfecta(AI [MIM: 104500]) refers to a genetically and phenotypically heterogeneous group of conditions characterized by inherited developmental enamel defects. The hereditary dentin disorders comprise a variety of autosomal-dominant genetic symptoms characterized by abnormal dentin structure affecting either the primary or both the primary and secondary teeth. The vital role of Ambn in amelogenesis has been confirmed experimentally using mouse models. Only two cases have been reported of mutations of AMBN associated with non-syndromic human AI. However, no AMBN missense mutations have been reported to be associated with both human AI and dentin disorders.We recruited one kindred with autosomal-dominant amelogenesis imperfecta(ADAI) and dentinogenesis imperfecta/dysplasia characterized by generalized severe enamel and dentin defects. Whole exome sequencing of the proband identified a novel heterozygous C-T point mutation at nucleotide position 1069 of the AMBN gene, causing a Pro to Ser mutation at the conserved amino acid position 357 of the protein. Exfoliated third molar teeth from the affected family members were found to have enamel and dentin of lower mineral density than control teeth, with thinner and easily fractured enamel, short and thick roots, and pulp obliteration. This study demonstrates, for the first time, that an AMBN missense mutation causes non-syndromic human AI and dentin disorders.
文摘BACKGROUND Cronkhite-Canada syndrome(CCS)is a rare,non-genetic disorder characterized by multiple gastrointestinal polyps,and ectodermal lesions such as alopecia,fingernail atrophy,and skin mucosal pigmentation.Unfortunately,the pathogenesis of CCS is currently unknown.CASE SUMMARY Here,we describe the case of an elderly female with diarrhea,fatigue,and hair loss,who experienced abdominal pain for over half a year and was found to have multiple gastrointestinal polyps.She was diagnosed with CCS and was treated with albumin supplementation and prednisone,and her electrolyte imbalance was corrected.Following treatment,her symptoms significantly improved.To elucidate the role of potential genetic events in the pathogenesis of CCS,we performed exome sequencing using an extract of her colorectal adenoma.CONCLUSION Our data revealed multiple somatic mutations and copy number variations.Our findings provide a novel insight into the potential mechanisms of CCS etiology.
基金the National Natural Science Foundation of China(No.81773273)。
文摘Circulating tumour cells(CTCs)were enriched in the peripheral blood of four patients with Stage I non-small cell lung cancer(NSCLC).Octamer-binding transcription factor-4 positive(OCT4+)and negative(OCT4−)CTCs were identified and captured by interphase fluorescence in situ hybridisation(iFISH).Single cell whole exome sequencing(WES)was performed and the corresponding bioinformatics data were analysed.OCT4+cells were successfully detected in peripheral blood collected from all four Stage I lung cancer patients.Moreover,the tumour mutational burden(TMB)values observed for OCT4+samples from the same patients were slightly smaller than those of the OCT4−samples;the difference was not statistically significant(P>0.05).Thirteen and six characteristic mutations were found in negative samples and positive samples,respectively.The findings indicate that this methodology provides a potential diagnostic index for the early detection of NSCLC.
基金supported in part by funds obtained through an Italian law that allows taxpayers to allocate 0.5 percent share of their income tax contribution to a research institution of their choice
文摘Background: Androgen insensitivity syndrome(AIS), a disorder of sexual development in 46, XY individuals, is caused by loss-of-function mutations in the androgen receptor(AR) gene. A variety of tumors have been reported in association with AIS, but no cases with colorectal cancer(CRC) have been described.Case presentation: Here, we present a male patient with AIS who developed multiple early-onset CRCs and his pedigree. His first cousin was diagnosed with AIS and harbored the same AR gene mutation, but with no signs of CRC. The difference in clinical management for the two patients was that testosterone treatment was given to the proband for a much longer time compared with the cousin. The CRC family history was negative, and no germline mutations in well-known CRC-related genes were identified. A single nucleotide polymorphism array revealed a microduplication on chromosome 22q11.22 that encompassed a micro RNA potentially related to CRC pathogenesis. In the proband, whole exome sequencing identified a polymorphism in an oncogene and 13 rare loss-of-function variants, of which two were in CRC-related genes and four were in genes associated with other human cancers.Conclusions: By pathway analysis, all inherited germline genetic events were connected in a unique network whose alteration in the proband, together with continuous testosterone stimulation, may have played a role in CRC pathogenesis.
