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 sequen...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 c.434G-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
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
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
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
Vogt–Koyanagi–Harada(VKH)disease is a leading cause of blindness in young and middle-aged people.However,the etiology of VKH disease remains unclear.Here,we performed the first trio-based whole-exome sequencing stud...Vogt–Koyanagi–Harada(VKH)disease is a leading cause of blindness in young and middle-aged people.However,the etiology of VKH disease remains unclear.Here,we performed the first trio-based whole-exome sequencing study,which enrolled 25 VKH patients and 50 controls,followed by a study of 2081 VKH patients from a Han Chinese population to uncover detrimental mutations.A total of 15 de novo mutations in VKH patients were identified,with one of the most important being the membrane palmitoylated protein 2(MPP2)p.K315N(MPP2-N315)mutation.The MPP2-N315 mutation was highly deleterious according to bioinformatic predictions.Additionally,this mutation appears rare,being absent from the 1000 Genome Project and Genome Aggregation Database,and it is highly conserved in 10 species,including humans and mice.Subsequent studies showed that pathological phenotypes and retinal vascular leakage were aggravated in MPP2-N315 mutation knock-in or MPP2-N315 adeno-associated virus-treated mice with experimental autoimmune uveitis(EAU).In vitro,we used clustered regularly interspaced short palindromic repeats(CRISPR‒Cas9)gene editing technology to delete intrinsic MPP2 before overexpressing wild-type MPP2 or MPP2-N315.Levels of cytokines,such as IL-1β,IL-17E,and vascular endothelial growth factor A,were increased,and barrier function was destroyed in the MPP2-N315 mutant ARPE19 cells.Mechanistically,the MPP2-N315 mutation had a stronger ability to directly bind to ANXA2 than MPP2-K315,as shown by LC‒MS/MS and Co-IP,and resulted in activation of the ERK3/IL-17E pathway.Overall,our results demonstrated that the MPP2-K315N mutation may increase susceptibility to VKH disease.展开更多
BACKGROUND Angelman syndrome(AS)is caused by maternal chromosomal deletions,imprinting defects,paternal uniparental disomy involving chromosome 15 and the ubiquitin-protein ligase UBE3A gene mutations.However the gene...BACKGROUND Angelman syndrome(AS)is caused by maternal chromosomal deletions,imprinting defects,paternal uniparental disomy involving chromosome 15 and the ubiquitin-protein ligase UBE3A gene mutations.However the genetic basis remains unclear for several patients.AIM To investigate the involvement of UBE3A gene in AS and identifying new potential genes using exome sequencing.METHODS We established a cohort study in 50 patients referred to Farhat Hached University Hospital between 2006 and 2021,with a strong suspicion of AS and absence of chromosomal aberrations.The UBE3A gene was screened for mutation detection.Two unrelated patients issued from consanguineous families were subjected to exome analysis.RESULTS We describe seven UBE3A variants among them 3 none previously described including intronic variants c.2220+14T>C(intron14),c.2507+43T>A(Exon15)and insertion in Exon7:c.30-47_30-46.The exome sequencing revealed 22 potential genes that could be involved in AS-like syndromes that should be investigated further.CONCLUSION Screening for UBE3A mutations in AS patients has been proven to be useful to confirm the diagnosis.Our exome findings could rise to new potential alternative target genes for genetic counseling.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
Background:Cerebrospinal fluid(CSF)has been demonstrated as a better source of circulating tumor DNA(ctDNA)than plasma for brain tumors.However,it is unclear whether whole exome sequencing(WES)is qualified for detecti...Background:Cerebrospinal fluid(CSF)has been demonstrated as a better source of circulating tumor DNA(ctDNA)than plasma for brain tumors.However,it is unclear whether whole exome sequencing(WES)is qualified for detection of ctDNA in CSF.The aim of this study was to determine if assessment of ctDNA in CSF by WES is a feasible approach to detect genomic alterations of glioblastoma.Methods:CSFs of ten glioblastoma patients were collected pre-operatively at the Department of Neurosurgery,Sun Yat-sen University Cancer Center.ctDNA in CSF and genome DNA in the resected tumor were extracted and subjected to WES.The identified glioblastoma-associated mutations from ctDNA in CSF and genome DNA in the resected tumor were compared.Results:Due to the ctDNA in CSF was unqualified for exome sequencing for one patient,nine patients were included into the final analysis.More glioblastoma-associated mutations tended to be