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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 41(2): 140-144, 2024 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-38311550

RESUMO

OBJECTIVE: To analyze the clinical and genetic characteristics of ten Chinese pedigrees affected with 7q11.23 duplication syndrome. METHODS: From December 2017 to January 2022, ten pedigrees diagnosed with 7q11.23 duplication syndrome at the First Affiliated Hospital of Zhengzhou University were enrolled as the study subjects. Clinical data of all subjects were collected, and some had subjected to copy number variation sequencing or single nucleotide polymorphism array to analyze the pattern of inheritance. RESULTS: The probands had included six fetuses and four adolescents. Four of the six prenatal cases showed abnormal ultrasound indicators, including three with soft indicators and one with abnormal fetal structural development. The clinical phenotype of the four adolescent cases had included mental retardation, delayed language development, and attention deficit hyperactivity disorder. The size of the copy number variations had ranged from 1.31 to 1.42 Mb, involving the classic region of 7q11.23 duplication syndrome. Of these, five cases had undergone parental origin testing, three cases were de novo, and two were hereditary. CONCLUSION: Individuals with 7q11.23 duplication syndrome may show substantial clinical phenotypic heterogeneity, hence the affected families should be provided with pre-pregnancy consultation and reproductive guidance.


Assuntos
Variações do Número de Cópias de DNA , Deficiência Intelectual , Gravidez , Feminino , Adolescente , Humanos , Linhagem , Deficiência Intelectual/genética , Síndrome , China
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 41(2): 167-173, 2024 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-38311554

RESUMO

OBJECTIVE: To explore the genetic etiology of two children with Spinal muscular atrophy with respiratory distress type 1 (SMARD1), and prevent the recurrence of birth defects. METHODS: Two unrelated families who had visited the Obstetrics and Gynecology Medical Center of Drum Tower Hospital from August to November 2021 were selected as the study subjects. Copy number of SMN1 gene exon 7 for the probands and their parents was detected by multiple ligation-dependent probe amplification (MLPA). and whole exome sequencing (WES) was carried out to screen the variants in the probands. Sanger sequencing was used to validate the variants within the families. Pathogenicity of the variants were predicted by bioinformatic analysis. Based on the results, prenatal diagnosis was performed for the fetuses. RESULTS: Both probands were found to harbor compound heterozygous variants of the IGHMBP2 gene, which were inherited from their parents. Among these, c.1144C>T, c.866delG and c.1666C>G were previously unreported and respectively classified as pathogenic variant (PVS1+PM2_Supporting+PP3+PP4), likely pathogenic variant (PM1+PM2_Supporting+PM4+PP3+PP4) and likely pathogenic variant (PM1+PM2_Supporting+PP2+PP3+PP4) based on the ACMG guidelines. Through preimplantation genetic testing for monogenic (PGT-M) and interventional prenatal diagnosis, transmission of the variants within the families was successfully blocked. CONCLUSION: The SMARD1 in both children may be attributed to the compound heterozygous variants of the IGHMBP2 gene, which has facilitated the genetic diagnosis and counselling, and provided reference for delineating the molecular pathogenesis of this disease.


Assuntos
Atrofia Muscular Espinal , Síndrome do Desconforto Respiratório do Recém-Nascido , Gravidez , Criança , Feminino , Humanos , Linhagem , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/genética , Diagnóstico Pré-Natal , China , Mutação , Proteínas de Ligação a DNA/genética , Fatores de Transcrição/genética
3.
Artigo em Chinês | MEDLINE | ID: mdl-38297846

