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1.
Genet Test Mol Biomarkers ; 23(6): 428-432, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31081706

RESUMO

Background: Autosomal recessive congenital ichthyoses (ARCI) are a group of rare nonsyndromic genodermatoses characterized by generalized scaly appearance of the epidermis with markedly impaired cutaneous barriers owing to defects in keratinization related genes. In this study, we ascertained a consanguineous Pakistani family affected with ARCI. Aims: To investigate genetic defect underlying disease phenotype in the affected family. Methods: All available members of the family (affected and unaffected) were sampled. Whole exome sequencing (WES) was performed on DNA of the proband and the data were analyzed for probable pathogenic variants. Segregation of the identified variant was validated by Sanger sequencing. Results: Analysis of the WES data identified a novel nonsense mutation, c.762C>G, in the PNPLA1 (patatin-like phospholipase domain containing 1) gene. The protein product of of this gene is involved in lipid organization during cornified cell envelope formation. The variant is predicted to result in the generation of a premature truncation site at amino acid position 254 (p.Tyr254*). This would result in the loss of a large C-terminal portion of the protein suggesting it to be rendered nonfunctional. In silico protein structure modeling confirmed a detrimental effect of the variation on protein structure. Conclusions: The study supports the evidence for the prevalence of PNPLA1 mutations in distant ethnic groups. Despite the significant number of reported ARCI cases with PNPLA1 variants, a straightforward genotype-phenotype correlation cannot be established.


Assuntos
Ictiose Lamelar/genética , Lipase/genética , Adulto , Idoso , Códon sem Sentido/genética , Grupos Étnicos/genética , Família , Feminino , Genes Recessivos/genética , Humanos , Ictiose Lamelar/metabolismo , Lipase/fisiologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Paquistão , Linhagem , Fenótipo , Sequenciamento Completo do Exoma/métodos
2.
Hum Genet ; 138(6): 673-679, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31069506

RESUMO

The study of Mendelian diseases and the identification of their causative genes are of great significance in the field of genetics. The evaluation of the pathogenicity of genes and the total number of Mendelian disease genes are both important questions worth studying. However, very few studies have addressed these issues to date, so we attempt to answer them in this study. We calculated the gene pathogenicity prediction (GPP) score by a machine learning approach (random forest algorithm) to evaluate the pathogenicity of genes. When we applied the GPP score to the testing gene set, we obtained an accuracy of 80%, recall of 93% and area under the curve of 0.87. Our results estimated that a total of 10,384 protein-coding genes were Mendelian disease genes. Furthermore, we found the GPP score was positively correlated with the severity of disease. Our results indicate that GPP score may provide a robust and reliable guideline to predict the pathogenicity of protein-coding genes. To our knowledge, this is the first trial to estimate the total number of Mendelian disease genes.


Assuntos
Algoritmos , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença/genética , Aprendizado de Máquina , Genes Dominantes/genética , Genes Recessivos/genética , Doenças Genéticas Inatas/diagnóstico , Humanos , Curva ROC
3.
Mol Med Rep ; 19(6): 4711-4718, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059048

RESUMO

Autosomal recessive cornea plana is a very rare hereditary ocular disease, characterized by a flattened corneal curvature, marked hyperopia due to low refractive power and frequently consequent accommodative esotropia. Other features include various cornea anterior segment abnormalities, without systemic problems. The purpose of the present study was to investigate the clinical and molecular alterations in a Chinese family with cornea plana. Full ophthalmic examinations of the patients were performed, including slit­lamp examination, fundus examination and ocular ultrasound. Whole­exome sequencing data were screened for pathological variants in the proband, which were confirmed by Sanger sequencing. One novel missense mutation, c.242A>G (p.N81S) and another novel 7 base­pair deletion mutation, c.772­779del (p.G258Cfs*30), were detected in the keratocan (KERA) gene; two affected siblings inherited these variations in a compound heterozygous state, which were derived from the clinically unaffected heterozygous father (c.772_779del) and mother (c.242A>G), respectively. Neither mutation was observed in unrelated healthy controls (n=200). Multiple computer software predictions supported the pathogenicity of the two variants. Furthermore, protein modeling prediction was performed to better understand the molecular basis of cornea plana, particularly the importance of the leucine­rich repeat domain. This study presents the 14th pathogenic KERA mutations identified worldwide and the first in East Asia so far, to the best of our knowledge. These findings guided prenatal diagnosis for the family in question and expand on the variant spectrum of KERA, therefore facilitating genetic counseling.


