BACKGROUND Adenomatous polyposis confers an increased risk of developing colorectal cancer.APC and MUTYH are the major genes investigated in patients suspected of having polyposis.In addition to APC and MUTYH genes,ot...BACKGROUND Adenomatous polyposis confers an increased risk of developing colorectal cancer.APC and MUTYH are the major genes investigated in patients suspected of having polyposis.In addition to APC and MUTYH genes,other genes,such as POLE,POLD1,NTHL1,MBD4,MSH3 and MLH3,have recently been associated with polyposis phenotypes,conferring heterogeneity in terms of the clinical,etiological and heritable aspects of patients with polyposis.AIM To investigate the underlying variant landscape in patients with suspected polyposis who lack variants in the APC and MUTYH genes using whole-exome sequencing.METHODS Twenty-seven participants were included in the study and subjected to germline whole-exome sequencing.In addition,their clinical-pathological,personal,and family history data were collected.RESULTS The mean age at diagnosis was 51 years,and most participants had attenuated forms of polyposis(88.9%),with 63.0%diagnosed with a primary tumor,mostly colorectal cancer(76.5%).Among the variants identified,17 were classified as pathogenic or likely pathogenic(in 12 participants),including variants in genes involved in the Wnt/β-catenin signaling pathway,such as ST7 L,A1CF,and DKK4,and variants in DNA-repair genes,such as NTHL1,PNKP,and PMS2,as well as a variant found at the FRK gene identified in a patient with classic polyposis at age 19 and with a family history of polyps.CONCLUSION This study identified novel genes potentially associated with polyposis in patients lacking germline pathogenic variants in the APC and MUTYH genes.These findings support the use of next-generation sequencing for screening,expanding the scope of polyposis-related variants beyond these two genes.展开更多
AIM:To identify the genetic factors underlying anophthalmia and microphthalmia(A/M),and to perform computational analysis to verify the pathophysiological mechanisms of the disease.METHODS:This study investigated a co...AIM:To identify the genetic factors underlying anophthalmia and microphthalmia(A/M),and to perform computational analysis to verify the pathophysiological mechanisms of the disease.METHODS:This study investigated a consanguineous Pakistani family with multiple affected individuals.Clinical evaluations were conducted using A-Scan and ophthalmic B-Scan ultrasonography(B-Scan).To identify the diseasecausing variant,whole exome sequencing(WES)and Sanger sequencing were performed.In silico functional analyses were carried out using AlphaFold(for protein modeling)and ClusPro(for protein docking analysis)tools,and the hydrodynamic properties of the protein were determined via molecular dynamics simulations.RESULTS:Clinical analysis of the five patients revealed severe phenotypes of bilateral anophthalmia.Ocular B-Scan did not detect ocular tissue or intraocular fluid,thus confirming the diagnosis of anophthalmia in all patients.Due to these structural defects,all patients exhibited complete blindness and absence of light perception;additionally,two patients had mild to moderate intellectual disability.Genetic analysis identified a splice site variant[NM_000693.2:c.884-2_885dup;p.(Asp296SerfsTer35)]in the 9^(th)exon of the ALDH1A3 gene.CONCLUSION:The present study expands the genetic spectrum of ALDH1A3 and contributes to establishing the genotype-phenotype correlation for this gene.展开更多
BACKGROUND Floating-harbor syndrome(FHS)is a rare genetic disorder caused by pathogenic variants in the SRCAP gene.Most individuals with FHS have short stature,delayed speech and language development,and dysmorphic fa...BACKGROUND Floating-harbor syndrome(FHS)is a rare genetic disorder caused by pathogenic variants in the SRCAP gene.Most individuals with FHS have short stature,delayed speech and language development,and dysmorphic facial features.However,the patients with FHS are not easy to diagnose due to the overlap of clinical phenotypes with other disorders.CASE SUMMARY We reported a 10-year-old boy who presented with severe short stature,developmental delay and distinctive facial features.Exome sequencing was provided for the proband and his parents.We identified a novel frameshift variant c.7235delinsGT(p.Thr2412fs)in SRCAP gene,and the variant was further validated by Sanger sequencing.The mother of the proband was referred to us for prenatal consultation during next pregnancy.We performed prenatal genetic diagnosis for the fetus.The result of Sanger sequencing for c.7235delinsGT(p.Thr2412fs)in SRCAP gene showed that the fetus did not carry the variant,so the fetus has been born successfully.The newborn does not show any similar symptom to the proband till one month.CONCLUSION This case confirms that the c.7235delinsGT(p.Thr2412fs)variant in the SRCAP gene is associated with FHS and expands the spectrum of SRCAP variants.展开更多
The study by Dos Santos et al marks a significant advancement in understanding the genetics of colorectal polyposis,particularly within the underrepresented Brazilian population.Utilizing whole-exome sequencing in 27 ...The study by Dos Santos et al marks a significant advancement in understanding the genetics of colorectal polyposis,particularly within the underrepresented Brazilian population.Utilizing whole-exome sequencing in 27 patients with unexplained polyposis,the researchers identified 16 candidate genes in 44.4%of cases-an impressive outcome given strict exclusion criteria.Many identified variants were linked to the Wnt/β-catenin signaling pathway,reinforcing their biological relevance.However,the study underscores key challenges in genomic medicine,especially the gap between gene discovery and clinical application.A substantial proportion of variants(60.1%)were classified as of uncertain sig-nificance,and the absence of functional validation or segregation analysis limits clinical interpretation.Notably,the potential for oligogenic inheritance com-plicates traditional monogenic models of hereditary cancer risk.The study’s focus on a genetically diverse Brazilian cohort emphasizes the need for population-specific genomic resources and interpretation guidelines.Moving forward,func-tional studies,including organoid models,loss-of-heterozygosity analyses,and genotype-phenotype correlations,are essential to validate findings.Clinically,discovering novel candidate genes may inform future screening and testing pro-tocols,though careful consideration is needed to manage uncertain results.Overall,the study represents a critical step in polyposis genetics,highlighting both progress made and the work still required for clinical translation.展开更多