detected in CSF compared with the corresponding tumor tissue samples(3.56±0.75 vs.2.22±0.32,P=0.097),while the statistical significance was limited by the small sample size.The average mutation frequencies were similar in CSF and tumor tissue samples(74.1%±6.0%vs.73.8%±6.0%,P=0.924).The R132H mutation of isocitrate dehydrogenase 1 and the G34V mutation of H3 histone,family 3A(H3F3A)which had been reported in the pathological diagnoses were also detected from ctDNA in CSF by WES.Patients who received temozolomide chemotherapy previously or those whose tumor involved subventricular zone tended to harbor more mutations in their CSF.Conclusion:Assessment of ctDNA in CSF by WES is a feasible approach to detect genomic alterations of glioblastoma,which may provide useful information for the decision of treatment strategy.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:Leber congenital amaurosis(LCA),primarily characterized by retinal degeneration is the most severe form of inherited retinal dystrophy(IRD)responsible for congenital blindness.The presence of phenotypic het...Background:Leber congenital amaurosis(LCA),primarily characterized by retinal degeneration is the most severe form of inherited retinal dystrophy(IRD)responsible for congenital blindness.The presence of phenotypic heterogeneity makes the diagnosis of LCA challenging,especially in the absence of pronounced disease pathognomonic,yet it can be well comprehended by employing molecular diagnosis.Therefore,the present study aimed to reveal the causative mutations in ten LCA patients with variable phenotypes using clinical exome sequencing(CES).Methods:CES was performed in ten unrelated LCA patients.Ophthalmic information and family history of all patients were obtained to make a meaningful interpretation.The clinical exome data was analyzed and prioritized using a bioinformatics pipeline to identify mutations,which was further validated by Sanger sequencing.Segregation analysis was also performed on available family members.Results:CES led to the identification of causative mutations in nine LCA patients.Seven patients harbored a mutation in six LCA candidate genes,including RPE65,LCA5(n=2),CRX,PRPH2,CEP290,and ALMS1,while two patients possess a mutation in IFT80 and RP1,known to cause other diseases.Three novel mutations in LCA5(c.1823del),CRX(c.848del)and CEP290(c.2483G>T)were identified.The current study reports for the first time,a mutation in PRPH2,CEP290,and ALMS1 from the Indian population.Additionally,we observed a novel association of LCA phenotype with IFT80 known to cause Jeune syndrome.Based on the genetic finding,the patient AS09,who harbored a mutation in the RP1 gene,was re-diagnosed with early-onset retinitis pigmentosa.Conclusion:In conclusion,the results underline the importance of CES in clinically diagnosed LCA patients with variable phenotypes.The correlation between mutations in candidate genes and clinical phenotypes,helps to refine the clinical diagnosis.However,molecular evaluation with a larger cohort of LCA patients is needed for better understanding of the mutational spectrum in southern India.展开更多
In order to explore the genomic basis for liver cancer metastasis,whole-exome sequencing(WES)was performed on patient-derived hepatocellular carcinoma(HCC)cell lines with differential metastatic potentials and analyze...In order to explore the genomic basis for liver cancer metastasis,whole-exome sequencing(WES)was performed on patient-derived hepatocellular carcinoma(HCC)cell lines with differential metastatic potentials and analyzed their clonal evolution relationships.An evolutionary tree based on genomic single nucleotide polymorphism(SNP)was constructed in MegaX software.The WES data showed that the average percentage of heterogeneous mutations in each HCC cell lines was 16.55%(range,15.38%e18.17%).C:G>T:A and T:A>C:G somatic transitions were the two most frequent substitutions.In these metastatic HCC cell lines,non-silent gene mutations were found in 21.88%of known driver genes and 10 classical signaling pathways.The protein interaction network was constructed by STRING,and hub genes were found in the shared trunk mutation genes and the heterogeneous branch mutations respectively.In cBioPortal database,some of the selected hub genes were found to be associated with poor overall survival(OS)of HCC patients.Among the mutated HCC driver genes,a novel KEAP1 mutation with a homozygous frameshift truncation at the c-terminal Nrf2 binding region was detected and verified in MHCC97-H and HCC97LM3 cells.In conclusion,WES data demonstrate that HCC cell lines from tumor biopsy specimens of the same patient have obtained different metastatic potentials through repeated selection in rodents in vivo,and they do indeed have a genetic relationship at the genomic level.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