RESUMO

Objective:To dentify the genetic and audiological characteristics of families affected by late-onset hearing loss due to GSDMEgene mutations, aiming to explore clinical characteristics and pathogenic mechanisms for providing genetic counseling and intervention guidance. Methods:Six families with late-onset hearing loss from the Chinese Deafness Genome Project were included. Audiological tests, including pure-tone audiometry, acoustic immittance, speech recognition scores, auditory brainstem response, and distortion product otoacoustic emission, were applied to evaluate the hearing levels of patients. Combining with medical history and physical examination to analyze the phenotypic differences between the probands and their family members. Next-generation sequencing was used to identify pathogenic genes in probands, and validations were performed on their relatives by Sanger sequencing. Pathogenicity analysis was performed according to the American College of Medical Genetics and Genomics Guidelines. Meanwhile, the pathogenic mechanisms of GSDME-related hearing loss were explored combining with domestic and international research progress. Results:Among the six families with late-onset hearing loss, a total of 30 individuals performed hearing loss. The onset of hearing loss in these families ranged from 10 to 50 years(mean age: 27.88±9.74 years). In the study, four splicing mutations of the GSDME were identified, including two novel variants: c. 991-7C>G and c. 1183+1G>T. Significantly, the c. 991-7C>G was a de novo variant. The others were previously reported variants: c. 991-1G>C and c. 991-15_991-13del, the latter was identified in three families. Genotype-phenotype correlation analysis revealed that probands with the c. 991-7C>G and c. 1183+1G>T performed a predominantly high-frequency hearing loss. The three families carrying the same mutation exhibited varying degrees of hearing loss, with an annual rate of hearing deterioration exceeding 0.94 dB HL/year. Furthermore, follow-up of interventions showed that four of six probands received intervention(66.67%), but the results of intervention varied. Conclusion:The study analyzed six families with late-onset non-syndromic hearing loss linked to GSDME mutations, identifying four splicing variants. Notably, c. 991-7C>G is the first reported de novo variant of GSDME globally. Audiological analysis revealed that the age of onset generally exceeded 10 years,with variable effectiveness of interventions.


Assuntos
Surdez , Perda Auditiva Neurossensorial , Perda Auditiva , Humanos , Adolescente , Adulto Jovem , Adulto , Criança , Perda Auditiva Neurossensorial/diagnóstico , Surdez/genética , Mutação , Perda Auditiva/genética , Linhagem
4.
Artigo em Chinês | MEDLINE | ID: mdl-38297847

RESUMO

Objective:To analyze the phenotype and genotype characteristics of autosomal recessive hearing loss caused by MYO15A gene variants, and to provide genetic diagnosis and genetic counseling for patients and their families. Methods:Identification of MYO15A gene variants by next generation sequencing in two sporadic cases of hearing loss at Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. The sequence variants were verified by Sanger sequencing.The pathogenicity of these variants was determined according to the American College of Medical Genetics and Genomics(ACMG) variant classification guidelines, in conjuction with clinical data. Results:The probands of the two families have bilateral,severe or complete hearing loss.Four variants of MYO15A were identified, including one pathogenic variant that has been reported, two likely pathogenic variants,and one splicing variant of uncertain significance. Patient I carries c. 3524dupA(p. Ser1176Valfs*14), a reported pathogenic variant, and a splicing variant c. 10082+3G>A of uncertain significance according to the ACMG guidelines. Patient I was treated with bilateral hearing aids with satisfactory effect, demonstrated average hearing thresholds of 37.5 dB in the right ear and 33.75 dB in the left ear. Patient Ⅱ carries c. 7441_7442del(p. Leu2481Glufs*86) and c. 10250_10252del(p. Ser3417del),a pair of as likely pathogenic variants according to the ACMG guidelines. Patient Ⅱ, who underwent right cochlear implantation eight years ago, achieved scores of 9 on the Categorical Auditory Performance-Ⅱ(CAP-Ⅱ) and 5 on the Speech Intelligibility Rating(SIR). Conclusion:This study's discovery of the rare c. 7441_7442del variant and the splicing variant c. 10082+3G>A in the MYO15A gene is closely associated with autosomal recessive hearing loss, expanding the MYO15A variant spectrum. Additionally, the pathogenicity assessment of the splicing variant facilitates classification of splicing variations.


Assuntos
Surdez , Perda Auditiva Neurossensorial , Perda Auditiva , Humanos , Linhagem , China , Surdez/genética , Perda Auditiva/genética , Fenótipo , Perda Auditiva Neurossensorial/genética , Mutação , Miosinas/genética
5.
Vet Rec ; 194(3): 121, 2024 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-38305517

RESUMO

Technology and estimated breeding values are the key to breeding dogs that will live long and have desired behaviour and good health and welfare, argue Aashild Roaldset and Eva Breuer Hustoft.


