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BACKGROUND: Despite advances in next generation sequencing technologies, the identification of variants of uncertain significance (VUS) can often hinder definitive diagnosis in patients with complex neurodevelopmental disorders. OBJECTIVE: The objective of this study was to identify and characterize the underlying cause of disease in a family with two children with severe developmental delay associated with generalized dystonia and episodic status dystonicus, chorea, epilepsy, and cataracts. METHODS: Candidate genes identified by autozygosity mapping and whole-exome sequencing were characterized using cellular and vertebrate model systems. RESULTS: Homozygous variants were found in three candidate genes: MED27, SLC6A7, and MPPE1. Although the patients had features of MED27-related disorder, the SLC6A7 and MPPE1 variants were functionally investigated. SLC6A7 variant in vitro overexpression caused decreased proline transport as a result of reduced cell-surface expression, and zebrafish knockdown of slc6a7 exhibited developmental delay and fragile motor neuron morphology that could not be rescued by L-proline transporter-G396S RNA. Lastly, patient fibroblasts displayed reduced cell-surface expression of glycophosphatidylinositol-anchored proteins linked to MPPE1 dysfunction. CONCLUSIONS: We report a family harboring a homozygous MED27 variant with additional loss-of-function SLC6A7 and MPPE1 gene variants, which potentially contribute to a blended phenotype caused by multilocus pathogenic variants. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Distonia , Distúrbios Distônicos , Transtornos dos Movimentos , Transtornos do Neurodesenvolvimento , Animais , Distonia/diagnóstico , Distonia/genética , Distúrbios Distônicos/genética , Transtornos dos Movimentos/genética , Transtornos do Neurodesenvolvimento/genética , Prolina , RNA , Peixe-Zebra/genéticaRESUMO
Hyper-IgE syndromes and chronic mucocutaneous candidiasis constitute rare primary immunodeficiency syndromes with an overlapping clinical phenotype. In recent years, a growing number of underlying genetic defects have been identified. To characterize the underlying genetic defects in a large international cohort of 275 patients, of whom 211 had been clinically diagnosed with hyper-IgE syndrome and 64 with chronic mucocutaneous candidiasis, targeted panel sequencing was performed, relying on Agilent HaloPlex and Illumina MiSeq technologies. The targeted panel sequencing approach allowed us to identify 87 (32 novel and 55 previously described) mutations in 78 patients, which generated a diagnostic success rate of 28.4%. Specifically, mutations in DOCK8 (26 patients), STAT3 (21), STAT1 (15), CARD9 (6), AIRE (3), IL17RA (2), SPINK5 (3), ZNF341 (2), CARMIL2/RLTPR (1), IL12RB1 (1), and WAS (1) have been detected. The most common clinical findings in this cohort were elevated IgE (81.5%), eczema (71.7%), and eosinophilia (62.9%). Regarding infections, 54.7% of patients had a history of radiologically proven pneumonia, and 28.3% have had other serious infections. History of fungal infection was noted in 53% of cases and skin abscesses in 52.9%. Skeletal or dental abnormalities were observed in 46.2% of patients with a characteristic face being the most commonly reported feature (23.1%), followed by retained primary teeth in 18.9% of patients. Targeted panel sequencing provides a cost-effective first-line genetic screening method which allows for the identification of mutations also in patients with atypical clinical presentations and should be routinely implemented in referral centers.
