Peutz-Jeghers syndrome （PJS）, a rare autosomal dominant inherited disorder, is characterized by hamartomatous gastrointestinal polyps and mucocutaneous pigmentation. Patients with this syndrome have a predisposition...Peutz-Jeghers syndrome （PJS）, a rare autosomal dominant inherited disorder, is characterized by hamartomatous gastrointestinal polyps and mucocutaneous pigmentation. Patients with this syndrome have a predisposition to a variety of cancers in multiple organs. Mutations in the serine/threonine kinase 11 （STK11） gene have been identified as a major cause of PJS. Here we present the clinical and molecular findings of two unrelated Thai individuals with PJS. Mutation analysis by Polymerase Chain Reaction-sequencing of the entire coding region of STK11 revealed two potentially pathogenic mutations. One harbored a single nucleotide deletion （c.182delG） in exon 1 resulting in a frameshift leading to premature termination at codon 63 （p.Gly61AlafsX63）. The other carried an in-frame 9-base-pair （bp） deletion in exon 7, c.907_915del9 （p.Ile303_GIn305del）. Both deletions were de novo and have never been previously described. This study has expanded the genotypic spectrum of the STK11 gene.展开更多
Objective To determine the nosogenetic factors of a 46,XY female with primary amenorrhea and unilateral mixed germ cell tumor.Methods Eight genes associated with 46,XY gonadal dysgenesis were detected in the patient a...Objective To determine the nosogenetic factors of a 46,XY female with primary amenorrhea and unilateral mixed germ cell tumor.Methods Eight genes associated with 46,XY gonadal dysgenesis were detected in the patient and her parents by target region captured-next generation sequencing.Results An insertion of a single nucleotide（adenine） at the coding site 230（c.230231insA） located in the high mobility group（HMG） domain of SRY was revealed,which led to a truncated protein（p.Lys77 fsX 27）. This mutation was at position 2655414 of the Y chromosome, supported with 127 unique mapped reads, however, this mutation was not found in the in-house dataset of 1 092 controls. Additionally, none of the candidate gene was detected in the patient’s parents, which indicated that it is a de novo mutation.Conclusion A novel SRY sporadic mutation due to a single nucleotide insertion at position 230（c.230231insA） was identified as the cause of the disease in this patient.Target region captured-next generation sequencing was found to be an effective method for the molecular genetic testing of 46,XY complete gonadal dysgenesis（46,XY CGD）.展开更多
Mutations in the X-linked androgen receptor （AR） gene cause androgen insensitivity syndrome （AIS）, resulting in an impaired embryonic sex differentiation in 46,XY genetic men. Complete androgen insensitivity （CAI...Mutations in the X-linked androgen receptor （AR） gene cause androgen insensitivity syndrome （AIS）, resulting in an impaired embryonic sex differentiation in 46,XY genetic men. Complete androgen insensitivity （CAIS） produces a female external phenotype, whereas cases with partial androgen insensitivity （PALS） have various ambiguities of the genitalia. Mild androgen insensitivity （MAIS） is characterized by undermasculinization and gynecomastia. Here we describe a 2-month-old 46,XY female patient, with all of the characteristics of CAIS. Defects in testosterone （T） and dihydrotestosterone （DHT） synthesis were excluded. Sequencing of the AR gene showed the presence in exon 6 of a T to C transition in the second base of codon 790, nucleotide position 2369, causing a novel missense Leu790Pro mutation in the ligand-binding domain of the AR protein. The identification of a novel AR mutation in a girl with CAIS provides significant information due to the importance of missense mutations in the ligand-binding domain of the AR, which are able to induce functional abnormalities in the androgen binding capability, stabilization of active conformation, or interaction with coactivators.展开更多
AIM:To detect and segregate causative mutations in congenital families with optic nerve hypoplasia(ONH).M E T H O D S:Two unrel a ted consanguineous Pakistani families with severe ONH,showing features of micropthalmia...AIM:To detect and segregate causative mutations in congenital families with optic nerve hypoplasia(ONH).M E T H O D S:Two unrel a ted consanguineous Pakistani families with severe ONH,showing features of micropthalmia,nystagmus,corneal opacity,and keratopathy were included.Genetic analysis was carried out by Target Panel Sequencing,and the nucleotide variant was confirmed by Sanger sequencing.In silico analyses were carried out to study the protein order-disorder functions and their effects on messenger ribonucleic acid(mRNA).RESULTS:Target panel sequencing revealed that the afflicted family members carried a novel frameshift mutation(NM_145178.4;c.91del G;p.Gly31Glyfs*55)that ensued in the conservation of an amino acid residue in the bHLH domain of ATOH7 protein.In silico studies predicted that the activity of the ATOH7 gene is probably affected by this mutation,which results in a shortened and nonfunctional protein.Three-dimensional structural analysis shows that DNA binding may be impacted by amino acid changes from non-polar to positively charged and vice versa(Arg42Pro and Pro18Arg),as well as from positively charged(Arg)to a small polar amino acid(Gly).CONCLUSION:A novel ATOH7 mutation is harmful.This study also emphasizes the potential effects of modified ATOH7 configurations on the stability and functionality of proteins.展开更多
First described by Meredith in 1987,retinal venous beading(RVB)is an extremely rare and potentially vision-threat-ening disease,^(1)which is characterized by beading or sausage-like configuration of retinal veins.It c...First described by Meredith in 1987,retinal venous beading(RVB)is an extremely rare and potentially vision-threat-ening disease,^(1)which is characterized by beading or sausage-like configuration of retinal veins.It can present with episodes of increased vascular permeability accom-panied by lipid exudation,foveal edema,recurrent branch vein occlusion,retinal ischemia with retinal neo-vascularization,and vitreous hemorrhage,^(1)or exist solely and asymptomatically.^(2)展开更多