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:Screening variants underlying the single-gene disorder in the general population can help reduce the incidences of birth defects.To determine the most prevalent pathogenic variants causing autosomal recessiv...Objective:Screening variants underlying the single-gene disorder in the general population can help reduce the incidences of birth defects.To determine the most prevalent pathogenic variants causing autosomal recessive diseases,we investigated the frequencies of these variants in six major geographic ancestry groups from Exome Aggregation Consortium(ExAC)database and 26 populations from the 1,000 Genome Project,including three Chinese ethnic groups.Methods:We selected 64 autosomal recessive diseases and collected corresponding causal genes and variants from ClinVar for the analysis.The RS(reference single-nucleotide polymorphism)IDs of these variants were used to search the corresponding VCF file from the 1,000 Genomes Project and ExAC databases.We calculated the frequencies of heterozygotes of each disease variants in the 1,000 Genomes Project and ExAC samples and compared the distribution of disease alleles among different populations.Results:Our analysis revealed that 1,151/212 variants were carried by 60,706/2,504 individuals sequenced in the ExAC/1,000 Genomes Project.The average number of autosomal recessive disease alleles carried by samples from ExAC and 1,000 Genomes Project were 0.53 and 0.68,respectively.These disease alleles showed differential distribution among populations,and some disease alleles were significantly enriched in certain ethnic groups.In addition,1-2 main pathogenic variants were identified in each disease.Meanwhile,several ClinVar variants with relatively high frequency(>1%)in the samples were found to be benign instead of“conflicting evaluations of pathogenicity.”Conclusions:Our observations revealed that main pathogenic variants existed in certain autosomal recessive disease,suggesting that screening of disease hypermutations in different populations is valuable in reducing the occurrence of birth defects.展开更多
In the present study we attempted a parente-child trio,whole exome sequencing(WES)approach to study Apert’s syndrome.Clinical characteristics of the child were noted down and WES was carried out using Ion Torrent Sys...In the present study we attempted a parente-child trio,whole exome sequencing(WES)approach to study Apert’s syndrome.Clinical characteristics of the child were noted down and WES was carried out using Ion Torrent System that revealed the presence of previously reported P253R mutation in FGFR2 gene.Presence of two SNPs rs1047057 and rs554851880 in FGFR2 gene with an allelic frequency of 0.5113 and 0.001176 respectively and 161 complete damaging mutations were found.This study is the first reported case of exome sequencing approach on an Apert’s syndrome patient aimed at providing better genetic counselling in a non-consanguineous relationship.展开更多
Retinitis pigmentosa(RP),a major cause of inherited blindness worldwide,is highly heterogeneous.This study aimed to identify mutations in a Chinese cohort of sporadic probands with presumptive RP.Whole exome sequencin...Retinitis pigmentosa(RP),a major cause of inherited blindness worldwide,is highly heterogeneous.This study aimed to identify mutations in a Chinese cohort of sporadic probands with presumptive RP.Whole exome sequencing represents a considerable advancement in the identification of mutations associated with Mendelian diseases,such as RP.In this study,whole exome sequencing analysis was performed in a Chinese cohort of 95 sporadic probands who were initially diagnosed with RP,in order to identify disease mutations.All detected variations were confirmed by direct Sanger sequencing,and potential pathogenicity was assessed by predictions of the mutations’functions.The overall mutation rate of presumptive RP genes for this cohort was 30.5%(n=29 of 95 probands).Forty-four mutations were identified in 19 RP genes,among which 40 mutations were novel.Eleven probands carried mutations in autosomal dominant genes(38.0%),16 probands carried mutations in autosomal recessive genes(55.2%),and 2 probands carried mutations in X-linked genes(6.9%).Twenty-eight mutations in 18 genes linked to other retinal diseases in 23 probands were also identified.Overall,mutations were detected in 52 probands(54.7%).The recurrent and novel mutations reported here will expand potential understanding of the pathogenesis of RP and other retinal diseases.展开更多