Objective To establish and validate a novel diabetic retinopathy(DR)risk-prediction model using a whole-exome sequencing(WES)-based machine learning(ML)method.Methods WES was performed to identify potential single nuc...Objective To establish and validate a novel diabetic retinopathy(DR)risk-prediction model using a whole-exome sequencing(WES)-based machine learning(ML)method.Methods WES was performed to identify potential single nucleotide polymorphism(SNP)or mutation sites in a DR pedigree comprising 10 members.A prediction model was established and validated in a cohort of 420 type 2 diabetic patients based on both genetic and demographic features.The contribution of each feature was assessed using Shapley Additive explanation analysis.The efficacies of the models with and without SNP were compared.Results WES revealed that seven SNPs/mutations(rs116911833 in TRIM7,1997T>C in LRBA,1643T>C in PRMT10,rs117858678 in C9orf152,rs201922794 in CLDN25,rs146694895 in SH3GLB2,and rs201407189 in FANCC)were associated with DR.Notably,the model including rs146694895 and rs201407189 achieved better performance in predicting DR(accuracy:80.2%;sensitivity:83.3%;specificity:76.7%;area under the receiver operating characteristic curve[AUC]:80.0%)than the model without these SNPs(accuracy:79.4%;sensitivity:80.3%;specificity:78.3%;AUC:79.3%).Conclusion Novel SNP sites associated with DR were identified in the DR pedigree.Inclusion of rs146694895 and rs201407189 significantly enhanced the performance of the ML-based DR prediction model.展开更多
Inflammatory bowel disease(IBD)is a group of chronic disorders that cause relapsing inflammation in the gastrointestinal tract(GIT).It results either from gene-environment interactions or as a monogenic disease result...Inflammatory bowel disease(IBD)is a group of chronic disorders that cause relapsing inflammation in the gastrointestinal tract(GIT).It results either from gene-environment interactions or as a monogenic disease resulting from pa-thogenic mutations causing impairment in the protective mechanism of the GIT.Around 10%-15%of patients with very early onset IBDs may have an underlying monogenic condition.Monogenic IBD is very different from complex forms of polygenic IBD in the underlying molecular basis of uncontrolled intestinal inflam-mation,age of onset,extraintestinal comorbidities as well as treatment modality.An in-depth understanding of this distinct form of IBD is essential for deciding an appropriate therapeutic approach as well as prognostication.In this review,we aim to discuss about the epidemiology,clinical presentation,diagnostic approach,therapeutic challenges and latest advances in patients with monogenic IBD.展开更多
Craniofacial microsomia(CFM)is a congenital malformation with maxillary and/or mandibular hypoplasia,skin tags,and ear malformations(Luo et al.,2023).Microtia,in its mildest form,can occur alone(Quiat et al.,2023).Wit...Craniofacial microsomia(CFM)is a congenital malformation with maxillary and/or mandibular hypoplasia,skin tags,and ear malformations(Luo et al.,2023).Microtia,in its mildest form,can occur alone(Quiat et al.,2023).With a prevalence of 3.8/100,000(Barisic et al.,2014),CFM is the second most common congenital craniofacial abnormality(Li et al.,2022;Luo et al.,2023).Most cases are sporadic,but familial ones suggest autosomal dominant(AD)or autosomal recessive(AR)(Beleza-Meireles et al.,2014).In 2023,Quiat et al.and Mao et al.successively identified FOXI3 variants in 16 pedigrees and 10 sporadic cases,respectively,accounting for 3.1%of CFM cases(Mao et al.,2023;Quiat et al.,2023).FOX/3 has surpassed SF3B2 as the most frequently identified pathogenic gene for CFM to date(Timberlake et al.,2021;Mao et al.,2023;Quiat et al.,2023).In this study,we performed whole-exome sequencing(WES)on 201 CFM pedigrees and detected FOX/3 variants in 8 AD-inherited pedigrees with 24 patients and 28 unaffected individuals(Fig.1A).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
BACKGROUND Different histological growth patterns(HGPs)of colorectal carcinoma(CRC)liver metastasis are associated with patients’prognosis and response to antiangiogenic therapy.However,the relationship between HGPs ...BACKGROUND Different histological growth patterns(HGPs)of colorectal carcinoma(CRC)liver metastasis are associated with patients’prognosis and response to antiangiogenic therapy.However,the relationship between HGPs of liver metastasis and clinicopathological and genomic characteristics of primary cancer has not been well established.AIM To assess whether certain clinicopathological and genomic features of primary CRC could predict the HGPs of liver metastasis.METHODS A total of 29 patients with paired resections of both primary CRC and liver metastasis were divided into two groups:A(15 cases with desmoplastic liver metastasis)and B(14 cases with replacement liver metastasis).Clinical information was obtained from patients’charts.Mismatch repair proteins,BRAFV600E,and PD-L1 were evaluated by immunohistochemistry.Five cases were selected randomly from each group for whole exome sequencing(WES)analysis.RESULTS In the primary tumor,expanding growth pattern,low tumor budding score(TBS),and Crohn’s disease-like response(CDR)were associated with desmoplastic liver metastasis and better overall survival,whereas infiltrating growth pattern alone of primary carcinoma could predict the replacement liver metastasis and worse overall survival(P<0.05).On WES analysis,primary carcinoma with desmoplastic liver metastasis showed mutations in APC(4/5);TP53(3/5);KRAS,PIK3CA,and FAT4(2/5);BRCA-1,BRCA2,BRAF,and DNAH5(1/5),whereas primary carcinoma with replacement liver metastasis showed mutations in APC and TP53(3/5);KRAS,FAT4,DNH5,SMAD,ERBB2,ERBB3,LRP1,and SDK1(1/5).CONCLUSION The HGPs,TBS,and CDR of primary CRC as well as the presence of specific genetic mutations such as those in PIK3CA could be used to predict the HGPs of liver metastasis,response to therapy,and patients’prognosis.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
Pediatric cardiomyopathies are clinically heterogeneous heart muscle disorders that are responsible for significant morbidity and mortality. Phenotypes include hypertrophic cardiomyopathy, dilated cardiomyopathy, rest...Pediatric cardiomyopathies are clinically heterogeneous heart muscle disorders that are responsible for significant morbidity and mortality. Phenotypes include hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy, left ventricular noncompaction and arrhythmogenic right ventricular cardiomyopathy. There is substantial evidence for a genetic contribution to pediatric cardiomyopathy. To date, more than 100 genes have been implicated in cardiomyopathy, but comprehensive genetic diagnosis has been problematic because of the large number of genes, the private nature of mutations, and difficulties in interpreting novel rare variants. This review will focus on current knowledge on the genetic etiologies of pediatric cardiomyopathy and their diagnostic relevance in clinical settings. Recent developments in sequencing technologies are greatly impacting the pace of gene discovery and clinical diagnosis. Understanding the genetic basis for pediatric cardiomyopathy and establishing genotypephenotype correlations may help delineate the molecular and cellular events necessary to identify potential novel therapeutic targets for heart muscle dysfunction in children.