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Candidíase Mucocutânea Crônica/genética , Síndrome de Job/genética , Adolescente , Adulto , Candidíase Mucocutânea Crônica/sangue , Criança , Pré-Escolar , Estudos de Coortes , Eczema/genética , Eosinofilia/genética , Feminino , Humanos , Imunoglobulina E/sangue , Lactente , Síndrome de Job/sangue , Masculino , Pessoa de Meia-Idade , Mutação , Adulto JovemRESUMO
PURPOSE: Genetic advances mean patients at risk of genetic conditions can be helped through testing, clinical screening, and preventive treatment, but they must first be identified to benefit. Ensuring quality of genetic care for patients requires genetic expertise in all health services, including primary care. To address an educational shortfall, a series of e-learning resources was developed in six languages to equip primary care professionals with genetic skills relevant for practice. The purpose of the study was to evaluate these resources using Kirkpatrick's framework for educational outcomes. METHODS: Mixed methods (qualitative and quantitative) were used over four phases of the study. RESULTS: A high level of satisfaction with the resources was reported. Knowledge and skills improved significantly after using the education material. Participants reported changes in confidence and practice behavior, including family history taking, seeking advice from specialists and referring patients. The resources helped users to learn how to explain genetics. Many visited the resources repeatedly and some used them to educate colleagues or students. CONCLUSION: Gen-Equip modules are effective in improving genetic knowledge, skills, and attitudes for primary care professionals. They provide both continuing professional development and just-in-time learning for a potentially large global audience at a practical level.
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Instrução por Computador/métodos , Genética/educação , Médicos de Atenção Primária/educação , Adulto , Competência Clínica , Feminino , Humanos , Idioma , Aprendizagem , Masculino , Atenção Primária à Saúde , Treinamento por Simulação/métodos , EstudantesRESUMO
This Article was originally published under Nature Research's License to Publish, but has now been made available under a [CC BY 4.0] license. The PDF and HTML versions of the Article have been modified accordingly.
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This paper sets out good practice for clinicians involved in interpreting variant reports for patients with inherited bleeding disorders. It is aimed primarily at doctors, nurses and allied healthcare professionals who may not have had specific training in genetic testing methodology or reporting. It deals with uncertainty in classification of variant pathogenicity and the handling of incidental findings.
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Transtornos Herdados da Coagulação Sanguínea/diagnóstico , Testes Genéticos , Transtornos Herdados da Coagulação Sanguínea/genética , Testes Respiratórios , Aberrações Cromossômicas , Genótipo , Humanos , Mosaicismo , Linhagem , Fenótipo , Incerteza , Reino UnidoRESUMO
BACKGROUND: At least 10 % of patients seen in primary care are said to have a condition in which genetics has an influence. However, patients at risk of genetic disease may not be recognised, while those who seek advice may not be referred or managed appropriately. Primary care practitioners lack knowledge of genetics and genetic testing relevant for daily practice and feel inadequate to deliver genetic services. The aim of this systematic review was to evaluate genetics educational interventions in the context of primary care. METHODS: Following the process for systematic reviews developed by the Centre for Reviews and Dissemination, we conducted a search of five relevant electronic databases. Primary research papers were eligible for inclusion if they included data on outcomes of interventions regarding genetics education for primary care practitioners. The results from each paper were coded and grouped under themes. RESULTS: Eleven studies were included in the review. The five major themes identified inductively (post hoc) were: prior experience, changes in confidence, changes in knowledge, changes in practice, satisfaction and feedback. In five of the studies, knowledge of practitioners was improved following the educational programmes, but this tended to be in specific topic areas, while practitioner confidence improved in six studies. However, there was little apparent change to practice. CONCLUSIONS: There are insufficient studies of relevant quality to inform educational interventions in genetics for primary care practitioners. Educational initiatives should be assessed using changes in practice, as well as in confidence and knowledge, to determine if they are effective in causing significant changes in practice in genetic risk assessment and appropriate management of patients.
