Background and objective Low-density computed tomography(LDCT)improved early lung cancer diagnosis but introduces an excess of false-positive pulmonary nodules data.Hence,accurate diagnosis of early-stage lung cancer ...Background and objective Low-density computed tomography(LDCT)improved early lung cancer diagnosis but introduces an excess of false-positive pulmonary nodules data.Hence,accurate diagnosis of early-stage lung cancer remains challenging.The purpose of the study was to assess the feasibility of using circulating tumour cells(CTCs)to differentiate malignant from benign pulmonary nodules.Materials and methods 122 patients with suspected malignant pulmonary nodules detected on chest CT in preparation for surgery were prospectively recruited.Peripheral blood samples were collected before surgery,and CTCs were identified upon isolation by size of epithelial tumour cells and morphological analysis.Laser capture microdissection,MALBAC amplification,and whole-exome sequencing were performed on 8 samples.The diagnostic efficacy of CTCs counting,and the genomic variation profile of benign and malignant CTCs samples were analysed.Results Using 2.5 cells/5 m L as the cut-off value,the area under the receiver operating characteristic curve was of 0.651(95%confidence interval:0.538-0.764),with a sensitivity and specificity of 0.526 and 0.800,respectively,and positive and negative predictive values of 91.1%and 30.3%,respectively.Distinct sequence variations differences in DNA damage repair-related and driver genes were observed in benign and malignant samples.TP53 mutations were identified in CTCs of four malignant cases;in particular,g.7578115T>C,g.7578645C>T,and g.7579472G>C were exclusively detected in all four malignant samples.Conclusion CTCs play an ancillary role in the diagnosis of pulmonary nodules.TP53 mutations in CTCs might be used to identify benign and malignant pulmonary nodules.展开更多
AIM: To detect the pathogenetic mutations responsible for nonsyndromic autosomal recessive retinitis pigmentosa(RP) in 2 nonconsanguineous Chinese families. METHODS: The clinical data, including detailed medical histo...AIM: To detect the pathogenetic mutations responsible for nonsyndromic autosomal recessive retinitis pigmentosa(RP) in 2 nonconsanguineous Chinese families. METHODS: The clinical data, including detailed medical history, best corrected visual acuity(BCVA), slit-lamp biomicroscope examination, fundus photography, optical coherence tomography, static perimetry, and full field electroretinogram, were collected from the members of 2 nonconsanguineous Chinese families preliminarily diagnosed with RP. Genomic DNA was extracted from the probands and other available family members;wholeexome sequencing was conducted with the DNA samples provided by the probands, and all mutations detected by whole-exome sequencing were verified using Sanger sequencing in the probands and the other available family members. The verified novel mutations were further sequenced in 192 ethnicity matched healthy controls.RESULTS: The patients from the 2 families exhibited the typical symptoms of RP, including night blindness and progressive constriction of the visual field, and the fundus examinations showed attenuated retinal arterioles, peripheral bone spicule pigment deposits, and waxy optic discs. Whole-exome sequencing revealed a novel nonsense mutation in FAM161 A(c.943 A>T, p.Lys315*) and compound heterozygous mutations in RP1 L1(c.56 C>A, p.Pro19 His;c.5470 C>T, p.Gln1824*). The nonsense c.5470 C>T, p.Gln1824* mutation was novel. All mutations were verified by Sanger sequencing. The mutation p.Lys315* in FAM161A co-segregated with the phenotype, and all the nonsense mutations were absent from the ethnicity matched healthy controls and all available databases.CONCLUSION: We identify 2 novel mutations in genes responsible for autosomal recessive RP, and the mutation in FAM161A is reported for the first time in a Chinese population. Our result not only enriches the knowledge of the mutation frequency and spectrum in the genes responsible for nonsyndromic RP but also provides a new target for future gene therapy.展开更多
AIM：To make a comprehensive analysis of the potential pathogenic genes related with Leber congenital amaurosis（LCA） in Chinese.METHODS：LCA subjects and their families were retrospectively collected from 2013 to 20...AIM：To make a comprehensive analysis of the potential pathogenic genes related with Leber congenital amaurosis（LCA） in Chinese.METHODS：LCA subjects and their families were retrospectively collected from 2013 to 2015.Firstly,whole-exome sequencing was performed in patients who had underwent gene mutation screening with nothing found,and then homozygous sites was selected,candidate sites were annotated,and pathogenic analysis was conducted using softwares including Sorting Tolerant from Intolerant（SIFT）,Polyphen-2,Mutation assessor,Condel,and Functional Analysis through Hidden Markov Models（FATHMM）.Furthermore,Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of pathogenic genes were performed followed by co-segregation analysis using Fisher exact Test.Sanger sequencing was used to validate single-nucleotide variations（SNVs）.Expanded verification was performed in the rest patients.RESULTS：Totally 51 LCA families with 53 patients and24 family members were recruited.A total of 104 SNVs（66 LCA-related genes and 15 co-segregated genes）were submitted for expand verification.The frequencies of homozygous mutation of KRT12 and CYP1A1 were simultaneously observed in 3 families.Enrichment analysis showed that the potential pathogenic genes were mainly enriched in functions related to cell adhesion,biological adhesion,retinoid metabolic process,and eye development biological adhesion.Additionally,WFS7 and STAU2 had the highest homozygous frequencies.CONCLUSION：LCA is a highly heterogeneous disease.Mutations in KRT12,CVP1A1,WFS1,and STAU2 may be involved in the development of LCA.展开更多
Dilated cardiomyopathy（DCM）is characterized by the dilated heart chambers and reduced systolic function in the absence of specific aetiology[1].Approximately one third of DCM cases are hereditary.In recent years,DCM...Dilated cardiomyopathy（DCM）is characterized by the dilated heart chambers and reduced systolic function in the absence of specific aetiology[1].Approximately one third of DCM cases are hereditary.In recent years,DCM concomitant with arrhythmias and sudden death resulting from gene mutation has been widely展开更多
AIMTo identify the disease-causing gene mutation in a Chinese pedigree with autosomal dominant cone-rod dystrophy (adCORD).METHODSA southern Chinese adCORD pedigree including 9 affected individuals was studied. Whole-...AIMTo identify the disease-causing gene mutation in a Chinese pedigree with autosomal dominant cone-rod dystrophy (adCORD).METHODSA southern Chinese adCORD pedigree including 9 affected individuals was studied. Whole-exome sequencing (WES), coupling the Agilent whole-exome capture system to the Illumina HiSeq 2000 DNA sequencing platform was used to search the specific gene mutation in 3 affected family members and 1 unaffected member. After a suggested variant was found through the data analysis, the putative mutation was validated by Sanger DNA sequencing of samples from all available family members.RESULTSThe results of both WES and Sanger sequencing revealed a novel nonsense mutation c.C766T (p.Q256X) within exon 5 of CRX gene which was pathogenic for adCORD in this family. The mutation could affect photoreceptor-specific gene expression with a dominant-negative effect and resulted in loss of the OTX tail, thus the mutant protein occupies the CRX-binding site in target promoters without establishing an interaction and, consequently, may block transactivation.CONCLUSIONAll modes of Mendelian inheritance in CORD have been observed, and genetic heterogeneity is a hallmark of CORD. Therefore, conventional genetic diagnosis of CORD would be time-consuming and labor-intensive. Our study indicated the robustness and cost-effectiveness of WES in the genetic diagnosis of CORD.展开更多