Assuntos
Bem-Estar do Animal , Doenças do Cão , Endogamia , Animais , Cães , Doenças do Cão/prevenção & controle , Linhagem , Tecnologia
6.
Int J Mol Sci ; 25(3)2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38339041

RESUMO

Sporadic hemophilia A (HA) enables the persistence of HA in the population. F8 gene inversion originates mainly in male germ cells during meiosis. To date, no studies have shown the origin and timing of HA sporadic noninversion variants (NIVs); herein, we assume that HA-sporadic NIVs are generated as a de novo variant. Of the 125 registered families with HA, 22 were eligible for inclusion. We conducted a linkage analysis using F8 gene markers and amplification refractory mutation system-quantitative polymerase chain reaction to confirm the origin of the sporadic NIVs (~0% mutant cells) or the presence of a mosaic variant, which requires further confirmation of the origin in the parent. Nine mothers, four maternal grandmothers, and six maternal grandfathers were confirmed to be the origin of sporadic NIVs, which most likely occurred in the zygote within the first few cell divisions and in single sperm cells, respectively. Three mothers had mosaic variants, which most likely occurred early in postzygotic embryogenesis. All maternal grandparents were free from sporadic NIV. In conclusion, F8 NIVs in sporadic HA were found to be caused primarily by de novo variants. Our studies are essential for understanding the genetic pathogenesis of HA and improving current genetic counseling.


Assuntos
Hemofilia A , Masculino , Humanos , Hemofilia A/genética , Hemofilia A/patologia , Linhagem , Sêmen , Mutação , Inversão Cromossômica , Fator VIII/genética
7.
Clin Lab ; 70(2)2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38345986

RESUMO

BACKGROUND: von Willebrand disease (vWD), caused by mutations in the von Willebrand factor (vWF) coding gene, is a disease characterized by abnormal coagulation activity and a severe tendency for hemorrhage. Therefore, identifying mutations in vWF is important for diagnosing congenital vWD. METHODS: We studied a 23-year-old male vWD patient and his parents. Clotting methods were used to determine activated partial thromboplastin time (aPTT), prothrombin time (PT), fibrinogen (FIB) levels, FVIII activity. Chromogenic substrate method was used to determine vWF antigen and activity. The platelet count was determined. Mutations were searched using whole-exome sequencing and certified by Sanger sequencing. Clinical data, including activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), fibrinogen levels, FX activity, FX antigen levels, and the platelet count were collected. A mixing study was performed to eliminate the presence of coagulation factor inhibitors and lupus anticoagulants. Mutations were screened by using whole-exome sequencing (WES) and were verified by using Sanger sequencing. RESULTS: The proband showed severely decreased vWF antigen, vWF activity, and FVIII activity. RIPA (RISTO-CETIN-induced platelet aggregation) was 0%. Data from WES showed that the proband carried compound heterozygous variants vWF: NM_000552.5 (c.3213C>A p.Cys1071Ter) and vWF: NM_000552.5 (c.6598+2T>C). The proband's mother carried variant vWF: NM_000552.5 (c.3213C>A p.Cys1071Ter) while the proband's father carried variant vWF: NM_000552.5 (c.6598+2T>C). All laboratory test indexes of the proband's parents, including vWF antigen, vWF activity, and FVIII activity, were within the normal ranges. CONCLUSIONS: We identified a compound heterozygosis with two novel mutations in vWF (c.3213C>A, c.6598+2T >C) in a family pedigree, and our results demonstrate that the compound heterozygous mutations probably exacerbate vWD.


Assuntos
Doenças de von Willebrand , Fator de von Willebrand , Masculino , Humanos , Adulto Jovem , Adulto , Fator de von Willebrand/genética , Doenças de von Willebrand/diagnóstico , Doenças de von Willebrand/genética , Linhagem , Mutação , Fibrinogênio , China
8.
Medicine (Baltimore) ; 103(5): e36977, 2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38306576

RESUMO

RATIONALE: Congenital heart disease (CHD) is the most common birth defect and an important cause of noninfectious deaths in infants and children. It has high prevalence globally, placing an enormous burden on society and families. Studies of individuals with hereditary or sporadic CHD have provided strong evidence for its genetic basis. The aim of this study was to identify causative gene variants in a Chinese family with congenital heart disease. PATIENT CONCERNS AND DIAGNOSES: Three generations of a CHD family were recruited. Proband III.9 was diagnosed with congenital heart disease at age 11 months, and the echocardiogram showed arterial ductus arteriosus, with a left-to-right shunt at the level of the arteries. Precedent III.10 was a twin of Proband III.9 who was diagnosed with congenital heart disease at age 11 months, in whom the echocardiogram revealed an arterial ductus arteriosus, an unenclosed patent ductus arteriosus, and a left to right shunt at the level of the arteries (second figure). III.8 was diagnosed with congenital heart disease at age 15, but echocardiography in this study showed no abnormalities. No cardiac abnormalities were detected in any of his parents, grandparents, or maternal grandparents. We performed whole-exome sequencing on CHD sufferers and their unexpressing family members to investigate the genetic causes of CHD in this family line. Exome sequencing identified 4 mutation sites in this family line. The variant c.3245A>G (p.His1082Arg) of the AMER1 gene was consistent with concomitant X-chromosome recessive inheritance, the variant c.238G>C (p.Val80Leu) of the KCNE1 gene was consistent with autosomal accessory inheritance, and the other 2 variants did not conform to the law of the mode of inheritance of the disease. OUTCOMES: The first identified variant, c.3245A>G (p.His1082Arg) of the AMER1 gene, with X-chromosome recessive inheritance, and the variant c.238G>C (p.Val80Leu) of the KCNE1 gene, which has been reported as autosomal dominant, may be the causative agent of CHD in this family line. These findings broaden the genetic scope of congenital heart disease and could help in the development of targeted drugs for the treatment of congenital heart disease.


