AIM: To discover the molecular pathogenic basis of the blepharophimosis, ptosis, and epicanthus inversus syndrome(BPES), and to predict the clinical subtype according to in vitro experiments, which is significant to t...AIM: To discover the molecular pathogenic basis of the blepharophimosis, ptosis, and epicanthus inversus syndrome(BPES), and to predict the clinical subtype according to in vitro experiments, which is significant to the prognosis.METHODS: A 3-year-old sporadic female patient with typical clinical manifestations of BPES was enrolled. The coding region of forkhead box L2(FOXL2) gene was sequenced, and the functional assays were performed in vitro by Western blotting, subcellular localization experiment, luciferase reporter assay, and quantitative realtime polymerase chain reaction.RESULTS: A novel FOXL2 point pathogenic variant(c.274G>T) was detected, resulting in a truncated protein(p.E92*). Functional studies demonstrated that the FOXL2 pathogenic variant induced the subcellular mislocalization and the abnormal transcriptional activity on promoters of the steroidogenic acute regulatory protein(StAR or STARD1) gene and the odd-skipped related 2 transcription factor(OSR2) gene.CONCLUSION: A novel pathogenic variant is identified to expand the spectrum of the known FOXL2 mutations. The in vitro experiments provide reference data and more insights to the molecular pathogenesis of BPES. The predicted high risk of ovarian insufficiency makes it significant for the patient enrolled to have further follow-up and therapy concerning female endocrinology.展开更多
AIM:To detect the pathogenic gene variant in a family with neurofibromatosis type 1(NF1).METHODS:This patient with NF1 was sequenced using target sequence capture and high-throughput sequencing technology.After detect...AIM:To detect the pathogenic gene variant in a family with neurofibromatosis type 1(NF1).METHODS:This patient with NF1 was sequenced using target sequence capture and high-throughput sequencing technology.After detecting the suspicious pathogenic variant type,the pathogenic variant sites of the patient and the patient’s family members were verified by multiple ligation dependent probe amplification and Sanger sequencing.Sift,polyphen-2,Mutation Taster and GERP++software were used to predict the pathogenicity of the unknown loci.The clinical data,diagnosis and treatment process of the patients were reviewed.Using the keyword“NF1;frameshift pathogenic variant”,relevant literature was gathered for analysis from Chinese and international databases,with articles dating from the establishment of each database to April 2022.RESULTS:A heterozygous frameshift pathogenic variant of NF1 in exon 33 was detected in the patient.The insertion of adenine in coding region 4486 resulted in the replacement of isoleucine with asparagine in protein 1497.Sanger sequencing validation and segregation analysis were performed,which demonstrated that the NF1 gene was cosegregated with the disease phenotype in this family.This study identified a novel NF1 heterozygous frameshift mutation c.4486dupA(p.I1497Nfs*12).Relevant literature retrieval found 7 Chinese articles and 12 foreign articles.With NF1 gene mutation,mutation types are diverse,including point mutation,frameshift mutation,splice site mutation,exon mutation,chimeric mutation and de novo mutation.Foreign reports are based on autosomal dominant inheritance.CONCLUSION:This study’s results demonstrate that a novel deletion in exon 33 caused NF1 in this Chinese family,expanding the mutational spectrum of the NF1 gene.展开更多
AIM:To describe the clinical,electrophysiological,and genetic features of an unusual case with an RDH12 homozygous pathogenic variant and reviewed the characteristics of the patients reported with the same variant.MET...AIM:To describe the clinical,electrophysiological,and genetic features of an unusual case with an RDH12 homozygous pathogenic variant and reviewed the characteristics of the patients reported with the same variant.METHODS:The patient underwent a complete ophthalmologic examination including best-corrected visual acuity,anterior segment and dilated fundus,visual field,spectral-domain optical coherence tomography(OCT)and electroretinogram(ERG).The retinal disease panel genes were sequenced through chip capture high-throughput sequencing and Sanger sequencing was used to confirm the result.Then we reviewed the characteristics of the patients reported with the same variant.RESULTS:A 30-year male presented with severe early retinal degeneration who complained night blindness,decreased visual acuity,vitreous floaters and amaurosis fugax.The best corrected vision was 0.04 OD and 0.12 OS,respectively.The fundus photo and OCT showed bilateral macular atrophy but larger areas of macular atrophy in the left eye.Autofluorescence shows bilateral symmetrical hypo-autofluorescence.ERG revealed that the amplitudes of a-and b-wave were severely decreased.Multifocal ERG showed decreased amplitudes in the local macular area.A homozygous missense variant c.146C>T(chr14:68191267)was found.The clinical characteristics of a total of 13 patients reported with the same pathologic variant varied.CONCLUSION:An unusual patient with a homozygous pathogenic variant in the c.146C>T of RDH12 which causes late-onset and asymmetric retinal degeneration are reported.The clinical manifestations of the patient with multimodal retinal imaging and functional examinations have enriched our understanding of this disease.展开更多
