RESUMO
BACKGROUND: Key discoveries and innovations in the field of human genetics have led to the foundation of molecular and personalized medicine. Here, we present the Genome Tunisia Project, a two-phased initiative (2022-2035) which aims to deliver the reference sequence of the Tunisian Genome and to support the implementation of personalized medicine in Tunisia, a North African country that represents a central hub of population admixture and human migration between African, European, and Asian populations. The main goal of this initiative is to develop a healthcare system capable of incorporating omics data for use in routine medical practice, enabling medical doctors to better prevent, diagnose, and treat patients. METHODS: A multidisciplinary partnership involving Tunisian experts from different institutions has come to discern all requirements that would be of high priority to fulfill the project's goals. One of the most urgent priorities is to determine the reference sequence of the Tunisian Genome. In addition, extensive situation analysis and revision of the education programs, community awareness, appropriate infrastructure including sequencing platforms and biobanking, as well as ethical and regulatory frameworks, have been undertaken towards building sufficient capacity to integrate personalized medicine into the Tunisian healthcare system. RESULTS: In the framework of this project, an ecosystem with all engaged stakeholders has been implemented including healthcare providers, clinicians, researchers, pharmacists, bioinformaticians, industry, policymakers, and advocacy groups. This initiative will also help to reinforce research and innovation capacities in the field of genomics and to strengthen discoverability in the health sector. CONCLUSIONS: Genome Tunisia is the first initiative in North Africa that seeks to demonstrate the major impact that can be achieved by Human Genome Projects in low- and middle-income countries to strengthen research and to improve disease management and treatment outcomes, thereby reducing the social and economic burden on healthcare systems. Sharing this experience within the African scientific community is a chance to turn a major challenge into an opportunity for dissemination and outreach. Additional efforts are now being made to advance personalized medicine in patient care by educating consumers and providers, accelerating research and innovation, and supporting necessary changes in policy and regulation.
Assuntos
Genoma Humano , Medicina de Precisão , Medicina de Precisão/métodos , Humanos , Tunísia , Genômica/métodos , África do NorteRESUMO
OBJECTIVE: To develop a high throughput sequencing panel for the diagnosis of developmental and epileptic encephalopathy in Tunisia and to clarify the frequency of disease-causing genes in this region. METHODS: We developed a custom panel for next generation sequencing of the coding sequences of 116 genes in individuals with developmental and epileptic encephalopathy from the Tunisian population. Segregation analyses as well as in silico studies have been conducted to assess the identified variants' pathogenicity. RESULTS: We report 12 pathogenic variants in SCN1A, CHD2, CDKL5, SZT2, KCNT1, GNAO1, PCDH19, MECP2, GRIN2A, and SYNGAP1 in patients with developmental and epileptic encephalopathy. Five of these variants are novel: "c.149delA, p.(Asn50MetfsTer26)" in CDKL5; "c.3616C>T, p.(Arg1206Ter)" in SZT2; "c.111_113del, p.(Leu39del)" in GNAO1; "c.1435G>C , p.(Asp479His)" in PCDH19; as well as "c.2143delC, p. (Arg716GlyfsTer10)"in SYNGAP1. Additionally, for four of our patients, the genetic result facilitated the choice of the appropriate treatment. SIGNIFICANCE: This is the first report of a custom gene panel to identify genetic variants implicated in developmental and epileptic encephalopathy in the Tunisian population as well as the North African region (Tunisia, Egypt, Libya, Algeria, Morocco) with a diagnostic rate of 30%. This high-throughput sequencing panel has considerably improved the rate of positive diagnosis of developmental and epileptic encephalopathy in the Tunisian population, which was less than 15% using Sanger sequencing. The benefit of genetic testing in these patients was approved by both physicians and parents.