Objective:The purpose of this work was to obtain the phenotypes and detect potential mutations in three Chinese patients with Marfan syndrome(MFS)or incomplete MFS phenotypes.Methods:Three unrelated patients with a de...Objective:The purpose of this work was to obtain the phenotypes and detect potential mutations in three Chinese patients with Marfan syndrome(MFS)or incomplete MFS phenotypes.Methods:Three unrelated patients with a defi nite or suspected clinical diagnosis of MFS and their family members were recruited for research.Genomic DNA was extracted from peripheral blood of these patients and their family members.All the exons were sequenced by next-generation sequencing and the variants were further validated by Sanger sequencing.The functional consequences of the mutations were analyzed with various genomic resources and bioinformatics tools.Results:Three FBN1 mutations were identifi ed in the three patients,including one novel mutation(2125G>A)and two previously reported mutations(4786C>T and 6325C>T).It was interesting to note that the parents of these patients were normal as assessed by clinical features or genetic testing,but all these mutations were detected in their offspring,except for the variant 6325C>T.We also found that a few young members of the family of probands(proband 1 and proband 2)have exhibited no manifestations of MFS so far,although they carry the same disease-causing mutation.Conclusions:We found three FBN1 mutations in three unrelated Chinese families with MFS by genome sequencing,and the relationship between genotypes and phenotypes in MFS patients needs further exploration.展开更多
Autism spectrum disorder(ASD)is a highly heritable neurodevelopmental disorder characterized by deficits in social interactions and repetitive behaviors.Although hundreds of ASD risk genes,implicated in synaptic forma...Autism spectrum disorder(ASD)is a highly heritable neurodevelopmental disorder characterized by deficits in social interactions and repetitive behaviors.Although hundreds of ASD risk genes,implicated in synaptic formation and transcriptional regulation,have been identified through human genetic studies,the East Asian ASD cohorts are still under-represented in genome-wide genetic studies.Here,we applied whole-exome sequencing to 369 ASD trios including probands and unaffected parents of Chinese origin.Using a joint-calling analytical pipeline based on GATK toolkits,we identified numerous de novo mutations including 55 high-impact variants and 165 moderate-impact variants,as well as de novo copy number variations containing known ASD-related genes.Importantly,combined with single-cell sequencing data from the developing human brain,we found that the expression of genes with de novo mutations was specifically enriched in the pre-,post-central gyrus(PRC,PC)and banks of the superior temporal(BST)regions in the human brain.By further analyzing the brain imaging data with ASD and healthy controls,we found that the gray volume of the right BST in ASD patients was significantly decreased compared to healthy controls,suggesting the potential structural deficits associated with ASD.Finally,we found a decrease in the seed-based functional connectivity between BST/PC/PRC and sensory areas,the insula,as well as the frontal lobes in ASD patients.This work indicated that combinatorial analysis with genome-wide screening,single-cell sequencing,and brain imaging data reveal the brain regions contributing to the etiology of ASD.展开更多
Nonobstructive azoospermia(NOA)is a severe condition in infertile men,and increasing numbers of causative genes have been identified during the last few decades.Although certain causative genes can explain the presenc...Nonobstructive azoospermia(NOA)is a severe condition in infertile men,and increasing numbers of causative genes have been identified during the last few decades.Although certain causative genes can explain the presence of NOA in some patients,a proportion of NOA patients remain to be addressed.This study aimed to investigate potential high-risk genes associated with spermatogenesis in idiopathic NOA patients by whole-exome sequencing.Whole-exome sequencing was performed in 46 male patients diagnosed with NOA.First,screening was performed for 119 genes known to be related to male infertility.Next,further screening was performed to determine potential high-risk causative genes for NOA by comparisons with 68 healthy male controls.Finally,risk genes with high/specific expression in the testes were selected and their expression fluctuations during spermatogenesis were graphed.The frequency of cystic fibrosis transmembrane conductance regulator(CFTR)gene pathogenic variant carriers was higher in the NOA patients compared with the healthy controls.Potential risk genes that may be causes of NOA were identified,including seven genes that were highly/specifically expressed in the testes.Four risk genes previously reported to be involved in spermatogenesis(MutS homolog 5[MSH5],cilia-and flagella-associated protein 54[CFAP54],MAP7 domain containing 3[MAP7D3],and coiled-coil domain containing 33[CCDC33])and three novel risk genes(coiled-coil domain containing 168[CCDC168],chromosome 16 open reading frame 96[C16orf96],and serine protease 48[PRSS48])were identified to be highly or specifically expressed in the testes and significantly different in the 46 NOA patients compared with 68 healthy controls.This study on clinical NOA patients provides further evidence for the four previously reported risk genes.The present findings pave the way for further functional investigations and provide candidate risk genes for genetic diagnosis of NOA.展开更多
A small fraction of patients diagnosed with obesity or diabetes mellitus has an underlying monogenic cause.Here,we constructed a targeted gene panel consisting of 83 genes reported to be causative for monogenic obesit...A small fraction of patients diagnosed with obesity or diabetes mellitus has an underlying monogenic cause.Here,we constructed a targeted gene panel consisting of 83 genes reported to be causative for monogenic obesity or diabetes.We performed this panel in 481 patients to detect causative variants and compared these results with whole-exome sequencing(WES)data available for 146 of these patients.The coverage of targeted gene panel sequencing was significantly higher than that of WES.The diagnostic yield in patients sequenced by the panel was 32.9%with subsequent WES leading to three additional diagnoses with two novel genes.In total,178 variants in 83 genes were detected in 146 patients by targeted sequencing.Three of the 178 variants were missed by WES,although the WES-only approach had a similar diagnostic yield.For the 335 samples only receiving targeted sequencing,the diagnostic yield was 32.2%.In conclusion,taking into account the lower costs,shorter turnaround time,and higher quality of data,targeted sequencing is a more effective screening method for monogenic obesity and diabetes compared to WES.Therefore,this approach could be routinely established and used as a first-tier test in clinical practice for specific patients.展开更多
Congenital heart disease （CHD） is the leading cause of birth defects, and its etiology is not completely understood. Atrial septal defect （ASD） is one of the most common defects of CHD. Previous studies have demon...Congenital heart disease （CHD） is the leading cause of birth defects, and its etiology is not completely understood. Atrial septal defect （ASD） is one of the most common defects of CHD. Previous studies have demonstrated that mutations in the transcription factor T-box 20 （TBX20） contribute to congenital ASD. Whole-exome sequencing in combination with a CHD-related gene filter was used to detect a family of three generations with ASD. A novel TBX20 mutation, c.526G〉A （p.D176N）, was identified and co-segregated in all affected members in this family. This mutation was predicted to be deleterious by bioinformatics programs （SIFT, Polyphen2, and MutationTaster）. This mutation was also not presented in the current Single Nucleotide Polymorphism Database （dbSNP） or National Heart, Lung, and Blood Institute （NHLBI） Exome Sequencing Project （ESP）. In conclusion, our finding expands the spectrum of TBX20 mutations and provides additional support that TBX20 plays important roles in cardiac development. Our study also provided a new and cost-effective analysis strategy for the genetic study in small CHD pedigree.展开更多