Pseudoachondroplasia(PSACH)is a relatively common skeletal dysplasia characterized by disproportionate short stature,joint laxity,early-onset osteoarthrosis,and dysplasia of the spine,epiphysis,and metaphysis.It is kn...Pseudoachondroplasia(PSACH)is a relatively common skeletal dysplasia characterized by disproportionate short stature,joint laxity,early-onset osteoarthrosis,and dysplasia of the spine,epiphysis,and metaphysis.It is known as an autosomal dominant disease which results exclusively from mutations in the gene for Cartilage Oligomeric Matrix Protein(COMP).We have identified a five year old Chinese boy who was diagnosed as pseudoachondroplasia according to clinical manifestations and X-ray symptoms.His mother seems like another effected individual because of the apparent short stature.Genomic DNA was extracted from peripheral blood lymphocytes.DNA sequencing analysis of the COMP gene revealed a heterozygous mutation(c.1219 T>C,p.Cys407Arg)in the patient.His mother was also affected with the same genetic change.Mutations in COMP gene is proved to change the Cartilage Oligomeric Matrix Protein.This missense mutation(c.1219 T>C)has not been reported before and it is not belongs to polymorphism sites.Our results extend the spectrum of mutations in COMP gene leading to pseudoachondroplasia.展开更多
AIM: To identify the disease-associated mutations in a Chinese Stargardt disease(STGD) family, extend the existing spectrum of disease-causing mutations and further define the genotype-phenotype correlations.METHODS: ...AIM: To identify the disease-associated mutations in a Chinese Stargardt disease(STGD) family, extend the existing spectrum of disease-causing mutations and further define the genotype-phenotype correlations.METHODS: A Chinese STGD family and 200 normal controls were collected. Whole exome sequencing(WES) and bioinformatics analysis were performed to find the pathogenic gene mutation. Physico-chemical parameters of mutant and wildtype proteins were computed by Prot Param tool. Domains analysis was performed by SMART online software. HOPE online software was used to analyze the structural effects of mutation. Immunofluorescence, quantitative real-time polymerase chain reaction and Western blotting were used for expression analysis.RESULTS: Using WES, a novel homozygous mutation(NM_000350: c.G3190 C, p.G1064 R) in ABCA4 gene was identified. This mutation showed co-segregation with phenotype in this family. It was not found in the 200 unrelated health controls and absent from any databases. It was considered "Deleterious" as predicted by five function prediction softwares, and was highly conserved during evolution. ABCA4 was expressed highly in the human eye and mouse retina. The p.G1064 R was located in AAA domain, may force the local backbone into an incorrect conformation, disturb the local structure, and reduce the activity of ATPase resulting in the disease pathology. CONCLUSION: We define a novel pathogenic mutation(c.G3190 C of ABCA4) of STGD. This extends the existing spectrum of disease-causing mutations and further defines the genotype-phenotype correlations.展开更多
Background： Myoclonic epilepsy with ragged red fibers （MERRF） syndrome is characterized by myoclonus, generalized epilepsy, cerebellar ataxia, and ragged red fibers （RRFs） in the muscle. T-to-C transition at nucl...Background： Myoclonic epilepsy with ragged red fibers （MERRF） syndrome is characterized by myoclonus, generalized epilepsy, cerebellar ataxia, and ragged red fibers （RRFs） in the muscle. T-to-C transition at nucleotide position 14709 in the mitochondrial tRNA glutamic acid （tRNA^Gla） gene has previously been associated with maternally inherited diabetes and deathess. However, the association between MERRF and mitochondrial T14709C mutation （m.TI4709C） has never been reported before. Methods： Clinical information of a 17-year-old patient was collected; muscle biopsy and next-generation sequencing （NGS） of whole mitochondrial and neuromuscular disease panel were then conducted. Finally, sanger sequencing was carried out to confirm the mutations. Results： The patient presented a typical MERRF phenotype with muscle weakness, epileptic seizure, clonic episodes, cerebellar ataxia, and spinal scoliosis. Muscle biopsy showed RRFs which indicated abnormal mitochondrial functions. NGS of whole mitochondrial gene revealed m.TI4709C mutation, confirmed by Sanger sequencing. Conclusion： We present a sporadic patient with typical MERRF presentation carrying the mutation ofm.T14709C, which expanded the spectrum of re.T14709C.展开更多
Background：H syndrome （OMIM 612391） is a recently described autosomal recessive genodermatosis characterized by indurated hyperpigmented and hypertrichotic skin,as well as other systemic manifestations.Most of the ...Background：H syndrome （OMIM 612391） is a recently described autosomal recessive genodermatosis characterized by indurated hyperpigmented and hypertrichotic skin,as well as other systemic manifestations.Most of the cases occurred in the Middle East areas or nearby countries such as Spain or India.The syndrome is caused by mutations in solute carrier family 29,member 3 （SLC29A3）,the gene encoding equilibrative nucleoside transporter 3.The aim of this study was to identify pathogenic SLC29A 3 mutations in a Chinese patient clinically diagnosed with H syndrome.Methods：Peripheral blood samples were collected from the patient and his parents.Genomic DNA was isolated by the standard method.All six SLC29A3 exons and their flanking intronic sequences were polymerase chain reaction （PCR）-amplified and the PCR products were subjected to direct sequencing.Results：The patient,an 18-year-old man born to a nonconsanguineous Chinese couple,had more extensive cutaneous lesions,involving both buttocks and knee.In his genomic DNA,we identified a novel homozygous insertion-deletion,c.1269_1270delinsA,in SLC29A3.Both of his parents were carriers of the mutation.Conclusions：We have identified a pathogenic mutation in a Chinese patient with H syndrome.展开更多