RESUMO
The mutations concerned with non-small cell lung cancer involving epidermal growth factor receptor of tyrosine kinase family have primarily targeted. In this study, we employed a scalable high-throughput virtual screening (HTVS) framework and a targeted compound library of over 50.000 Erlotinib-derived compounds as noncovalent reversible EGFRL858R/T790M inhibitors. Our HTVS work flow leverages include HTVS, SP (Standard Precision) and XP (Extra Precision) docking protocol along with its relative binding free energy calculation, cluster analysis study and ADMET properties. Then we used multiple ns-time scale molecular dynamics (MD) simulations and density functional theory (DFT) precise calculation techniques to elucidate how the bound ligand interact with the complexes conformational states involving motions both proximal and distal to the binding site. Based on glide score and protein-ligand interactions, the highest scoring molecule was selected for molecular dynamic simulation providing a complete insight into the conformational stability. A hyperfine analysis of DFT based refinement strategy highly supported their stability by strong intermolecular interactions. Together, our results demonstrate that the virtually screened top retained molecules present the best moieties introduced to Erlotinib. They exhibit interesting pharmacokinetic properties that can act as potent antitumor drug candidates than the lead compound drug and in some extent tackling the drug resistance problem which offer a springboard for further therapeutic experiments and applications.Communicated by Ramaswamy H. Sarma.
RESUMO
In the process of neuronal development, the protein Purα (encoded by the PURA gene) is essential for neuronal proliferation, dendritic maturation, and the transportation of mRNA to translation sites. Mutations in the PURA gene may alter normal brain development and impair neuronal function, contributing to developmental delays and seizures. Recently, PURA syndrome is described as developmental encephalopathy with or without epilepsy, neonatal hypotonia, feeding difficulties, global developmental delay, and severe intellectual disability. In our study, we aimed to perform a genetic analysis by whole exome sequencing (WES) in a Tunisian patient presented with developmental and epileptic encephalopathy to provide a molecular explanation for the developed phenotype. We collected, also, clinical data of all PURA p.(Phe233del) patients reported yet and compared the clinical features with those of our patient. Results revealed the presence of the known PURA c.697_699del, p.(Phe233del) variant. Our studied case shares some clinical features including hypotonia, feeding difficulties, severe developmental delay, epilepsy, and language delay (nonverbal) but presents a radiological finding undescribed before. Our finding defines and expands the phenotypic and genotypic spectrum of the PURA syndrome supporting the absence of reliable genotype-phenotype correlations and the existence of a highly variable, wide-ranging clinical spectrum.
Assuntos
Epilepsia , Deficiência Intelectual , Humanos , Encéfalo , Proteínas de Ligação a DNA/genética , Epilepsia/genética , Deficiência Intelectual/genética , Hipotonia Muscular/genética , Mutação/genética , Fenótipo , Fatores de Transcrição/genéticaRESUMO
Pathogenic germline variants in the PIGT gene are associated with the "multiple congenital anomalies-hypotonia-seizures syndrome 3" (MCAHS3) phenotype. So far, fifty patients have been reported, most of whom suffer from intractable epilepsy. Recently, a comprehensive analysis of a cohort of 26 patients with PIGT variants has broadened the phenotypical spectrum and indicated that both p.Asn527Ser and p.Val528Met are associated with a milder epilepsy phenotype and less severe outcomes. Since all reported patients are of Caucasian/Polish origin and most harbor the same variant (p.Val528Met), the ability to draw definitive conclusions regarding the genotype-phenotype correlation remains limited. We report a new case with a homozygous variant p.Arg507Trp in the PIGT gene, detected on clinical exome sequencing. The North African patient in question displays a predominantly neurological phenotype with global developmental delay, hypotonia, brain abnormalities, and well-controlled epileptic seizures. Homozygous and heterozygous variants in codon 507 have been reported to cause PIGT deficiency without biochemical confirmation. In this study, FACS analysis of knockout HEK293 cells that had been transfected with wild-type or mutant cDNA constructs demonstrated that the p.Arg507Trp variant leads to mildly reduced activity. Our result confirm the pathogenicity of this variant and strengthen recently reported evidence on the genotype-phenotype correlation of the PIGT variant.