Assuntos
Doenças da Córnea/genética , Genes Recessivos/genética , Proteoglicanas/genética , Grupo com Ancestrais do Continente Asiático , Sequência de Bases , China , Córnea/anormalidades , Córnea/patologia , Doenças da Córnea/diagnóstico , Doenças da Córnea/patologia , Distrofias Hereditárias da Córnea/diagnóstico , Distrofias Hereditárias da Córnea/genética , Análise Mutacional de DNA , Éxons/genética , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Feminino , Humanos , Mutação de Sentido Incorreto , Linhagem , Análise de Sequência , Deleção de Sequência , Sequenciamento Completo do Exoma
4.
Hum Genet ; 138(6): 593-600, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30982135

RESUMO

Postaxial polydactyly (PAP) is a common limb malformation that often leads to cosmetic and functional complications. Molecular evaluation of polydactyly can serve as a tool to elucidate genetic and signaling pathways that regulate limb development, specifically, the anterior-posterior specification of the limb. To date, only five genes have been identified for nonsyndromic PAP: FAM92A, GLI1, GLI3, IQCE and ZNF141. In this study, two Pakistani multiplex consanguineous families with autosomal recessive nonsyndromic PAP were clinically and molecularly evaluated. From both pedigrees, a DNA sample from an affected member underwent exome sequencing. In each family, we identified a segregating frameshift (c.591dupA [p.(Q198Tfs*21)]) and nonsense variant (c.2173A > T [p.(K725*)]) in KIAA0825 (also known as C5orf36). Although KIAA0825 encodes a protein of unknown function, it has been demonstrated that its murine ortholog is expressed during limb development. Our data contribute to the establishment of a catalog of genes important in limb patterning, which can aid in diagnosis and obtaining a better understanding of the biology of polydactyly.


Assuntos
Dedos/anormalidades , Genes Recessivos/genética , Predisposição Genética para Doença/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação , Polidactilia/genética , Dedos do Pé/anormalidades , Animais , Consanguinidade , Saúde da Família , Feminino , Dedos/patologia , Genótipo , Humanos , Masculino , Camundongos Endogâmicos C57BL , Linhagem , Fenótipo , Polidactilia/patologia , Dedos do Pé/patologia , Sequenciamento Completo do Exoma/métodos
5.
Genet Test Mol Biomarkers ; 23(3): 204-208, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30758234

RESUMO

AIMS: Autosomal recessive nonsyndromic hearing loss (ARNSHL) is the most common form of hereditary deafness. Despite its frequency, the diagnosis of this disorder continues to be a challenging task given its extreme genetic heterogeneity. The purpose of this study was to identify the causative mutation in a consanguineous United Arab Emirates (UAE) family with ARNSHL. MATERIALS AND METHODS: Clinical exome sequencing (CES) followed by segregation analysis via Sanger sequencing was used to identify the causative mutation. In addition, 109 deaf individuals and 50 deafness-free controls from the UAE population were screened for the identified mutation. RESULTS AND DISCUSSION: CES identified the STRC frameshift mutation c.4510del (p.Glu1504Argfs*32) as the causative mutation in this family. Moreover, segregation analysis confirmed the above finding. In addition, the absence of this variant in 109 unrelated deaf individuals and 50 healthy controls indicates that it is rare in the UAE population. CONCLUSION: The present study represents the first STRC mutation reported in the UAE population. It also reinforces the power of next-generation sequencing in the diagnosis of heterogenous disorders such as nonsyndromic hearing loss.