BACKGROUND Dyskeratosis congenita is a rare disease characterized by bone marrow failure and a clinical triad of oral leukoplakia,nail dystrophy,and abnormal skin pigmentation.The genetics of dyskeratosis congenita in...BACKGROUND Dyskeratosis congenita is a rare disease characterized by bone marrow failure and a clinical triad of oral leukoplakia,nail dystrophy,and abnormal skin pigmentation.The genetics of dyskeratosis congenita include mutations in genes involved in telomere maintenance,including TINF2.CASE SUMMARY Here,we report a female patient who presented thrombocytopenia,anemia,reticulate hyperpigmentation,dystrophy in fingernails and toenails,and leukoplakia on the tongue.A histopathological study of the skin showed dyskeratocytes;however,a bone marrow biopsy revealed normal cell morphology.The patient was diagnosed with dyskeratosis congenita,but her family history did not reveal significant antecedents.Whole-exome sequencing showed a novel heterozygous punctual mutation in exon 6 from the TINF2 gene,namely,NM_001099274.1:-c.854delp.(Val285-Alafs*32).An analysis of telomere length showed short telomeres relative to the patient’s age.CONCLUSION The disease in this patient was caused by a germline novel mutation of TINF2 in one of her parents.展开更多
BACKGROUND Acute intermittent porphyria(AIP)is a rare autosomal dominant porphyrin metabolic disease caused by a mutation in the hydroxymethylbilane synthase(HMBS)gene.This study aimed to explore the clinical manifest...BACKGROUND Acute intermittent porphyria(AIP)is a rare autosomal dominant porphyrin metabolic disease caused by a mutation in the hydroxymethylbilane synthase(HMBS)gene.This study aimed to explore the clinical manifestations of a patient with AIP,to identify a novel HMBS gene mutation in the proband and some of her family members,and to confirm the pathogenicity of the variant.CASE SUMMARY A 22-year-old Chinese woman developed severe abdominal pain,lumbago,sinus tachycardia,epileptic seizure,hypertension,and weakness in lower limbs in March,2018.Biochemical examinations indicated hypohepatia and hyponatremia.Her last menstrual period was 45 d prior to admission,and she was unaware of the pregnancy,which was confirmed by a pregnancy test after admission.Sunlight exposure of her urine sample for 1 h turned it from yellow to wine red.Urinary porphyrin test result was positive.Based on these clinical manifestations,AIP was diagnosed.After increasing her daily glucose intake(250–300 g/d),abdominal pain was partially relieved.Three days after hospitalization,spontaneous vaginal bleeding occurred,which was confirmed as spontaneous abortion;thereafter,her clinical symptoms completely resolved.Genetic testing revealed a novel heterozygous splicing variant of the HMBS gene in exon 10(c.648_651+1delCCAGG)in the proband and four other family members.The pathogenicity of the variant was verified through bioinformatic methods and a minigene assay.CONCLUSION We identified a novel HMBS gene mutation in a Chinese patient with AIP and confirmed its pathogenicity.展开更多
BACKGROUND Primary ciliary dyskinesia(PCD)is a rare genetic disorder caused by motile cilia dysfunction.Identifying pathogenic variants is essential for diagnosis and personalized care,especially in consanguineous pop...BACKGROUND Primary ciliary dyskinesia(PCD)is a rare genetic disorder caused by motile cilia dysfunction.Identifying pathogenic variants is essential for diagnosis and personalized care,especially in consanguineous populations like Saudi Arabia.CASE SUMMARY This report presents a Saudi pediatric patient diagnosed with PCD who exhibited persistent neonatal tachypnea,chronic productive cough,and recurrent otitis media.Whole-exome sequencing revealed a novel homozygous nonsense variant in the C3orf67 gene(NM_198463.2:c.508C>T),resulting in a truncated,nonfunctional protein.This mutation likely impairs ciliary motility due to the production of a truncated,non-functional protein.The clinical findings were supported by multiple positive sputum cultures and a significant family history of similar symptoms,suggesting a genetic etiology consistent with autosomal recessive inheritance.CONCLUSION This case highlights the importance of genetic studies in diagnosing PCD,particularly in communities with a high rate of consanguinity.The identification of a novel homozygous variant in the C3orf67 gene expands the known genetic landscape of the disease.Further research is essential to clarify the functional role of C3orf67 in ciliary biology and its contribution to PCD pathogenesis.展开更多
Dear Editor,I am Dr.Ungsoo Samuel Kim.from Kim＇s Eye Hospital,Konyang University,Seoul,Korea.I write to present a novel mutation of GPR143 in Korean patients with X-linked congenital nystagmus by using exome sequenci...Dear Editor,I am Dr.Ungsoo Samuel Kim.from Kim＇s Eye Hospital,Konyang University,Seoul,Korea.I write to present a novel mutation of GPR143 in Korean patients with X-linked congenital nystagmus by using exome sequencing.Congenital nystagmus is an inherited ocular disorder that can occur as an X-linked condition.展开更多
The rare disease of chronic infantile neurological cutaneous and articular(CINCA)syndrome,is caused by the over-secretion of interleukin(IL)-1βdue to a gain-of-function NLRP3 gene mutation in the autosomal chromosome...The rare disease of chronic infantile neurological cutaneous and articular(CINCA)syndrome,is caused by the over-secretion of interleukin(IL)-1βdue to a gain-of-function NLRP3 gene mutation in the autosomal chromosome which often involves in eyes.In this report,we studied a 9-year-old girl with CINCA.The eyes were also involved and presented bilateral papilledema.Genetic testing revealed that the symptoms were caused by a novel gene mutation site(c.913G>A,p.D305N)in conservative domain exon-3 of NLRP3 which is gain-function gene of CINCA.The patient had the characteristic facial features,frontal fossa and saddle nose,manifested the generalized urticaria-like skin rash at two weeks after birth,periodic fever 6 months after birth,sensorineural deafness at 7 years old,and bilateral papilledema,aseptic meningitis and knee arthropathy at 9 years old.White cell counts,C-reactive protein increased and intracranial pressure raised to 300 mmH2O.The meningeal thickening enhanced by gadolinium in magnetic resonance imaging(MRI).Based on clinical features and genetic test,the girl was diagnosed bilateral papilledema secondary to CINCA and administered prednisone and lowered intracranial pressure medicine to resolve symptoms.With 3-year follow-up,patient had no inflammatory flare-up with visual acuity improvement.The finding of novel genetic mutation site(p.D305N)in NLRP3 gene expanded genotype spectrum associated with CINCA.This case also expanded the cause spectrum of papilledema and it highlighted systemic disease history for patients with bilateral papilledema.展开更多