BACKGROUND Congenital glaucoma associated with Roberts syndrome(RS)is an unusual and unique condition.No previous report describes this association.A multidisciplinary approach including molecular studies were conduct...BACKGROUND Congenital glaucoma associated with Roberts syndrome(RS)is an unusual and unique condition.No previous report describes this association.A multidisciplinary approach including molecular studies were conducted to reach the final diagnosis.CASE SUMMARY We present a rare case of a 1-wk-old male with RS associated with bilateral congenital glaucoma,left ectopic kidney,and left-hand rudimentary digits.A comprehensive approach was applied by which bilateral non-penetrating glaucoma surgery was performed with good control of intraocular pressure for more than 6 mo.Cytogenetic and molecular testing were conducted and revealed normal measurements.CONCLUSION This report described a case of a male baby with clinical features of RS but with a negative molecular analysis,presenting with left-hand rudimentary digits,bilateral congenital glaucoma,and left ectopic kidney.To the best of our knowledge,this is the first case reported with phocomelia,bilateral congenital glaucoma,and unilateral ectopic kidney.展开更多
BACKGROUND Dilated cardiomyopathy(DCM)is a genetically heterogeneous cardiac disorder characterized by left ventricular dilation and contractile dysfunction.The substantial genetic heterogeneity evident in patients wi...BACKGROUND Dilated cardiomyopathy(DCM)is a genetically heterogeneous cardiac disorder characterized by left ventricular dilation and contractile dysfunction.The substantial genetic heterogeneity evident in patients with DCM contributes to variable disease severity and complicates overall prognosis,which can be very poor.AIM To identify pathogenic genes in DCM through pedigree analysis.METHODS Our research team identified a patient with DCM in the clinic.Through invest-igation,we found that the family of this patient has a typical DCM pedigree.High-throughput sequencing technology,next-generation sequencing,was used to sequence the whole exomes of seven samples in the pedigree.RESULTS A novel and potentially pathogenic gene mutation-ANK2p.F3067L-was discovered.The mutation was completely consistent with the clinical information for this DCM pedigree.Sanger sequencing was used to further verify the locus of the mutation in pedigree samples.These results were consistent with those of high-throughput sequencing.CONCLUSIONS ANK2p.F3067L is considered a novel and potentially pathogenic gene mutation in DCM.展开更多
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 c.434G-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.
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We thank the families for participation in this study,and we thank Novogene Technology Co.,Ltd.,for the WES sequencing and analysis.This work was supported by the National Natural Science Foundation Project of China(82070951,82271078)the National Natural Science Foundation Key Program(81930023)+3 种基金The Innovative Research Group Project of Chongqing Education Commission(CXQT19015)the Innovation Supporting Plan of Overseas Study of Chongqing(cx2018010)the National Key Clinical Specialties Construction Program of China,the Chongqing Branch of the National Clinical Research Center for Ocular Diseases,the Chongqing Key Laboratory of Ophthalmology(CSTC,2008CA5003)the Program for Youth Innovation in Future Medicine,Chongqing Medical University(w0047).
文摘Vogt–Koyanagi–Harada(VKH)disease is a leading cause of blindness in young and middle-aged people.However,the etiology of VKH disease remains unclear.Here,we performed the first trio-based whole-exome sequencing study,which enrolled 25 VKH patients and 50 controls,followed by a study of 2081 VKH patients from a Han Chinese population to uncover detrimental mutations.A total of 15 de novo mutations in VKH patients were identified,with one of the most important being the membrane palmitoylated protein 2(MPP2)p.K315N(MPP2-N315)mutation.The MPP2-N315 mutation was highly deleterious according to bioinformatic predictions.Additionally,this mutation appears rare,being absent from the 1000 Genome Project and Genome Aggregation Database,and it is highly conserved in 10 species,including humans and mice.Subsequent studies showed that pathological phenotypes and retinal vascular leakage were aggravated in MPP2-N315 mutation knock-in or MPP2-N315 adeno-associated virus-treated mice with experimental autoimmune uveitis(EAU).In vitro,we used clustered regularly interspaced short palindromic repeats(CRISPR‒Cas9)gene editing technology to delete intrinsic MPP2 before overexpressing wild-type MPP2 or MPP2-N315.Levels of cytokines,such as IL-1β,IL-17E,and vascular endothelial growth factor A,were increased,and barrier function was destroyed in the MPP2-N315 mutant ARPE19 cells.Mechanistically,the MPP2-N315 mutation had a stronger ability to directly bind to ANXA2 than MPP2-K315,as shown by LC‒MS/MS and Co-IP,and resulted in activation of the ERK3/IL-17E pathway.Overall,our results demonstrated that the MPP2-K315N mutation may increase susceptibility to VKH disease.