Assuntos
Surdez/genética , Proteínas de Membrana/genética , Adulto , Exoma/genética , Feminino , Mutação da Fase de Leitura/genética , Genes Recessivos/genética , Perda Auditiva Neurossensorial/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Proteínas de Membrana/fisiologia , Mutação , Linhagem , Emirados Árabes Unidos , Sequenciamento Completo do Exoma
7.
J Genet ; 97(5): 1451-1456, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30555093

RESUMO

Yardlong bean (Vigna unguiculata ssp. sesquipedalis), a type of cowpea, is an important vegetable legume of Asia. Cercospora leaf spot (CLS) caused by Cercospora canescens and Psuedocercospora cruenta is an important phytopathological problem of the yardlong bean grown in tropical regions. The objectives of this study were to (i) determine mode of inheritance of resistance to CLS caused by C. canescens and P. cruenta, (ii) estimate the heritability of the resistance, (iii) estimate genetic effects on the resistance using six basic populations generated from the cross between the susceptible yardlong bean 'CSR12906' and the resistant grain cowpea (V.unguiculata spp. unguiculata) 'IT90K-59-120'. Segregation for the resistance to both fungi in the F2 population fitted both 3 : 1 ratio and 13 : 3 ratio of susceptible:resistant, while that in the BC2 ((CSR12906×IT90K-59-120)×IT90K- 59-120) population fitted a 1 : 1 ratio, suggesting one recessive gene or two genes with inhibitory gene action control the resistance. Generation mean analysis showed that a simple additive-dominance model was adequate to explain the genetic control of CLS disease resistance, indicating that a single gene controls the resistance. The average number of major genes (effective factors) controlling the resistance was estimated to be 1.05 and 0.92 for C. canescens and P. cruenta, respectively. The broad-sense heritability calculated for resistance to both diseases was higher than 0.90. Altogether, these results indicated that the resistance to CLS disease caused by C. canescens and P. cruenta in grain cowpea IT90K-59-120 is a highly heritable trait governed by a single major recessive gene.


Assuntos
Resistência à Doença/genética , Grão Comestível/genética , Doenças das Plantas/genética , Vigna/genética , Algoritmos , Ascomicetos/fisiologia , Grão Comestível/microbiologia , Genes Recessivos/genética , Genética Populacional , Interações Hospedeiro-Patógeno , Padrões de Herança/genética , Modelos Genéticos , Doenças das Plantas/microbiologia , Vigna/microbiologia
8.
Orv Hetil ; 159(28): 1163-1169, 2018 Jul.
Artigo em Húngaro | MEDLINE | ID: mdl-29983107

RESUMO

Next generation sequencing (NGS) technologies reshape the diagnostics of rare neurological diseases. In the background of certain neurological symptoms, such as ataxia, many acquired and genetic causes may be present. Variations in a given gene can present with variable phenotypes, too. Because of this phenomenon, the conventional one gene sequencing approach often fails to identify the genetic background of a disease. Next generation sequencing panels allow to sequence 50-100 genes simultaneously, and if the disease stratification is not possible based on the clinical symptoms, whole exome sequencing can help in the diagnostic of genetic disorders with atypical presentation. This case study is about the exome sequencing of a patient with cerebellar ataxia. Genetic investigations identified rare variants in the SPG11 gene in association with the clinical phenotype, which gene was originally described in the background of hereditary spastic paraparesis. Our article highlights that in certain cases the variability of the leading presenting symptom makes it hard to select the correct gene panel. In our case the variants in the gene, formerly associated to hereditary spastic paraparesis, resulted in cerebellar ataxia initially, so even an ataxia NGS gene panel would not detect those. Orv Hetil. 2018; 159(28): 1163-1169.


Assuntos
Ataxia/genética , Testes Genéticos/métodos , Paraplegia Espástica Hereditária/genética , Sequenciamento Completo do Exoma , Ataxia/diagnóstico , Genes Recessivos/genética , Predisposição Genética para Doença , Humanos , Doenças do Sistema Nervoso/genética , Doenças Raras , Paraplegia Espástica Hereditária/diagnóstico
9.
Handb Clin Neurol ; 155: 73-89, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29891078

RESUMO

Recessive ataxias (spinocerebellar ataxias, recessive or SCARs) are a heterogeneous group of rare, mostly neurodegenerative genetic disorders which usually start in childhood or early adult life. They can be subdivided into two major groups: predominant sensory or afferent ataxias, which are disorders mainly of the peripheral input to the cerebellum, and predominant cerebellar ataxias, in which the cerebellum is primarily affected. Next-generation sequencing technology has enabled the identification of >100 novel SCAR genes in the last 5 years, although most of them are ultrarare. To guide clinical workup and management in SCARs, we provide an up-to-date overview of the most frequent SCARs and their phenotypic features. These include Friedreich ataxia, spastic paraplegia type 7-related ataxia, autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) and spectrin repeat-containing nuclear envelope protein (SYNE)-related ataxia. In some restricted populations ARSACS or ataxia with vitamin E deficiency (AVED) is most common. All require a high index of suspicion in patients who present with an early-onset disorder of balance, especially children, in whom normal development and the lack of typical clinical characteristics seen in later stages of the respective SCARs can confuse the clinical picture. We summarize the diagnostic features which can help guide diagnosis, the natural history for common SCARs, and the approach to therapy, both in current use and in ongoing clinical trials. We also provide a summary table for other clinically relevant SCARs. Based on the frequency data, phenotypes, and the cost-effectiveness of recent next-generation sequencing approaches, we conclude with a diagnostic algorithm for the workup of patients with unexplained SCAR.