Dear editor,I am Dr.Jie Peng,from the Department of Ophthalmology,Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai,China.I write to present a case report of a novel in-frame del...Dear editor,I am Dr.Jie Peng,from the Department of Ophthalmology,Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai,China.I write to present a case report of a novel in-frame deletion mutation c.17779del TAC of neurofibromatosis type 1 in a Chinese boy with bilateral blindness.Neurofibromatosis type 1(NF1;OMIM#162200),an autosomal dominant disease,is caused by mutations in the NF1gene.The incidence of this disease is around 1 in 3500展开更多
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
BACKGROUND Renal cysts and diabetes(RCAD)syndrome is an autosomal dominant diabetic renal disease.Precise molecular diagnosis of RCAD syndrome has proven valuable for understanding its mechanism and personalized thera...BACKGROUND Renal cysts and diabetes(RCAD)syndrome is an autosomal dominant diabetic renal disease.Precise molecular diagnosis of RCAD syndrome has proven valuable for understanding its mechanism and personalized therapy.CASE SUMMARY A RCAD patient and her family were studied to investigate potential responsible genes by the whole exome sequencing(WES).Candidate pathogenic variants were validated by Sanger sequencing.The clinical characteristics of RCAD patient were collected from medical records.Unlike those typical RCAD patients,we observed renal manifestation and prediabetes phenotype,but not reproductive organ phenotype and hypomagnesaemia.A novel 7-bp deletion mutation in exon 4 of the hepatocyte nuclear factor 1B,NM_000458:c.882_888del(p.V294fs),was identified by WES and confirmed by Sanger sequencing.CONCLUSION This novel mutation identified in a Chinese family with RCAD syndrome might be the molecular pathogenic basis of this disorder.展开更多
AIM:To assess the clinical and genetic characteristics of children diagnosed with retinoblastoma(RB)at Gazi University Faculty of Medicine’s Department of Pediatric Oncology.METHODS:All cases diagnosed with RB and re...AIM:To assess the clinical and genetic characteristics of children diagnosed with retinoblastoma(RB)at Gazi University Faculty of Medicine’s Department of Pediatric Oncology.METHODS:All cases diagnosed with RB and received treatment and follow-up in the Ophthalmology and Pediatric Oncology Department,October 2016 to May 2021 were evaluated retrospectively.The RB1 gene was analyzed by next-generation sequencing(NGS)technique in DNAs obtained from peripheral blood samples of the patients.RESULTS:This study included 53 cases with 67 RBaffected eyes during the study period.The mean age was 24.6(median:18.5,range:3–151)mo.There were 15(22.3%)Group D eyes and 39(58.2%)Group E eyes.The RB1 gene was sequenced by the NGS method in 19 patients.Heterozygous RB1:NM_000321.3:c.54_76del(p.Glu19AlafsTer4)variant was detected in a 15-month-old female with bilateral RB.Heterozygous RB1:NM_000321.3:c.1814+3A>T variant was detected in a 5.5-month-old male with bilateral RB.The intronic RB1:NM_000321.3:c.1332+4A>G variant was detected in patient 14,a 13-month-old male with unilateral RB.The RB1:NM_000321.3:c.575_576del(p.Lys192SerfsTer10)variant was found in an 18-month-old female with an allele frequency of 37%.These variants have not been reported in the literature and mutation databases.CONCLUSION:Four novel variants are described and one of them is found in two different patients.This data is crucial for assessing prognosis.It serves as a guide for estimating the long-term risk of secondary malignancy as well as the short-term risk of developing additional malignancies in the same eye and the other eye.展开更多
Background: Mutations in the RPGR gene are associated with rod-cone or cone-rod dystrophy, the latter associated with mutations at the distal end. Cone-rod dystrophy (CRD) is a subgroup of hereditary retinal disorders...Background: Mutations in the RPGR gene are associated with rod-cone or cone-rod dystrophy, the latter associated with mutations at the distal end. Cone-rod dystrophy (CRD) is a subgroup of hereditary retinal disorders characterized by the primary degeneration of cone photoreceptors often followed by progressive loss of rod photoreceptors in the peripheral visual field. Purpose: The aim of this study was to describe the milder CRD phenotype associated with a novel pathogenic variant c.1905 + 223C > T (p.Q710X) found in RPGR which results in shortening of the photoreceptor specific isoform RPGR <sup>ORF15</sup>. Method: An 11-year-old boy with symptoms of CRD and two female relatives were referred for detailed ophthalmic examinations. Genetic testing was performed by next-generation sequencing of clinical exome followed by Sanger sequencing for segregation analysis. Results: Genetic analysis identified a novel variant in ORF15 of the RPGR gene (c.1905 + 223C > T, p.Q710X) in the proband considered as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) standards. Segregation study identified the mutation in a heterozygous state in the mother and her sister. Detailed ophthalmological examination revealed slightly reduced color vision and scattered grayish point-like deposits in the posterior pole of the fundus in the male patient. All mutation carriers were myopic. Conclusion: We report a novel pathogenic RPGR variant in a Bulgarian patient with clinical features compatible with the CRD diagnosis. This condition is inherited as an X-linked dominant trait in its familial form presenting with a mild CRD phenotype in the male hemizygous proband and a moderate to high myopia in the female heterozygous carriers.展开更多