Assuntos
Permeabilidade do Canal Arterial , Cardiopatias Congênitas , Criança , Lactente , Humanos , Adolescente , Sequenciamento do Exoma , Linhagem , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/diagnóstico , Mutação , Permeabilidade do Canal Arterial/genética
9.
Mol Biol Rep ; 51(1): 302, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38355773

RESUMO

BACKGROUND: Severe Combined Immunodeficiency (SCID) is an autosomal recessive inborn error of immunity (IEI) characterized by recurrent chest and gastrointestinal (GI) infections and in some cases associated with life-threatening disorders. METHODOLOGY AND RESULTS: This current study aims to unwind the molecular etiology of SCID and also extended the patients' phenotype associated with identified particular variants. Herein, we present 06 disease-causing variants identified in 07 SCID-patients in three different SCID related genes. Whole Exome Sequencing (WES) followed by Sanger Sequencing was employed to explore genetic variations. The results included identification of two previously reported heterozygous variants in homozygous form for the first time in RAG1gene [(p.Arg410Gln);(p.Arg737His)], followed by a recurrent variant (p.Trp959*) in RAG1, a novel variant in IL2RG (p.Asp48Lfs*24), a recurrent variant in IL2RG (p.Gly271Glu) and a recurrent variant in DCLRE1C (p.Arg191*) gene. CONCLUSION: To conclude, the immune-profiling and WES revealed two novel, two as homozygous state for the first time, and two recurrent disease causing variants contributing valuably to our existing knowledge of SCID.


Assuntos
Imunodeficiência Combinada Severa , Humanos , Imunodeficiência Combinada Severa/genética , Consanguinidade , Paquistão , Homozigoto , Fenótipo , Mutação/genética , Linhagem
10.
Pediatr Neurol ; 152: 200-208, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38306901

RESUMO

BACKGROUND: Fatty acid 2-hydroxylase (FA2H) is encoded by the FA2H gene, with mutations therein leading to the neurodegenerative condition, spastic paraplegia-35 (SPG35). We aim to elucidate the genetic underpinnings of a nonconsanguineous Chinese family diagnosed with SPG35 by examining the clinical manifestations, scrutinizing genetic variants, and establishing the role of FA2H mutation in lipid metabolism. METHODS: Using next-generation sequencing analysis to identify the pathogenic gene in this pedigree and family cosegregation verification. The use of lipidomics of patient pedigree peripheral blood mononuclear cells further substantiated alterations in lipid metabolism attributable to the FA2H exon 1 deletion. RESULTS: The proband exhibited gait disturbance from age 5 years; he developed further clinical manifestations such as scissor gait and dystonia. His younger sister also presented with a spastic gait from the same age. We identified a homozygous deletion in the region of FA2H exon 1, spanning from chr16:74807867 to chr16: 74810391 in the patients. Lipidomic analysis revealed significant differences in 102 metabolites compared with healthy controls, with 62 metabolites increased and 40 metabolites decreased. We specifically zeroed in on 19 different sphingolipid metabolites, which comprised ceramides, ganglioside, etc., with only three of these sphingolipids previously reported. CONCLUSIONS: This is the first study of lipid metabolism in the blood of patients with SPG35. The results broaden our understanding of the SPG35 gene spectrum, offering insights for future molecular mechanism research and laying groundwork for determining metabolic markers.