Assuntos
Genes Recessivos/genética , Ataxias Espinocerebelares/genética , Ataxia/complicações , Ataxia/genética , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico por imagem , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Humanos , Técnicas de Diagnóstico Molecular , Mutação/genética , Proteínas do Tecido Nervoso/genética , Neuroimagem , Proteínas Nucleares/genética , Ataxias Espinocerebelares/classificação , Ataxias Espinocerebelares/diagnóstico por imagem , Deficiência de Vitamina E/complicações , Deficiência de Vitamina E/genética
10.
J Dermatol ; 45(6): 742-745, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29500833

RESUMO

Dystrophic epidermolysis bullosa (DEB), pretibial, a rare subtype of epidermolysis bullosa (EB), is characterized by recurrent blisters and erosions predominantly on the pretibial region. We report the case of a 60-year-old Japanese woman with persistent blistering eruptions and scar formation on the pretibial region and elbows. Mutational analysis revealed a previously reported c.5797C>T mutation in exon 70 (p.R1933X) and a novel c.6348+1G>A mutation in intron 76 of COL7A1. Reverse transcription polymerase chain reaction revealed that the c.6348+1G>A mutation resulted in the skipping of exon 76 (69 bp) and the retention of intron 76 (75 bp), and both transcripts were in-frame. From these results, we diagnosed the patient as having recessive DEB, pretibial. A review of previously reported mutations in DEB, pretibial, revealed that one-third of DEB, pretibial, cases showed a recessive inheritance pattern, and no case had a combination of premature termination codon (PTC)/PTC mutations. The DEB, pretibial, case described herein is the first reported case of a compound heterozygote with PTC/in-frame mutations. Although no special characteristic features of the mutations were identified, a high diversity of COL7A1 mutations was shown even in DEB, pretibial.


Assuntos
Colágeno Tipo VII/genética , Epidermólise Bolhosa Distrófica/genética , Genes Recessivos/genética , Sítios de Splice de RNA/genética , Códon sem Sentido/genética , Colágeno Tipo VII/metabolismo , Análise Mutacional de DNA , Epiderme/patologia , Epidermólise Bolhosa Distrófica/diagnóstico , Epidermólise Bolhosa Distrófica/patologia , Éxons/genética , Feminino , Humanos , Íntrons/genética , Pessoa de Meia-Idade , Processamento de RNA/genética
11.
Int J Hematol ; 107(4): 436-441, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29383625

RESUMO

Coagulation factor XII deficiency is a rare autosomal recessive disorder, which could be found in a consanguineous family. We studied a Chinese family in which the activated partial thromboplastin time (APTT) of the proband had clearly prolonged up to 101.7 s, associated with low FXII activity of 3% and FXII antigen < 1%. To analyze the gene mutation in this FXII-deficient patient, we performed FXII mutation screening, and analyzed the DNA sequence of the F12 gene. A ClustalX-2.1-win and four online bioinformatics software services were used to study the conservatism and effects of the mutation. A transient in vitro expression study was performed to elucidate the possible pathological mechanism. Sequence analysis revealed a homozygous c.1681 G > A point mutation in exon 14, causing a novel Gly542Ser mutation in the catalytic domain. The results of the conservatism and bioinformatics analyses both indicated that the mutation likely affects the function of the protein. Additional expression studies in COS-7 cells showed that the antigen level of mutant FXII (FXII-Gly542Ser) was lower than wild type in culture medium, whereas the corresponding level of FXII antigen in cell lysates was equivalent. These results suggest that the Gly542Ser mutation causes FXII deficiency through intracellular degradation.