Background Retinitis pigmentosa(RP)is a genetically and clinically heterogeneous group of hereditary degenerative disorders affecting approximately one in every 4000 people worldwide.Abnormalities in the retina's ...Background Retinitis pigmentosa(RP)is a genetically and clinically heterogeneous group of hereditary degenerative disorders affecting approximately one in every 4000 people worldwide.Abnormalities in the retina's photoreceptors can cause night blindness or even complete vision loss.Retinitis Pigmentosa 1(RP1),also known as the oxygen-regulated protein-1,is a microtubule-associated protein(MAP)that organizes the outer segment of the photoreceptor.Besides,mutations in the RP1 gene are associated with dominant or recessive form of RP.This study aims to identify the potential pathogenic genes in Chinese RP patients and to elucidate the association relationship between the mutant gene and the phenotypes.Methods Multiple ophthalmic examinations,whole-exome sequencing,sanger sequencing,and in silico analysis were performed to evaluate the clinical features and pathogenic genes in a five-generation Chinese family diagnosed with RP.Results Our findings revealed a novel truncating mutation c.2015_2018del p.(Lys672Argfs∗9)in RP1 that may result in the translation of a protein with deleterious effects on photoreceptors.Therefore,resulting in autosomal dominant retinitis pigmentosa(ADRP).Conclusions This study broaden the range of genetic mutations associated with RP1 in ADRP and make a valuable contribution to the ongoing endeavors aimed at characterizing the molecular aspects of Chinese ADRP.Future studies would pay more attention in determining the characterization of the mutantations in RP1 gene and the relationship between genotype and phenotype in RP patients.展开更多
基金Supported by Chulalongkorn University,National Science and Technology Development Agency,and the Thailand Research Fund
文摘Peutz-Jeghers syndrome （PJS）, a rare autosomal dominant inherited disorder, is characterized by hamartomatous gastrointestinal polyps and mucocutaneous pigmentation. Patients with this syndrome have a predisposition to a variety of cancers in multiple organs. Mutations in the serine/threonine kinase 11 （STK11） gene have been identified as a major cause of PJS. Here we present the clinical and molecular findings of two unrelated Thai individuals with PJS. Mutation analysis by Polymerase Chain Reaction-sequencing of the entire coding region of STK11 revealed two potentially pathogenic mutations. One harbored a single nucleotide deletion （c.182delG） in exon 1 resulting in a frameshift leading to premature termination at codon 63 （p.Gly61AlafsX63）. The other carried an in-frame 9-base-pair （bp） deletion in exon 7, c.907_915del9 （p.Ile303_GIn305del）. Both deletions were de novo and have never been previously described. This study has expanded the genotypic spectrum of the STK11 gene.
基金supported by grants of the Tianjin Binhai New Area Science and Technology Commission(No.2011-BK120011)Shenzhen Engineering Laboratory for Clinical Molecular Diagnostic,the Shenzhen Municipal Government of China(No.CXZZ20130517144604091)and China National GeneB ank-Shenzhen
文摘Objective To determine the nosogenetic factors of a 46,XY female with primary amenorrhea and unilateral mixed germ cell tumor.Methods Eight genes associated with 46,XY gonadal dysgenesis were detected in the patient and her parents by target region captured-next generation sequencing.Results An insertion of a single nucleotide（adenine） at the coding site 230（c.230231insA） located in the high mobility group（HMG） domain of SRY was revealed,which led to a truncated protein（p.Lys77 fsX 27）. This mutation was at position 2655414 of the Y chromosome, supported with 127 unique mapped reads, however, this mutation was not found in the in-house dataset of 1 092 controls. Additionally, none of the candidate gene was detected in the patient’s parents, which indicated that it is a de novo mutation.Conclusion A novel SRY sporadic mutation due to a single nucleotide insertion at position 230（c.230231insA） was identified as the cause of the disease in this patient.Target region captured-next generation sequencing was found to be an effective method for the molecular genetic testing of 46,XY complete gonadal dysgenesis（46,XY CGD）.
文摘Mutations in the X-linked androgen receptor （AR） gene cause androgen insensitivity syndrome （AIS）, resulting in an impaired embryonic sex differentiation in 46,XY genetic men. Complete androgen insensitivity （CAIS） produces a female external phenotype, whereas cases with partial androgen insensitivity （PALS） have various ambiguities of the genitalia. Mild androgen insensitivity （MAIS） is characterized by undermasculinization and gynecomastia. Here we describe a 2-month-old 46,XY female patient, with all of the characteristics of CAIS. Defects in testosterone （T） and dihydrotestosterone （DHT） synthesis were excluded. Sequencing of the AR gene showed the presence in exon 6 of a T to C transition in the second base of codon 790, nucleotide position 2369, causing a novel missense Leu790Pro mutation in the ligand-binding domain of the AR protein. The identification of a novel AR mutation in a girl with CAIS provides significant information due to the importance of missense mutations in the ligand-binding domain of the AR, which are able to induce functional abnormalities in the androgen binding capability, stabilization of active conformation, or interaction with coactivators.
文摘AIM:To detect and segregate causative mutations in congenital families with optic nerve hypoplasia(ONH).M E T H O D S:Two unrel a ted consanguineous Pakistani families with severe ONH,showing features of micropthalmia,nystagmus,corneal opacity,and keratopathy were included.Genetic analysis was carried out by Target Panel Sequencing,and the nucleotide variant was confirmed by Sanger sequencing.In silico analyses were carried out to study the protein order-disorder functions and their effects on messenger ribonucleic acid(mRNA).RESULTS:Target panel sequencing revealed that the afflicted family members carried a novel frameshift mutation(NM_145178.4;c.91del G;p.Gly31Glyfs*55)that ensued in the conservation of an amino acid residue in the bHLH domain of ATOH7 protein.In silico studies predicted that the activity of the ATOH7 gene is probably affected by this mutation,which results in a shortened and nonfunctional protein.Three-dimensional structural analysis shows that DNA binding may be impacted by amino acid changes from non-polar to positively charged and vice versa(Arg42Pro and Pro18Arg),as well as from positively charged(Arg)to a small polar amino acid(Gly).CONCLUSION:A novel ATOH7 mutation is harmful.This study also emphasizes the potential effects of modified ATOH7 configurations on the stability and functionality of proteins.