Assuntos
Transtornos Heredodegenerativos do Sistema Nervoso , Lipidômica , Paraplegia Espástica Hereditária , Masculino , Humanos , Pré-Escolar , Homozigoto , Leucócitos Mononucleares/patologia , Deleção de Sequência/genética , Mutação , Éxons/genética , Linhagem , Paraplegia Espástica Hereditária/genética , Paraplegia Espástica Hereditária/diagnóstico , Paraplegia
11.
Medicina (Kaunas) ; 60(2)2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38399542

RESUMO

Background and Objectives. Retinitis pigmentosa (RP) is the most common inherited rod-cone dystrophy (RCD), resulting in nyctalopia, progressive visual field, and visual acuity decay in the late stages. The autosomal dominant form (ADRP) accounts for about 20% of RPs. Among the over 30 genes found to date related to ADRP, RP1 pathogenic variants have been identified in 5-10% of cases. In a cohort of RCD patients from the Palermo province on the island of Sicily, we identified a prevalent nonsense variant in RP1, which was associated with ADRP. The objective of our study was to analyse the clinical and molecular data of this patient cohort and to evaluate the potential presence of a founder effect. Materials and Methods. From 2005 to January 2023, 84 probands originating from Western Sicily (Italy) with a diagnosis of RCD or RP and their relatives underwent deep phenotyping, which was performed in various Italian clinical institutions. Molecular characterisation of patients and familial segregation of pathogenic variants were carried out in different laboratories using Sanger and/or next-generation sequencing (NGS). Results. Among 84 probands with RCD/RP, we found 28 heterozygotes for the RP1 variant c.2219C>G, p.Ser740* ((NM_006269.2)*, which was therefore significantly prevalent in this patient cohort. After a careful interview process, we ascertained that some of these patients shared the same pedigree. Therefore, we were ultimately able to define 20 independent family groups with no traceable consanguinity. Lastly, analysis of clinical data showed, in our patients, that the p.Ser740* nonsense variant was often associated with a late-onset and relatively mild phenotype. Conclusions. The high prevalence of the p.Ser740* variant in ADRP patients from Western Sicily suggests the presence of a founder effect, which has useful implications for the molecular diagnosis of RCD in patients coming from this Italian region. This variant can be primarily searched for in RP-affected subjects displaying compatible modes of transmission and phenotypes, with an advantage in terms of the required costs and time for analysis. Moreover, given its high prevalence, the RP1 p.Ser740* variant could represent a potential candidate for the development of therapeutic strategies based on gene editing or translational read-through therapy for suppression of nonsense variants.


Assuntos
Distrofias de Cones e Bastonetes , Retinite Pigmentosa , Humanos , Distrofias de Cones e Bastonetes/genética , Sicília/epidemiologia , Efeito Fundador , Proteínas do Olho , Retinite Pigmentosa/genética , Retinite Pigmentosa/diagnóstico , Fenótipo , Linhagem , Mutação , Análise Mutacional de DNA , Proteínas Associadas aos Microtúbulos/genética
12.
Anim Sci J ; 95(1): e13928, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38400774

RESUMO

Three methods of predicting the response to truncated selection based on BLUP of breeding values (BVs) were compared under conditions in which the phenotypic values for the progenies of selected animals were not available. The following methods were used to predict the response to selection: (1) based on the mean of estimated breeding values (EBV) in the candidate population for selection ( ∆ g 1 $$ \Delta {\mathrm{g}}_1 $$ ), (2) based on the variance of EBV in the candidate population for selection ( ∆ g 2 $$ \Delta {\mathrm{g}}_2 $$ ), and (3) based on diagonal elements of the inverse matrix on the left-hand side of the mixed model equation ( ∆ g 3 $$ \Delta {\mathrm{g}}_3 $$ ). The deviation of the average BV of the selected animals from the average BV of the candidate population for selection was taken as the true response to selection. The pedigree information and phenotypic values used for comparison were generated by Monte Carlo computer simulation. The results showed that ∆ g 1 $$ \Delta {\mathrm{g}}_1 $$ had the smallest absolute mean error and ∆ g 2 $$ \Delta {\mathrm{g}}_2 $$ had the smallest root-mean-square error. We concluded that it is desirable to use ∆ g 1 $$ \Delta {\mathrm{g}}_1 $$ or ∆ g 2 $$ \Delta {\mathrm{g}}_2 $$ to predict the response to truncated selection based on BLUP of BVs. However, in the population where selection is ongoing, the prediction accuracy of selection response is likely to be affected by the distortion of the distribution and the Bulmer effect for ∆ g 2 $$ \Delta {\mathrm{g}}_2 $$ .