Monognnic diabetes is often misdiagnosed with type 2 diabetes due to overlapping characteristics. This study aimed to discover novel causative mutations of monogenic diabetes in patients with clinically diagnosed type...Monognnic diabetes is often misdiagnosed with type 2 diabetes due to overlapping characteristics. This study aimed to discover novel causative mutations of monogenic diabetes in patients with clinically diagnosed type 2 diabetes and to explore potential molecular mechanisms. Whole-exome sequencing was performed on 31 individuals clinically diagnosed with type 2 diabetes. One novel heterozygnus mutation （p^la2Thr） in INS was identified. It was further gnnotyped in an additional case-control population （6523 cases and 4635 controls）, and this variant was observed in 0.09% of cases. IntraceUular trafficking of insulin proteins was assessed in INSl-E and HEK293T cells, p.Ala2Thr preproinsuUn-GFP was markedly retained in the endoplasmic reticulum （ER） in INS1-E cells. Activation of the PERK-elF2a-ATF4, IREla-XBP1, and ATF6 pathways as well as upregulated ER chaperones were detected in INS1-E cells transfected with the p.Ala2Thr mutant. In conclusion, we identified a causative mutation in IN5 respon- sible for maturity-onset diabetes of the young 10 （MODYIO） in a Chinese population and demonstrated that this mutation affected 13 cell function by inducing ER stress.展开更多
Background： Restrictive cardiomyopathy （RCM） is the least common cardiomyopathy in which the walls are rigid and the heart is restricted from stretching and filling properly. Cardiac troponin I （cTnI） mutation-ca...Background： Restrictive cardiomyopathy （RCM） is the least common cardiomyopathy in which the walls are rigid and the heart is restricted from stretching and filling properly. Cardiac troponin I （cTnI） mutation-caused myofibril Ca2＋ hypersensitivity has been shown to be associated with impaired diastolic function. This study aimed to investigate the linkage between the genotype and clinical therapy of RCM. Methods： Five sporadic pediatric RCM patients confirmed by echocardiography were enrolled in this study.Whole-exome sequencing （WES） was performed for the cohort to find out candidate causative gene variants. Sanger sequencing confirmed the WES-identified variants. Results： TNNI3 variants were found in all of the five patients. R192H mutation was shared in four patients while R204H mutation was found only in one patient. Structure investigation showed that the C terminus of TNNI3 was flexible and mutation on the C terminus was possible to cause the RCM. Catechins were prescribed for the five patients once genotype was confirmed. Ventricular diastolic function was improved in three patients during the follow-up. Conclusions： Our data demonstrated that TNNI3 mutation-induced RCM1 is the most common type of pediatric RCM in this study. In addition, WES is a reliable approach to identify likely pathogenic genes of RCM and might be useful for the guidance of clinical treatment scheme.展开更多
Multiple epiphyseal dysplasia （MED; EDMI, OMIM 132400; EDM2, OMIM 600204; EDM3, OMIM 600969; EDM4, OMIM 226900; EDM5~ OMIM 607078; EDM6, OMIM 614135） is an autosomal dominant inherited disease of the skeletal system...Multiple epiphyseal dysplasia （MED; EDMI, OMIM 132400; EDM2, OMIM 600204; EDM3, OMIM 600969; EDM4, OMIM 226900; EDM5~ OMIM 607078; EDM6, OMIM 614135） is an autosomal dominant inherited disease of the skeletal system, characterized by mild short stature and early-onset degenerative joint disease, caused by heterogeneous genotypes involving more than six genes （COMP, COL9A 1, COL9A2, COL9A3, MATN3, DTDST）.However, in approximately 10-20% of all samples analyzed, a mutation cannot be identified in any of the six genes mentioned above, suggesting that the presence of other unidentified causative genes is also involved in the pathogenesis of MED.展开更多
Abstract Charcot-Marie-Tooth disease type 4B2 with early-onset glaucoma （CMT4B2, OMIM 604563） is a genetically-heterogeneous childhood-onset neuromuscular disorder. Here, we report the case of a 15-year-old male ado...Abstract Charcot-Marie-Tooth disease type 4B2 with early-onset glaucoma （CMT4B2, OMIM 604563） is a genetically-heterogeneous childhood-onset neuromuscular disorder. Here, we report the case of a 15-year-old male adolescent with lower extremity weakness, gait abnormalities, foot deformities and early-onset glaucoma. Since clinical diagnosis alone was insufficient for providing pathogenetic evidence to indicate that the condition belonged to a consanguineous family, we applied whole-exome sequencing to samples from the patient, his parents and his younger brother, assuming that the patient＇s condition is transmitted in an autosomal recessive pattern. A frame-shift mutation, c.4571delG （P.Gly1524Glufs＊42）, was revealed in the CMT4B2-related gene SBF2 （also known as MTMR13, MIM 607697）, and this mutation was found to be homozygous in the proband and heterozygous in his parents and younger brother. Together with the results of clinical diagnosis, this case was diagnosed as CMT4B2. Our finding further demonstrates the use of whole-exome sequencing in the diagnosis and treatment of rare diseases.展开更多
Importance:Pathogenic variants in theRBM20 gene are associated with aggressive dilated cardiomyopathy(DCM).Recently,RBM20 was found to be associated with left ventricular non-compaction cardiomyopathy(LVNC).Thus far,o...Importance:Pathogenic variants in theRBM20 gene are associated with aggressive dilated cardiomyopathy(DCM).Recently,RBM20 was found to be associated with left ventricular non-compaction cardiomyopathy(LVNC).Thus far,only five families with LVNC have been reported to carry variants inRBM20.It remains unknown whether the variants inRBM20 associated with DCM can also cause LVNC.Objective:To elucidate the causativeRBM20 variant in two unrelated patients with both LVNC and DCM,and to identify the clinical characteristics associated with variants inRBM20.Methods:Trio whole-exome sequencing(WES)was performed.Variants were filtered and classified in accordance with the guidelines of the American College of Medical Genetics and Genomics(ACMG).Results:We identified two distinctde novo variants inRBM20(one per patient)in these two patients with LVNC.Both variants have been reported in patients with DCM,without the LVNC phenotype.Patient 1 was an 11-year-old girl who had DCM,LVNC,and heart failure;the ratio of noncompacted-to-compacted myocardium was 2.7:1.Ade novo heterozygous variant c.1907G>A(p.Arg636His)in exon 9 was identified in this patient.Patient 2 was a 13-year-old boy who had clinical phenotypes identical to those of Patient 1;the ratio of noncompacted-to-compacted myocardium was 3.2:1 in this patient.WES revealed ade novo heterozygous variant c.1909A>G(p.Ser637Gly)in exon 9.Both variants were previously characterized as pathogenic,and our study classified them as pathogenic variants based on the ACMG guidelines.Interpretation:We found that two patients with LVNC had variants inRBM20.Our results extended the clinical spectrum of the twoRBM20 variants and illustrated that the same variant inRBM20 can cause DCM,with or without the LVNC phenotype.展开更多
Bardet-Biedl syndrome(BBS) is a genetically heterogeneous disorder characterized by retinal dystrophy, polydactyly, obesity,developmental delay, and renal defects. At least 21 candidate BBS-associated genes(BBS1-19, N...Bardet-Biedl syndrome(BBS) is a genetically heterogeneous disorder characterized by retinal dystrophy, polydactyly, obesity,developmental delay, and renal defects. At least 21 candidate BBS-associated genes(BBS1-19, NPHP1, and IFT172) have previously been identified, and all of them play important roles in ciliary function. Here, we collected a BBS pedigree with four members and performed whole-exome sequencing on the proband. The variants were analyzed and evaluated to confirm their pathogenicity. We found compound heterozygous variants(c.1192C>T, p.Q398* and c.1175C>T, p.T392M) in MKKS in both the siblings, and these were likely to be pathogenic variants. We also found a missense variant(c.2029G>C, p.E677Q) in NPHP1 and a missense variant(c.2470C>T, p.R824C) in BBS9 in the proband only, which are variants of uncertain significance. The compound heterozygous variants were probably responsible for the BBS phenotype in this Chinese pedigree and the missense mutations in NPHP1 and BBS9 might contribute to the mutation load.展开更多