基金supported by the National Natural Science Foundation of China(No.82070975,82301213)the Shanghai Science and Technology Commission of China(No.21ZR1411400)the Shanghai Hospital Development Center Foundation(SHDC12023116).
文摘First described by Meredith in 1987,retinal venous beading(RVB)is an extremely rare and potentially vision-threat-ening disease,^(1)which is characterized by beading or sausage-like configuration of retinal veins.It can present with episodes of increased vascular permeability accom-panied by lipid exudation,foveal edema,recurrent branch vein occlusion,retinal ischemia with retinal neo-vascularization,and vitreous hemorrhage,^(1)or exist solely and asymptomatically.^(2)
基金We thank the members for the participation.This study was supported by the grants from the Key Program of Chongqing Health and Family Planning Commission(NO.[2013]39:2013-1-029).
文摘Pseudoachondroplasia(PSACH)is a relatively common skeletal dysplasia characterized by disproportionate short stature,joint laxity,early-onset osteoarthrosis,and dysplasia of the spine,epiphysis,and metaphysis.It is known as an autosomal dominant disease which results exclusively from mutations in the gene for Cartilage Oligomeric Matrix Protein(COMP).We have identified a five year old Chinese boy who was diagnosed as pseudoachondroplasia according to clinical manifestations and X-ray symptoms.His mother seems like another effected individual because of the apparent short stature.Genomic DNA was extracted from peripheral blood lymphocytes.DNA sequencing analysis of the COMP gene revealed a heterozygous mutation(c.1219 T>C,p.Cys407Arg)in the patient.His mother was also affected with the same genetic change.Mutations in COMP gene is proved to change the Cartilage Oligomeric Matrix Protein.This missense mutation(c.1219 T>C)has not been reported before and it is not belongs to polymorphism sites.Our results extend the spectrum of mutations in COMP gene leading to pseudoachondroplasia.
基金Supported by the National Natural Science Foundation of China(No.81500763,No.81800805,No.81600721)Young and Middle-aged Scientists Research Awards Fund of Shandong Province(No.BS2015YY014)+1 种基金China Postdoctoral Science Foundation(No.2019M652311)Medical and Health Science and Technology Development Project of Shandong Province(No.2017WS012)。
文摘AIM: To identify the disease-associated mutations in a Chinese Stargardt disease(STGD) family, extend the existing spectrum of disease-causing mutations and further define the genotype-phenotype correlations.METHODS: A Chinese STGD family and 200 normal controls were collected. Whole exome sequencing(WES) and bioinformatics analysis were performed to find the pathogenic gene mutation. Physico-chemical parameters of mutant and wildtype proteins were computed by Prot Param tool. Domains analysis was performed by SMART online software. HOPE online software was used to analyze the structural effects of mutation. Immunofluorescence, quantitative real-time polymerase chain reaction and Western blotting were used for expression analysis.RESULTS: Using WES, a novel homozygous mutation(NM_000350: c.G3190 C, p.G1064 R) in ABCA4 gene was identified. This mutation showed co-segregation with phenotype in this family. It was not found in the 200 unrelated health controls and absent from any databases. It was considered "Deleterious" as predicted by five function prediction softwares, and was highly conserved during evolution. ABCA4 was expressed highly in the human eye and mouse retina. The p.G1064 R was located in AAA domain, may force the local backbone into an incorrect conformation, disturb the local structure, and reduce the activity of ATPase resulting in the disease pathology. CONCLUSION: We define a novel pathogenic mutation(c.G3190 C of ABCA4) of STGD. This extends the existing spectrum of disease-causing mutations and further defines the genotype-phenotype correlations.
基金This work was supported by a grant of the National Natural Science Foundation of China （No. 81771358）.
文摘Background： Myoclonic epilepsy with ragged red fibers （MERRF） syndrome is characterized by myoclonus, generalized epilepsy, cerebellar ataxia, and ragged red fibers （RRFs） in the muscle. T-to-C transition at nucleotide position 14709 in the mitochondrial tRNA glutamic acid （tRNA^Gla） gene has previously been associated with maternally inherited diabetes and deathess. However, the association between MERRF and mitochondrial T14709C mutation （m.TI4709C） has never been reported before. Methods： Clinical information of a 17-year-old patient was collected; muscle biopsy and next-generation sequencing （NGS） of whole mitochondrial and neuromuscular disease panel were then conducted. Finally, sanger sequencing was carried out to confirm the mutations. Results： The patient presented a typical MERRF phenotype with muscle weakness, epileptic seizure, clonic episodes, cerebellar ataxia, and spinal scoliosis. Muscle biopsy showed RRFs which indicated abnormal mitochondrial functions. NGS of whole mitochondrial gene revealed m.TI4709C mutation, confirmed by Sanger sequencing. Conclusion： We present a sporadic patient with typical MERRF presentation carrying the mutation ofm.T14709C, which expanded the spectrum of re.T14709C.
文摘Background：H syndrome （OMIM 612391） is a recently described autosomal recessive genodermatosis characterized by indurated hyperpigmented and hypertrichotic skin,as well as other systemic manifestations.Most of the cases occurred in the Middle East areas or nearby countries such as Spain or India.The syndrome is caused by mutations in solute carrier family 29,member 3 （SLC29A3）,the gene encoding equilibrative nucleoside transporter 3.The aim of this study was to identify pathogenic SLC29A 3 mutations in a Chinese patient clinically diagnosed with H syndrome.Methods：Peripheral blood samples were collected from the patient and his parents.Genomic DNA was isolated by the standard method.All six SLC29A3 exons and their flanking intronic sequences were polymerase chain reaction （PCR）-amplified and the PCR products were subjected to direct sequencing.Results：The patient,an 18-year-old man born to a nonconsanguineous Chinese couple,had more extensive cutaneous lesions,involving both buttocks and knee.In his genomic DNA,we identified a novel homozygous insertion-deletion,c.1269_1270delinsA,in SLC29A3.Both of his parents were carriers of the mutation.Conclusions：We have identified a pathogenic mutation in a Chinese patient with H syndrome.