RESUMO
Investment in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing in Africa over the past year has led to a major increase in the number of sequences that have been generated and used to track the pandemic on the continent, a number that now exceeds 100,000 genomes. Our results show an increase in the number of African countries that are able to sequence domestically and highlight that local sequencing enables faster turnaround times and more-regular routine surveillance. Despite limitations of low testing proportions, findings from this genomic surveillance study underscore the heterogeneous nature of the pandemic and illuminate the distinct dispersal dynamics of variants of concern-particularly Alpha, Beta, Delta, and Omicron-on the continent. Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve while the continent faces many emerging and reemerging infectious disease threats. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century.
Assuntos
COVID-19 , Monitoramento Epidemiológico , Pandemias , SARS-CoV-2 , África/epidemiologia , COVID-19/epidemiologia , COVID-19/virologia , Genômica , Humanos , SARS-CoV-2/genéticaRESUMO
BACKGROUND: In the Tunisian population, the molecular analysis of hearing impairment remains based on conventional approaches, which makes the task laborious and enormously expensive. Exploration of the etiology of Hearing Impairment and the early diagnosis of causal mutations by next-generation sequencing help significantly alleviate social and economic problems. METHODS: We elaborated a custom SureSelectQXT panel for next-generation sequencing of the coding sequences of 42 genes involved in isolated hearing impairment or along with defects of the retina, the thyroid, and the kidneys. RESULTS: We report eight pathogenic variants, four of which are novel in patients with isolated hearing impairment, hearing impairment, and renal tubular acidosis, Usher syndrome and Pendred syndrome. Functional studies using molecular modeling showed the severe impact of the novel missense mutations on the concerned proteins. Basically, we identified mutations in nuclear as well as mitochondrial genes in a Tunisian family with isolated hearing impairment, which explains definitely the phenotype detected since 2006. CONCLUSION: Our results expanded the mutation spectrum and genotype-phenotype correlation of isolated and syndromic hearing loss and also emphasized the importance of combining both targeted next-generation sequencing and detailed clinical evaluation to elaborate a more accurate diagnosis for hearing impairment and related phenotypes especially in North African populations.
Assuntos
Glândula Tireoide , Síndromes de Usher , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Rim , Mutação , Retina , Síndromes de Usher/diagnóstico , Síndromes de Usher/genéticaRESUMO
OBJECTIVES: Since the onset of the COVID-19 pandemic, cases of reinfection with SARS-CoV-2 have been reported, raising additional public health concerns. SARS-CoV-2 reinfection was assessed in healthcare workers (HCWs) in Tunisia because they are at the greatest exposure to infection by different variants. METHODS: We conducted whole-genome sequencing of the viral RNA from clinical specimens collected during the initial infection and the suspected reinfection from 4 HCWs, who were working at the Habib Bourguiba University Hospital (Sfax, Tunisia) and retested positive for SARS-CoV-2 through reverse transcriptase-polymerase chain reaction (RT-PCR) after recovery from a first infection. A total of 8 viral RNAs from the patients' respiratory specimens were obtained, which allowed us to characterize the differences between viral genomes from initial infection and positive retest. The serology status for total Ig, IgG, and IgM against SARS-CoV-2 was also determined and followed after the first infection. RESULTS: We confirmed through whole-genome sequencing of the viral samples that all 4 cases experienced a reinfection event. The interval between the 2 infection events ranged between 45 and 141 days, and symptoms were milder in the second infection for 2 patients and more severe for the remaining 2 patients. Reinfection occurred in all 4 patients despite the presence of antibodies in 3 of them. CONCLUSION: This study adds to the rapidly growing evidence of COVID-19 reinfection, where viral sequences were used to confirm infection by distinct isolates of SARS-CoV-2 in HCWs. These findings suggest that individuals who are exposed to different SARS-CoV-2 variants might not acquire sufficiently protective immunity through natural infection and emphasize the necessity of their vaccination and the regular follow-up of their immune status both in quantitative and qualitative terms.