Importance:Cytochrome P450 oxidoreductase deficiency (PORD) is a rare disease exhibiting a variety of clinical manifestations.This condition specifically leads to disordered steroidogenesis,which can affect the develo...Importance:Cytochrome P450 oxidoreductase deficiency (PORD) is a rare disease exhibiting a variety of clinical manifestations.This condition specifically leads to disordered steroidogenesis,which can affect the development of the reproductive system,skeleton,and other parts of the body.The severe form of PORD is difficult to differentiate with Antley-Bixler syndrome (ABS).The genetic characters and clinical evaluation of PORD are still unclear in China.Objective:To perform an exome analysis and identify the pathogenic cause in order to assist clinicians to obtain a proper evaluation on the genetic condition.Methods:The proband underwent detailed physical evaluations.DNA of the proband and his parents was isolated and whole-exome sequencing (WES) was performed.Variants were analyzed and evaluation according to the ACMG guideline.Results:A 1-year-old Chinese boy with midface hypoplasia,choanal stenosis,multiple joint contractures,micropenis and right cryptorchidism was misdiagnosed with Crouzon syndrome.By trio-whole-exome sequencing,we identified an unreported compound heterozygous mutation (c.667C＞T,p.R223* and c.1370G＞A,p.R457H) in POR in the proband.This mutation was inherited from healthy heterozygous parents,supporting the diagnosis of PORD,which was further confirmed by biochemical characteristics.Interpretation:We have identified a pathogenic variant with an unreported compound heterozygous POR mutation,which expands the clinical and genetic spectra of PORD and emphasizes the usefulness of WES for genetic diagnosis.展开更多
Understanding the association between the genetic and clinical phenotypes in children with nephrotic syndrome(NS)of different etiologies is critical for early clinical guidance.We employed whole-exome sequencing(WES)t...Understanding the association between the genetic and clinical phenotypes in children with nephrotic syndrome(NS)of different etiologies is critical for early clinical guidance.We employed whole-exome sequencing(WES)to detect monogenic causes of NS in a multicenter cohort of 637 patients.In this study,a genetic cause was identified in 30.0%of the idiopathic steroid-resistant nephrotic syndrome(SRNS)patients.Other than congenital nephrotic syndrome(CNS),there were no significant differences in the incidence of monogenic diseases based on the age at manifestation.Causative mutations were detected in 39.5%of patients with focal segmental glomerulosclerosis(FSGS)and 9.2%of those with minimal change disease(MCD).In terms of the patterns in patients with different types of steroid resistance,a single gene mutation was identified in 34.8%of patients with primary resistance,2.9%with secondary resistance,and 71.4%of children with multidrug resistance.Among the various intensified immunosuppressive therapies,tacrolimus(TAC)showed the highest response rate,with 49.7%of idiopathic SRNS patients achieving complete remission.Idiopathic SRNS patients with monogenic disease showed a similar multidrug resistance pattern,and only 31.4%of patients with monogenic disease achieved a partial remission on TAC.During an average 4.1-year follow-up,21.4%of idiopathic SRNS patients with monogenic disease progressed to end-stage renal disease(ESRD).Collectively,this study provides evidence that genetic testing is necessary for presumed steroid-resistant and idiopathic SRNS patients,especially those with primary and/or multidrug resistance.展开更多
The incidence of multiple primary malignancies(MPMs)has been increasing rapidly in recent years,however,the genetic pathogenesis is largely unknown on account of rare cases,especially for those patients who are diagno...The incidence of multiple primary malignancies(MPMs)has been increasing rapidly in recent years,however,the genetic pathogenesis is largely unknown on account of rare cases,especially for those patients who are diagnosed with three or more tumors.Under these circumstances,whole-exome sequencing(WES)may help to provide more comprehensive genomic information and guidance to proper therapeutic strategies.Here,we presented a rare case of a 66-year-old Chinese male patient who was diagnosed with synchronous triple primary malignancies:esophageal squamous cell carcinoma(ESCC),lung adenocarcinoma(LA),and hepatocellular carcinoma(HCC).Tumors were surgically removed within 3 months.WES was performed when the patient suffered from cancer recurrence and tumor-specific neoantigens were predicted.Each tumor displayed a distinct somatic mutation profile,providing direct evidence of independent origins.No shared driver gene mutation or neoantigen was detected among the three tumors.Two germline alterations of cancer susceptibility genes—SPINK1 c.194+2T>C and JAK3 c.425G>A were identified.This case is the first report of synchronous primary triple cancers covering the esophagus,lung,and liver.Our findings highlight the complexities of MPMs that even when under identical germline genetic backgrounds,the occurrence of MPMs can be a random event and driven by distinct somatic gene mutations.Synchronous multiple primary cancers that originated from different organs may not have common therapeutic gene targets,and it can be difficult to find a treatment to cover all the tumors.展开更多
Destruction of the lung parenchyma may result in the forma- tion of cysts, cavities and bullae. Definition of the type of destructive lesion is best achieved by high-resolution computed tomography （HRCT） scans of th...Destruction of the lung parenchyma may result in the forma- tion of cysts, cavities and bullae. Definition of the type of destructive lesion is best achieved by high-resolution computed tomography （HRCT） scans of the chest （Trotman- Dickenson, 2014）. The loss of lung parenchyma may result in respiratory compromise and pneumothoraces. In the case of cystic lung destruction, multiple causes have been identified, with the cysts being a manifestation of inherited and non- inherited diseases （Sahn and Heffner, 2000）. Compared with sporadic cases, familial lung cysts/spontaneous pneumothorax are rare and are manifestation of some Mendelian genetic diseases.展开更多
基金supported by the grant from China-Japan Friendship Hospital Talent Introduction Research Start-up Fund(to Guang ying ZHU)(No.2016-RC-4)。
文摘Background and objective Low-density computed tomography(LDCT)improved early lung cancer diagnosis but introduces an excess of false-positive pulmonary nodules data.Hence,accurate diagnosis of early-stage lung cancer remains challenging.The purpose of the study was to assess the feasibility of using circulating tumour cells(CTCs)to differentiate malignant from benign pulmonary nodules.Materials and methods 122 patients with suspected malignant pulmonary nodules detected on chest CT in preparation for surgery were prospectively recruited.Peripheral blood samples were collected before surgery,and CTCs were identified upon isolation by size of epithelial tumour cells and morphological analysis.Laser capture microdissection,MALBAC amplification,and whole-exome sequencing were performed on 8 samples.The diagnostic efficacy of CTCs counting,and the genomic variation profile of benign and malignant CTCs samples were analysed.Results Using 2.5 cells/5 m L as the cut-off value,the area under the receiver operating characteristic curve was of 0.651(95%confidence interval:0.538-0.764),with a sensitivity and specificity of 0.526 and 0.800,respectively,and positive and negative predictive values of 91.1%and 30.3%,respectively.Distinct sequence variations differences in DNA damage repair-related and driver genes were observed in benign and malignant samples.TP53 mutations were identified in CTCs of four malignant cases;in particular,g.7578115T>C,g.7578645C>T,and g.7579472G>C were exclusively detected in all four malignant samples.Conclusion CTCs play an ancillary role in the diagnosis of pulmonary nodules.TP53 mutations in CTCs might be used to identify benign and malignant pulmonary nodules.