文摘BACKGROUND Dyskeratosis congenita is a rare disease characterized by bone marrow failure and a clinical triad of oral leukoplakia,nail dystrophy,and abnormal skin pigmentation.The genetics of dyskeratosis congenita include mutations in genes involved in telomere maintenance,including TINF2.CASE SUMMARY Here,we report a female patient who presented thrombocytopenia,anemia,reticulate hyperpigmentation,dystrophy in fingernails and toenails,and leukoplakia on the tongue.A histopathological study of the skin showed dyskeratocytes;however,a bone marrow biopsy revealed normal cell morphology.The patient was diagnosed with dyskeratosis congenita,but her family history did not reveal significant antecedents.Whole-exome sequencing showed a novel heterozygous punctual mutation in exon 6 from the TINF2 gene,namely,NM_001099274.1:-c.854delp.(Val285-Alafs*32).An analysis of telomere length showed short telomeres relative to the patient’s age.CONCLUSION The disease in this patient was caused by a germline novel mutation of TINF2 in one of her parents.
文摘BACKGROUND Acute intermittent porphyria(AIP)is a rare autosomal dominant porphyrin metabolic disease caused by a mutation in the hydroxymethylbilane synthase(HMBS)gene.This study aimed to explore the clinical manifestations of a patient with AIP,to identify a novel HMBS gene mutation in the proband and some of her family members,and to confirm the pathogenicity of the variant.CASE SUMMARY A 22-year-old Chinese woman developed severe abdominal pain,lumbago,sinus tachycardia,epileptic seizure,hypertension,and weakness in lower limbs in March,2018.Biochemical examinations indicated hypohepatia and hyponatremia.Her last menstrual period was 45 d prior to admission,and she was unaware of the pregnancy,which was confirmed by a pregnancy test after admission.Sunlight exposure of her urine sample for 1 h turned it from yellow to wine red.Urinary porphyrin test result was positive.Based on these clinical manifestations,AIP was diagnosed.After increasing her daily glucose intake(250–300 g/d),abdominal pain was partially relieved.Three days after hospitalization,spontaneous vaginal bleeding occurred,which was confirmed as spontaneous abortion;thereafter,her clinical symptoms completely resolved.Genetic testing revealed a novel heterozygous splicing variant of the HMBS gene in exon 10(c.648_651+1delCCAGG)in the proband and four other family members.The pathogenicity of the variant was verified through bioinformatic methods and a minigene assay.CONCLUSION We identified a novel HMBS gene mutation in a Chinese patient with AIP and confirmed its pathogenicity.
文摘BACKGROUND Primary ciliary dyskinesia(PCD)is a rare genetic disorder caused by motile cilia dysfunction.Identifying pathogenic variants is essential for diagnosis and personalized care,especially in consanguineous populations like Saudi Arabia.CASE SUMMARY This report presents a Saudi pediatric patient diagnosed with PCD who exhibited persistent neonatal tachypnea,chronic productive cough,and recurrent otitis media.Whole-exome sequencing revealed a novel homozygous nonsense variant in the C3orf67 gene(NM_198463.2:c.508C>T),resulting in a truncated,nonfunctional protein.This mutation likely impairs ciliary motility due to the production of a truncated,non-functional protein.The clinical findings were supported by multiple positive sputum cultures and a significant family history of similar symptoms,suggesting a genetic etiology consistent with autosomal recessive inheritance.CONCLUSION This case highlights the importance of genetic studies in diagnosing PCD,particularly in communities with a high rate of consanguinity.The identification of a novel homozygous variant in the C3orf67 gene expands the known genetic landscape of the disease.Further research is essential to clarify the functional role of C3orf67 in ciliary biology and its contribution to PCD pathogenesis.
文摘Dear Editor,I am Dr.Ungsoo Samuel Kim.from Kim＇s Eye Hospital,Konyang University,Seoul,Korea.I write to present a novel mutation of GPR143 in Korean patients with X-linked congenital nystagmus by using exome sequencing.Congenital nystagmus is an inherited ocular disorder that can occur as an X-linked condition.
文摘The rare disease of chronic infantile neurological cutaneous and articular(CINCA)syndrome,is caused by the over-secretion of interleukin(IL)-1βdue to a gain-of-function NLRP3 gene mutation in the autosomal chromosome which often involves in eyes.In this report,we studied a 9-year-old girl with CINCA.The eyes were also involved and presented bilateral papilledema.Genetic testing revealed that the symptoms were caused by a novel gene mutation site(c.913G>A,p.D305N)in conservative domain exon-3 of NLRP3 which is gain-function gene of CINCA.The patient had the characteristic facial features,frontal fossa and saddle nose,manifested the generalized urticaria-like skin rash at two weeks after birth,periodic fever 6 months after birth,sensorineural deafness at 7 years old,and bilateral papilledema,aseptic meningitis and knee arthropathy at 9 years old.White cell counts,C-reactive protein increased and intracranial pressure raised to 300 mmH2O.The meningeal thickening enhanced by gadolinium in magnetic resonance imaging(MRI).Based on clinical features and genetic test,the girl was diagnosed bilateral papilledema secondary to CINCA and administered prednisone and lowered intracranial pressure medicine to resolve symptoms.With 3-year follow-up,patient had no inflammatory flare-up with visual acuity improvement.The finding of novel genetic mutation site(p.D305N)in NLRP3 gene expanded genotype spectrum associated with CINCA.This case also expanded the cause spectrum of papilledema and it highlighted systemic disease history for patients with bilateral papilledema.