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 Despite an expanding number of studies on intraductal papillary neoplasm of the bile duct(IPNB),distant metastasis remains unexplained especially in cases of carcinoma in situ.In the present study,we report...BACKGROUND Despite an expanding number of studies on intraductal papillary neoplasm of the bile duct(IPNB),distant metastasis remains unexplained especially in cases of carcinoma in situ.In the present study,we report a rare and interesting case of IPNB without invasive components that later metastasized to lungs and brain.CASE SUMMARY A 69-year-old male was referred to our hospital due to suspected cholangiocarcinoma.Laboratory tests on admission reported a mild elevation of alkaline phosphatase,γ-glutamyl transpeptidase,and total bilirubin in serum.Endoscopic retrograde cholangiography revealed a filling defect in the common bile duct(CBD)extending to the left hepatic duct.Peroral cholangioscopy delineated a tumor in the CBD that had a papillary pattern.Multidetector computed tomography and magnetic resonance cholangiopancreatography detected partial blockage ot interlude in the CBD leading to cholestasis without evidence of metastasis.Therefore,a diagnosis of IPNB cT1N0M0 was established.Left hepatectomy with bile duct reconstruction was performed.Pathological examination confirmed an intraepithelial neoplasia pattern without an invasive component and an R0 resection achievement.The patient was monitored carefully by regular examinations.However,at 32 mo after the operation,a 26 mm tumor in the lungs and a 12 mm lesion in the brain were detected following a suspicious elevated CA 19-9 level.Video-assisted thoracoscopic surgery of left upper lobectomy and stereotactic radiotherapy are indicated.In addition to histopathological results,a genomic profiling analysis using whole exome sequencing subsequently confirmed lung metastasis originating from bile duct cancer.CONCLUSION This case highlights the important role of genomic profiling analysis using whole exome sequencing in identifying the origin of metastasis in patients with IPNB.展开更多
BACKGROUND Most cases of Apert syndrome(AS)are found after birth.Cases of AS diagnosed by ultrasound combined with magnetic resonance imaging(MRI)and whole exome sequencing(WES)during pregnancy are rare.CASE SUMMARY W...BACKGROUND Most cases of Apert syndrome(AS)are found after birth.Cases of AS diagnosed by ultrasound combined with magnetic resonance imaging(MRI)and whole exome sequencing(WES)during pregnancy are rare.CASE SUMMARY We present the case of a 34-year old female patient(gravida 2,para 1)whose fetus was diagnosed with AS during pregnancy.Fetal ultrasound performed at 30,2/7 wk of pregnancy showed abnormalities.MRI and three-dimensional ultrasound performed at 31,1/7 wk of pregnancy showed the possibility of AS.Chromosome examination and core family WES were conducted at 31,5/7 wk of pregnancy.The results showed that FGFR2 in the fetus had a c.755C>G missense mutation in its nucleotide,and AS was confirmed.CONCLUSION This case highlights the importance of imaging examinations.Prenatal ultrasound combined with MRI can identify fetal morphological abnormalities accurately,which can be confirmed by WES.展开更多
AIM： To identify the potentially pathogenic gene variants that contributes to the etiology of strabismus. METHODS： A Chinese pedigree with strabismus was collected and the exomes of two affected individuals were se...AIM： To identify the potentially pathogenic gene variants that contributes to the etiology of strabismus. METHODS： A Chinese pedigree with strabismus was collected and the exomes of two affected individuals were sequenced using the next-generation sequencing technology. The resulting variants from exome sequencing were filtered by subsequent bioinformatics methods and the candidate mutation was verified as heterozygous in the affected proposita and her mother by sanger sequencing. RESULTS： Whole exome sequencing and filtering identified a nonsynonymous mutation Co434G-T transition in paired box 3 （PAX3） in the two affected individuals, which were predicted to be deleterious by more than 4 bioinformatics programs. This altered amino acid residue was located in the conserved PAX domain of PAX3. This gene encodes a member of the PAX family of transcription factors, which play critical roles during fetal development. Mutations in PAX3 were associated with Waardenburg syndrome with strabismus. CONCLUSION： Our results report that the c.434G-T mutation （p.R145L） in PAX3 may contribute to strabismus, expanding our understanding of the causally relevant genes for this disorder.展开更多
Summary:Non-Herlitz junctional epidermolysis bullosa(JEB-nH),an autosomal recessive bullous genodermatosis,is characterized by generalized skin blistering from birth onward,dental anomalies,universal alopecia and nail...Summary:Non-Herlitz junctional epidermolysis bullosa(JEB-nH),an autosomal recessive bullous genodermatosis,is characterized by generalized skin blistering from birth onward,dental anomalies,universal alopecia and nail dystrophy.The underlying defect is mutation of the COLI7AI gene encoding the type XVⅡcollagen,resulting in losing structure for attachment of basal epithelial cells to the matrix.In present study,we described one case of congenitally affected female child aged 10 years,with skin blistering.Dermatologic examination revealed sparse,mild blisters on the face and hand,with profound enamel pitting of the teeth.Skin biopsy from proband's bullous skin displayed subepidermal bulla formation without acantholysis.The immunofluorescence of anti-type XVⅡcollagen antibody staining showed loss of type XVⅡcollagen staining at the basement membrane zone.A combination of whole exome sequencing(WES)and Sanger sequencing revealed the novel heterozygous mutations(C.4324C>T;p.Q1442^*and C.I 834G>C;p.G612R)in COLI7AI gene,which could be associated with the observed JEB-nH.One allele had a novel nonsense mutation(c.4324C>T;p.Q1442^*),resulting in nonsense-mediated mRNA decay and truncated collagen XVⅡ;the other allelc had a novel misscnse mutation of c.1834G>C;p.G612R in exon 22,causing a glycine-to-arginine substitution in the Gly-X-Y triple helical repeating motifs and decreasing the thermal stability of collagen XVⅡ.Our findings indicate that the genetic test based on WES can be useful in diagnosing JEB-nH patients.The novel pathogenic mutations identified would further expand our understanding of the mutation spectrum of COLI7AI gene in association with the inherited blistering diseases.展开更多
Some patients with chronic hepatitis B virus(HBV)infection failed to clear HBV,even persistently continue to produce antibodies to HBV.Here we performed a two stage genome wide association study in a cohort of Chinese...Some patients with chronic hepatitis B virus(HBV)infection failed to clear HBV,even persistently continue to produce antibodies to HBV.Here we performed a two stage genome wide association study in a cohort of Chinese patients designed to discover single nucleotide variants that associate with HBV infection and clearance of HBV.The first stage involved genome wide exome sequencing of 101 cases(HBsAg plus anti-HBs positive)compared with 102 control patients(antiHBs positive,HBsAg negative).Over 80%of individual sequences displayed 209 sequence coverage.Adapters,uncertain bases[10%or low-quality base calls([50%)were filtered and compared to the human reference genome hg19.In the second stage,579 chronic HBV infected cases and 439 HBV clearance controls were sequenced with selected genes from the first stage.Although there were no significant associated gene variants in the first stage,two significant gene associations were discovered when the two stages were assessed in a combined analysis.One association showed rs506121-“T”allele[within the dedicator of cytokinesis 8(DOCK8)gene]was higher in chronic HBV infection group than that in clearance group(P=0.002,OR=0.77,95%CI[0.65,0.91]).The second association involved rs2071676—A allele within the Carbonic anhydrase(CA9)gene that was significantly elevated in chronic HBV infection group compared to the clearance group(P=0.0003,OR=1.35,95%CI[1.15,1.58]).Upon replication these gene associations would suggest the influence of DOCK8 and CA9 as potential risk genetic factors in the persistence of HBV infection.展开更多