基金Supported by the National Natural Science Foundation of China(No.81360154)
文摘AIM: To detect the pathogenetic mutations responsible for nonsyndromic autosomal recessive retinitis pigmentosa(RP) in 2 nonconsanguineous Chinese families. METHODS: The clinical data, including detailed medical history, best corrected visual acuity(BCVA), slit-lamp biomicroscope examination, fundus photography, optical coherence tomography, static perimetry, and full field electroretinogram, were collected from the members of 2 nonconsanguineous Chinese families preliminarily diagnosed with RP. Genomic DNA was extracted from the probands and other available family members;wholeexome sequencing was conducted with the DNA samples provided by the probands, and all mutations detected by whole-exome sequencing were verified using Sanger sequencing in the probands and the other available family members. The verified novel mutations were further sequenced in 192 ethnicity matched healthy controls.RESULTS: The patients from the 2 families exhibited the typical symptoms of RP, including night blindness and progressive constriction of the visual field, and the fundus examinations showed attenuated retinal arterioles, peripheral bone spicule pigment deposits, and waxy optic discs. Whole-exome sequencing revealed a novel nonsense mutation in FAM161 A(c.943 A>T, p.Lys315*) and compound heterozygous mutations in RP1 L1(c.56 C>A, p.Pro19 His;c.5470 C>T, p.Gln1824*). The nonsense c.5470 C>T, p.Gln1824* mutation was novel. All mutations were verified by Sanger sequencing. The mutation p.Lys315* in FAM161A co-segregated with the phenotype, and all the nonsense mutations were absent from the ethnicity matched healthy controls and all available databases.CONCLUSION: We identify 2 novel mutations in genes responsible for autosomal recessive RP, and the mutation in FAM161A is reported for the first time in a Chinese population. Our result not only enriches the knowledge of the mutation frequency and spectrum in the genes responsible for nonsyndromic RP but also provides a new target for future gene therapy.
基金Supported by National Natural Science Foundation of China(No.81470642No.81271045)
文摘AIM：To make a comprehensive analysis of the potential pathogenic genes related with Leber congenital amaurosis（LCA） in Chinese.METHODS：LCA subjects and their families were retrospectively collected from 2013 to 2015.Firstly,whole-exome sequencing was performed in patients who had underwent gene mutation screening with nothing found,and then homozygous sites was selected,candidate sites were annotated,and pathogenic analysis was conducted using softwares including Sorting Tolerant from Intolerant（SIFT）,Polyphen-2,Mutation assessor,Condel,and Functional Analysis through Hidden Markov Models（FATHMM）.Furthermore,Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of pathogenic genes were performed followed by co-segregation analysis using Fisher exact Test.Sanger sequencing was used to validate single-nucleotide variations（SNVs）.Expanded verification was performed in the rest patients.RESULTS：Totally 51 LCA families with 53 patients and24 family members were recruited.A total of 104 SNVs（66 LCA-related genes and 15 co-segregated genes）were submitted for expand verification.The frequencies of homozygous mutation of KRT12 and CYP1A1 were simultaneously observed in 3 families.Enrichment analysis showed that the potential pathogenic genes were mainly enriched in functions related to cell adhesion,biological adhesion,retinoid metabolic process,and eye development biological adhesion.Additionally,WFS7 and STAU2 had the highest homozygous frequencies.CONCLUSION：LCA is a highly heterogeneous disease.Mutations in KRT12,CVP1A1,WFS1,and STAU2 may be involved in the development of LCA.
基金the funds of "the Youth Fund of Nantong Health Bureau 2015",ID:WQ2015009
文摘Dilated cardiomyopathy（DCM）is characterized by the dilated heart chambers and reduced systolic function in the absence of specific aetiology[1].Approximately one third of DCM cases are hereditary.In recent years,DCM concomitant with arrhythmias and sudden death resulting from gene mutation has been widely
基金Supported by the Zhejiang Provincial Natural Science Foundation of China (No.LY12H12001)the Ningbo Key Foundation of Society Development (No.2014C50091)+2 种基金the Ningbo Natural Science Foundation (No.2012A610192)the Ningbo Yinzhou District S&T Foundation (No.YK2013-90)the Shenzhen Municipal Government of China (No.GJHZ20130417140916986)
文摘AIMTo identify the disease-causing gene mutation in a Chinese pedigree with autosomal dominant cone-rod dystrophy (adCORD).METHODSA southern Chinese adCORD pedigree including 9 affected individuals was studied. Whole-exome sequencing (WES), coupling the Agilent whole-exome capture system to the Illumina HiSeq 2000 DNA sequencing platform was used to search the specific gene mutation in 3 affected family members and 1 unaffected member. After a suggested variant was found through the data analysis, the putative mutation was validated by Sanger DNA sequencing of samples from all available family members.RESULTSThe results of both WES and Sanger sequencing revealed a novel nonsense mutation c.C766T (p.Q256X) within exon 5 of CRX gene which was pathogenic for adCORD in this family. The mutation could affect photoreceptor-specific gene expression with a dominant-negative effect and resulted in loss of the OTX tail, thus the mutant protein occupies the CRX-binding site in target promoters without establishing an interaction and, consequently, may block transactivation.CONCLUSIONAll modes of Mendelian inheritance in CORD have been observed, and genetic heterogeneity is a hallmark of CORD. Therefore, conventional genetic diagnosis of CORD would be time-consuming and labor-intensive. Our study indicated the robustness and cost-effectiveness of WES in the genetic diagnosis of CORD.