Assuntos
Consanguinidade , Deficiência do Fator XII/genética , Mutação de Sentido Incorreto , Animais , Grupo com Ancestrais do Continente Asiático/genética , Células COS , Células Cultivadas , Cercopithecus aethiops , Biologia Computacional , Deficiência do Fator XII/sangue , Feminino , Genes Recessivos/genética , Humanos , Masculino , Tempo de Tromboplastina Parcial , Software
12.
Handb Clin Neurol ; 147: 187-209, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29325611

RESUMO

The autosomal-recessive cerebellar ataxias comprise more than half of the known genetic forms of ataxia and represent an extensive group of clinically heterogeneous disorders that can occur at any age but whose onset is typically prior to adulthood. In addition to ataxia, patients often present with polyneuropathy and clinical symptoms outside the nervous system. The most common of these diseases is Friedreich ataxia, caused by mutation of the frataxin gene, but recent advances in genetic analysis have greatly broadened the ever-expanding number of causative genes to over 50. In this review, the clinical neurogenetics of the recessive cerebellar ataxias will be discussed, including updates on recently identified novel ataxia genes, advancements in unraveling disease-specific molecular pathogenesis leading to ataxia, potential treatments under development, technologic improvements in diagnostic testing such as clinical exome sequencing, and what the future holds for clinicians and geneticists.


Assuntos
Ataxia de Friedreich/genética , Genes Recessivos/genética , Proteínas de Ligação ao Ferro/genética , Humanos
13.
Birth Defects Res ; 110(2): 92-97, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29377642

RESUMO

BACKGROUND: The number of malformations attributed to mutations with autosomal or X-linked patterns of inheritance has increased steadily since the cataloging began in the 1960s. These diagnoses have been based primarily on the pattern of phenotypic features among close relatives. A malformations surveillance program conducted in consecutive pregnancies can identify both known and "new" hereditary disorders. METHODS: The Active Malformations Surveillance Program was carried out among 289,365 births over 41 years (1972-2012) at Brigham and Women's Hospital in Boston. The findings recorded by examining pediatricians and all consultants were reviewed by study clinicians to establish the most likely diagnoses. The findings in laboratory testing in the newborn period were reviewed, as well. RESULTS: One hundred ninety-six (0.06%) infants among 289,365 births had a malformation or malformation syndrome that was attributed to Mendelian inheritance. A total of 133 (68%) of the hereditary malformations were attributed to autosomal dominant inheritance, with 94 (71%) attributed to apparent spontaneous mutations. Forty-six (23%) were attributed to mutations with autosomal recessive inheritance, 17 associated with consanguinity. Seventeen (9%) were attributed to X-linked inheritance. Fifteen novel familial phenotypes were identified. The family histories showed that most (53 to 71%) of the affected infants were born, as a surprise, to healthy, unaffected parents. CONCLUSION: It is important for clinicians to discuss with surprised healthy parents how they can have an infant with an hereditary condition. Future studies, using DNA samples from consecutive populations of infants with malformations and whole genome sequencing, will identify many more mutations in loci associated with mendelizing phenotypes. Birth Defects Research 110:92-97, 2018.© 2018 Wiley Periodicals, Inc.


Assuntos
Anormalidades Múltiplas/epidemiologia , Genes Recessivos/genética , Genes Ligados ao Cromossomo X/genética , Anormalidades Múltiplas/genética , Consanguinidade , Feminino , Humanos , Recém-Nascido , Linhagem , Gravidez , Diagnóstico Pré-Natal/métodos , Estados Unidos/epidemiologia
14.
Gene ; 641: 279-286, 2018 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-29080837