BACKGROUND The DYNC1H1 gene encodes a part of the dynamic protein,and the protein mutations may further affect the growth and development of neurons,resulting in degeneration of anterior horn cells of the spinal cord,...BACKGROUND The DYNC1H1 gene encodes a part of the dynamic protein,and the protein mutations may further affect the growth and development of neurons,resulting in degeneration of anterior horn cells of the spinal cord,and a variety of clinical phenotypes finally resulting in axonal Charcot-Marie-Tooth disease type 20(CMT20),mental retardation 13(MRD13)and spinal muscular atrophy with lower extremity predominant 1(SMA-LED).The incidence of the disease is low,and it is difficult to diagnose,especially in children.Here,we report a case of DYNC1H1 gene mutation and review the related literature to improve the pediatrician’s understanding of DYNC1H1 gene-related disease to make an early correct diagnosis and provide better services for children.CASE SUMMARY A 4-mo-old Chinese female child with adducted thumbs,high arch feet,and epileptic seizure presented slow response,delayed development,and low limb muscle strength.Electroencephalogram showed abnormal waves,a large number of multifocal sharp waves,sharp slow waves,and multiple spasms with a series of attacks.High-throughput sequencing and Sanger sequencing identified a heterozygous mutation,c.5885 G>A(p.R1962H),in the DYNC1H1 gene(NM 001376)of the proband,which was not identified in her parents.Combined with the clinical manifestations and pedigree of this family,this mutation is likely pathogenic based on the American Academy of Medical Genetics and Genomics guidelines.The child was followed when she was 1 year and 2 mo old.The magnetic resonance imaging result was consistent with the findings of white matter myelinated dysplasia and congenital giant gyrus.The extensive neurogenic damage to the extremities was considered,as the results of electromyography showed that the motor conduction velocity and sensory conduction of the nerves of the extremities were not abnormal,and the degree of fit of the children with severe contraction was poor.At present,the child is 80 cm in length and 9 kg in weight,with slender limbs and low muscle strength,and still does not raise her head.She cannot sit or speak.Speech,motor,and mental development was significantly delayed.There is still no effective treatment for this disease.CONCLUSION We herein report a de novo variant of DYNC1H1 gene,c.5885 G>A(p.R1962H),leading to overlapping phenotypes(seizure,general growth retardation,and muscle weakness)of CMT20,MRD13,and SMA-LED,but there is no effective treatment for such condition.Our case enriches the DYNC1H1 gene mutation spectrum and provides an important basis for clinical diagnosis and treatment and genetic counseling.展开更多
BACKGROUND Chronic intestinal pseudo-obstruction(CIPO)is a syndrome of intestinal motor dysfunction caused by intestinal nerve,muscle,and/or Cajal stromal cell lesions.CIPO is a serious category of gastrointestinal dy...BACKGROUND Chronic intestinal pseudo-obstruction(CIPO)is a syndrome of intestinal motor dysfunction caused by intestinal nerve,muscle,and/or Cajal stromal cell lesions.CIPO is a serious category of gastrointestinal dynamic dysfunction,which can eventually lead to the death of patients with intestinal failure.Due to considerable phenotypic heterogeneity,the estimated incidence of CIPO is 1/476190 and 1/416666 in men and women,respectively.According to the etiology,CIPO can be divided into idiopathic and secondary,of which the latter is the most common,often secondary to tumor,virus infection,connective tissue disease,neurological diseases,and endocrine diseases.Idiopathic CIPO in the intestinal tract is divided into visceral myopathy,neuropathy,and stromal cell lesions according to the location.Surgery is usually not recommended for CIPO,because it often does not benefit patients with CIPO,and postoperative intestinal obstruction is likely to occur,which may even worsen the condition.CASE SUMMARY Here,we describe the case of a 43-year-old male Han Chinese patient with a 15-year history of recurrent abdominal distention with no clear cause.The results of physical,biochemical,and other relevant examinations showed no clear abnormalities.Contrast-enhanced computed tomography(CT)indicated a large duodenum,clear expansion of the intestinal lumen,and CIPO.Whole exome sequencing(WES)of the patient and his mother confirmed the diagnosis of primary familial visceral myopathy type 2 chronic pseudoileus with a rare heterozygous gene mutation in MYH11.This is the second reported case of CIPO with a heterozygous MYH11[NM_001040113.1:c.5819delC(p.Pro1940Hisfs*91)]mutation.CONCLUSION This case report indicates that physicians can perform routine clinical examinations,CT,and WES to achieve a diagnosis and treatment of CIPO in early disease stages.展开更多
Precision medicine is defined by the administration of drugs based on the tumor's particular genetic characteristics. It is developing quickly in the field of cancer therapy. For example, KRAS, NRAS and BRAF genet...Precision medicine is defined by the administration of drugs based on the tumor's particular genetic characteristics. It is developing quickly in the field of cancer therapy. For example, KRAS, NRAS and BRAF genetic testing demonstrates its efficiency for precision medicine in colorectal cancer(CRC). Besides for these well-known mutations, the purpose of performing larger genetic testing in this pathology is unknown. Recent reports have shown that using the poly ADP ribose polymerase(PARP) inhibitor olaparib in patients with homologous repair enzyme deficiency gave positive clinical results in breast, ovarian and prostate cancers. We have reported here the cases of 2 patients with multi-treated metastatic CRC who underwent somatic and constitutional exome analyses. The analyses revealed a loss of function mutation in a homologous repair enzyme resulting in the loss of heterozygosity for both patients(Check2 for the first patient and RAD51 C for the second one). Both patients were treated with off-label usage of olaparib. While the first patient showed clinical benefit, reduction of carcinoembryonic antigen tumor marker and radiologic response, the second patient quickly presented a progression of the tumor. Additional genetic analyses revealed a frameshift truncating mutation of the TP53BP1 gene in the patient who progressed. Interestingly, deficiency in TP53BP1 was previously described to confer resistance to olaparib in mice breast cancer models. Our findings suggest that exome analysis may be a helpful tool to highlight targetable mutations in CRC and that olaparib may be efficient in patients with a homologous repair deficiency.展开更多
基金Supported by the National Oncology Care Support Program,No.25000.056766/2015-64.