Assuntos
COVID-19 , SARS-CoV-2 , Anticorpos Antivirais , COVID-19/diagnóstico , COVID-19/epidemiologia , Atenção à Saúde , Pessoal de Saúde , Hospitais , Humanos , Pandemias , Reinfecção/epidemiologia , SARS-CoV-2/genéticaRESUMO
Hereditary hearing impairment (HI) is a heterogeneous condition with over 130 genes associated with genetic non-syndromic HI (NSHI) and Usher syndrome (USH). Approximately 80% of hereditary NSHI cases have autosomal recessive (AR) mode of inheritance. The high rate of consanguinity and endogamy in the Maghreb countries, including Tunisia, Algeria and Morocco, represents a major contributing factor to the development of ARHI. Since the 90s, those populations, with their particular large familiar structure, represented an effective key towards the discovery of the first HI loci and genes. In this study, we performed a deep literature database search to analyze the mutational spectrum and the distribution of pathogenic variants responsible of USH and the NSHI among those populations. To date, 124 pathogenic variants were identified in 32 genes of which over 70% represent population-specific variants. The particular variants' distribution is related to the high rate of consanguinity as well as the multiple shared features such as demographic history of migrations and social behavior that promoted the spreading of several founder mutations within those countries. This is the first study to report lessons from the past and current actualities of HI within the three Maghreb countries. However, despite the great impact placed by such population for the HI genetic studies, only a few next-generation sequencing platforms have so far been implemented with those countries. We, therefore, believe that those countries should be supported to implement this technology that would definitely be of great value in the discovery of additional novel HI genes/variants.
Assuntos
Síndromes de Usher , África do Norte , Consanguinidade , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação , Linhagem , Síndromes de Usher/genéticaRESUMO
Hereditary hearing impairment (HI) is a common disease with the highest incidence among sensory defects. Several genes have been identified to affect stereocilia structure causing HI, including the unconventional myosin3A. Interestingly, we noticed that variants in MYO3A gene have been previously found to cause variable HI onset and severity. Using clinical exome sequencing, we identified a novel pathogenic variant p.(Lys50Arg) in the MYO3A kinase domain (MYO3A-KD). Previous in vitro studies supported its damaging effect as a 'kinase-dead' mutant. We further analyzed this variation through molecular dynamics which predicts that changes in flexibility of MYO3A structure would influence the protein-ATP binding properties. This Lys50Arg mutation segregated with congenital profound non-syndromic HI. To better investigate this variability, we collected previously identified MYO3A-KDs variants, p.(Tyr129Cys), p.(His142Gln) and p.(Pro189Thr), and built both wild type and mutant 3 D MYO3A-KD models to assess their impact on the protein structure and function. Our results suggest that KD mutations could either cause a congenital profound form of HI, when particularly affecting the kinase activity and preventing the auto-phosphorylation of the motor, or a late onset and progressive form, when partially or completely inactivating the MYO3A protein. In conclusion, we report a novel pathogenic variant affecting the ATP-binding site within the MYO3A-KD causing congenital profound HI. Through computational approaches we provide a deeper understanding on the correlation between the effects of MYO3A-KD mutations and the variable hearing phenotypes. To the best of our knowledge this is the first study to correlate mutations' genotypes with the variable phenotypes of DFNB30.Communicated by Ramaswamy H. Sarma.