RESUMO

BACKGROUND: Uncertainty remains on the pathogenetic mechanisms, model of inheritance as well as genotype-phenotype correlation of FMF disease. OBJECTIVE: To investigate the impact of genetic factors on the FMF phenotype and the disease inheritance model. METHODS: A total of 107 FMF patients were enrolled. Patients were diagnosed clinically. All patients underwent genetic analysis of the FMF locus on 16p13.3. RESULTS: 9 distinct mutations were detected. Specifically, the 85.98% of patients showed a heterozygous genotype. The most common genotypes were p.Met680Ile/wt and p.Met694Val/wt. The most frequent clinical findings were fever, abdominal pain, joint pain, thoracic pain, and erysipelas-like erythema. Analysis of clinical data did not detect any significant difference in clinical phenotype among heterozygous, homozygous as well as compound homozygous subjects, further supporting the evidence that, contrary to the recessive autosomal inheritance, heterozygous patients fulfilled the criteria of clinical FMF. Moreover, subjects with p.Met694Val/wt and p.Met680Ile/wt genotype reported the most severe clinical phenotype. p.Ala744Ser/wt, p.Glu148Gln/Met680Ile, p.Met680Ile/Met680Ile, p.Met680Ile/Met694Val, p.Pro369Ser/wt, p.Met694Ile/wt, p.Glu148Gln/Glu148Gln, p.Lys695Arg/wt resulted in 100% pathogenicity. CONCLUSIONS: The existence of a "non classic" autosomal recessive inheritance as well as of an "atypical" dominant autosomal inheritance with incomplete penetrance and variable expressivity cannot be excluded in FMF.


Assuntos
Febre Familiar do Mediterrâneo/genética , Genes Recessivos/genética , Feminino , Estudos de Associação Genética/métodos , Loci Gênicos/genética , Genótipo , Heterozigoto , Homozigoto , Humanos , Masculino , Mutação/genética , Linhagem , Fenótipo
15.
BMC Genomics ; 18(1): 858, 2017 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-29121877

RESUMO

BACKGROUND: Lethal recessive variation can cause prenatal death of homozygous offspring. Although usually present at low-frequency in populations, the impact on individual fitness can be substantial. Until recently, the presence of recessive embryonic lethal variation could only be measured indirectly through reduced fertility. In this study, we estimate the presence of genetic loci associated with both early and late termination of development during gestation in pigs from the wealth of genome data routinely generated by a commercial breeding company. RESULTS: We examined three commercial pig (Sus scrofa) populations for potentially deleterious genetic variation based on 80 K SNP-chip genotypes, and estimate the effects on reproductive traits. 24,000 pigs from three populations were analyzed for missing or depletion of homozygous haplotypes. We identified 145 haplotypes (ranging from 0.5-4 Mb in size) in the genome with complete absence or depletion of homozygous animals. Thirty-five haplotypes show a negative effect on at least one of the analysed reproductive traits (total number born, number of stillborn, and number of mummified piglets). One variant in particular appeared to result in relative late termination of development of fetuses, responsible for a significant fraction of observed stillborn piglets ('mummies'), as they die mid-gestation. Moreover, we identified the BMPER gene as a likely candidate underlying this phenomenon. CONCLUSIONS: Our study shows that although lethal recessive variation is present, the frequency of these alleles is invariably low in these highly managed populations. Nevertheless, due to cumulative effects of deleterious variants, large numbers of affected offspring are produced. Furthermore, our study demonstrates the use of a large-scale commercial genetic experiment to systematically screen for 'natural knockouts' that can increase understanding of gene function.


Assuntos
Genes Recessivos/genética , Polimorfismo de Nucleotídeo Único , Sus scrofa/genética , Animais , Haplótipos , Homozigoto , Inquéritos e Questionários
16.
J Clin Immunol ; 37(8): 811-819, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29058101

RESUMO

PURPOSE: The dedicator of cytokinesis 8 (DOCK8) deficiency is an autosomal recessive-combined immunodeficiency whose clinical spectra include recurrent infections, autoimmunity, malignancies, elevated serum IgE, eczema, and food allergies. Here, we report on patients with loss of function DOCK8 mutations with profound immune dysregulation suggestive of an immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX)-like disorder. METHODS: Immunophenotyping of lymphocyte subpopulations and analysis of DOCK8 protein expression were evaluated by flow cytometry. T regulatory (Treg) cells were isolated by cell sorting, and their suppressive activity was analyzed by flow cytometry. Gene mutational analysis was performed by whole-exome and Sanger sequencing. RESULTS: Patient 1 (P1) presented at 10 months of age with chronic severe diarrhea and active colitis in the absence of an infectious trigger, severe eczema with elevated serum IgE, and autoimmune hemolytic anemia, suggestive of an IPEX-related disorder. Whole-exome sequencing revealed a homozygous nonsense mutation in DOCK8 at the DOCK-homology region (DHR)-1 (c.1498C>T; p. R500X). Patient P2, a cousin of P1 who carries the same DOCK8 nonsense mutation, presented with eczema and recurrent ear infections in early infancy, and she developed persistent diarrhea by 3 years of age. Patient P3 presented with lymphoproliferation, severe eczema with allergic dysregulation, and chronic diarrhea with colitis. She harbored a homozygous loss of function DOCK8 mutation (c.2402 -1G→A). Treg cell function was severely compromised by both DOCK8 mutations. CONCLUSION: DOCK8 deficiency may present severe immune dysregulation with features that may overlap with those of IPEX and other IPEX-like disorders.