BACKGROUND The prevalence of germline pathogenic variants in high hereditary risk breast and/or ovarian cancer patients and unaffected subjects referred for testing is an unmet need in low and middle-income countries....BACKGROUND The prevalence of germline pathogenic variants in high hereditary risk breast and/or ovarian cancer patients and unaffected subjects referred for testing is an unmet need in low and middle-income countries.AIM To determine the prevalence of germline pathogenic variants in high hereditary risk patients with breast and/or ovarian cancer and unaffected individuals.METHODS We retrospectively reviewed records of patients and unaffected subjects referred for germline pathogenic variant testing due to high hereditary risk between 2010-2020.Data was collected and analyzed on Excel sheet.RESULTS In total,358 individuals were included,including 257 patients and 101 unaffected individuals with relatives with breast or ovarian cancer.The prevalence of breast cancer susceptibility gene(BRCA)1/2 pathogenic variants was 8.63%(19/220)in patients with breast cancer,and 15.1%(5/33)in those with ovarian cancer.Among the 25 of 220 patients with breast cancer tested by next-generation sequencing,3 patients had pathogenic variants other than BRCA1/2.The highest risk was observed in those aged 40 years with breast cancer and a positive family history,where the BRCA1/2 prevalence was 20.1%(9/43).Among the unaffected subjects,31.1%(14/45)had the same BRCA1/2 pathogenic variants in their corresponding relatives.Among the subjects referred because of a positive family history of cancer without known hereditary factors,5.35%(3/56)had pathogenic variants of BRCA1 and BRCA2.The c.131G>T nucleotide change was noted in one patient and two unrelated unaffected subjects with a BRCA1 pathogenic variant.CONCLUSION This study showed a 8.63%prevalence of pathogenic variants in patients with breast cancer and a 15.1%prevalence in patients with ovarian cancer.Among the relatives of patients with BRCA1/2 pathogenic variants,31%tested positive for the same variant,while 5.3%of subjects who tested positive due to a family history of breast cancer had a BRCA pathogenic variant.展开更多
Cornelia de Lange Syndrome(CdLS)is an intellectual disability syndrome characterized by distinctive clinical features including growth retardation,limb malformation,and a characteristic facial dysmorphism.1 Six genes,...Cornelia de Lange Syndrome(CdLS)is an intellectual disability syndrome characterized by distinctive clinical features including growth retardation,limb malformation,and a characteristic facial dysmorphism.1 Six genes,including NIPBL and MAU2,are associated with CdLS,all encoding components or partners of the cohesin protein complex.Cohesins play a central role in gene expression regulation by organizing chromatin and modulating transcription.2 CdLS is classified as a transcriptomopathy due to dysregulated transcription resulting from pathogenic variants in cohesin-related genes.NIPBL mutations are the most common cause of CdLS,impairing cohesin loading onto DNA.展开更多
G protein subunit alpha O1(GNAO1)-related disorders represent a broad spectrum of neurological diseases mainly caused by de novo mutations in GNAO1 encoding for G protein alpha subunit o(Gαo).As the major transducer ...G protein subunit alpha O1(GNAO1)-related disorders represent a broad spectrum of neurological diseases mainly caused by de novo mutations in GNAO1 encoding for G protein alpha subunit o(Gαo).As the major transducer of neuronal G protein-coupled receptors(GPCRs),Gαo is essential for the signaling involved in neuronal excitability and neurodevelopment.The most severe neomorphic GNAO1-mutations lead to developmental and epileptic encephalopathy-17(DEE17;OMIM#615473)or neurodevelopmental disorder with involuntary movements(NEDIM;OMIM#617493),the latter with or without epileptic seizures.1 Movement disorders are present in almost all patients,with hypo/hyperkinetic features and profound impairment of postural development.2 Milder phenotypes including late-onset dystonia and parkinsonism with different extents of cognitive impairment have recently emerged from mutations leading to loss-of-function and haploinsufficiency.3 However,clear genotype–phenotype correlations and underlying pathogenic mechanisms are still poorly understood.展开更多
To the Editor:Maturity-onset diabetes of the young(MODY)is characterized as a non-autoimmune form of diabetes with an autosomal dominant inheritance pattern.Due to the overlapping clinical phenotypes among MODY,such a...To the Editor:Maturity-onset diabetes of the young(MODY)is characterized as a non-autoimmune form of diabetes with an autosomal dominant inheritance pattern.Due to the overlapping clinical phenotypes among MODY,such as type 1 diabetes mellitus(T1DM)and type 2 diabetes mellitus(T2DM),over 80%of MODY patients are initially misdiagnosed.[1]In recent decades,the advent and development of next-generation sequencing technology have facilitated a deeper understanding of MODY.High-throughput sequencing has remarkably expanded our knowledge of the pathogenic patterns of MODY across diverse populations.展开更多