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Educação Médica Continuada/métodos , Testes Genéticos , Genética/educação , Atenção Primária à Saúde , Competência Clínica , Humanos , Padrões de Prática Médica , AutoeficáciaRESUMO
BACKGROUND: Inherited peripheral neuropathy (IPN) is a clinically and genetically heterogeneous group of disorders with more than 90 genes associated with the different subtypes. Sequential gene screening is gradually being replaced by next generation sequencing (NGS) applications. METHODS: We designed and validated a targeted NGS panel assay including 56 genes associated with known causes of IPN. We report our findings following NGS panel testing of 448 patients with different types of clinically-suspected IPN. RESULTS: Genetic diagnosis was achieved in 137 patients (31%) and involved 195 pathogenic variants in 31 genes. 93 patients had pathogenic variants in genes where a resulting phenotype follows dominant inheritance, 32 in genes where this would follow recessive inheritance, and 12 presented with X-linked disease. Almost half of the diagnosed patients (64) had a pathogenic variant either in genes not previously available for routine diagnostic testing in a UK laboratory (50 patients) or in genes whose primary clinical association was not IPN (14). Seven patients had a pathogenic variant in a gene not hitherto indicated from their phenotype and three patients had more than one pathogenic variant, explaining their complex phenotype and providing information essential for accurate prediction of recurrence risks. CONCLUSIONS: Our results demonstrate that targeted gene panel testing is an unbiased approach which overcomes the limitations imposed by limited existing knowledge for rare genes, reveals high heterogeneity, and provides high diagnostic yield. It is therefore a highly efficient and cost effective tool for achieving a genetic diagnosis for IPN.
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Testes Genéticos/métodos , Variação Genética , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/patologia , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Linhagem , Doenças do Sistema Nervoso Periférico/genética , Fenótipo , Reprodutibilidade dos Testes , Análise de Sequência de DNA/economia , Análise de Sequência de DNA/métodosRESUMO
The ß-tropomyosin gene encodes a component of the sarcomeric thin filament. Rod-shaped dimers of tropomyosin regulate actin-myosin interactions and ß-tropomyosin mutations have been associated with nemaline myopathy, cap myopathy, Escobar syndrome and distal arthrogryposis types 1A and 2B. In this study, we expand the allelic spectrum of ß-tropomyosin-related myopathies through the identification of a novel ß-tropomyosin mutation in two clinical contexts not previously associated with ß-tropomyosin. The first clinical phenotype is core-rod myopathy, with a ß-tropomyosin mutation uncovered by whole exome sequencing in a family with autosomal dominant distal myopathy and muscle biopsy features of both minicores and nemaline rods. The second phenotype, observed in four unrelated families, is autosomal dominant trismus-pseudocamptodactyly syndrome (distal arthrogryposis type 7; previously associated exclusively with myosin heavy chain 8 mutations). In all four families, the mutation identified was a novel 3-bp in-frame deletion (c.20_22del) that results in deletion of a conserved lysine at the seventh amino acid position (p.K7del). This is the first mutation identified in the extreme N-terminus of ß-tropomyosin. To understand the potential pathogenic mechanism(s) underlying this mutation, we performed both computational analysis and in vivo modelling. Our theoretical model predicts that the mutation disrupts the N-terminus of the α-helices of dimeric ß-tropomyosin, a change predicted to alter protein-protein binding between ß-tropomyosin and other molecules and to disturb head-to-tail polymerization of ß-tropomyosin dimers. To create an in vivo model, we expressed wild-type or p.K7del ß-tropomyosin in the developing zebrafish. p.K7del ß-tropomyosin fails to localize properly within the thin filament compartment and its expression alters sarcomere length, suggesting that the mutation interferes with head-to-tail ß-tropomyosin polymerization and with overall sarcomeric structure. We describe a novel ß-tropomyosin mutation, two clinical-histopathological phenotypes not previously associated with ß-tropomyosin and pathogenic data from the first animal model of ß-tropomyosin-related myopathies.