文摘BACKGROUND Angelman syndrome(AS)is caused by maternal chromosomal deletions,imprinting defects,paternal uniparental disomy involving chromosome 15 and the ubiquitin-protein ligase UBE3A gene mutations.However the genetic basis remains unclear for several patients.AIM To investigate the involvement of UBE3A gene in AS and identifying new potential genes using exome sequencing.METHODS We established a cohort study in 50 patients referred to Farhat Hached University Hospital between 2006 and 2021,with a strong suspicion of AS and absence of chromosomal aberrations.The UBE3A gene was screened for mutation detection.Two unrelated patients issued from consanguineous families were subjected to exome analysis.RESULTS We describe seven UBE3A variants among them 3 none previously described including intronic variants c.2220+14T>C(intron14),c.2507+43T>A(Exon15)and insertion in Exon7:c.30-47_30-46.The exome sequencing revealed 22 potential genes that could be involved in AS-like syndromes that should be investigated further.CONCLUSION Screening for UBE3A mutations in AS patients has been proven to be useful to confirm the diagnosis.Our exome findings could rise to new potential alternative target genes for genetic counseling.
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This work was supported by the National Natural Science Foundation of China(No.81872324)Science and Technology Planning Project of Guangdong Province,China(No.2018A030313754)+1 种基金Science and Technology Program of Guangzhou,China(Nos.201704020133,201707010169)Science and Technology Planning Project of Jiangmen,China(No.2018630100110019805).
文摘Background:Cerebrospinal fluid(CSF)has been demonstrated as a better source of circulating tumor DNA(ctDNA)than plasma for brain tumors.However,it is unclear whether whole exome sequencing(WES)is qualified for detection of ctDNA in CSF.The aim of this study was to determine if assessment of ctDNA in CSF by WES is a feasible approach to detect genomic alterations of glioblastoma.Methods:CSFs of ten glioblastoma patients were collected pre-operatively at the Department of Neurosurgery,Sun Yat-sen University Cancer Center.ctDNA in CSF and genome DNA in the resected tumor were extracted and subjected to WES.The identified glioblastoma-associated mutations from ctDNA in CSF and genome DNA in the resected tumor were compared.Results:Due to the ctDNA in CSF was unqualified for exome sequencing for one patient,nine patients were included into the final analysis.More glioblastoma-associated mutations tended to be detected in CSF compared with the corresponding tumor tissue samples(3.56±0.75 vs.2.22±0.32,P=0.097),while the statistical significance was limited by the small sample size.The average mutation frequencies were similar in CSF and tumor tissue samples(74.1%±6.0%vs.73.8%±6.0%,P=0.924).The R132H mutation of isocitrate dehydrogenase 1 and the G34V mutation of H3 histone,family 3A(H3F3A)which had been reported in the pathological diagnoses were also detected from ctDNA in CSF by WES.Patients who received temozolomide chemotherapy previously or those whose tumor involved subventricular zone tended to harbor more mutations in their CSF.Conclusion:Assessment of ctDNA in CSF by WES is a feasible approach to detect genomic alterations of glioblastoma,which may provide useful information for the decision of treatment strategy.
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.
基金supported by the Department of Biotechnology under Grant BT/NNT/28/SP18830/2018.
文摘Background:Leber congenital amaurosis(LCA),primarily characterized by retinal degeneration is the most severe form of inherited retinal dystrophy(IRD)responsible for congenital blindness.The presence of phenotypic heterogeneity makes the diagnosis of LCA challenging,especially in the absence of pronounced disease pathognomonic,yet it can be well comprehended by employing molecular diagnosis.Therefore,the present study aimed to reveal the causative mutations in ten LCA patients with variable phenotypes using clinical exome sequencing(CES).Methods:CES was performed in ten unrelated LCA patients.Ophthalmic information and family history of all patients were obtained to make a meaningful interpretation.The clinical exome data was analyzed and prioritized using a bioinformatics pipeline to identify mutations,which was further validated by Sanger sequencing.Segregation analysis was also performed on available family members.Results:CES led to the identification of causative mutations in nine LCA patients.Seven patients harbored a mutation in six LCA candidate genes,including RPE65,LCA5(n=2),CRX,PRPH2,CEP290,and ALMS1,while two patients possess a mutation in IFT80 and RP1,known to cause other diseases.Three novel mutations in LCA5(c.1823del),CRX(c.848del)and CEP290(c.2483G>T)were identified.The current study reports for the first time,a mutation in PRPH2,CEP290,and ALMS1 from the Indian population.Additionally,we observed a novel association of LCA phenotype with IFT80 known to cause Jeune syndrome.Based on the genetic finding,the patient AS09,who harbored a mutation in the RP1 gene,was re-diagnosed with early-onset retinitis pigmentosa.Conclusion:In conclusion,the results underline the importance of CES in clinically diagnosed LCA patients with variable phenotypes.The correlation between mutations in candidate genes and clinical phenotypes,helps to refine the clinical diagnosis.However,molecular evaluation with a larger cohort of LCA patients is needed for better understanding of the mutational spectrum in southern India.