Assuntos
Perda Auditiva Neurossensorial , Perda Auditiva , Miosina Tipo III , Humanos , Perda Auditiva Neurossensorial/genética , Perda Auditiva/genética , Perda Auditiva/metabolismo , Mutação , Trifosfato de Adenosina , Cadeias Pesadas de Miosina/genética , Miosina Tipo III/genéticaRESUMO
Intellectual disability (ID) often co-occurs with other neurologic phenotypes making molecular diagnosis more challenging particularly in consanguineous populations with the co-segregation of more than one ID-related gene in some cases. In this study, we investigated the phenotype of three patients from a large Tunisian family with significant ID phenotypic variability and microcephaly and performed a clinical exome sequencing in two cases. We identified, within the first branch, a homozygous variant in the TRAPPC9 gene (p.Arg472Ter) in two cases presenting severe ID, absent speech, congenital/secondary microcephaly in addition to autistic features, supporting the implication of TRAPPC9 in the "secondary" autism spectrum disorders and congenital microcephaly. In the second branch, we identified a homozygous variant (p.Lys189ArgfsTer15) in the CDK5RAP2 gene associated with an heterozygous TRAPPC9 variant (p.Arg472Ter) in one case harbouring primary hereditary microcephaly (MCPH) associated with an inter-hypothalamic adhesion, mixed hearing loss, selective thinning in the retinal nerve fiber layer and parafoveal ganglion cell complex, and short stature. Our findings expand the spectrum of the recently reported neurosensorial abnormalities and revealed the variable phenotype expressivity of CDK5RAP2 defect. Our study highlights the complexity of the genetic background of microcephaly/ID and the efficiency of the exome sequencing to provide an accurate diagnosis and to improve the management and follow-up of such patients.
Assuntos
Proteínas de Ciclo Celular/genética , Deficiência Intelectual/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Microcefalia/genética , Proteínas do Tecido Nervoso/genética , Criança , Consanguinidade , Feminino , Variação Genética/genética , Homozigoto , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Malformações do Sistema Nervoso/genética , Linhagem , Fenótipo , Distúrbios da Fala/genética , TunísiaRESUMO
The progression of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in Africa has so far been heterogeneous, and the full impact is not yet well understood. In this study, we describe the genomic epidemiology using a dataset of 8746 genomes from 33 African countries and two overseas territories. We show that the epidemics in most countries were initiated by importations predominantly from Europe, which diminished after the early introduction of international travel restrictions. As the pandemic progressed, ongoing transmission in many countries and increasing mobility led to the emergence and spread within the continent of many variants of concern and interest, such as B.1.351, B.1.525, A.23.1, and C.1.1. Although distorted by low sampling numbers and blind spots, the findings highlight that Africa must not be left behind in the global pandemic response, otherwise it could become a source for new variants.
Assuntos
COVID-19/epidemiologia , Monitoramento Epidemiológico , Genômica , Pandemias , SARS-CoV-2/genética , África/epidemiologia , COVID-19/transmissão , COVID-19/virologia , Variação Genética , Humanos , SARS-CoV-2/isolamento & purificaçãoRESUMO
BACKGROUND: 8q21.11 microdeletion syndrome is a rare chromosomal disorder characterized by recurrent dysmorphic features, a variable degree of intellectual disability and ocular, cardiac and hand/feet abnormalities. To date, ZFHX4 is the only candidate gene implicated in the ocular findings. In this study, we evaluated a patient with a de novo 8q21.13-21.3 deletion to define a new small region of overlap (SRO) for this entity. METHODS: We conducted a clinical evaluation and comparative genomic hybridization (CGH) 4x44K microarrays in a patient with de novo unbalanced translocation t(8;16)(q21; q11.2). RESULTS: The case, a 6-year-old boy, presented dysmorphic features including an elongated face, brachycephaly with a high forehead, an underdeveloped ala, thin upper lip, micrognathia, low-set ears, hypotonia, mild intellectual disability, cortical atrophy with thin corpus callosum defect, and an atrial septal defect. No ocular abnormalities were found. Microarray analysis revealed a 9.6 Mb interstitial 8q21.11-21.3 deletion, not including the ZFHX4 gene. This microdeletion was confirmed in our patient through qPCR analysis, and both parents had a normal profile. Alignment analysis of our case defined a new SRO encompassing five genes. Among them, the HEY1 gene is involved in the embryonic development of the heart, central nervous system, and vascular system. Hrt1/Hey1 null mice show perinatal lethality due to congenital malformations of the aortic arch and its branch arteries. HEY1 has also been linked to the maintenance of neural stem cells, inhibition of oligodendrocyte differentiation, and myelin gene expression. CONCLUSION: HEY1 is a candidate gene for both neurological and cardiac features of the 8q21.11 microdeletion syndrome and might, therefore, explain specific components of its pathophysiology.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proteínas de Ciclo Celular/genética , Deleção Cromossômica , Cromossomos Humanos Par 8/genética , Cardiopatias Congênitas/genética , Transtornos do Neurodesenvolvimento/genética , Criança , Cardiopatias Congênitas/patologia , Humanos , Masculino , Transtornos do Neurodesenvolvimento/patologiaRESUMO