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Lisina/genética , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Deleção de Sequência , Tropomiosina/genética , Adolescente , Adulto , Sequência de Aminoácidos , Animais , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Doenças Musculares/patologia , Tropomiosina/química , Adulto Jovem , Peixe-ZebraRESUMO
Neurodegenerative disorders with high iron in the basal ganglia encompass an expanding collection of single gene disorders collectively known as neurodegeneration with brain iron accumulation. These disorders can largely be distinguished from one another by their associated clinical and neuroimaging features. The aim of this study was to define the phenotype that is associated with mutations in WDR45, a new causative gene for neurodegeneration with brain iron accumulation located on the X chromosome. The study subjects consisted of WDR45 mutation-positive individuals identified after screening a large international cohort of patients with idiopathic neurodegeneration with brain iron accumulation. Their records were reviewed, including longitudinal clinical, laboratory and imaging data. Twenty-three mutation-positive subjects were identified (20 females). The natural history of their disease was remarkably uniform: global developmental delay in childhood and further regression in early adulthood with progressive dystonia, parkinsonism and dementia. Common early comorbidities included seizures, spasticity and disordered sleep. The symptoms of parkinsonism improved with l-DOPA; however, nearly all patients experienced early motor fluctuations that quickly progressed to disabling dyskinesias, warranting discontinuation of l-DOPA. Brain magnetic resonance imaging showed iron in the substantia nigra and globus pallidus, with a 'halo' of T1 hyperintense signal in the substantia nigra. All patients harboured de novo mutations in WDR45, encoding a beta-propeller protein postulated to play a role in autophagy. Beta-propeller protein-associated neurodegeneration, the only X-linked disorder of neurodegeneration with brain iron accumulation, is associated with de novo mutations in WDR45 and is recognizable by a unique combination of clinical, natural history and neuroimaging features.
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Encéfalo/metabolismo , Proteínas de Transporte/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Ferro/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Adolescente , Adulto , Estudos de Coortes , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Doenças Neurodegenerativas/diagnóstico , Adulto JovemRESUMO
Mutations in the nuclear-encoded mitochondrial maintenance gene RRM2B are an important cause of familial mitochondrial disease in both adults and children and represent the third most common cause of multiple mitochondrial DNA deletions in adults, following POLG [polymerase (DNA directed), gamma] and PEO1 (now called C10ORF2, encoding the Twinkle helicase) mutations. However, the clinico-pathological and molecular features of adults with RRM2B-related disease have not been clearly defined. In this multicentre study of 26 adult patients from 22 independent families, including five additional cases published in the literature, we show that extra-ocular neurological complications are common in adults with genetically confirmed RRM2B mutations. We also demonstrate a clear correlation between the clinical phenotype and the underlying genetic defect. Myopathy was a prominent manifestation, followed by bulbar dysfunction and fatigue. Sensorineural hearing loss and gastrointestinal disturbance were also important findings. Severe multisystem neurological disease was associated with recessively inherited compound heterozygous mutations with a mean age of disease onset at 7 years. Dominantly inherited heterozygous mutations were associated with a milder predominantly myopathic phenotype with a later mean age of disease onset at 46 years. Skeletal muscle biopsies revealed subsarcolemmal accumulation of mitochondria and/or cytochrome c oxidase-deficient fibres. Multiple mitochondrial DNA deletions were universally present in patients who underwent a muscle biopsy. We identified 18 different heterozygous RRM2B mutations within our cohort of patients, including five novel mutations that have not previously been reported. Despite marked clinical overlap between the mitochondrial maintenance genes, key clinical features such as bulbar dysfunction, hearing loss and gastrointestinal disturbance should help prioritize genetic testing towards RRM2B analysis, and sequencing of the gene may preclude performance of a muscle biopsy.