Assuntos
Modelos Genéticos , Animais , Simulação por Computador , Linhagem , Genótipo , Fenótipo
13.
Genes (Basel) ; 15(2)2024 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-38397216

RESUMO

Y-chromosomal short tandem repeats (Y-STRs) are widely used in forensic, genealogical, and population genetics. With the recent increase in the number of rapidly mutating (RM) Y-STRs, an unprecedented level of male differentiation can be achieved, widening and improving the applications of Y-STRs in various fields, including forensics. The growing complexity of Y-STR data increases the need for automated data analyses, but dedicated software tools are scarce. To address this, we present the Male Pedigree Toolbox (MPT), a software tool for the automated analysis of Y-STR data in the context of patrilineal genealogical relationships. The MPT can estimate mutation rates and male relative differentiation rates from input Y-STR pedigree data. It can aid in determining ancestral haplotypes within a pedigree and visualize the genetic variation within pedigrees in all branches of family trees. Additionally, it can provide probabilistic classifications using machine learning, helping to establish or prove the structure of the pedigree and the level of relatedness between males, even for closely related individuals with highly similar haplotypes. The tool is flexible and easy to use and can be adjusted to any set of Y-STR markers by modifying the intuitive input file formats. We introduce the MPT software tool v1.0 and make it publicly available with the goal of encouraging and supporting forensic, genealogical, and other geneticists in utilizing the full potential of Y-STRs for both research purposes and practical applications, including criminal casework.


Assuntos
Genética Populacional , Taxa de Mutação , Masculino , Humanos , Linhagem , Haplótipos/genética , Cromossomos Humanos Y/genética
14.
PLoS One ; 19(2): e0298883, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38386645

RESUMO

Many forms of childhood glaucoma have been associated with underlying genetic changes, and variants in many genes have been described. Currently, testing is variable as there are no widely accepted guidelines for testing. This systematic review aimed to summarize the literature describing genetic changes and testing practices in childhood glaucoma. This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic review and Meta-Analyses (PRISMA) 2020 guidelines and registered with Prospero (ID CRD42023400467). A comprehensive review of Pubmed, Embase, and Cochrane databases was performed from inception through March 2, 2023 using the search terms: (glaucoma) AND (pediatric OR childhood OR congenital OR child OR infant OR infantile) AND (gene OR genetic OR genotype OR locus OR genomic OR mutation OR variant OR test OR screen OR panel). Information was extracted regarding genetic variants including genotype-phenotype correlation. Risk of bias was assessed using the Newcastle-Ottawa Scale. Of 1,916 records screened, 196 studies met inclusion criteria and 53 genes were discussed. Among study populations, mean age±SD at glaucoma diagnosis was 8.94±9.54 years and 50.4% were male. The most common gene discussed was CYP1B1, evaluated in 109 (55.6%) studies. CYP1B1 variants were associated with region and population-specific prevalence ranging from 5% to 86% among those with primary congenital glaucoma. MYOC variants were discussed in 31 (15.8%) studies with prevalence up to 36% among patients with juvenile open angle glaucoma. FOXC1 variants were discussed in 25 (12.8%) studies, which demonstrated phenotypic severity dependent on degree of gene expression and type of mutation. Overall risk of bias was low; the most common domains of bias were selection and comparability. Numerous genes and genetic changes have been associated with childhood glaucoma. Understanding the most common genes as well as potential genotype-phenotype correlation has the potential to improve diagnostic and prognostic outcomes for children with glaucoma.


Assuntos
Glaucoma de Ângulo Aberto , Glaucoma , Lactente , Humanos , Masculino , Criança , Adolescente , Feminino , Glaucoma de Ângulo Aberto/genética , Linhagem , Glaucoma/epidemiologia , Mutação , Genótipo
15.
BMC Med Genomics ; 17(1): 54, 2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38373942