基金Supported by A Senior Research Award from the Crohn’s to Cardinale CJColitis Foundation of America to Hakonarson Ha special purpose fund from the Edmunds Family Foundation for Ulcerative Colitis Studies to Baldassano RN
文摘Approaches to understanding the genetic contribution to inflammatory bowel disease(IBD)have continuously evolved from family-and population-based epidemiology,to linkage analysis,and most recently,to genome-wide association studies(GWAS).The next stage in this evolution seems to be the sequencing of the exome,that is,the regions of the human genome which encode proteins.The GWAS approach has been very fruitful in identifying at least 163 loci as being associated with IBD,and now,exome sequencing promises to take our genetic understanding to the next level.In this review we will discuss the possible contributions that can be made by an exome sequencing approach both at the individual patient level to aid with disease diagnosis and future therapies,as well as in advancing knowledge of the pathogenesis of IBD.
基金the National Key Research and Development Program of China(2016YFC0905100)National Natural Science Foundation of China(31625015 and 31521003)+2 种基金Shanghai Medical Center of Key Programs for Female Reproductive Diseases(2017ZZ01016)Shanghai Municipal Science and Technology Major Project(2017SHZDZX01)Shanghai Municipal Commission for Science and Technology(19QA1407500).
文摘Dozens of genes are associated with idiopathic hypogonadotropic hypogonadism(IHH)and an oligogenic etiology has been suggested.However,the associated genes may account for only approximately 50%cases.In addition,a genomic systematic pedigree analysis is still lacking.Here,we conducted whole exome sequencing(WES)on 18 unrelated men affected by IHH and their corresponding parents.Notably,one reported and 10 novel variants in eight known IHH causative genes(AXL,CCDC141,CHD7,DMXL2,FGFR1,PNPLA6,POLR3A,and PR0KR2),nine variants in nine recently reported candidate genes(DCAF17,DCC,EGF,IGSF10,NOTCH1,PDE3A,RELN,SLIT2,and TRAPPC9),and four variants in four novel candidate genes for IHH(CCDC88C,CDON,GADL1,and SPRED3)were identified in 77.8%(14/18)of IHH cases.Among them,eight(8/18,44.4%)cases carried more than one variant in IHH-related genes,supporting the oligogenic model.Interestingly,we found that those variants tended to be maternally inherited(maternal with n=17 vs paternal with n=7;P=0.028).Our further retrospective investigation of published reports replicated the maternal bias(maternal with n=46 i^s paternal with n=28;P=0.024).Our study extended a variant spectrum for IHH and provided the first evidence that women are probably more tolerant to variants of IHH-related genes than men.
基金supported by the Science and Technology Specific Project of Zhejiang Province(No.2009C03010-2),China
文摘Objective： Nance-Horan syndrome （NHS） is a rare X-linked disorder characterized by congenital nuclear cataracts, dental anomalies, and craniofacial dysmorphisms. Mental retardation was present in about 30% of the reported cases. The purpose of this study was to investigate the genetic and clinical features of NHS in a Chinese family. Methods： Whole exome sequencing analysis was performed on DNA from an affected male to scan for can- didate mutations on the X-chromosome. Sanger sequencing was used to verify these candidate mutations in the whole family. Clinical and ophthalmological examinations were performed on all members of the family. Results： A combi- nation of exome sequencing and Sanger sequencing revealed a nonsense mutation c.322G〉T （E108X）in exon 1 of NHS gene, co-segregating with the disease in the family. The nonsense mutation led to the conversion of glutamic acid to a stop codon （E108X）, resulting in truncation of the NHS protein. Multiple sequence alignments showed that codon 108, where the mutation （c.322G〉T） occurred, was located within a phylogenetically conserved region. The clinical features in all affected males and female carriers are described in detail. Conclusions： We report a nonsense mutation c.322G〉T （E108X） in a Chinese family with NHS. Our findings broaden the spectrum of NHS mutations and provide molecular insight into future NHS clinical genetic diagnosis.
基金We would like to thank the families for their participation in this study.We would also like to thank our funding sources:This study was supported by National Science Funding of China No.81772115 and 81571930 to BW.