Hodgkin lymphoma(HL)is a heterogenous lymphoproliferative disorder of B-cell origin and represents one of the most common malignancies in children and young adults.In addition to well-known underlying factors-such as ...Hodgkin lymphoma(HL)is a heterogenous lymphoproliferative disorder of B-cell origin and represents one of the most common malignancies in children and young adults.In addition to well-known underlying factors-such as Epstein-Barr virus infection-the familial aggregation demonstrated in large population studies suggested a genetic predisposition.First-degree relatives of patients with HL have an approximately threefold increased risk of developing the disease compared to the general population.These observations have recently prompted several whole-genome studies in affected families,identifying variants possibly implicated in lymphomagenesis,including alterations in DICER1(a member of the ribonuclease III family),POT1(protection of telomeres 1),KDR(kinase insert domain receptor),KLHDC8B(kelch domain-containing protein 8B),PAX5(paired box protein 5),GATA3(GATA binding protein 3),IRF7(interferon regulatory factor 7),EEF2KMT(eukaryotic elongation factor 2 lysine methyltransferase),and POLR1E(RNA polymerase I subunit E).In this article,we review current insights into the etiopathogenesis and risks of familial HL,and present case reports involving two sisters diagnosed with HL nearly 17 years apart.Recognizing the risk for first-degree relatives may potentially increase awareness of early symptoms among family members of HL patients,leading to earlier diagnosis and better outcomes.Conversely,understanding that the hereditary risk,though higher than in the general population,remains relatively low may provide reassurance for affected families.展开更多
Porcine reproductive and respiratory syndrome virus (PRRSV) has been recognized as one of the most important pathogens of pigs throughout the world. In 2006, more than 10 provinces of China have experienced an epizoot...Porcine reproductive and respiratory syndrome virus (PRRSV) has been recognized as one of the most important pathogens of pigs throughout the world. In 2006, more than 10 provinces of China have experienced an epizootic outbreak of pig diseases characterized by high fever, reddened skin and high morbidity and mortality. From June 2006 to April 2007, we have investigated some clinical samples in Hubei province by RT-PCR and cloned several major genes, N, GP5 and NSP2 gene, shown in this study. Phylogenetic analysis of these genes revealed that the highly pathogenic PRRSV variant, ZB, was responsible for 2006 emergent outbreak of pig disease in Hubei province similar with those variants isolated from other provinces in China in 2006, and belongs to the NA-type PRRSV. In the PRRSV variants, the N and GP5 shear about 90% identity with prototypic ATCC VR-2332 and some typical NA-type Chinese isolates, except the 2850bp NSP2 gene (only shares 65% identity with ATCC VR-2332). But they all shear more than and 97% identity with other highly pathogenetic Chinese PRRSV strains. Additionally, there are extensive amino acid (aa) mutations in the GP5 protein and 2 deletions in the Nsp2 protein when compared with the previous isolates. Most of the variants found in 2006 epizootic outbreak of pig diseases in China were the farthest variants from the typical NA-type PRRSV in phylogenetic distance, and these diversities may be responsible for the differences in the pathogenicity observed between these variants and original Chinese PRRSV strains.展开更多
Background The molecular mechanisms of early-onset multigenerational diabetes remain unknown.This study aimed to investigate the clinical and genetic characteristics of early-onset diabetes involving at least two cons...Background The molecular mechanisms of early-onset multigenerational diabetes remain unknown.This study aimed to investigate the clinical and genetic characteristics of early-onset diabetes involving at least two consecutive generations.Methods From 1296 inpatients with diabetes,we selected individuals who were≤30 years of age and who were clinically suspected of having familial monogenic diabetes.Clinical data were collected from the probands and their family members.Whole-exome sequencing(WES)was used to identify possible causal variants for diabetes.Candidate pathogenic variants were verified by Sanger sequencing,assessed for cosegregation in family members,and evaluated on the basis of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology(ACMG/AMP)guidelines.Moreover,missense and synonymous variants were subjected to in silico pathogenicity prediction via MutationTaster and PolyPhen-2.RNAfold was used to predict RNA structural alterations for synonymous variants.Results Twenty-five early-onset diabetes patients with a history of familial diabetes were enrolled.Pathogenic/likely pathogenic variants(p.Gly292fs in HNF1A,p.Gly245Argfs*22 in PDX1,p.Asp329His in KCNJ11,p.Leu734Phe and p.Val606Gly in WFS1)were detected in four patients,who were diagnosed accurately and treated with reasonable hypoglycemic agents based on genetic testing results.The variants of uncertain significance(ABCC8 c.3039 G>A(p.Ser1013=Ser),MAPK8IP1 p.Gln144_Gly145insSerGln,and TBC1D4 p.Arg1249Trp)were identified in three probands.Conclusion Patients with early-onset diabetes involving at least two consecutive generations may harbor genetic variants.Genetic testing in this population enables precision diagnosis,informs individualized treatment,and facilitates genetic counseling.展开更多
BACKGROUND Cerebrotendinous xanthomatosis(CTX)is a rare autosomal recessive lipid-storage disorder caused by mutations in CYP27A1.Psychiatric manifestations in CTX are rare and nonspecific,and they often lead to consi...BACKGROUND Cerebrotendinous xanthomatosis(CTX)is a rare autosomal recessive lipid-storage disorder caused by mutations in CYP27A1.Psychiatric manifestations in CTX are rare and nonspecific,and they often lead to considerable diagnostic and treatment delay.CASE SUMMARY A 33-year-old female patient admitted to the psychiatric ward for presentation of delusions,hallucinations,and behavioral disturbance is reported.The patient presented with cholestasis,cataract,Achilles tendon xanthoma,and cerebellar signs in adulthood and with intellectual disability and learning difficulties in childhood.After the characteristic CTX findings on imaging were obtained,a pathological examination of the Achilles tendon xanthoma was refined.Replacement therapy was then initiated after the diagnosis was clarified by genetic analysis.During hospitalization in the psychiatric ward,the nonspecific psychiatric manifestations of the patient posed difficulty in diagnosis.After the patient’s history of CTX was identified,the patient was diagnosed with organic schizophrenia-like disorder,and psychotic symptoms were controlled by replacement therapy combined with antipsychotic medication.CONCLUSION Psychiatrists should be aware of CTX,its psychiatric manifestations,and clinical features and avoid misdiagnosis of CTX for timely intervention.展开更多