文摘BACKGROUND Adenomatous polyposis confers an increased risk of developing colorectal cancer.APC and MUTYH are the major genes investigated in patients suspected of having polyposis.In addition to APC and MUTYH genes,other genes,such as POLE,POLD1,NTHL1,MBD4,MSH3 and MLH3,have recently been associated with polyposis phenotypes,conferring heterogeneity in terms of the clinical,etiological and heritable aspects of patients with polyposis.AIM To investigate the underlying variant landscape in patients with suspected polyposis who lack variants in the APC and MUTYH genes using whole-exome sequencing.METHODS Twenty-seven participants were included in the study and subjected to germline whole-exome sequencing.In addition,their clinical-pathological,personal,and family history data were collected.RESULTS The mean age at diagnosis was 51 years,and most participants had attenuated forms of polyposis(88.9%),with 63.0%diagnosed with a primary tumor,mostly colorectal cancer(76.5%).Among the variants identified,17 were classified as pathogenic or likely pathogenic(in 12 participants),including variants in genes involved in the Wnt/β-catenin signaling pathway,such as ST7 L,A1CF,and DKK4,and variants in DNA-repair genes,such as NTHL1,PNKP,and PMS2,as well as a variant found at the FRK gene identified in a patient with classic polyposis at age 19 and with a family history of polyps.CONCLUSION This study identified novel genes potentially associated with polyposis in patients lacking germline pathogenic variants in the APC and MUTYH genes.These findings support the use of next-generation sequencing for screening,expanding the scope of polyposis-related variants beyond these two genes.
基金Supported by Taif University,Taif,Saudi Arabia(TU-DSPP-2024-05).
文摘AIM:To identify the genetic factors underlying anophthalmia and microphthalmia(A/M),and to perform computational analysis to verify the pathophysiological mechanisms of the disease.METHODS:This study investigated a consanguineous Pakistani family with multiple affected individuals.Clinical evaluations were conducted using A-Scan and ophthalmic B-Scan ultrasonography(B-Scan).To identify the diseasecausing variant,whole exome sequencing(WES)and Sanger sequencing were performed.In silico functional analyses were carried out using AlphaFold(for protein modeling)and ClusPro(for protein docking analysis)tools,and the hydrodynamic properties of the protein were determined via molecular dynamics simulations.RESULTS:Clinical analysis of the five patients revealed severe phenotypes of bilateral anophthalmia.Ocular B-Scan did not detect ocular tissue or intraocular fluid,thus confirming the diagnosis of anophthalmia in all patients.Due to these structural defects,all patients exhibited complete blindness and absence of light perception;additionally,two patients had mild to moderate intellectual disability.Genetic analysis identified a splice site variant[NM_000693.2:c.884-2_885dup;p.(Asp296SerfsTer35)]in the 9^(th)exon of the ALDH1A3 gene.CONCLUSION:The present study expands the genetic spectrum of ALDH1A3 and contributes to establishing the genotype-phenotype correlation for this gene.
基金Supported by National Key Research and Development Program of China,No.2022YFC2703302.
文摘BACKGROUND Floating-harbor syndrome(FHS)is a rare genetic disorder caused by pathogenic variants in the SRCAP gene.Most individuals with FHS have short stature,delayed speech and language development,and dysmorphic facial features.However,the patients with FHS are not easy to diagnose due to the overlap of clinical phenotypes with other disorders.CASE SUMMARY We reported a 10-year-old boy who presented with severe short stature,developmental delay and distinctive facial features.Exome sequencing was provided for the proband and his parents.We identified a novel frameshift variant c.7235delinsGT(p.Thr2412fs)in SRCAP gene,and the variant was further validated by Sanger sequencing.The mother of the proband was referred to us for prenatal consultation during next pregnancy.We performed prenatal genetic diagnosis for the fetus.The result of Sanger sequencing for c.7235delinsGT(p.Thr2412fs)in SRCAP gene showed that the fetus did not carry the variant,so the fetus has been born successfully.The newborn does not show any similar symptom to the proband till one month.CONCLUSION This case confirms that the c.7235delinsGT(p.Thr2412fs)variant in the SRCAP gene is associated with FHS and expands the spectrum of SRCAP variants.
文摘The study by Dos Santos et al marks a significant advancement in understanding the genetics of colorectal polyposis,particularly within the underrepresented Brazilian population.Utilizing whole-exome sequencing in 27 patients with unexplained polyposis,the researchers identified 16 candidate genes in 44.4%of cases-an impressive outcome given strict exclusion criteria.Many identified variants were linked to the Wnt/β-catenin signaling pathway,reinforcing their biological relevance.However,the study underscores key challenges in genomic medicine,especially the gap between gene discovery and clinical application.A substantial proportion of variants(60.1%)were classified as of uncertain sig-nificance,and the absence of functional validation or segregation analysis limits clinical interpretation.Notably,the potential for oligogenic inheritance com-plicates traditional monogenic models of hereditary cancer risk.The study’s focus on a genetically diverse Brazilian cohort emphasizes the need for population-specific genomic resources and interpretation guidelines.Moving forward,func-tional studies,including organoid models,loss-of-heterozygosity analyses,and genotype-phenotype correlations,are essential to validate findings.Clinically,discovering novel candidate genes may inform future screening and testing pro-tocols,though careful consideration is needed to manage uncertain results.Overall,the study represents a critical step in polyposis genetics,highlighting both progress made and the work still required for clinical translation.
基金supported by the National Natural Science Foundation of China[Grant No.62206185]。
文摘Objective To establish and validate a novel diabetic retinopathy(DR)risk-prediction model using a whole-exome sequencing(WES)-based machine learning(ML)method.Methods WES was performed to identify potential single nucleotide polymorphism(SNP)or mutation sites in a DR pedigree comprising 10 members.A prediction model was established and validated in a cohort of 420 type 2 diabetic patients based on both genetic and demographic features.The contribution of each feature was assessed using Shapley Additive explanation analysis.The efficacies of the models with and without SNP were compared.Results WES revealed that seven SNPs/mutations(rs116911833 in TRIM7,1997T>C in LRBA,1643T>C in PRMT10,rs117858678 in C9orf152,rs201922794 in CLDN25,rs146694895 in SH3GLB2,and rs201407189 in FANCC)were associated with DR.Notably,the model including rs146694895 and rs201407189 achieved better performance in predicting DR(accuracy:80.2%;sensitivity:83.3%;specificity:76.7%;area under the receiver operating characteristic curve[AUC]:80.0%)than the model without these SNPs(accuracy:79.4%;sensitivity:80.3%;specificity:78.3%;AUC:79.3%).Conclusion Novel SNP sites associated with DR were identified in the DR pedigree.Inclusion of rs146694895 and rs201407189 significantly enhanced the performance of the ML-based DR prediction model.