Assuntos
Transtornos Cromossômicos/diagnóstico , Diabetes Mellitus Tipo 1/congênito , Diarreia/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Fatores de Troca do Nucleotídeo Guanina/genética , Hipersensibilidade/diagnóstico , Doenças do Sistema Imunitário/congênito , Infecção/diagnóstico , Mutação/genética , Linfócitos T Reguladores/imunologia , Anemia Hemolítica , Pré-Escolar , Diabetes Mellitus Tipo 1/diagnóstico , Feminino , Genes Recessivos/genética , Humanos , Doenças do Sistema Imunitário/diagnóstico , Imunoglobulina E/metabolismo , Imunofenotipagem , Lactente
17.
Presse Med ; 46(9): 853-863, 2017 Sep.
Artigo em Francês | MEDLINE | ID: mdl-28683959

RESUMO

Auto-immune polyendocrine syndrome type 1 (APS1) also called Auto-immune Polyendocrinopathy Candidiasis Ectodermal Dystrophy (APECED) is a rare monogenic childhood-onset auto-immune disease. This autosomal recessive disorder is caused by mutations in the auto-immune regulator (AIRE) gene, and leads to autoimmunity targeting peripheral tissues. There is a wide variability in clinical phenotypes in patients with APSI, with auto-immune endocrine and non-endocrine disorders, and chronic mucocutaneous candidiasis. These patients suffer from oral diseases such as dental enamel hypoplasia and candidiasis. Both are frequently described, and in recent series, enamel hypoplasia and candidiasis are even the most frequent components of APS1 together with hypoparathyroidism. Both often occur during childhood (before 5 years old for canrdidiasis, and before 15 years old for enamel hypoplasia). Oral candidiasis is recurrent all life long, could become resistant to azole antifungal after years of treatment, and be carcinogenic, leading to severe oral squamous cell carcinoma. Oral components of APS1 should be diagnosed and rigorously treated. Dental enamel hypoplasia and/or recurrent oral candidiasis in association with auto-immune diseases in a young child should prompt APS1 diagnosis.


Assuntos
Doenças da Boca/diagnóstico , Poliendocrinopatias Autoimunes/diagnóstico , Odontopatias/diagnóstico , Adolescente , Adulto , Candidíase Bucal/diagnóstico , Candidíase Bucal/genética , Criança , Pré-Escolar , Análise Mutacional de DNA , Hipoplasia do Esmalte Dentário/diagnóstico , Hipoplasia do Esmalte Dentário/genética , Diagnóstico Diferencial , Genes Recessivos/genética , Humanos , Lactente , Doenças da Boca/genética , Fenótipo , Poliendocrinopatias Autoimunes/classificação , Poliendocrinopatias Autoimunes/genética , Odontopatias/genética , Fatores de Transcrição/genética
18.
Genet Sel Evol ; 49(1): 57, 2017 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-28709397