BACKGROUND Large intracranial dissecting aneurysm(IDA)in the anterior cerebral circulation is rare in children.There has been no consensus on the diagnosis and treatment for IDA in children.CASE SUMMARY We report a 3-...BACKGROUND Large intracranial dissecting aneurysm(IDA)in the anterior cerebral circulation is rare in children.There has been no consensus on the diagnosis and treatment for IDA in children.CASE SUMMARY We report a 3-year-old boy with a large ruptured IDA in the right middle cerebral artery(16 mm×14 mm).The IDA was successfully managed with clipping and angioplasty.Next-generation sequencing of the blood sample followed by bioinformatics analysis suggested that the rs78977446 variant of the ADAMTS13 gene is a risk for pediatric IDA.Three years after surgery,the boy was developmentally normal.CONCLUSION Clipping and angioplasty are effective treatments for ruptured IDA in the anterior cerebral circulation.ADAMTS13 rs78977446 is a risk factor for pediatric IDA.展开更多
Hereditary cancer syndromes(HCSs)are arguably the most frequent category of Mendelian genetic diseases,as at least 2%of presumably healthy subjects carry highly-penetrant tumor-predisposing pathogenic variants(PVs).He...Hereditary cancer syndromes(HCSs)are arguably the most frequent category of Mendelian genetic diseases,as at least 2%of presumably healthy subjects carry highly-penetrant tumor-predisposing pathogenic variants(PVs).Hereditary breast-ovarian cancer and Lynch syndrome make the highest contribution to cancer morbidity;in addition,there are several dozen less frequent types of familial tumors.The development of the majority albeit not all hereditary malignancies involves two-hit mechanism,i.e.the somatic inactivation of the remaining copy of the affected gene.Earlier studies on cancer families suggested nearly fatal penetrance for the majority of HCS genes;however,population-based investigations and especially large-scale next-generation sequencing data sets demonstrate that the presence of some highly-penetrant PVs is often compatible with healthy status.Hereditary cancer research initially focused mainly on cancer detection and prevention.Recent studies identified multiple HCS-specific drug vulnerabilities,which translated into the development of highly efficient therapeutic options.展开更多
Objective:Neurofibromatosis type 1,resulting from NF1 mutation,is estimated to affect one in 3,000 people worldwide.NF1 is a pathogenic gene with one of the highest mutation rates in humans.This study was aimed to rep...Objective:Neurofibromatosis type 1,resulting from NF1 mutation,is estimated to affect one in 3,000 people worldwide.NF1 is a pathogenic gene with one of the highest mutation rates in humans.This study was aimed to report a case in which members of a Chinese family had two distinct NF1 variants.Methods:DNA was isolated from the peripheral blood of the proband,his wife and affected son.Whole-exome sequencing was performed on the proband,while next-generation sequencing was used to detect NF1 and other related genes in his wife and son.Sanger sequencing was conducted to confirm the variants.Results:An unreported variant c.6143T>G and a recurrent variant c.1063-2A>G of NF1 were identified in the proband and his affected son,respectively.The latter variant was not found in the peripheral blood lymphocytes of the proband and his wife.Paternity testing confirmed their parent-child relationship.We summarized the findings of similar reported cases.Conclusion:Our study described a rare phenomenon in which one Chinese family had independent de novo NF1 variants.The findings indicate that clinicians need to sequence the entire NF1 gene of all family members rather than merely verifying the suspect variant detected in the proband.展开更多
Introduction Lynch syndrome(LS)is one of the most common hereditary cancer syndromes,increasing risk for colorectal,endometrial,ovarian and other cancers.It is an autosomal dominant genetic disease caused by pathogeni...Introduction Lynch syndrome(LS)is one of the most common hereditary cancer syndromes,increasing risk for colorectal,endometrial,ovarian and other cancers.It is an autosomal dominant genetic disease caused by pathogenic germline variants in mismatch repair(MMR)genes,including MLH1,MSH2,MSH6,and PMS2,or deletion in the EPCAM gene[1].Pathogenic variants in these genes impair the correction of nucleotide mismatches caused by replication slippage errors,resulting in characteristic microsatellite instability(MSI)in tumors.展开更多
SPAG1(sperm-associated antigen 1)is one of over 50 genes whose pathogenic variants underlie primary ciliary dyskinesia(PCD;OMIM244400),an inherited disorder affecting the function of motile cilia,1 highly conserved or...SPAG1(sperm-associated antigen 1)is one of over 50 genes whose pathogenic variants underlie primary ciliary dyskinesia(PCD;OMIM244400),an inherited disorder affecting the function of motile cilia,1 highly conserved organelles protruding from the surface of eukaryotic cells.Pathogenic SPAG1 variants impair the assembly of dynein arms,essential elements of cilia.展开更多