Background: Variants in the HARS2 gene have been reported to be associated with nonsyndromic hearing loss (HL) and Perrault syndrome (PS), a rare recessive disorder marked by bilateral sensorineural HL and ovarian dysgenesis. Given the low number of pathogenic variants described in the HARS2 gene, no genotype/phenotype correlations have been established between variants in this gene and the clinical data. Materials and Methods: Whole blood was collected from four members of a Lebanese family with PS. An affected woman was evaluated for HL by clinical examination and audiological tests. Primary ovarian failure was analyzed according to age of primary or secondary amenorrhea, follicle stimulating hormone levels, and pelvic ultrasound. The existence of neurological symptoms and other associated conditions was checked. To identify the causative variant, we used a custom HaloPlexHS panel for next-generation sequencing of the coding sequences of six genes implicated in this syndrome. Results: We identified a novel homozygous HARS2 missense variant (c.260G>A; p.Arg87His), which is only the second homozygous variant in the HARS2 gene identified to date worldwide. This variant is predicted to be deleterious by multiple in silico analysis tools, moreover the Arg87 amino acid nearly is invariant among eight species. Based on molecular modeling analysis, this variation is predicted to disturb the proper folding of HARS2, which may reduce its aminoacylation efficiency. Clinical data are compared with the other cases recorded in the literature to help gain further knowledge with regard to the phenotype. Conclusion: Our results provide strong evidence corroborating the etiological association of this mutation with the HARS2-PS phenotype. HARS2 variants need to be searched for in patients with early-onset bilateral sensorineural HL and ovarian dysfunction in women so as to guarantee accurate endocrinological surveillance and management to minimize secondary complications.
Assuntos
Aminoacil-tRNA Sintetases/genética , Disgenesia Gonadal 46 XX/genética , Perda Auditiva Neurossensorial/genética , Adulto , Aminoacil-tRNA Sintetases/metabolismo , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Disgenesia Gonadal 46 XX/metabolismo , Disgenesia Gonadal 46 XX/patologia , Perda Auditiva Neurossensorial/metabolismo , Perda Auditiva Neurossensorial/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Mutação de Sentido Incorreto , Linhagem , FenótipoRESUMO
Introduction: Hearing impairment (HI) is characterized by complex genetic heterogeneity. The evolution of next generation sequencing, including targeted enrichment panels, has revolutionized HI diagnosis. Objectives: In this study, we investigated genetic causes in 22 individuals with non-GJB2 HI. Methods: We customized a HaloplexHS kit to include 30 genes known to be associated with autosomal recessive nonsyndromic HI (ARNSHI) and Usher syndrome in North Africa. Results: In accordance with the ACMG/AMP guidelines, we report 11 pathogenic variants; as follows; five novel variants including three missense (ESRRB-Tyr295Cys, MYO15A-Phe2089Leu and MYO7A-Tyr560Cys) and two nonsense (USH1C-Gln122Ter and CIB2-Arg104Ter) mutations; two previously reported mutations (OTOF-Glu57Ter and PNPT1-Glu475Gly), but first time identified among Tunisian families; and four other identified mutations namely WHRN-Gly808AspfsX11, SLC22A4-Cys113Tyr and two MYO7A compound heterozygous splice site variants that were previously described in Tunisia. Pathogenic variants in WHRN and CIB2 genes, in patients with convincing phenotype ruling out retinitis pigmentosa, provide strong evidence supporting their association with ARNSHI. Moreover, we shed lights on the pathogenic implication of mutations in PNPT1 gene in auditory function providing new evidence for its association with ARNSHI. Lack of segregation of a previously identified causal mutation OTOA-Val603Phe further supports its classification as variant of unknown significance. Our study reports absence of otoacoustic emission in subjects using bilateral hearing aids for several years indicating the importance of screening genetic alteration in OTOF gene for proper management of those patients. Conclusion: In conclusion, our findings do not only expand the spectrum of HI mutations in Tunisian patients, but also improve our knowledge about clinical relevance of HI causing genes and variants.