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Proteínas de Ciclo Celular/genética , Deleção de Genes , Miopatias Mitocondriais/diagnóstico , Miopatias Mitocondriais/genética , Doenças Neuromusculares/genética , Ribonucleotídeo Redutases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Encefalopatias/complicações , Encefalopatias/genética , Estudos de Coortes , Heterozigoto , Humanos , Pessoa de Meia-Idade , Miopatias Mitocondriais/complicações , Miopatias Mitocondriais/patologia , Modelos Genéticos , Músculo Esquelético/patologia , Mutação de Sentido Incorreto/genética , Doenças Neuromusculares/complicações , FenótipoRESUMO
Phospholipase associated neurodegeneration (PLAN) comprises a heterogeneous group of autosomal recessive neurological disorders caused by mutations in the PLA2G6 gene. Direct gene sequencing detects approximately 85% mutations in infantile neuroaxonal dystrophy. We report the novel use of multiplex ligation-dependent probe amplification (MLPA) analysis to detect novel PLA2G6 duplications and deletions. The identification of such copy number variants (CNVs) expands the PLAN mutation spectrum and may account for up to 12.5% of PLA2G6 mutations. MLPA should thus be employed to detect CNVs of PLA2G6 in patients who show clinical features of PLAN but in whom both disease-causing mutations cannot be identified on routine sequencing.
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Fosfolipases A2 do Grupo VI/genética , Técnicas de Amplificação de Ácido Nucleico/métodos , Sequência de Bases , Encéfalo/patologia , Pré-Escolar , Consanguinidade , Deleção de Genes , Duplicação Gênica , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Dados de Sequência Molecular , Mutação , Patologia MolecularRESUMO
Four reports have been published on an association between acute myeloid leukaemia (AML) and primary lymphedema, with or without congenital deafness. We report seven new cases, including one extended family, confirming this entity as a genetic syndrome. The lymphedema typically presents in one or both lower limbs, before the hematological abnormalities, with onset between infancy and puberty and frequently affecting the genitalia. The AML is often preceded by pancytopenia or myelodysplasia with a high incidence of monosomy 7 in the bone marrow (five propositi and two relatives). Associated anomalies included hypotelorism, epicanthic folds, long tapering fingers and/or neck webbing (four patients), recurrent cellulitis in the affected limb (four patients), generalized warts (two patients), and congenital, high frequency sensorineural deafness (one patient). Children with lower limb and genital lymphedema should be screened for hematological abnormalities and immunodeficiency.
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Linfedema/complicações , Síndromes Mielodisplásicas/complicações , Anormalidades Múltiplas , Adolescente , Adulto , Criança , Pré-Escolar , Cromossomos Humanos Par 7 , Feminino , Genitália/anormalidades , Humanos , Lactente , Recém-Nascido , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/genética , Deformidades Congênitas das Extremidades Inferiores , Linfedema/genética , Masculino , Monossomia , Síndromes Mielodisplásicas/genética , Adulto JovemRESUMO
Oculopharyngeal muscular dystrophy (OPMD) is a late onset myopathy usually presenting in the 5th or 6th decade of life with progressive ptosis, dysphagia and proximal muscle weakness. It is usually dominantly inherited; however, a rare recessive form has also been described although documentation of such cases in the literature is very sparse. Here we report two siblings with recessive OPMD, in one of whom the clinical picture is complicated by ankylosing spondilitis and pneumonia. They exhibit later onset and milder symptoms than is typical for patients with dominantly inherited OPMD. This and the possibility that OPMD may be masked by symptoms of other diseases of the elderly may account for the paucity of cases of recessive OPMD reported in the literature.
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Distrofia Muscular Oculofaríngea/genética , Distrofia Muscular Oculofaríngea/patologia , Irmãos , Idoso , Feminino , Humanos , MasculinoRESUMO
Genetics and genomics are increasingly relevant to primary healthcare but training is unavailable to many practitioners. Education that can be accessed by practitioners without cost or travel is essential. The Gen-Equip project was formed to provide effective education in genetics for primary healthcare in Europe and so improve patient care. Partners include patient representatives and specialists in genetics and primary care from six countries. Here, we report the progress and challenges involved in creating a European online educational program in genetics.