RESUMO

BACKGROUND: MECP2 duplication syndrome (MDS) is a rare X-linked genomic disorder that primarily affects males. It is characterized by delayed or absent speech development, severe motor and cognitive impairment, and recurrent respiratory infections. MDS is caused by the duplication of a chromosomal region located on chromosome Xq28, which contains the methyl CpG binding protein-2 (MECP2) gene. MECP2 functions as a transcriptional repressor or activator, regulating genes associated with nervous system development. The objective of this study is to provide a clinical description of MDS, including imaging changes observed from the fetal period to the neonatal period. METHODS: Conventional G-banding was employed to analyze the chromosome karyotypes of all pedigrees under investigation. Subsequently, whole exome sequencing (WES), advanced biological information analysis, and pedigree validation were conducted, which were further confirmed by copy number variation sequencing (CNV-seq). RESULTS: Chromosome karyotype analysis revealed that a male patient had a chromosome karyotype of 46,Y,dup(X)(q27.2q28). Whole-exon duplication in the MECP2 gene was revealed through WES results. CNV-seq validation confirmed the presence of Xq27.1q28 duplicates spanning 14.45 Mb, which was inherited from a mild phenotype mother. Neither the father nor the mother's younger brother carried this duplication. CONCLUSION: In this study, we examined a male child in a family who exhibited developmental delay and recurrent respiratory tract infections as the main symptoms. We conducted thorough family investigations and genetic testing to determine the underlying causes of the disease. Our findings will aid in early diagnosis, genetic counseling for male patients in this family, as well as providing prenatal diagnosis and reproductive guidance for female carriers.


Assuntos
Variações do Número de Cópias de DNA , Duplicação Gênica , Retardo Mental Ligado ao Cromossomo X , Criança , Recém-Nascido , Humanos , Masculino , Feminino , Linhagem , China
16.
Invest Ophthalmol Vis Sci ; 65(2): 9, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38315492

RESUMO

Purpose: This observational study aimed to identify mutations in monogenic syndromic high myopia (msHM) using data from reported samples (n = 9370) of the Myopia Associated Genetics and Intervention Consortium (MAGIC) project. Methods: The targeted panel containing 298 msHM-related genes was constructed and screening of clinically actionable variants was performed based on whole exome sequencing. Capillary sequencing was used to verify the identified gene mutations in the probands and perform segregation analysis with their relatives. Results: A total of 381 candidate variants in 84 genes and 85 eye diseases were found to contribute to msHM in 3.6% (335/9370) of patients with HM. Among them, the 22 genes with the most variations accounted for 62.7% of the diagnostic cases. In the genotype-phenotype association analysis, 60% (201/335) of suspected msHM cases were recalled and 25 patients (12.4%) received a definitive genetic diagnosis. Pathogenic variants were distributed in 18 msHM-related diseases, mainly involving retinal dystrophy genes (e.g. TRPM1, CACNA1F, and FZD4), connective tissue disease genes (e.g. FBN1 and COL2A1), corneal or lens development genes (HSF4, GJA8, and MIP), and other genes (TEK). The msHM gene mutation types were allocated to four categories: nonsense mutations (36%), missense mutations (36%), frameshift mutations (20%), and splice site mutations (8%). Conclusions: This study highlights the importance of thorough molecular subtyping of msHM to provide appropriate genetic counselling and multispecialty care for children and adolescents with HM.


Assuntos
Miopia , Distrofias Retinianas , Canais de Cátion TRPM , Criança , Adolescente , Humanos , Sequenciamento do Exoma , Mutação , Miopia/diagnóstico , Miopia/genética , Mutação da Fase de Leitura , Distrofias Retinianas/genética , Linhagem , Receptores Frizzled/genética , Canais de Cátion TRPM/genética
17.
BMC Ophthalmol ; 24(1): 55, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38317096

RESUMO

BACKGROUND: Inherited retinal degenerations (IRDs) are a group of rare genetic conditions affecting retina of the eye that range in prevalence from 1 in 2000 to 1 in 4000 people globally. This review is based on a retrospective analysis of research articles reporting IRDs associated genetic findings in Pakistani families between 1999 and April 2023. METHODS: Articles were retrieved through survey of online sources, notably, PubMed, Google Scholar, and Web of Science. Following a stringent selection criterion, a total of 126 research articles and conference abstracts were considered. All reported variants were cross-checked and validated for their correct genomic nomenclature using different online resources/databases, and their pathogenicity scores were explained as per ACMG guidelines. RESULTS: A total of 277 unique sequence variants in 87 distinct genes, previously known to cause IRDs, were uncovered. In around 70% cases, parents of the index patient were consanguineously married, and approximately 88.81% of the detected variants were found in a homozygous state. Overall, more than 95% of the IRDs cases were recessively inherited. Missense variants were predominant (41.88%), followed by Indels/frameshift (26.35%), nonsense (19.13%), splice site (12.27%) and synonymous change (0.36%). Non-syndromic IRDs were significantly higher than syndromic IRDs (77.32% vs. 22.68%). Retinitis pigmentosa (RP) was the most frequently observed IRD followed by Leber's congenital amaurosis (LCA). Altogether, mutations in PDE6A gene was the leading cause of IRDs in Pakistani families followed by mutations in TULP1 gene. CONCLUSION: In summary, Pakistani families are notable in expressing recessively inherited monogenic disorders including IRDs likely due to the highest prevalence of consanguinity in the country that leads to expression of rare pathogenic variants in homozygous state.