Dear Editor,Scoliosis is an abnormal lateral curvature of the spine with Cobb angle more than 10◦.1 The detailed genetic etiology and underlying mechanisms of this disease are still unclear.We identified three pathoge...Dear Editor,Scoliosis is an abnormal lateral curvature of the spine with Cobb angle more than 10◦.1 The detailed genetic etiology and underlying mechanisms of this disease are still unclear.We identified three pathogenic variants in the RUNX2 gene(p.Ala173LeufsTer3,p.Arg225Gln,and pArg190Trp)in three patients with scoliosis by whole-exome or-genome sequencing and confirmed by BAM files(Figure 1A).展开更多
基金Supported by Funds of Plastic Surgery Hospital of the Chinese Academy of Medical Sciences,Peking Union Medical College (No.YS202010)。
文摘AIM: To discover the molecular pathogenic basis of the blepharophimosis, ptosis, and epicanthus inversus syndrome(BPES), and to predict the clinical subtype according to in vitro experiments, which is significant to the prognosis.METHODS: A 3-year-old sporadic female patient with typical clinical manifestations of BPES was enrolled. The coding region of forkhead box L2(FOXL2) gene was sequenced, and the functional assays were performed in vitro by Western blotting, subcellular localization experiment, luciferase reporter assay, and quantitative realtime polymerase chain reaction.RESULTS: A novel FOXL2 point pathogenic variant(c.274G>T) was detected, resulting in a truncated protein(p.E92*). Functional studies demonstrated that the FOXL2 pathogenic variant induced the subcellular mislocalization and the abnormal transcriptional activity on promoters of the steroidogenic acute regulatory protein(StAR or STARD1) gene and the odd-skipped related 2 transcription factor(OSR2) gene.CONCLUSION: A novel pathogenic variant is identified to expand the spectrum of the known FOXL2 mutations. The in vitro experiments provide reference data and more insights to the molecular pathogenesis of BPES. The predicted high risk of ovarian insufficiency makes it significant for the patient enrolled to have further follow-up and therapy concerning female endocrinology.
基金Supported by National High Level Hospital Clinical Research Funding(No.2022-PUMCH-A-031)。
文摘AIM:To detect the pathogenic gene variant in a family with neurofibromatosis type 1(NF1).METHODS:This patient with NF1 was sequenced using target sequence capture and high-throughput sequencing technology.After detecting the suspicious pathogenic variant type,the pathogenic variant sites of the patient and the patient’s family members were verified by multiple ligation dependent probe amplification and Sanger sequencing.Sift,polyphen-2,Mutation Taster and GERP++software were used to predict the pathogenicity of the unknown loci.The clinical data,diagnosis and treatment process of the patients were reviewed.Using the keyword“NF1;frameshift pathogenic variant”,relevant literature was gathered for analysis from Chinese and international databases,with articles dating from the establishment of each database to April 2022.RESULTS:A heterozygous frameshift pathogenic variant of NF1 in exon 33 was detected in the patient.The insertion of adenine in coding region 4486 resulted in the replacement of isoleucine with asparagine in protein 1497.Sanger sequencing validation and segregation analysis were performed,which demonstrated that the NF1 gene was cosegregated with the disease phenotype in this family.This study identified a novel NF1 heterozygous frameshift mutation c.4486dupA(p.I1497Nfs*12).Relevant literature retrieval found 7 Chinese articles and 12 foreign articles.With NF1 gene mutation,mutation types are diverse,including point mutation,frameshift mutation,splice site mutation,exon mutation,chimeric mutation and de novo mutation.Foreign reports are based on autosomal dominant inheritance.CONCLUSION:This study’s results demonstrate that a novel deletion in exon 33 caused NF1 in this Chinese family,expanding the mutational spectrum of the NF1 gene.
基金Supported by Shenzhen Science and Technology Program,Shenzhen,China(No.JCYJ20200109145001814,No.SGDX20211123120001001)the National Natural Science Foundation of China(No.81970790)Sanming Project of Medicine in Shenzhen(No.SZSM202011015).
文摘AIM:To describe the clinical,electrophysiological,and genetic features of an unusual case with an RDH12 homozygous pathogenic variant and reviewed the characteristics of the patients reported with the same variant.METHODS:The patient underwent a complete ophthalmologic examination including best-corrected visual acuity,anterior segment and dilated fundus,visual field,spectral-domain optical coherence tomography(OCT)and electroretinogram(ERG).The retinal disease panel genes were sequenced through chip capture high-throughput sequencing and Sanger sequencing was used to confirm the result.Then we reviewed the characteristics of the patients reported with the same variant.RESULTS:A 30-year male presented with severe early retinal degeneration who complained night blindness,decreased visual acuity,vitreous floaters and amaurosis fugax.The best corrected vision was 0.04 OD and 0.12 OS,respectively.The fundus photo and OCT showed bilateral macular atrophy but larger areas of macular atrophy in the left eye.Autofluorescence shows bilateral symmetrical hypo-autofluorescence.ERG revealed that the amplitudes of a-and b-wave were severely decreased.Multifocal ERG showed decreased amplitudes in the local macular area.A homozygous missense variant c.146C>T(chr14:68191267)was found.The clinical characteristics of a total of 13 patients reported with the same pathologic variant varied.CONCLUSION:An unusual patient with a homozygous pathogenic variant in the c.146C>T of RDH12 which causes late-onset and asymmetric retinal degeneration are reported.The clinical manifestations of the patient with multimodal retinal imaging and functional examinations have enriched our understanding of this disease.