文摘Inflammatory bowel disease(IBD)is a group of chronic disorders that cause relapsing inflammation in the gastrointestinal tract(GIT).It results either from gene-environment interactions or as a monogenic disease resulting from pa-thogenic mutations causing impairment in the protective mechanism of the GIT.Around 10%-15%of patients with very early onset IBDs may have an underlying monogenic condition.Monogenic IBD is very different from complex forms of polygenic IBD in the underlying molecular basis of uncontrolled intestinal inflam-mation,age of onset,extraintestinal comorbidities as well as treatment modality.An in-depth understanding of this distinct form of IBD is essential for deciding an appropriate therapeutic approach as well as prognostication.In this review,we aim to discuss about the epidemiology,clinical presentation,diagnostic approach,therapeutic challenges and latest advances in patients with monogenic IBD.
基金support in this study.This work was supported by the National Natural Science Foundation of China(82271889,82172105)the National Key Research and Development Program of China(2021YFC2701000)Shanghai Natural Science Foundation(23ZR1409400,24ZR1409400).
文摘Craniofacial microsomia(CFM)is a congenital malformation with maxillary and/or mandibular hypoplasia,skin tags,and ear malformations(Luo et al.,2023).Microtia,in its mildest form,can occur alone(Quiat et al.,2023).With a prevalence of 3.8/100,000(Barisic et al.,2014),CFM is the second most common congenital craniofacial abnormality(Li et al.,2022;Luo et al.,2023).Most cases are sporadic,but familial ones suggest autosomal dominant(AD)or autosomal recessive(AR)(Beleza-Meireles et al.,2014).In 2023,Quiat et al.and Mao et al.successively identified FOXI3 variants in 16 pedigrees and 10 sporadic cases,respectively,accounting for 3.1%of CFM cases(Mao et al.,2023;Quiat et al.,2023).FOX/3 has surpassed SF3B2 as the most frequently identified pathogenic gene for CFM to date(Timberlake et al.,2021;Mao et al.,2023;Quiat et al.,2023).In this study,we performed whole-exome sequencing(WES)on 201 CFM pedigrees and detected FOX/3 variants in 8 AD-inherited pedigrees with 24 patients and 28 unaffected individuals(Fig.1A).
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.
基金the Human Resources Development Program for the Outstanding Talents in The Fifth People’s Hospital of Shanghai,Fudan University,No.2017WYRCJY09the Key Medical Speciality of The Fifth People’s Hospital of Shanghai,Fudan University,No.2017WY202K08
文摘BACKGROUND Different histological growth patterns(HGPs)of colorectal carcinoma(CRC)liver metastasis are associated with patients’prognosis and response to antiangiogenic therapy.However,the relationship between HGPs of liver metastasis and clinicopathological and genomic characteristics of primary cancer has not been well established.AIM To assess whether certain clinicopathological and genomic features of primary CRC could predict the HGPs of liver metastasis.METHODS A total of 29 patients with paired resections of both primary CRC and liver metastasis were divided into two groups:A(15 cases with desmoplastic liver metastasis)and B(14 cases with replacement liver metastasis).Clinical information was obtained from patients’charts.Mismatch repair proteins,BRAFV600E,and PD-L1 were evaluated by immunohistochemistry.Five cases were selected randomly from each group for whole exome sequencing(WES)analysis.RESULTS In the primary tumor,expanding growth pattern,low tumor budding score(TBS),and Crohn’s disease-like response(CDR)were associated with desmoplastic liver metastasis and better overall survival,whereas infiltrating growth pattern alone of primary carcinoma could predict the replacement liver metastasis and worse overall survival(P<0.05).On WES analysis,primary carcinoma with desmoplastic liver metastasis showed mutations in APC(4/5);TP53(3/5);KRAS,PIK3CA,and FAT4(2/5);BRCA-1,BRCA2,BRAF,and DNAH5(1/5),whereas primary carcinoma with replacement liver metastasis showed mutations in APC and TP53(3/5);KRAS,FAT4,DNH5,SMAD,ERBB2,ERBB3,LRP1,and SDK1(1/5).CONCLUSION The HGPs,TBS,and CDR of primary CRC as well as the presence of specific genetic mutations such as those in PIK3CA could be used to predict the HGPs of liver metastasis,response to therapy,and patients’prognosis.
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Supported by The Children’s Cardiomyopathy FoundationCincinnati Children’s Hospital’s Clinical and Translational Science Award,No.NIH-ULl RR026314(Ware SM)and AHA Postdoctoral Fellowship Award,No.12POST10370002(Tariq M)
文摘Pediatric cardiomyopathies are clinically heterogeneous heart muscle disorders that are responsible for significant morbidity and mortality. Phenotypes include hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy, left ventricular noncompaction and arrhythmogenic right ventricular cardiomyopathy. There is substantial evidence for a genetic contribution to pediatric cardiomyopathy. To date, more than 100 genes have been implicated in cardiomyopathy, but comprehensive genetic diagnosis has been problematic because of the large number of genes, the private nature of mutations, and difficulties in interpreting novel rare variants. This review will focus on current knowledge on the genetic etiologies of pediatric cardiomyopathy and their diagnostic relevance in clinical settings. Recent developments in sequencing technologies are greatly impacting the pace of gene discovery and clinical diagnosis. Understanding the genetic basis for pediatric cardiomyopathy and establishing genotypephenotype correlations may help delineate the molecular and cellular events necessary to identify potential novel therapeutic targets for heart muscle dysfunction in children.
基金funded in part by the Beijing Natural Science Foundation(JQ20032 to N.W.and to 7191007 to Z.W.)National Natural Science Foundation of China(81822030 and 82072391 to N.W.,81772299and 81930068 to Z.W.,81772301 and 81972132 to G.Q.,81672123and 81972037 to J.Z.)+7 种基金Capital's Funds for Health Improvement and Research(2020-4-40114 to N.W.)Tsinghua University-Peking Union Medical College Hospital Initiative Scientific Research ProgramNational Key Research and Development Program of China(2018YFC0910500 to N.W.and Z.W.,2016YFC0901501 to S.Z.)the PUMC Youth Fund and the Fundamental Research Funds for the Central Universities(3332019052 to Y.M.)the CAMS Initiative Fund for Medical Sciences(2016-I2M-3-003 to G.Q.and N.W.,2016-I2M-2-006 and 2017-I2M-2-001 to Z.W.)the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2019PT320025 to N.W.)sponsored by GeneScience Pharmaceuticals Co.,Ltd.(Changchun,China)funded by the United States National Institutes of Health(UM1HG006542 and K08 HG008986)。
文摘Short stature is among the most common endocrinological disease phenotypes of childhood and may occur as an isolated finding or in conjunction with other clinical manifestations.Although the diagnostic utility of clinical genetic testing in short stature has been implicated,the genetic architecture and the utility of genomic studies such as exome sequencing(ES)in a sizable cohort of patients with short stature have not been investigated systematically.In this study,we recruited 561 individuals with short stature from two centers in China during a 4-year period.We performed ES for all patients and available parents.All patients were retrospectively divided into two groups:an isolated short stature group(group I,n=257)and an apparently syndromic short stature group(group II,n=304).Causal variants were identified in 135 of 561(24.1%)patients.In group I,29 of 257(11.3%)of the patients were solved by variants in 24 genes.In group II,106 of 304(34.9%)patients were solved by variants in 57 genes.Genes involved in fundamental cellularprocess played an important role in the genetic architecture of syndromic short stature.Distinct genetic architectures and pathophysiological processes underlie isolated and syndromic short stature.