文摘Dear editor,I am Dr.Jie Peng,from the Department of Ophthalmology,Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai,China.I write to present a case report of a novel in-frame deletion mutation c.17779del TAC of neurofibromatosis type 1 in a Chinese boy with bilateral blindness.Neurofibromatosis type 1(NF1;OMIM#162200),an autosomal dominant disease,is caused by mutations in the NF1gene.The incidence of this disease is around 1 in 3500
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.
文摘BACKGROUND Renal cysts and diabetes(RCAD)syndrome is an autosomal dominant diabetic renal disease.Precise molecular diagnosis of RCAD syndrome has proven valuable for understanding its mechanism and personalized therapy.CASE SUMMARY A RCAD patient and her family were studied to investigate potential responsible genes by the whole exome sequencing(WES).Candidate pathogenic variants were validated by Sanger sequencing.The clinical characteristics of RCAD patient were collected from medical records.Unlike those typical RCAD patients,we observed renal manifestation and prediabetes phenotype,but not reproductive organ phenotype and hypomagnesaemia.A novel 7-bp deletion mutation in exon 4 of the hepatocyte nuclear factor 1B,NM_000458:c.882_888del(p.V294fs),was identified by WES and confirmed by Sanger sequencing.CONCLUSION This novel mutation identified in a Chinese family with RCAD syndrome might be the molecular pathogenic basis of this disorder.
文摘AIM:To assess the clinical and genetic characteristics of children diagnosed with retinoblastoma(RB)at Gazi University Faculty of Medicine’s Department of Pediatric Oncology.METHODS:All cases diagnosed with RB and received treatment and follow-up in the Ophthalmology and Pediatric Oncology Department,October 2016 to May 2021 were evaluated retrospectively.The RB1 gene was analyzed by next-generation sequencing(NGS)technique in DNAs obtained from peripheral blood samples of the patients.RESULTS:This study included 53 cases with 67 RBaffected eyes during the study period.The mean age was 24.6(median:18.5,range:3–151)mo.There were 15(22.3%)Group D eyes and 39(58.2%)Group E eyes.The RB1 gene was sequenced by the NGS method in 19 patients.Heterozygous RB1:NM_000321.3:c.54_76del(p.Glu19AlafsTer4)variant was detected in a 15-month-old female with bilateral RB.Heterozygous RB1:NM_000321.3:c.1814+3A>T variant was detected in a 5.5-month-old male with bilateral RB.The intronic RB1:NM_000321.3:c.1332+4A>G variant was detected in patient 14,a 13-month-old male with unilateral RB.The RB1:NM_000321.3:c.575_576del(p.Lys192SerfsTer10)variant was found in an 18-month-old female with an allele frequency of 37%.These variants have not been reported in the literature and mutation databases.CONCLUSION:Four novel variants are described and one of them is found in two different patients.This data is crucial for assessing prognosis.It serves as a guide for estimating the long-term risk of secondary malignancy as well as the short-term risk of developing additional malignancies in the same eye and the other eye.
文摘Background: Mutations in the RPGR gene are associated with rod-cone or cone-rod dystrophy, the latter associated with mutations at the distal end. Cone-rod dystrophy (CRD) is a subgroup of hereditary retinal disorders characterized by the primary degeneration of cone photoreceptors often followed by progressive loss of rod photoreceptors in the peripheral visual field. Purpose: The aim of this study was to describe the milder CRD phenotype associated with a novel pathogenic variant c.1905 + 223C > T (p.Q710X) found in RPGR which results in shortening of the photoreceptor specific isoform RPGR <sup>ORF15</sup>. Method: An 11-year-old boy with symptoms of CRD and two female relatives were referred for detailed ophthalmic examinations. Genetic testing was performed by next-generation sequencing of clinical exome followed by Sanger sequencing for segregation analysis. Results: Genetic analysis identified a novel variant in ORF15 of the RPGR gene (c.1905 + 223C > T, p.Q710X) in the proband considered as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) standards. Segregation study identified the mutation in a heterozygous state in the mother and her sister. Detailed ophthalmological examination revealed slightly reduced color vision and scattered grayish point-like deposits in the posterior pole of the fundus in the male patient. All mutation carriers were myopic. Conclusion: We report a novel pathogenic RPGR variant in a Bulgarian patient with clinical features compatible with the CRD diagnosis. This condition is inherited as an X-linked dominant trait in its familial form presenting with a mild CRD phenotype in the male hemizygous proband and a moderate to high myopia in the female heterozygous carriers.
基金funded by the Project from the Science Technology Department of Zhejiang Province[No.LGC19H120002]the Natural Science Foundation of Zhejiang Province[No.LQ22C070004]National Natural Science Foundation of China[No.82271065 and No.82471154].
文摘Background Retinitis pigmentosa(RP)is a genetically and clinically heterogeneous group of hereditary degenerative disorders affecting approximately one in every 4000 people worldwide.Abnormalities in the retina's photoreceptors can cause night blindness or even complete vision loss.Retinitis Pigmentosa 1(RP1),also known as the oxygen-regulated protein-1,is a microtubule-associated protein(MAP)that organizes the outer segment of the photoreceptor.Besides,mutations in the RP1 gene are associated with dominant or recessive form of RP.This study aims to identify the potential pathogenic genes in Chinese RP patients and to elucidate the association relationship between the mutant gene and the phenotypes.Methods Multiple ophthalmic examinations,whole-exome sequencing,sanger sequencing,and in silico analysis were performed to evaluate the clinical features and pathogenic genes in a five-generation Chinese family diagnosed with RP.Results Our findings revealed a novel truncating mutation c.2015_2018del p.(Lys672Argfs∗9)in RP1 that may result in the translation of a protein with deleterious effects on photoreceptors.Therefore,resulting in autosomal dominant retinitis pigmentosa(ADRP).Conclusions This study broaden the range of genetic mutations associated with RP1 in ADRP and make a valuable contribution to the ongoing endeavors aimed at characterizing the molecular aspects of Chinese ADRP.Future studies would pay more attention in determining the characterization of the mutantations in RP1 gene and the relationship between genotype and phenotype in RP patients.