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Facioscapulohumeral dystrophy (FSHD) is a rare inherited neuromuscular disease estimated to affect 1/15,000 people. Through basic research, remarkable progress has been made towards the development of targeted therapies. Patient identification, through registries or other means is essential for trial-readiness. The UK FSHD Patient Registry is a patient initiated registry that collects standardised and internationally agreed dataset of self-reported clinical details combined with professionally verified genetic information. It includes four additional questionnaires to capture patient reported outcomes related to pain, quality of life and scapular fixation. Between 2013 and 2015, 518 patients registered 243 males, 241 females with a mean age of 47.8 years. Most of the patients have FSHD type 1 (91.7 %), and weakness of the facial (59.2 %) was the most prevalent symptom at onset, followed by shoulder-girdle muscles (53.3 %) and distal (22.45 %) or proximal lower limb weakness (14.8 %). 85.57 % patients were ambulant or ambulant with assistance at the time of registration, 7.9 % report respiratory insufficiency. The registry has demonstrated utility with the recruitment of patients for a natural history study of infantile onset FSHD, and the longitudinal analysis of patient-related outcomes will provide much-needed baseline information to power future trials. The internationally agreed core dataset enables national registries to participate in a "Global FSHD registry". We suggest that the registry's ability to interoperate with other large datasets will be instrumental for sharing and exploiting data globally.
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Distrofia Muscular Facioescapuloumeral/diagnóstico , Distrofia Muscular Facioescapuloumeral/epidemiologia , Sistema de Registros , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Bases de Dados Factuais/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Distrofia Muscular Facioescapuloumeral/classificação , Estudos Retrospectivos , Inquéritos e Questionários , Reino Unido , Adulto JovemRESUMO
This paper explores how social psychology has theorized the relationship between the individual and society. This is done through a genealogical analysis of the Social Identity Tradition (SIT). It is argued that the current state of SIT is profoundly shaped by a range of intellectual and moral strategies derived from the work of Henri Tajfel. This 'Tajfel effect' manifests itself as a way of settling theoretical, practical and moral disputes through the invocation of Tajfel as a founding figure. However, this strategy also ties SIT into a model of the subject and an understanding of society that is increasingly seen as problematic. The paper then goes on to show how a range of core concepts at the heart of SIT may be usefully reformulated by drawing on the work of Deleuze and Guattari. Their work offers SIT a way of thinking about individuals and groups as sites for connection and differentiation. This is illustrated using the example of Nazi social relations that was originally deployed by Tajfel. Potential issues and direction for SIT as reinvigorated by the encounter with Deleuze and Guattari are then sketched out.
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Teoria Psicológica , Identificação Social , Humanos , Socialismo Nacional , Psicologia Social , TerritorialidadeRESUMO
We report an allelic series of eight mutations in GATA2 underlying Emberger syndrome, an autosomal dominant primary lymphedema associated with a predisposition to acute myeloid leukemia. GATA2 is a transcription factor that plays an essential role in gene regulation during vascular development and hematopoietic differentiation. Our findings indicate that haploinsufficiency of GATA2 underlies primary lymphedema and predisposes to acute myeloid leukemia in this syndrome.
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Fator de Transcrição GATA2/genética , Predisposição Genética para Doença , Leucemia Mieloide Aguda/genética , Linfedema/congênito , Adolescente , Adulto , Alelos , Criança , Feminino , Fator de Transcrição GATA2/metabolismo , Regulação Neoplásica da Expressão Gênica , Genótipo , Haploinsuficiência , Células-Tronco Hematopoéticas/metabolismo , Humanos , Recém-Nascido , Linfedema/genética , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , SíndromeRESUMO
Bohring-Opitz syndrome (BOS) is a rare congenital disorder of unknown etiology diagnosed on the basis of distinctive clinical features. We suggest diagnostic criteria for this condition, describe ten previously unreported patients, and update the natural history of four previously reported patients. This is the largest series reported to date, providing a unique opportunity to document the key clinical features and course through childhood. Investigations undertaken to try and elucidate the underlying pathogenesis of BOS using array comparative genomic hybridization and tandem mass spectrometry of cholesterol precursors did not show any pathogenic changes responsible.