文摘BACKGROUND Despite an expanding number of studies on intraductal papillary neoplasm of the bile duct(IPNB),distant metastasis remains unexplained especially in cases of carcinoma in situ.In the present study,we report a rare and interesting case of IPNB without invasive components that later metastasized to lungs and brain.CASE SUMMARY A 69-year-old male was referred to our hospital due to suspected cholangiocarcinoma.Laboratory tests on admission reported a mild elevation of alkaline phosphatase,γ-glutamyl transpeptidase,and total bilirubin in serum.Endoscopic retrograde cholangiography revealed a filling defect in the common bile duct(CBD)extending to the left hepatic duct.Peroral cholangioscopy delineated a tumor in the CBD that had a papillary pattern.Multidetector computed tomography and magnetic resonance cholangiopancreatography detected partial blockage ot interlude in the CBD leading to cholestasis without evidence of metastasis.Therefore,a diagnosis of IPNB cT1N0M0 was established.Left hepatectomy with bile duct reconstruction was performed.Pathological examination confirmed an intraepithelial neoplasia pattern without an invasive component and an R0 resection achievement.The patient was monitored carefully by regular examinations.However,at 32 mo after the operation,a 26 mm tumor in the lungs and a 12 mm lesion in the brain were detected following a suspicious elevated CA 19-9 level.Video-assisted thoracoscopic surgery of left upper lobectomy and stereotactic radiotherapy are indicated.In addition to histopathological results,a genomic profiling analysis using whole exome sequencing subsequently confirmed lung metastasis originating from bile duct cancer.CONCLUSION This case highlights the important role of genomic profiling analysis using whole exome sequencing in identifying the origin of metastasis in patients with IPNB.
文摘BACKGROUND Most cases of Apert syndrome(AS)are found after birth.Cases of AS diagnosed by ultrasound combined with magnetic resonance imaging(MRI)and whole exome sequencing(WES)during pregnancy are rare.CASE SUMMARY We present the case of a 34-year old female patient(gravida 2,para 1)whose fetus was diagnosed with AS during pregnancy.Fetal ultrasound performed at 30,2/7 wk of pregnancy showed abnormalities.MRI and three-dimensional ultrasound performed at 31,1/7 wk of pregnancy showed the possibility of AS.Chromosome examination and core family WES were conducted at 31,5/7 wk of pregnancy.The results showed that FGFR2 in the fetus had a c.755C>G missense mutation in its nucleotide,and AS was confirmed.CONCLUSION This case highlights the importance of imaging examinations.Prenatal ultrasound combined with MRI can identify fetal morphological abnormalities accurately,which can be confirmed by WES.
文摘AIM： To identify the potentially pathogenic gene variants that contributes to the etiology of strabismus. METHODS： A Chinese pedigree with strabismus was collected and the exomes of two affected individuals were sequenced using the next-generation sequencing technology. The resulting variants from exome sequencing were filtered by subsequent bioinformatics methods and the candidate mutation was verified as heterozygous in the affected proposita and her mother by sanger sequencing. RESULTS： Whole exome sequencing and filtering identified a nonsynonymous mutation Co434G-T transition in paired box 3 （PAX3） in the two affected individuals, which were predicted to be deleterious by more than 4 bioinformatics programs. This altered amino acid residue was located in the conserved PAX domain of PAX3. This gene encodes a member of the PAX family of transcription factors, which play critical roles during fetal development. Mutations in PAX3 were associated with Waardenburg syndrome with strabismus. CONCLUSION： Our results report that the c.434G-T mutation （p.R145L） in PAX3 may contribute to strabismus, expanding our understanding of the causally relevant genes for this disorder.
基金This work was supported by the National Natural Science Foundation of China(No.81700032).
文摘Summary:Non-Herlitz junctional epidermolysis bullosa(JEB-nH),an autosomal recessive bullous genodermatosis,is characterized by generalized skin blistering from birth onward,dental anomalies,universal alopecia and nail dystrophy.The underlying defect is mutation of the COLI7AI gene encoding the type XVⅡcollagen,resulting in losing structure for attachment of basal epithelial cells to the matrix.In present study,we described one case of congenitally affected female child aged 10 years,with skin blistering.Dermatologic examination revealed sparse,mild blisters on the face and hand,with profound enamel pitting of the teeth.Skin biopsy from proband's bullous skin displayed subepidermal bulla formation without acantholysis.The immunofluorescence of anti-type XVⅡcollagen antibody staining showed loss of type XVⅡcollagen staining at the basement membrane zone.A combination of whole exome sequencing(WES)and Sanger sequencing revealed the novel heterozygous mutations(C.4324C>T;p.Q1442^*and C.I 834G>C;p.G612R)in COLI7AI gene,which could be associated with the observed JEB-nH.One allele had a novel nonsense mutation(c.4324C>T;p.Q1442^*),resulting in nonsense-mediated mRNA decay and truncated collagen XVⅡ;the other allelc had a novel misscnse mutation of c.1834G>C;p.G612R in exon 22,causing a glycine-to-arginine substitution in the Gly-X-Y triple helical repeating motifs and decreasing the thermal stability of collagen XVⅡ.Our findings indicate that the genetic test based on WES can be useful in diagnosing JEB-nH patients.The novel pathogenic mutations identified would further expand our understanding of the mutation spectrum of COLI7AI gene in association with the inherited blistering diseases.