文摘Objective:The purpose of this work was to obtain the phenotypes and detect potential mutations in three Chinese patients with Marfan syndrome(MFS)or incomplete MFS phenotypes.Methods:Three unrelated patients with a defi nite or suspected clinical diagnosis of MFS and their family members were recruited for research.Genomic DNA was extracted from peripheral blood of these patients and their family members.All the exons were sequenced by next-generation sequencing and the variants were further validated by Sanger sequencing.The functional consequences of the mutations were analyzed with various genomic resources and bioinformatics tools.Results:Three FBN1 mutations were identifi ed in the three patients,including one novel mutation(2125G>A)and two previously reported mutations(4786C>T and 6325C>T).It was interesting to note that the parents of these patients were normal as assessed by clinical features or genetic testing,but all these mutations were detected in their offspring,except for the variant 6325C>T.We also found that a few young members of the family of probands(proband 1 and proband 2)have exhibited no manifestations of MFS so far,although they carry the same disease-causing mutation.Conclusions:We found three FBN1 mutations in three unrelated Chinese families with MFS by genome sequencing,and the relationship between genotypes and phenotypes in MFS patients needs further exploration.
基金This work was supported by the National Natural Science Foundation of China(31625013,81941015,32000726,and 61973086)the Shanghai Brain-Intelligence Project from STCSM(16JC1420501)+2 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDBS01060200)the Program of Shanghai Academic Research LeaderThe Open Large Infrastructure Research of the Chinese Academy of Sciences,and the Shanghai Municipal Science and Technology Major Project(2018SHZDZX01).
文摘Autism spectrum disorder(ASD)is a highly heritable neurodevelopmental disorder characterized by deficits in social interactions and repetitive behaviors.Although hundreds of ASD risk genes,implicated in synaptic formation and transcriptional regulation,have been identified through human genetic studies,the East Asian ASD cohorts are still under-represented in genome-wide genetic studies.Here,we applied whole-exome sequencing to 369 ASD trios including probands and unaffected parents of Chinese origin.Using a joint-calling analytical pipeline based on GATK toolkits,we identified numerous de novo mutations including 55 high-impact variants and 165 moderate-impact variants,as well as de novo copy number variations containing known ASD-related genes.Importantly,combined with single-cell sequencing data from the developing human brain,we found that the expression of genes with de novo mutations was specifically enriched in the pre-,post-central gyrus(PRC,PC)and banks of the superior temporal(BST)regions in the human brain.By further analyzing the brain imaging data with ASD and healthy controls,we found that the gray volume of the right BST in ASD patients was significantly decreased compared to healthy controls,suggesting the potential structural deficits associated with ASD.Finally,we found a decrease in the seed-based functional connectivity between BST/PC/PRC and sensory areas,the insula,as well as the frontal lobes in ASD patients.This work indicated that combinatorial analysis with genome-wide screening,single-cell sequencing,and brain imaging data reveal the brain regions contributing to the etiology of ASD.
基金supported by grants from the National Natural Science Foundation of China (No.81971440)the Beijing Natural Science Foundation (No.7212129).
文摘Nonobstructive azoospermia(NOA)is a severe condition in infertile men,and increasing numbers of causative genes have been identified during the last few decades.Although certain causative genes can explain the presence of NOA in some patients,a proportion of NOA patients remain to be addressed.This study aimed to investigate potential high-risk genes associated with spermatogenesis in idiopathic NOA patients by whole-exome sequencing.Whole-exome sequencing was performed in 46 male patients diagnosed with NOA.First,screening was performed for 119 genes known to be related to male infertility.Next,further screening was performed to determine potential high-risk causative genes for NOA by comparisons with 68 healthy male controls.Finally,risk genes with high/specific expression in the testes were selected and their expression fluctuations during spermatogenesis were graphed.The frequency of cystic fibrosis transmembrane conductance regulator(CFTR)gene pathogenic variant carriers was higher in the NOA patients compared with the healthy controls.Potential risk genes that may be causes of NOA were identified,including seven genes that were highly/specifically expressed in the testes.Four risk genes previously reported to be involved in spermatogenesis(MutS homolog 5[MSH5],cilia-and flagella-associated protein 54[CFAP54],MAP7 domain containing 3[MAP7D3],and coiled-coil domain containing 33[CCDC33])and three novel risk genes(coiled-coil domain containing 168[CCDC168],chromosome 16 open reading frame 96[C16orf96],and serine protease 48[PRSS48])were identified to be highly or specifically expressed in the testes and significantly different in the 46 NOA patients compared with 68 healthy controls.This study on clinical NOA patients provides further evidence for the four previously reported risk genes.The present findings pave the way for further functional investigations and provide candidate risk genes for genetic diagnosis of NOA.
基金supported by grants from Shanghai Outstanding Academic Leaders(20XD1433300)Medical-Engineering Cross Foundation of Shanghai Jiao Tong University(YG2021ZD20)+3 种基金Shuguang Project(21SG11),Innovative Research Team of High-level Local Universities in Shanghai(SHSMU-ZDCX20212700)Shanghai Research Center for Endocrine,Metabolic Diseases(2022ZZ01002)Shanghai Sixth People’s Hospital Grant(ynhg202204)Shanghai Municipal Key Clinical Specialty.
文摘A small fraction of patients diagnosed with obesity or diabetes mellitus has an underlying monogenic cause.Here,we constructed a targeted gene panel consisting of 83 genes reported to be causative for monogenic obesity or diabetes.We performed this panel in 481 patients to detect causative variants and compared these results with whole-exome sequencing(WES)data available for 146 of these patients.The coverage of targeted gene panel sequencing was significantly higher than that of WES.The diagnostic yield in patients sequenced by the panel was 32.9%with subsequent WES leading to three additional diagnoses with two novel genes.In total,178 variants in 83 genes were detected in 146 patients by targeted sequencing.Three of the 178 variants were missed by WES,although the WES-only approach had a similar diagnostic yield.For the 335 samples only receiving targeted sequencing,the diagnostic yield was 32.2%.In conclusion,taking into account the lower costs,shorter turnaround time,and higher quality of data,targeted sequencing is a more effective screening method for monogenic obesity and diabetes compared to WES.Therefore,this approach could be routinely established and used as a first-tier test in clinical practice for specific patients.