文摘Purpose The present study aimed to evaluate the genetic diagnostic yield and accuracy of exome sequencing in Chinese patients with split hand–foot malformation(SHFM),a severe heterogeneous congenital anomaly characterized by hypodevelopment of the central ray of the hands and feet.Methods A cohort of seven families and five sporadic patients with SHFM was investigated.Genomic DNA was prepared from the peripheral blood of affected as well as unaffected individuals.Whole exome sequencing(WES)was performed to identify the pathogenic mutations.Array-based comparative genomic hybridization(aCGH),CytoScan,quantitative polymerase chain reaction(qPCR),and Sanger sequencing were performed to validate the findings of WES.WES data of an additional cohort of 24 patients with non-SHFM congenital hand anomalies were analyzed as the control.Results Pathogenic variants of TP63,c.G956A p.R319H,and c.T602A:p.L201H,were identified in two families by WES.In the remaining patients,copy number analysis of the WES data by XHMM software identified pathogenic 10q 24 duplication in five individuals from three families,which was further validated via CytoScan and qPCR;however,WES could not detect duplication in 10q24 in an additional cohort of 24 individuals with non-SHFM congenital hand anomaly.Importantly,qPCR analysis of the 10q24 region copy number revealed a definite consistency with WES data in all individuals.Genotype–phenotype analysis did not present any unique feature that could differentiate between the families with TP63 mutation and 10q24 duplication.Conclusions Our study demonstrated that WES is an accurate and sensitive method to detect the pathogenic 10q24 duplication.Collectively,with TP63 mutation,a single WES testing could yield a diagnosis rate of about 40%(5/12)for the SHFM patients,at least in our cohort.As the genotype–phenotype correlation remains unclear,WES could be used as a cost-effective method for the genetic diagnosis of SHFM.
基金supported by the Shanghai Municipal Commission of Science and Technology Research Project(China)(No.19JC1411001)the National Key Research and Development Program from the Ministry of Science and Technology of the People’s Republic of China(No.2021YFC2700800)+4 种基金the National Natural Science Foundation of China(No.31972880,32170615,31611130035,31371274)the National Key Research and Development Plan for Stem Cell and Transformation Research(China)(No.2017YFA0104202)the Collaborative Innovation Center Project Construction for Shanghai Women and Children’s Health,the Open Research Fund of National Health Commission Key Laboratory of Birth Defects Prevention&Henan Key Laboratory of Population Defects Prevention(China)(No.ZD202309)The Medical Science and Technology Research Program Project of Henan Province,China(No.LHGJ20230368)the Postdoctoral Research Fund of the Third Affiliated Hospital of Zhengzhou University(No.BSH20230101).
文摘Global developmental delay/intellectual disability(GDD/ID)with a prevalence of 1%e3%represents one of the biggest medical and social challenges in our society.^(1)Genetic factors are the main causes of GDD/ID and early diagnosis is crucial to improving the prognosis of GDD/ID children.^(2)Chromosomal microarray analysis,as a first-tier clinical test,^(3)remains limited because of the insufficient to detect small variations while whole exome sequencing(WES)can detect both single-nucleotide variants(SNVs)and copy-number variants(CNVs),effectively improving the diagnostic yield of GDD/ID.
基金National Foundation of Natural Science of China(82011530440#,WXP).
文摘Dear Editor,It was our pleasure to read this letter,which responded with positive comments to our research article entitled“Brain iron deposition and whole-exome sequencing of non-Wilson's disease hypoceruloplasminemia in a family”.1 Hepatolenticular degeneration,also known as Wilson's disease(WD),was first described in 1912 by Samuel Alexander Kinnier Wilson,a neurologist from the Queen Square Institute of Neurology,in his doctoral dissertation.WD is caused by mutations in the ATPase copper transporting beta(ATP7B)gene,located on chromosome 13q,which result in the defective biliary excretion of copper.The subsequent excessive copper accumulation in multiple organs,such as the brain and liver,causes symptoms that include movement disorders,cognitive/psychiatric symptoms,and liver disease.
基金Supported by Taif University,Taif,Saudi Arabia(TU-DSPP-2024-05).
文摘AIM:To identify the genetic factors underlying anophthalmia and microphthalmia(A/M),and to perform computational analysis to verify the pathophysiological mechanisms of the disease.METHODS:This study investigated a consanguineous Pakistani family with multiple affected individuals.Clinical evaluations were conducted using A-Scan and ophthalmic B-Scan ultrasonography(B-Scan).To identify the diseasecausing variant,whole exome sequencing(WES)and Sanger sequencing were performed.In silico functional analyses were carried out using AlphaFold(for protein modeling)and ClusPro(for protein docking analysis)tools,and the hydrodynamic properties of the protein were determined via molecular dynamics simulations.RESULTS:Clinical analysis of the five patients revealed severe phenotypes of bilateral anophthalmia.Ocular B-Scan did not detect ocular tissue or intraocular fluid,thus confirming the diagnosis of anophthalmia in all patients.Due to these structural defects,all patients exhibited complete blindness and absence of light perception;additionally,two patients had mild to moderate intellectual disability.Genetic analysis identified a splice site variant[NM_000693.2:c.884-2_885dup;p.(Asp296SerfsTer35)]in the 9^(th)exon of the ALDH1A3 gene.CONCLUSION:The present study expands the genetic spectrum of ALDH1A3 and contributes to establishing the genotype-phenotype correlation for this gene.