基金supported by grant from the International Science&Technology Cooperation Program of China(No.2014DFR31200)the National Infrastructure of Chinese Genetic Resources(YCZYPT[2017]01-6)+1 种基金federal funds from the National Cancer Institute,National Institutes of Health,USA(No.N01-CO12400)the National Natural Science Foundation of China(No.30671855)。
文摘Some patients with chronic hepatitis B virus(HBV)infection failed to clear HBV,even persistently continue to produce antibodies to HBV.Here we performed a two stage genome wide association study in a cohort of Chinese patients designed to discover single nucleotide variants that associate with HBV infection and clearance of HBV.The first stage involved genome wide exome sequencing of 101 cases(HBsAg plus anti-HBs positive)compared with 102 control patients(antiHBs positive,HBsAg negative).Over 80%of individual sequences displayed 209 sequence coverage.Adapters,uncertain bases[10%or low-quality base calls([50%)were filtered and compared to the human reference genome hg19.In the second stage,579 chronic HBV infected cases and 439 HBV clearance controls were sequenced with selected genes from the first stage.Although there were no significant associated gene variants in the first stage,two significant gene associations were discovered when the two stages were assessed in a combined analysis.One association showed rs506121-“T”allele[within the dedicator of cytokinesis 8(DOCK8)gene]was higher in chronic HBV infection group than that in clearance group(P=0.002,OR=0.77,95%CI[0.65,0.91]).The second association involved rs2071676—A allele within the Carbonic anhydrase(CA9)gene that was significantly elevated in chronic HBV infection group compared to the clearance group(P=0.0003,OR=1.35,95%CI[1.15,1.58]).Upon replication these gene associations would suggest the influence of DOCK8 and CA9 as potential risk genetic factors in the persistence of HBV infection.
基金Supported by Jinan Science and Technology Project,No.201805014。
文摘BACKGROUND The DYNC1H1 gene encodes a part of the dynamic protein,and the protein mutations may further affect the growth and development of neurons,resulting in degeneration of anterior horn cells of the spinal cord,and a variety of clinical phenotypes finally resulting in axonal Charcot-Marie-Tooth disease type 20(CMT20),mental retardation 13(MRD13)and spinal muscular atrophy with lower extremity predominant 1(SMA-LED).The incidence of the disease is low,and it is difficult to diagnose,especially in children.Here,we report a case of DYNC1H1 gene mutation and review the related literature to improve the pediatrician’s understanding of DYNC1H1 gene-related disease to make an early correct diagnosis and provide better services for children.CASE SUMMARY A 4-mo-old Chinese female child with adducted thumbs,high arch feet,and epileptic seizure presented slow response,delayed development,and low limb muscle strength.Electroencephalogram showed abnormal waves,a large number of multifocal sharp waves,sharp slow waves,and multiple spasms with a series of attacks.High-throughput sequencing and Sanger sequencing identified a heterozygous mutation,c.5885 G>A(p.R1962H),in the DYNC1H1 gene(NM 001376)of the proband,which was not identified in her parents.Combined with the clinical manifestations and pedigree of this family,this mutation is likely pathogenic based on the American Academy of Medical Genetics and Genomics guidelines.The child was followed when she was 1 year and 2 mo old.The magnetic resonance imaging result was consistent with the findings of white matter myelinated dysplasia and congenital giant gyrus.The extensive neurogenic damage to the extremities was considered,as the results of electromyography showed that the motor conduction velocity and sensory conduction of the nerves of the extremities were not abnormal,and the degree of fit of the children with severe contraction was poor.At present,the child is 80 cm in length and 9 kg in weight,with slender limbs and low muscle strength,and still does not raise her head.She cannot sit or speak.Speech,motor,and mental development was significantly delayed.There is still no effective treatment for this disease.CONCLUSION We herein report a de novo variant of DYNC1H1 gene,c.5885 G>A(p.R1962H),leading to overlapping phenotypes(seizure,general growth retardation,and muscle weakness)of CMT20,MRD13,and SMA-LED,but there is no effective treatment for such condition.Our case enriches the DYNC1H1 gene mutation spectrum and provides an important basis for clinical diagnosis and treatment and genetic counseling.
文摘BACKGROUND Chronic intestinal pseudo-obstruction(CIPO)is a syndrome of intestinal motor dysfunction caused by intestinal nerve,muscle,and/or Cajal stromal cell lesions.CIPO is a serious category of gastrointestinal dynamic dysfunction,which can eventually lead to the death of patients with intestinal failure.Due to considerable phenotypic heterogeneity,the estimated incidence of CIPO is 1/476190 and 1/416666 in men and women,respectively.According to the etiology,CIPO can be divided into idiopathic and secondary,of which the latter is the most common,often secondary to tumor,virus infection,connective tissue disease,neurological diseases,and endocrine diseases.Idiopathic CIPO in the intestinal tract is divided into visceral myopathy,neuropathy,and stromal cell lesions according to the location.Surgery is usually not recommended for CIPO,because it often does not benefit patients with CIPO,and postoperative intestinal obstruction is likely to occur,which may even worsen the condition.CASE SUMMARY Here,we describe the case of a 43-year-old male Han Chinese patient with a 15-year history of recurrent abdominal distention with no clear cause.The results of physical,biochemical,and other relevant examinations showed no clear abnormalities.Contrast-enhanced computed tomography(CT)indicated a large duodenum,clear expansion of the intestinal lumen,and CIPO.Whole exome sequencing(WES)of the patient and his mother confirmed the diagnosis of primary familial visceral myopathy type 2 chronic pseudoileus with a rare heterozygous gene mutation in MYH11.This is the second reported case of CIPO with a heterozygous MYH11[NM_001040113.1:c.5819delC(p.Pro1940Hisfs*91)]mutation.CONCLUSION This case report indicates that physicians can perform routine clinical examinations,CT,and WES to achieve a diagnosis and treatment of CIPO in early disease stages.
文摘Precision medicine is defined by the administration of drugs based on the tumor's particular genetic characteristics. It is developing quickly in the field of cancer therapy. For example, KRAS, NRAS and BRAF genetic testing demonstrates its efficiency for precision medicine in colorectal cancer(CRC). Besides for these well-known mutations, the purpose of performing larger genetic testing in this pathology is unknown. Recent reports have shown that using the poly ADP ribose polymerase(PARP) inhibitor olaparib in patients with homologous repair enzyme deficiency gave positive clinical results in breast, ovarian and prostate cancers. We have reported here the cases of 2 patients with multi-treated metastatic CRC who underwent somatic and constitutional exome analyses. The analyses revealed a loss of function mutation in a homologous repair enzyme resulting in the loss of heterozygosity for both patients(Check2 for the first patient and RAD51 C for the second one). Both patients were treated with off-label usage of olaparib. While the first patient showed clinical benefit, reduction of carcinoembryonic antigen tumor marker and radiologic response, the second patient quickly presented a progression of the tumor. Additional genetic analyses revealed a frameshift truncating mutation of the TP53BP1 gene in the patient who progressed. Interestingly, deficiency in TP53BP1 was previously described to confer resistance to olaparib in mice breast cancer models. Our findings suggest that exome analysis may be a helpful tool to highlight targetable mutations in CRC and that olaparib may be efficient in patients with a homologous repair deficiency.