基金Project supported by the National Natural Science Foundation of China （Nos. 81370204, 81300072, and 81101475） Electronic supplementary materials： The online version of this article （htlp：//dx.doi.org/10.1631/jzus.B1400062） contains supplementary materials, which are available to authorized users
文摘Congenital heart disease （CHD） is the leading cause of birth defects, and its etiology is not completely understood. Atrial septal defect （ASD） is one of the most common defects of CHD. Previous studies have demonstrated that mutations in the transcription factor T-box 20 （TBX20） contribute to congenital ASD. Whole-exome sequencing in combination with a CHD-related gene filter was used to detect a family of three generations with ASD. A novel TBX20 mutation, c.526G〉A （p.D176N）, was identified and co-segregated in all affected members in this family. This mutation was predicted to be deleterious by bioinformatics programs （SIFT, Polyphen2, and MutationTaster）. This mutation was also not presented in the current Single Nucleotide Polymorphism Database （dbSNP） or National Heart, Lung, and Blood Institute （NHLBI） Exome Sequencing Project （ESP）. In conclusion, our finding expands the spectrum of TBX20 mutations and provides additional support that TBX20 plays important roles in cardiac development. Our study also provided a new and cost-effective analysis strategy for the genetic study in small CHD pedigree.
文摘Monognnic diabetes is often misdiagnosed with type 2 diabetes due to overlapping characteristics. This study aimed to discover novel causative mutations of monogenic diabetes in patients with clinically diagnosed type 2 diabetes and to explore potential molecular mechanisms. Whole-exome sequencing was performed on 31 individuals clinically diagnosed with type 2 diabetes. One novel heterozygnus mutation （p^la2Thr） in INS was identified. It was further gnnotyped in an additional case-control population （6523 cases and 4635 controls）, and this variant was observed in 0.09% of cases. IntraceUular trafficking of insulin proteins was assessed in INSl-E and HEK293T cells, p.Ala2Thr preproinsuUn-GFP was markedly retained in the endoplasmic reticulum （ER） in INS1-E cells. Activation of the PERK-elF2a-ATF4, IREla-XBP1, and ATF6 pathways as well as upregulated ER chaperones were detected in INS1-E cells transfected with the p.Ala2Thr mutant. In conclusion, we identified a causative mutation in IN5 respon- sible for maturity-onset diabetes of the young 10 （MODYIO） in a Chinese population and demonstrated that this mutation affected 13 cell function by inducing ER stress.
文摘Background： Restrictive cardiomyopathy （RCM） is the least common cardiomyopathy in which the walls are rigid and the heart is restricted from stretching and filling properly. Cardiac troponin I （cTnI） mutation-caused myofibril Ca2＋ hypersensitivity has been shown to be associated with impaired diastolic function. This study aimed to investigate the linkage between the genotype and clinical therapy of RCM. Methods： Five sporadic pediatric RCM patients confirmed by echocardiography were enrolled in this study.Whole-exome sequencing （WES） was performed for the cohort to find out candidate causative gene variants. Sanger sequencing confirmed the WES-identified variants. Results： TNNI3 variants were found in all of the five patients. R192H mutation was shared in four patients while R204H mutation was found only in one patient. Structure investigation showed that the C terminus of TNNI3 was flexible and mutation on the C terminus was possible to cause the RCM. Catechins were prescribed for the five patients once genotype was confirmed. Ventricular diastolic function was improved in three patients during the follow-up. Conclusions： Our data demonstrated that TNNI3 mutation-induced RCM1 is the most common type of pediatric RCM in this study. In addition, WES is a reliable approach to identify likely pathogenic genes of RCM and might be useful for the guidance of clinical treatment scheme.
文摘Multiple epiphyseal dysplasia （MED; EDMI, OMIM 132400; EDM2, OMIM 600204; EDM3, OMIM 600969; EDM4, OMIM 226900; EDM5~ OMIM 607078; EDM6, OMIM 614135） is an autosomal dominant inherited disease of the skeletal system, characterized by mild short stature and early-onset degenerative joint disease, caused by heterogeneous genotypes involving more than six genes （COMP, COL9A 1, COL9A2, COL9A3, MATN3, DTDST）.However, in approximately 10-20% of all samples analyzed, a mutation cannot be identified in any of the six genes mentioned above, suggesting that the presence of other unidentified causative genes is also involved in the pathogenesis of MED.
基金supported by the National Natural Science Foundation of China (Grant No. 81172681)
文摘Abstract Charcot-Marie-Tooth disease type 4B2 with early-onset glaucoma （CMT4B2, OMIM 604563） is a genetically-heterogeneous childhood-onset neuromuscular disorder. Here, we report the case of a 15-year-old male adolescent with lower extremity weakness, gait abnormalities, foot deformities and early-onset glaucoma. Since clinical diagnosis alone was insufficient for providing pathogenetic evidence to indicate that the condition belonged to a consanguineous family, we applied whole-exome sequencing to samples from the patient, his parents and his younger brother, assuming that the patient＇s condition is transmitted in an autosomal recessive pattern. A frame-shift mutation, c.4571delG （P.Gly1524Glufs＊42）, was revealed in the CMT4B2-related gene SBF2 （also known as MTMR13, MIM 607697）, and this mutation was found to be homozygous in the proband and heterozygous in his parents and younger brother. Together with the results of clinical diagnosis, this case was diagnosed as CMT4B2. Our finding further demonstrates the use of whole-exome sequencing in the diagnosis and treatment of rare diseases.
文摘Importance:Pathogenic variants in theRBM20 gene are associated with aggressive dilated cardiomyopathy(DCM).Recently,RBM20 was found to be associated with left ventricular non-compaction cardiomyopathy(LVNC).Thus far,only five families with LVNC have been reported to carry variants inRBM20.It remains unknown whether the variants inRBM20 associated with DCM can also cause LVNC.Objective:To elucidate the causativeRBM20 variant in two unrelated patients with both LVNC and DCM,and to identify the clinical characteristics associated with variants inRBM20.Methods:Trio whole-exome sequencing(WES)was performed.Variants were filtered and classified in accordance with the guidelines of the American College of Medical Genetics and Genomics(ACMG).Results:We identified two distinctde novo variants inRBM20(one per patient)in these two patients with LVNC.Both variants have been reported in patients with DCM,without the LVNC phenotype.Patient 1 was an 11-year-old girl who had DCM,LVNC,and heart failure;the ratio of noncompacted-to-compacted myocardium was 2.7:1.Ade novo heterozygous variant c.1907G>A(p.Arg636His)in exon 9 was identified in this patient.Patient 2 was a 13-year-old boy who had clinical phenotypes identical to those of Patient 1;the ratio of noncompacted-to-compacted myocardium was 3.2:1 in this patient.WES revealed ade novo heterozygous variant c.1909A>G(p.Ser637Gly)in exon 9.Both variants were previously characterized as pathogenic,and our study classified them as pathogenic variants based on the ACMG guidelines.Interpretation:We found that two patients with LVNC had variants inRBM20.Our results extended the clinical spectrum of the twoRBM20 variants and illustrated that the same variant inRBM20 can cause DCM,with or without the LVNC phenotype.