文摘BACKGROUND The prevalence of germline pathogenic variants in high hereditary risk breast and/or ovarian cancer patients and unaffected subjects referred for testing is an unmet need in low and middle-income countries.AIM To determine the prevalence of germline pathogenic variants in high hereditary risk patients with breast and/or ovarian cancer and unaffected individuals.METHODS We retrospectively reviewed records of patients and unaffected subjects referred for germline pathogenic variant testing due to high hereditary risk between 2010-2020.Data was collected and analyzed on Excel sheet.RESULTS In total,358 individuals were included,including 257 patients and 101 unaffected individuals with relatives with breast or ovarian cancer.The prevalence of breast cancer susceptibility gene(BRCA)1/2 pathogenic variants was 8.63%(19/220)in patients with breast cancer,and 15.1%(5/33)in those with ovarian cancer.Among the 25 of 220 patients with breast cancer tested by next-generation sequencing,3 patients had pathogenic variants other than BRCA1/2.The highest risk was observed in those aged 40 years with breast cancer and a positive family history,where the BRCA1/2 prevalence was 20.1%(9/43).Among the unaffected subjects,31.1%(14/45)had the same BRCA1/2 pathogenic variants in their corresponding relatives.Among the subjects referred because of a positive family history of cancer without known hereditary factors,5.35%(3/56)had pathogenic variants of BRCA1 and BRCA2.The c.131G>T nucleotide change was noted in one patient and two unrelated unaffected subjects with a BRCA1 pathogenic variant.CONCLUSION This study showed a 8.63%prevalence of pathogenic variants in patients with breast cancer and a 15.1%prevalence in patients with ovarian cancer.Among the relatives of patients with BRCA1/2 pathogenic variants,31%tested positive for the same variant,while 5.3%of subjects who tested positive due to a family history of breast cancer had a BRCA pathogenic variant.
基金the Institutional Review Board of the Rouen University Hospital(CERDE notification E2023-65).
文摘Cornelia de Lange Syndrome(CdLS)is an intellectual disability syndrome characterized by distinctive clinical features including growth retardation,limb malformation,and a characteristic facial dysmorphism.1 Six genes,including NIPBL and MAU2,are associated with CdLS,all encoding components or partners of the cohesin protein complex.Cohesins play a central role in gene expression regulation by organizing chromatin and modulating transcription.2 CdLS is classified as a transcriptomopathy due to dysregulated transcription resulting from pathogenic variants in cohesin-related genes.NIPBL mutations are the most common cause of CdLS,impairing cohesin loading onto DNA.
文摘G protein subunit alpha O1(GNAO1)-related disorders represent a broad spectrum of neurological diseases mainly caused by de novo mutations in GNAO1 encoding for G protein alpha subunit o(Gαo).As the major transducer of neuronal G protein-coupled receptors(GPCRs),Gαo is essential for the signaling involved in neuronal excitability and neurodevelopment.The most severe neomorphic GNAO1-mutations lead to developmental and epileptic encephalopathy-17(DEE17;OMIM#615473)or neurodevelopmental disorder with involuntary movements(NEDIM;OMIM#617493),the latter with or without epileptic seizures.1 Movement disorders are present in almost all patients,with hypo/hyperkinetic features and profound impairment of postural development.2 Milder phenotypes including late-onset dystonia and parkinsonism with different extents of cognitive impairment have recently emerged from mutations leading to loss-of-function and haploinsufficiency.3 However,clear genotype–phenotype correlations and underlying pathogenic mechanisms are still poorly understood.
基金supported by grants from the National Natural Science Foundation of China for Distinguished Young Scholars(No.82325010)Medical-Engineering Cross Foundation of Shanghai Jiao Tong University(No.YG2021ZD20)+6 种基金Shuguang Project(No.21SG11)Innovative Research Team of High-level Local Universities in Shanghai(No.SHSMU-ZDCX20212700)Shanghai Sixth People’s Hospital Grant(No.ynhg202204)National Natural Science Foundation of China for Young Scientists(No.82300891)Shanghai Research Center for Endocrine and Metabolic Diseases(No.2022ZZ01002)National Key Clinical Specialty(No.Z155080000004)Shanghai Municipal Key Clinical Specialty.
文摘To the Editor:Maturity-onset diabetes of the young(MODY)is characterized as a non-autoimmune form of diabetes with an autosomal dominant inheritance pattern.Due to the overlapping clinical phenotypes among MODY,such as type 1 diabetes mellitus(T1DM)and type 2 diabetes mellitus(T2DM),over 80%of MODY patients are initially misdiagnosed.[1]In recent decades,the advent and development of next-generation sequencing technology have facilitated a deeper understanding of MODY.High-throughput sequencing has remarkably expanded our knowledge of the pathogenic patterns of MODY across diverse populations.
文摘Hodgkin lymphoma(HL)is a heterogenous lymphoproliferative disorder of B-cell origin and represents one of the most common malignancies in children and young adults.In addition to well-known underlying factors-such as Epstein-Barr virus infection-the familial aggregation demonstrated in large population studies suggested a genetic predisposition.First-degree relatives of patients with HL have an approximately threefold increased risk of developing the disease compared to the general population.These observations have recently prompted several whole-genome studies in affected families,identifying variants possibly implicated in lymphomagenesis,including alterations in DICER1(a member of the ribonuclease III family),POT1(protection of telomeres 1),KDR(kinase insert domain receptor),KLHDC8B(kelch domain-containing protein 8B),PAX5(paired box protein 5),GATA3(GATA binding protein 3),IRF7(interferon regulatory factor 7),EEF2KMT(eukaryotic elongation factor 2 lysine methyltransferase),and POLR1E(RNA polymerase I subunit E).In this article,we review current insights into the etiopathogenesis and risks of familial HL,and present case reports involving two sisters diagnosed with HL nearly 17 years apart.Recognizing the risk for first-degree relatives may potentially increase awareness of early symptoms among family members of HL patients,leading to earlier diagnosis and better outcomes.Conversely,understanding that the hereditary risk,though higher than in the general population,remains relatively low may provide reassurance for affected families.