RESUMO

BACKGROUND: Lethal recessive genetic variants are maintained at relatively low frequencies in a population in the heterozygous state, but by definition are fatal and therefore unobserved in the homozygous state. Since haplotypes allow the tagging of rare and untyped genetic variants, they have potential for studying lethal recessive variants. In this study, we used a large commercial population to identify putative lethal recessive haplotypes that impact either the total number born (TNB) or the number born alive (NBA) as a proportion of the total number born (NBA/TNB). We also compared the use of haplotypes with a single nucleotide polymorphism (SNP)-by-SNP approach and examined the benefits of using additional haplotypes imputed from low-density genotype data for the detection of lethal recessive variants. Candidate haplotypes were identified using population-wide haplotype frequencies and within-family analyses. These candidate haplotypes were subsequently assessed for putative lethal recessive effects on TNB and NBA/TNB by comparing carrier-to-carrier matings with carrier-to-non-carrier matings. RESULTS: Using both medium-density and imputed low-density genotype data six regions were identified as containing putative lethal recessive haplotypes that had an effect on TNB. It is likely that these regions were related to at least four putative lethal recessive variants, each located on a different chromosome. Evidence for putative lethal recessive effects on TNB was found on chromosomes 1, 6, 10 and 14 using haplotypes. Using haplotypes from individuals genotyped only at medium-density or a SNP-by-SNP approach did not detect any lethal recessive effects. No lethal recessive haplotypes or SNPs were detected that had an effect on NBA/TNB. CONCLUSIONS: We show that the use of haplotypes from combining medium-density and imputed low-density genotype data is superior for the identification of lethal recessive variants compared to both a SNP-by-SNP approach and to the use of only medium-density data. We developed a formal statistical framework that provided sufficient power to detect lethal recessive variants in species, which produce large full-sib families, while reducing false positive or type I errors. Applying this framework results in improvements in reproductive performance by purging lethal recessive alleles from a population in a timely and cost-effective manner.


Assuntos
Genes Letais/genética , Genes Recessivos/genética , Haplótipos/genética , Sus scrofa/genética , Animais , Frequência do Gene , Genótipo , Polimorfismo de Nucleotídeo Único , Suínos
19.
Nat Genet ; 49(9): 1403-1407, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28714977

RESUMO

The more than 1.5 billion people who live in South Asia are correctly viewed not as a single large population but as many small endogamous groups. We assembled genome-wide data from over 2,800 individuals from over 260 distinct South Asian groups. We identified 81 unique groups, 14 of which had estimated census sizes of more than 1 million, that descend from founder events more extreme than those in Ashkenazi Jews and Finns, both of which have high rates of recessive disease due to founder events. We identified multiple examples of recessive diseases in South Asia that are the result of such founder events. This study highlights an underappreciated opportunity for decreasing disease burden among South Asians through discovery of and testing for recessive disease-associated genes.


Assuntos
Doença/genética , Efeito Fundador , Predisposição Genética para Doença/genética , Genética Populacional/métodos , Algoritmos , Ásia , Grupo com Ancestrais do Continente Asiático/genética , Doença/classificação , Frequência do Gene , Genes Recessivos/genética , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla , Genótipo , Geografia , Haplótipos , Humanos , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal
20.
Nervenarzt ; 88(7): 720-727, 2017 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-28600743

RESUMO

Hereditary ataxias and spastic paraplegias are genetic disorders with age-dependent nearly complete penetrance. The mostly monogenetic etiology allows one to establish the diagnosis, study pathogenesis and to develop new causative therapeutic approaches for these diseases. Both the causative genes as well as the clinical presentation overlap considerably between hereditary ataxias and spastic paraplegias. This strongly argues towards a united classification for these two groups of diseases. Next generation sequencing technologies have greatly expanded the number of genes known to be causative for hereditary ataxias and spastic paraplegias and allow simultaneous time- and cost-effective diagnostic testing of > 200 genes. However, repeat expansions and large genomic deletions must be considered separately. Here, we suggest a pragmatic algorithm for genetic testing in hereditary ataxias and spastic paraplegias that we have developed in our specialized outpatient clinics. Detailed phenotyping remains crucial to interpret the multitude of genetic variants discovered by high throughput sequencing techniques. Despite recent technical advances, a substantial proportion of ataxia and spastic paraplegia families are still without a molecular diagnosis. Beside new and so far undetected ataxia and spasticity genes, unusual mutation types including noncoding variants and polygenic inheritance patterns may contribute. Because of these clinical, genetic, and technological challenges, patients with hereditary ataxias and spastic paraplegias should be referred to specialized centers offering research and clinical studies. This will also help to recruit representative patient cohorts for upcoming interventional trials.


Assuntos
Paraplegia Espástica Hereditária/genética , Ataxias Espinocerebelares/genética , Aberrações Cromossômicas , Genes Dominantes/genética , Genes Recessivos/genética , Testes Genéticos , Variação Genética/genética , Humanos , Fenótipo , Análise de Sequência de DNA , Paraplegia Espástica Hereditária/classificação , Paraplegia Espástica Hereditária/diagnóstico , Ataxias Espinocerebelares/diagnóstico
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