基金This work was supported by the National Natural Science Foundation of China(NSFC,NO.81172066,NO.81472858NO.91529103)+1 种基金Innovation Team Fund of Second Affiliated Hospital of Chongqing Medical UniversityThe authors would like to thank Dr.Zhou-You Tang,Professor&Director,Liver Cancer Institute,Fudan University,for providing the three HCC cell lines(MHCC97-L,MHCC97-H,HCC97LM3).
文摘In order to explore the genomic basis for liver cancer metastasis,whole-exome sequencing(WES)was performed on patient-derived hepatocellular carcinoma(HCC)cell lines with differential metastatic potentials and analyzed their clonal evolution relationships.An evolutionary tree based on genomic single nucleotide polymorphism(SNP)was constructed in MegaX software.The WES data showed that the average percentage of heterogeneous mutations in each HCC cell lines was 16.55%(range,15.38%e18.17%).C:G>T:A and T:A>C:G somatic transitions were the two most frequent substitutions.In these metastatic HCC cell lines,non-silent gene mutations were found in 21.88%of known driver genes and 10 classical signaling pathways.The protein interaction network was constructed by STRING,and hub genes were found in the shared trunk mutation genes and the heterogeneous branch mutations respectively.In cBioPortal database,some of the selected hub genes were found to be associated with poor overall survival(OS)of HCC patients.Among the mutated HCC driver genes,a novel KEAP1 mutation with a homozygous frameshift truncation at the c-terminal Nrf2 binding region was detected and verified in MHCC97-H and HCC97LM3 cells.In conclusion,WES data demonstrate that HCC cell lines from tumor biopsy specimens of the same patient have obtained different metastatic potentials through repeated selection in rodents in vivo,and they do indeed have a genetic relationship at the genomic level.
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.
文摘Objective:Screening variants underlying the single-gene disorder in the general population can help reduce the incidences of birth defects.To determine the most prevalent pathogenic variants causing autosomal recessive diseases,we investigated the frequencies of these variants in six major geographic ancestry groups from Exome Aggregation Consortium(ExAC)database and 26 populations from the 1,000 Genome Project,including three Chinese ethnic groups.Methods:We selected 64 autosomal recessive diseases and collected corresponding causal genes and variants from ClinVar for the analysis.The RS(reference single-nucleotide polymorphism)IDs of these variants were used to search the corresponding VCF file from the 1,000 Genomes Project and ExAC databases.We calculated the frequencies of heterozygotes of each disease variants in the 1,000 Genomes Project and ExAC samples and compared the distribution of disease alleles among different populations.Results:Our analysis revealed that 1,151/212 variants were carried by 60,706/2,504 individuals sequenced in the ExAC/1,000 Genomes Project.The average number of autosomal recessive disease alleles carried by samples from ExAC and 1,000 Genomes Project were 0.53 and 0.68,respectively.These disease alleles showed differential distribution among populations,and some disease alleles were significantly enriched in certain ethnic groups.In addition,1-2 main pathogenic variants were identified in each disease.Meanwhile,several ClinVar variants with relatively high frequency(>1%)in the samples were found to be benign instead of“conflicting evaluations of pathogenicity.”Conclusions:Our observations revealed that main pathogenic variants existed in certain autosomal recessive disease,suggesting that screening of disease hypermutations in different populations is valuable in reducing the occurrence of birth defects.