文摘Bardet-Biedl syndrome(BBS) is a genetically heterogeneous disorder characterized by retinal dystrophy, polydactyly, obesity,developmental delay, and renal defects. At least 21 candidate BBS-associated genes(BBS1-19, NPHP1, and IFT172) have previously been identified, and all of them play important roles in ciliary function. Here, we collected a BBS pedigree with four members and performed whole-exome sequencing on the proband. The variants were analyzed and evaluated to confirm their pathogenicity. We found compound heterozygous variants(c.1192C>T, p.Q398* and c.1175C>T, p.T392M) in MKKS in both the siblings, and these were likely to be pathogenic variants. We also found a missense variant(c.2029G>C, p.E677Q) in NPHP1 and a missense variant(c.2470C>T, p.R824C) in BBS9 in the proband only, which are variants of uncertain significance. The compound heterozygous variants were probably responsible for the BBS phenotype in this Chinese pedigree and the missense mutations in NPHP1 and BBS9 might contribute to the mutation load.
基金National Natural Science Foundation of China(81670789,31401171)%Ministry of Science and Technology of China(2016YFC1000306)%The Beijing Municipal Science and Technology Commission Foundation(Z141100002114009)%Beijing Municipal Commission of Health and Family Planning Foundation(PXM2017_026274_000001)%Beijing Municipal Administration of Hospitals Foundation(QML20161201)
文摘Importance:Cytochrome P450 oxidoreductase deficiency (PORD) is a rare disease exhibiting a variety of clinical manifestations.This condition specifically leads to disordered steroidogenesis,which can affect the development of the reproductive system,skeleton,and other parts of the body.The severe form of PORD is difficult to differentiate with Antley-Bixler syndrome (ABS).The genetic characters and clinical evaluation of PORD are still unclear in China.Objective:To perform an exome analysis and identify the pathogenic cause in order to assist clinicians to obtain a proper evaluation on the genetic condition.Methods:The proband underwent detailed physical evaluations.DNA of the proband and his parents was isolated and whole-exome sequencing (WES) was performed.Variants were analyzed and evaluation according to the ACMG guideline.Results:A 1-year-old Chinese boy with midface hypoplasia,choanal stenosis,multiple joint contractures,micropenis and right cryptorchidism was misdiagnosed with Crouzon syndrome.By trio-whole-exome sequencing,we identified an unreported compound heterozygous mutation (c.667C＞T,p.R223* and c.1370G＞A,p.R457H) in POR in the proband.This mutation was inherited from healthy heterozygous parents,supporting the diagnosis of PORD,which was further confirmed by biochemical characteristics.Interpretation:We have identified a pathogenic variant with an unreported compound heterozygous POR mutation,which expands the clinical and genetic spectra of PORD and emphasizes the usefulness of WES for genetic diagnosis.
基金This cohort study is funded by the China National Natural Science Foundation(No.81970618)China National Clinical Research Centre Foundation(No.NCRC-2019-GP-02)+2 种基金Chongqing Science and Technology Commission project(No.cstc2016jcyjA0440)Chongqing Science and Technology plan project of Yuzhong District(No.2017045),Science and Technology Research Project of Chongqing Education Commission(No.KJZD-M201900401)the central government directs special funds for local science and technology development.
文摘Understanding the association between the genetic and clinical phenotypes in children with nephrotic syndrome(NS)of different etiologies is critical for early clinical guidance.We employed whole-exome sequencing(WES)to detect monogenic causes of NS in a multicenter cohort of 637 patients.In this study,a genetic cause was identified in 30.0%of the idiopathic steroid-resistant nephrotic syndrome(SRNS)patients.Other than congenital nephrotic syndrome(CNS),there were no significant differences in the incidence of monogenic diseases based on the age at manifestation.Causative mutations were detected in 39.5%of patients with focal segmental glomerulosclerosis(FSGS)and 9.2%of those with minimal change disease(MCD).In terms of the patterns in patients with different types of steroid resistance,a single gene mutation was identified in 34.8%of patients with primary resistance,2.9%with secondary resistance,and 71.4%of children with multidrug resistance.Among the various intensified immunosuppressive therapies,tacrolimus(TAC)showed the highest response rate,with 49.7%of idiopathic SRNS patients achieving complete remission.Idiopathic SRNS patients with monogenic disease showed a similar multidrug resistance pattern,and only 31.4%of patients with monogenic disease achieved a partial remission on TAC.During an average 4.1-year follow-up,21.4%of idiopathic SRNS patients with monogenic disease progressed to end-stage renal disease(ESRD).Collectively,this study provides evidence that genetic testing is necessary for presumed steroid-resistant and idiopathic SRNS patients,especially those with primary and/or multidrug resistance.
基金This work was funded by the Sichuan Science and Technology Program(Grant No.2019YJ0022)from Sichuan Provincial Science and Technology Department.We thank Jian Bai from Berry Oncology Co.,Ltd for academic support.
文摘The incidence of multiple primary malignancies(MPMs)has been increasing rapidly in recent years,however,the genetic pathogenesis is largely unknown on account of rare cases,especially for those patients who are diagnosed with three or more tumors.Under these circumstances,whole-exome sequencing(WES)may help to provide more comprehensive genomic information and guidance to proper therapeutic strategies.Here,we presented a rare case of a 66-year-old Chinese male patient who was diagnosed with synchronous triple primary malignancies:esophageal squamous cell carcinoma(ESCC),lung adenocarcinoma(LA),and hepatocellular carcinoma(HCC).Tumors were surgically removed within 3 months.WES was performed when the patient suffered from cancer recurrence and tumor-specific neoantigens were predicted.Each tumor displayed a distinct somatic mutation profile,providing direct evidence of independent origins.No shared driver gene mutation or neoantigen was detected among the three tumors.Two germline alterations of cancer susceptibility genes—SPINK1 c.194+2T>C and JAK3 c.425G>A were identified.This case is the first report of synchronous primary triple cancers covering the esophagus,lung,and liver.Our findings highlight the complexities of MPMs that even when under identical germline genetic backgrounds,the occurrence of MPMs can be a random event and driven by distinct somatic gene mutations.Synchronous multiple primary cancers that originated from different organs may not have common therapeutic gene targets,and it can be difficult to find a treatment to cover all the tumors.
基金supported by the National High Technology Research and Development Program of China (863 Program) (No. 2012AA02A201)supported by the Intramural Research Program,National Institutes of Health, National Heart, Lung and Blood Institute,USA
文摘Destruction of the lung parenchyma may result in the forma- tion of cysts, cavities and bullae. Definition of the type of destructive lesion is best achieved by high-resolution computed tomography （HRCT） scans of the chest （Trotman- Dickenson, 2014）. The loss of lung parenchyma may result in respiratory compromise and pneumothoraces. In the case of cystic lung destruction, multiple causes have been identified, with the cysts being a manifestation of inherited and non- inherited diseases （Sahn and Heffner, 2000）. Compared with sporadic cases, familial lung cysts/spontaneous pneumothorax are rare and are manifestation of some Mendelian genetic diseases.