Assuntos
Perda Auditiva/diagnóstico , Perda Auditiva/genética , Adulto , Pré-Escolar , Surdez/diagnóstico , Surdez/genética , Exorribonucleases , Feminino , Heterogeneidade Genética , Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Proteínas de Membrana , Mutação , Mutação de Sentido Incorreto , Linhagem , Fenótipo , Tunísia , Síndromes de Usher/diagnóstico , Síndromes de Usher/genética , Adulto JovemRESUMO
In this study, data available from GISAID on the whole-genome sequences of SARS-CoV-2 variants circulating in Tunisia were analyzed, and the prevalences of those variants in Tunisia were compared to their prevalences in other North African countries and around the world. Our results show new mutations and different prevalences of some lineages. In particular, new sets of mutations were identified in the spike protein of the virus during the analysis of 85 Tunisian samples, and the lineage B1.160 was found to be the most prevalent (18%) lineage in Tunisia. The prevalence of this lineage in Tunisia was significantly higher than its prevalence worldwide and in samples from neighboring countries (3%). This preliminary study shows the importance of tracking virus variants by next-generation sequencing in order to assess the dynamics of the COVID-19 pandemic and the impact of vaccination on the evolution of the virus.
RESUMO
Pathogenic variants in Steroid 5 alpha reductase type 3 (SRD5A3) cause rare inherited congenital disorder of glycosylation known as SRD5A3-CDG (MIM# 612379). To date, 43 affected individuals have been reported. Despite the development of various dysmorphic features in significant number of patients, facial recognition entity has not yet been established for SRD5A3-CDG. Herein, we reported a novel SRD5A3 missense pathogenic variant c.460 T > C p.(Ser154Pro). The 3D structural modeling of the SRD5A3 protein revealed additional transmembrane α-helices and predicted that the p.(Ser154Pro) variant is located in a potential active site and is capable of reducing its catalytic efficiency. Based on phenotypes of our patients and all published SRD5A3-CDG cases, we identified the most common clinical features as well as some recurrent dysmorphic features such as arched eyebrows, wide eyes, shallow nasal bridge, short nose, and large mouth. Based on facial digital 2D images, we successfully designed and validated a SRD5A3-CDG computer based dysmorphic facial analysis, which achieved 92.5% accuracy. The current work integrates genotypic, 3D structural modeling and phenotypic characteristics of CDG-SRD5A3 cases with the successful development of computer tool for accurate facial recognition of CDG-SRD5A3 complex cases to assist in the diagnosis of this particular disorder globally.
Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Anormalidades Múltiplas/genética , Catarata/genética , Defeitos Congênitos da Glicosilação/genética , Proteínas de Membrana/genética , Atrofia Muscular/genética , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/ultraestrutura , Anormalidades Múltiplas/patologia , Adolescente , Catarata/complicações , Catarata/patologia , Criança , Pré-Escolar , Defeitos Congênitos da Glicosilação/complicações , Defeitos Congênitos da Glicosilação/patologia , Olho/patologia , Reconhecimento Facial , Fácies , Feminino , Humanos , Proteínas de Membrana/ultraestrutura , Atrofia Muscular/complicações , Atrofia Muscular/patologia , Mutação de Sentido Incorreto/genéticaRESUMO
BACKGROUND: Otosclerosis (OTSC) is among the most common causes of a late-onset hearing loss in adults and is characterized by an abnormal bone growth in the otic capsule. Alteration in the osteoprotegerin (OPG) expression has been suggested in the implication of OTSC pathogenesis. METHODS: A case-control association study of rs2228568, rs7844539, rs3102734 and rs2073618 single nucleotide polymorphisms (SNPs) in the OPG gene was performed in a Tunisian-North African population composed of 183 unrelated OTSC patients and 177 healthy subjects. In addition, a multilocus association and a meta-analysis of existing studies were conducted. RESULTS: Rs3102734 (p = 0.013) and rs2073618 (p = 0.007) were significantly associated with OTSC, which were predominantly detected in females after multiple corrections. Among the OPG studied SNPs, the haplotypes A-A-C-G (p = 0.0001) and A-A-C-C (p = 0.0004) were significantly associated with OTSC in females. Multilocus association revealed that the SNPs: rs2073618 in OPG, rs1800472 in TGFß1, rs39335, rs39350 and rs39374 in RELN, and rs494252 in chromosome 11 showed significant OTSC-associated alleles in Tunisian individuals. In addition, meta-analysis of the rs2073618 SNP in Tunisian, Indian and Italian populations revealed evidence of an association with OTSC (OR of 0.826, 95% CI [0.691-0.987], p = 0.035). CONCLUSIONS: Our findings suggest that rs3102734 and rs2073618 variants are associated with OTSC in North African ethnic Tunisian population. Meta-analysis of the rs2073618 in three different ethnic population groups indicated an association with OTSC.
Assuntos
Epistasia Genética , Loci Gênicos , Predisposição Genética para Doença , Osteoprotegerina/genética , Otosclerose/genética , Polimorfismo de Nucleotídeo Único , Alelos , Estudos de Casos e Controles , Mapeamento Cromossômico , Feminino , Frequência do Gene , Estudos de Associação Genética , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Modelos Biológicos , Razão de Chances , Otosclerose/diagnóstico , Proteína ReelinaRESUMO
In the originally published article, the first names and family names of the authors were interchanged, hence not correct. The correct presentation of names is presented above.
RESUMO
Otospiralin (OTOSP) is a small protein of unknown function, expressed in fibrocytes of the inner ear and required for normal cochlear auditory function. Despite its conservation from fish to mammals, expression of otospiralin was only investigated in mammals. Here, we report for the first time the expression profile of OTOS orthologous genes in zebrafish (Danio rerio): otospiralin and si:ch73-23l24.1 (designated otospiralin-like). In situ hybridization analyses in zebrafish embryos showed a specific expression of otospiralin-like in notochord (from 14 to 48 hpf) and similar expression patterns for otospiralin and otospiralin-like in gut (from 72 to 120 hpf), swim bladder (from 96 to 120 hpf) and inner ear (at 120 hpf). Morpholino knockdown of otospiralin and otospiralin-like showed no strong change of the body structure of the embryos at 5 dpf and the inner ear was normally formed. Nevertheless, knockdown embryos showed a reduced number of kinocilia in the lateral crista, indicating that these genes play an important role in kinocilium formation. RT-qPCR revealed that otospiralin is highly expressed in adult zebrafish inner ear comparing to the others analyzed tissues as previously shown for mice. Interestingly, otospiralin-like was not detected in the inner ear which suggests that otospiralin have a more important function in hearing than otospiralin-like. Phylogenetic analysis of otospiralin proteins in vertebrates indicated the presence of two subgroups and supported the functional divergence observed in zebrafish for otospiralin and otospiralin-like genes. This study offers the first insight into the expression of otospiralin and otospiralin-like in zebrafish. Expression data point to an important role for otospiralin in zebrafish hearing and a specific role for otospiralin-like in notochord vacuolization.