基金supported in part by a National Key Technologies R&D Program (2006BAD06A01) National "973 Project" (2005CB523000, 2006CB- 933102) from the Ministry of Science and Technology, People’s Republic of China.
文摘Porcine reproductive and respiratory syndrome virus (PRRSV) has been recognized as one of the most important pathogens of pigs throughout the world. In 2006, more than 10 provinces of China have experienced an epizootic outbreak of pig diseases characterized by high fever, reddened skin and high morbidity and mortality. From June 2006 to April 2007, we have investigated some clinical samples in Hubei province by RT-PCR and cloned several major genes, N, GP5 and NSP2 gene, shown in this study. Phylogenetic analysis of these genes revealed that the highly pathogenic PRRSV variant, ZB, was responsible for 2006 emergent outbreak of pig disease in Hubei province similar with those variants isolated from other provinces in China in 2006, and belongs to the NA-type PRRSV. In the PRRSV variants, the N and GP5 shear about 90% identity with prototypic ATCC VR-2332 and some typical NA-type Chinese isolates, except the 2850bp NSP2 gene (only shares 65% identity with ATCC VR-2332). But they all shear more than and 97% identity with other highly pathogenetic Chinese PRRSV strains. Additionally, there are extensive amino acid (aa) mutations in the GP5 protein and 2 deletions in the Nsp2 protein when compared with the previous isolates. Most of the variants found in 2006 epizootic outbreak of pig diseases in China were the farthest variants from the typical NA-type PRRSV in phylogenetic distance, and these diversities may be responsible for the differences in the pathogenicity observed between these variants and original Chinese PRRSV strains.
基金supported by Diabetes Talent Research Project of China,International Medical Foundation 2019(No.2018-N-1).
文摘Background The molecular mechanisms of early-onset multigenerational diabetes remain unknown.This study aimed to investigate the clinical and genetic characteristics of early-onset diabetes involving at least two consecutive generations.Methods From 1296 inpatients with diabetes,we selected individuals who were≤30 years of age and who were clinically suspected of having familial monogenic diabetes.Clinical data were collected from the probands and their family members.Whole-exome sequencing(WES)was used to identify possible causal variants for diabetes.Candidate pathogenic variants were verified by Sanger sequencing,assessed for cosegregation in family members,and evaluated on the basis of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology(ACMG/AMP)guidelines.Moreover,missense and synonymous variants were subjected to in silico pathogenicity prediction via MutationTaster and PolyPhen-2.RNAfold was used to predict RNA structural alterations for synonymous variants.Results Twenty-five early-onset diabetes patients with a history of familial diabetes were enrolled.Pathogenic/likely pathogenic variants(p.Gly292fs in HNF1A,p.Gly245Argfs*22 in PDX1,p.Asp329His in KCNJ11,p.Leu734Phe and p.Val606Gly in WFS1)were detected in four patients,who were diagnosed accurately and treated with reasonable hypoglycemic agents based on genetic testing results.The variants of uncertain significance(ABCC8 c.3039 G>A(p.Ser1013=Ser),MAPK8IP1 p.Gln144_Gly145insSerGln,and TBC1D4 p.Arg1249Trp)were identified in three probands.Conclusion Patients with early-onset diabetes involving at least two consecutive generations may harbor genetic variants.Genetic testing in this population enables precision diagnosis,informs individualized treatment,and facilitates genetic counseling.
基金National Natural Science Foundation of China,No.82172061the Key Research and Development Plan in Jiangsu,No.BE2022677and the 16th Batch of Six Talent Peak Projects in Jiangsu,No.WSN-166.
文摘BACKGROUND Cerebrotendinous xanthomatosis(CTX)is a rare autosomal recessive lipid-storage disorder caused by mutations in CYP27A1.Psychiatric manifestations in CTX are rare and nonspecific,and they often lead to considerable diagnostic and treatment delay.CASE SUMMARY A 33-year-old female patient admitted to the psychiatric ward for presentation of delusions,hallucinations,and behavioral disturbance is reported.The patient presented with cholestasis,cataract,Achilles tendon xanthoma,and cerebellar signs in adulthood and with intellectual disability and learning difficulties in childhood.After the characteristic CTX findings on imaging were obtained,a pathological examination of the Achilles tendon xanthoma was refined.Replacement therapy was then initiated after the diagnosis was clarified by genetic analysis.During hospitalization in the psychiatric ward,the nonspecific psychiatric manifestations of the patient posed difficulty in diagnosis.After the patient’s history of CTX was identified,the patient was diagnosed with organic schizophrenia-like disorder,and psychotic symptoms were controlled by replacement therapy combined with antipsychotic medication.CONCLUSION Psychiatrists should be aware of CTX,its psychiatric manifestations,and clinical features and avoid misdiagnosis of CTX for timely intervention.