文摘In the present study we attempted a parente-child trio,whole exome sequencing(WES)approach to study Apert’s syndrome.Clinical characteristics of the child were noted down and WES was carried out using Ion Torrent System that revealed the presence of previously reported P253R mutation in FGFR2 gene.Presence of two SNPs rs1047057 and rs554851880 in FGFR2 gene with an allelic frequency of 0.5113 and 0.001176 respectively and 161 complete damaging mutations were found.This study is the first reported case of exome sequencing approach on an Apert’s syndrome patient aimed at providing better genetic counselling in a non-consanguineous relationship.
基金This study was supported by the National Key Scientific Research Program(No.2016YFC0905200,toZY)the National Natural Science Foundation of China(No.81170883,81790643 and 81430008(to ZY),81300802 and 81670895(to LH),81271048(to JY),81570848 and 81100693(to CQ))+1 种基金by the Department of Science and Technology of Sichuan Province,China(No.2014SZ0169,2015SZ0052(to ZY),2015JQO057(to LH),2016HH0072(to LH),2017JQ0024(to LH),2015SZ0060(to YL),2013JY0195(to LH),2015SZ0060(to YL),2014FZ0124(to DYL)and 2015JZ0004(to CQ))High-level Talents Program of UESTC Y03001023601021016(to LH).
文摘Retinitis pigmentosa(RP),a major cause of inherited blindness worldwide,is highly heterogeneous.This study aimed to identify mutations in a Chinese cohort of sporadic probands with presumptive RP.Whole exome sequencing represents a considerable advancement in the identification of mutations associated with Mendelian diseases,such as RP.In this study,whole exome sequencing analysis was performed in a Chinese cohort of 95 sporadic probands who were initially diagnosed with RP,in order to identify disease mutations.All detected variations were confirmed by direct Sanger sequencing,and potential pathogenicity was assessed by predictions of the mutations’functions.The overall mutation rate of presumptive RP genes for this cohort was 30.5%(n=29 of 95 probands).Forty-four mutations were identified in 19 RP genes,among which 40 mutations were novel.Eleven probands carried mutations in autosomal dominant genes(38.0%),16 probands carried mutations in autosomal recessive genes(55.2%),and 2 probands carried mutations in X-linked genes(6.9%).Twenty-eight mutations in 18 genes linked to other retinal diseases in 23 probands were also identified.Overall,mutations were detected in 52 probands(54.7%).The recurrent and novel mutations reported here will expand potential understanding of the pathogenesis of RP and other retinal diseases.
文摘BACKGROUND Congenital glaucoma associated with Roberts syndrome(RS)is an unusual and unique condition.No previous report describes this association.A multidisciplinary approach including molecular studies were conducted to reach the final diagnosis.CASE SUMMARY We present a rare case of a 1-wk-old male with RS associated with bilateral congenital glaucoma,left ectopic kidney,and left-hand rudimentary digits.A comprehensive approach was applied by which bilateral non-penetrating glaucoma surgery was performed with good control of intraocular pressure for more than 6 mo.Cytogenetic and molecular testing were conducted and revealed normal measurements.CONCLUSION This report described a case of a male baby with clinical features of RS but with a negative molecular analysis,presenting with left-hand rudimentary digits,bilateral congenital glaucoma,and left ectopic kidney.To the best of our knowledge,this is the first case reported with phocomelia,bilateral congenital glaucoma,and unilateral ectopic kidney.
基金Supported by the Jilin Provincial Healthcare Talent Special Program,No.2019SCZT08.
文摘BACKGROUND Dilated cardiomyopathy(DCM)is a genetically heterogeneous cardiac disorder characterized by left ventricular dilation and contractile dysfunction.The substantial genetic heterogeneity evident in patients with DCM contributes to variable disease severity and complicates overall prognosis,which can be very poor.AIM To identify pathogenic genes in DCM through pedigree analysis.METHODS Our research team identified a patient with DCM in the clinic.Through invest-igation,we found that the family of this patient has a typical DCM pedigree.High-throughput sequencing technology,next-generation sequencing,was used to sequence the whole exomes of seven samples in the pedigree.RESULTS A novel and potentially pathogenic gene mutation-ANK2p.F3067L-was discovered.The mutation was completely consistent with the clinical information for this DCM pedigree.Sanger sequencing was used to further verify the locus of the mutation in pedigree samples.These results were consistent with those of high-throughput sequencing.CONCLUSIONS ANK2p.F3067L is considered a novel and potentially pathogenic gene mutation in DCM.