Assuntos
Distrofias Retinianas , Retinite Pigmentosa , Humanos , Paquistão/epidemiologia , Estudos Retrospectivos , Distrofias Retinianas/epidemiologia , Distrofias Retinianas/genética , Retina/patologia , Retinite Pigmentosa/genética , Mutação , Linhagem , Proteínas do Olho/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/genética
18.
BMC Ophthalmol ; 24(1): 60, 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38347443

RESUMO

BACKGROUND: Inherited retinal dystrophies are hereditary diseases which have in common the progressive degeneration of photoreceptors. They are a group of diseases with clinical, genetic, and allelic heterogeneity. There is limited information regarding the genetic landscape of inherited retinal diseases in Mexico, therefore, the present study was conducted in the northeast region of the country. METHODS: Patients with inherited retinal dystrophies were included. A complete history, full ophthalmological and medical genetics evaluations, and genetic analysis through a targeted NGS panel for inherited retinal dystrophies comprising at least 293 genes were undertaken. RESULTS: A total of 126 patients were included. Cases were solved in 74.6% of the study's population. Retinitis pigmentosa accounted for the most found inherited retinal disease. Ninety-nine causal variants were found, being USH2A and ABCA4 the most affected genes (26 and 15 cases, respectively). CONCLUSIONS: The present study documents the most prevalent causative genes in IRDs, as USH2A, in northeastern Mexico. This contrasts with previous reports of IRDs in other zones of the country. Further studies, targeting previously unstudied populations in Mexico are important to document the genetic background of inherited retinal dystrophies in the country.


Assuntos
Distrofias Retinianas , Retinite Pigmentosa , Síndromes de Usher , Humanos , Mutação , México/epidemiologia , Distrofias Retinianas/epidemiologia , Distrofias Retinianas/genética , Retinite Pigmentosa/genética , Linhagem , Transportadores de Cassetes de Ligação de ATP/genética
19.
Bioinformatics ; 40(2)2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38310342

RESUMO

SUMMARY: Pedigree-based analyses' prime role is to unravel relationships between individuals in breeding programs and germplasms. This is critical information for decoding the genetics underlying main inherited traits of relevance, and unlocking the genotypic variability of a species to carry out genomic selections and predictions. Despite the great interest, current lineage visualizations become quite limiting in terms of public display, exploration, and tracing of traits up to ancestral donors. PERSEUS is a user-friendly, intuitive, and interactive web-based tool for pedigree visualizations represented as directed graph networks distributed using a force-repulsion method. The visualizations do not only showcase individual relationships among accessions, but also facilitate a seamless search and download of phenotypic traits along the pedigrees. PERSEUS is a promising tool for breeders and scientists, advantageous for evolutionary, genealogy, and diversity analyses among related accessions and species. AVAILABILITY AND IMPLEMENTATION: PERSEUS is freely accessible at https://bioinformatics.cragenomica.es/perseus and GitHub code is available at https://github.com/aranzana-lab/PERSEUS.


Assuntos
Genômica , Software , Humanos , Linhagem , Genoma , Internet
20.
Exp Dermatol ; 33(2): e15031, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38375898

RESUMO

The pathogenesis of dyschromatosis symmetrica hereditaria (DSH) has not been well defined. In this study, we sought to investigate the influence of the ADAR1 gene on DSH both in vitro and in vivo. Morpholino knockdown of adar1 in zebrafish produced phenotypes characterized by polarity changes, and abnormal migration and distribution of melanocytes. Differential expression of C-KIT and distinct patterns of apoptosis between hyperpigmented and hypopigmented areas in DSH patient were detected by means of immunohistochemical methods and TUNEL assays, respectively. This study revealed that adar1 knockdown in a zebrafish model resulted in abnormal migration and changes in the cell polarity of melanocytes, and provided novel insight into the mechanism of DSH pathogenesis.


Assuntos
Adenosina Desaminase , Transtornos da Pigmentação/congênito , Peixe-Zebra , Humanos , Animais , Peixe-Zebra/genética , Mutação , Adenosina Desaminase/genética , Proteínas de Ligação a RNA/genética , Linhagem
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