基金Supported by National Natural Science Foundation of China,No.81571144。
文摘BACKGROUND Large intracranial dissecting aneurysm(IDA)in the anterior cerebral circulation is rare in children.There has been no consensus on the diagnosis and treatment for IDA in children.CASE SUMMARY We report a 3-year-old boy with a large ruptured IDA in the right middle cerebral artery(16 mm×14 mm).The IDA was successfully managed with clipping and angioplasty.Next-generation sequencing of the blood sample followed by bioinformatics analysis suggested that the rs78977446 variant of the ADAMTS13 gene is a risk for pediatric IDA.Three years after surgery,the boy was developmentally normal.CONCLUSION Clipping and angioplasty are effective treatments for ruptured IDA in the anterior cerebral circulation.ADAMTS13 rs78977446 is a risk factor for pediatric IDA.
基金Supported by The Russian Science Foundation,No.17-75-30027。
文摘Hereditary cancer syndromes(HCSs)are arguably the most frequent category of Mendelian genetic diseases,as at least 2%of presumably healthy subjects carry highly-penetrant tumor-predisposing pathogenic variants(PVs).Hereditary breast-ovarian cancer and Lynch syndrome make the highest contribution to cancer morbidity;in addition,there are several dozen less frequent types of familial tumors.The development of the majority albeit not all hereditary malignancies involves two-hit mechanism,i.e.the somatic inactivation of the remaining copy of the affected gene.Earlier studies on cancer families suggested nearly fatal penetrance for the majority of HCS genes;however,population-based investigations and especially large-scale next-generation sequencing data sets demonstrate that the presence of some highly-penetrant PVs is often compatible with healthy status.Hereditary cancer research initially focused mainly on cancer detection and prevention.Recent studies identified multiple HCS-specific drug vulnerabilities,which translated into the development of highly efficient therapeutic options.
基金the support of grants from the National Nature Science Foundation of China(Nos.82073422 and 82273504).
文摘Objective:Neurofibromatosis type 1,resulting from NF1 mutation,is estimated to affect one in 3,000 people worldwide.NF1 is a pathogenic gene with one of the highest mutation rates in humans.This study was aimed to report a case in which members of a Chinese family had two distinct NF1 variants.Methods:DNA was isolated from the peripheral blood of the proband,his wife and affected son.Whole-exome sequencing was performed on the proband,while next-generation sequencing was used to detect NF1 and other related genes in his wife and son.Sanger sequencing was conducted to confirm the variants.Results:An unreported variant c.6143T>G and a recurrent variant c.1063-2A>G of NF1 were identified in the proband and his affected son,respectively.The latter variant was not found in the peripheral blood lymphocytes of the proband and his wife.Paternity testing confirmed their parent-child relationship.We summarized the findings of similar reported cases.Conclusion:Our study described a rare phenomenon in which one Chinese family had independent de novo NF1 variants.The findings indicate that clinicians need to sequence the entire NF1 gene of all family members rather than merely verifying the suspect variant detected in the proband.
基金supported by the National Cancer Center Climbing Program Fund[NCC202414003].
文摘Introduction Lynch syndrome(LS)is one of the most common hereditary cancer syndromes,increasing risk for colorectal,endometrial,ovarian and other cancers.It is an autosomal dominant genetic disease caused by pathogenic germline variants in mismatch repair(MMR)genes,including MLH1,MSH2,MSH6,and PMS2,or deletion in the EPCAM gene[1].Pathogenic variants in these genes impair the correction of nucleotide mismatches caused by replication slippage errors,resulting in characteristic microsatellite instability(MSI)in tumors.
基金funded by the National Science Centre,Poland(No.2018/29/N/NZ5/00810 to A.R.2018/31/B/NZ2/03248 to E.Z.)by the Institute of Human Genetics PAS,Poland(Minigrant No.2021/01 to A.R.).
文摘SPAG1(sperm-associated antigen 1)is one of over 50 genes whose pathogenic variants underlie primary ciliary dyskinesia(PCD;OMIM244400),an inherited disorder affecting the function of motile cilia,1 highly conserved organelles protruding from the surface of eukaryotic cells.Pathogenic SPAG1 variants impair the assembly of dynein arms,essential elements of cilia.
基金supported by the National Natural Science Foundation of China(NSFC)(grants 82394445,82030067,and 82161160342 to D.C.and 82202656 to Z.L.)Shenzhen Medical Research Funds B2502005 to D.C.+4 种基金the CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-I2M-1-051 to N.W.,2021-I2M-1-052 and 2022-I2M-2001 to Z.W.)Beijing Natural Science Foundation(7244389 to L.Z.)the National High Level Hospital Clinical Research Funding(2022-PUMCH-D-004 to N.W.,2022-PUMCHD-002 to Z.W.)the National Key Research and Development Program of China(2023YFC2507700 and 2022YFC2703102 to N.W.,2022YFC2703901 to Z.W.)the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2019PT320025 to N.W.).
文摘Dear Editor,Scoliosis is an abnormal lateral curvature of the spine with Cobb angle more than 10◦.1 The detailed genetic etiology and underlying mechanisms of this disease are still unclear.We identified three pathogenic variants in the RUNX2 gene(p.Ala173LeufsTer3,p.Arg225Gln,and pArg190Trp)in three patients with scoliosis by whole-exome or-genome sequencing and confirmed by BAM files(Figure 1A).
