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Prenat Diagn ; 38(1): 33-43, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29096039


OBJECTIVE: Rare genetic disorders resulting in prenatal or neonatal death are genetically heterogeneous, but testing is often limited by the availability of fetal DNA, leaving couples without a potential prenatal test for future pregnancies. We describe our novel strategy of exome sequencing parental DNA samples to diagnose recessive monogenic disorders in an audit of the first 50 couples referred. METHOD: Exome sequencing was carried out in a consecutive series of 50 couples who had 1 or more pregnancies affected with a lethal or prenatal-onset disorder. In all cases, there was insufficient DNA for exome sequencing of the affected fetus. Heterozygous rare variants (MAF < 0.001) in the same gene in both parents were selected for analysis. Likely, disease-causing variants were tested in fetal DNA to confirm co-segregation. RESULTS: Parental exome analysis identified heterozygous pathogenic (or likely pathogenic) variants in 24 different genes in 26/50 couples (52%). Where 2 or more fetuses were affected, a genetic diagnosis was obtained in 18/29 cases (62%). In most cases, the clinical features were typical of the disorder, but in others, they result from a hypomorphic variant or represent the most severe form of a variable phenotypic spectrum. CONCLUSION: We conclude that exome sequencing of parental samples is a powerful strategy with high clinical utility for the genetic diagnosis of lethal or prenatal-onset recessive disorders. © 2017 The Authors Prenatal Diagnosis published by John Wiley & Sons Ltd.

Anormalidades Congênitas/genética , Doenças Genéticas Inatas/diagnóstico , Pais , Diagnóstico Pré-Natal/métodos , Sequenciamento Completo do Exoma , Feminino , Genes Recessivos , Humanos , Masculino , Gravidez
Muscle Nerve ; 57(4): 622-627, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28881457


INTRODUCTION: There are limited data on the natural history of untreated myasthenia gravis (MG) with ocular presentation. METHODS: We analyzed 93 patients from symptom onset who presented to the Birmingham Midlands Eye Centre (BMEC) between January 2004 and July 2015. We used multiple stepwise logistic regression to identify predictive factors of generalization and Kaplan-Meier analysis on time to generalization. RESULTS: Forty-six percent of patients developed generalized symptoms during the study period. Median time to generalization was 7 months. Time to generalization was earlier in patients seropositive for acetylcholine receptor (AChR) antibody (median 5 months vs. 21 months, P < 0.0001) and bilateral ptosis at onset (P = 0.015). Multivariate analysis identified AChR seropositivity [hazard ratio (HR) 5.03; 95% confidence interval (CI) 1.48-17.14; P = 0.001] and disease onset < 50 years (HR 3.58; 95% CI 1.18-10.90; P = 0.035) as risk factors for generalization. DISCUSSION: As patients were steroid-naive before generalization, our cohort approximated the natural history of the condition. Muscle Nerve 57: 622-627, 2018.

Br Med Bull ; 120(1): 123-138, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27941041


INTRODUCTION: Constitutional mutations in genes controlling DNA repair, cell-cycle regulation and cell apoptosis can determine an individual's tendency to develop cancer. Hereditary cancer predisposition syndromes present with multiple cancers at a young age and underlie a significant burden of morbidity and mortality. Recent advances in the recognition and management of hereditary cancer will be illustrated with specific examples of developments in diagnosis and treatment. SOURCES OF DATA: Key recent published literature. AREAS OF AGREEMENT: The identification of individuals with hereditary cancer offers important opportunities for cancer prevention, early intervention and personalized management. AREAS OF CONTROVERSY: Individuals at risk of hereditary cancer remain under-recognized. There is a need to develop evidence-based guidelines for the recognition and management of hereditary cancer predisposition conditions. GROWING POINTS: The study of Mendelian cancer susceptibility syndromes has added to our understanding of hereditary and sporadic cancers and facilitated the development of targeted agents directed against cancer-driving mutations. Increasingly, cancer patients with constitutional gene mutations treated with targeted therapies have improved clinical outcomes. AREAS FOR TIMELY RESEARCH: Building the infrastructure to enable constitutional gene mutation testing to become integrated into routine cancer care, including the parallel development of robust referral pathways alongside genomic sequencing technologies.

Detecção Precoce de Câncer/tendências , Predisposição Genética para Doença/genética , Testes Genéticos/tendências , Terapia de Alvo Molecular/tendências , Mutação/genética , Síndromes Neoplásicas Hereditárias/diagnóstico , Medicina de Precisão/tendências , Feminino , Humanos , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/prevenção & controle , Linhagem
Can J Cardiol ; 24(10): e73-4, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18841264


Behçet's disease is an autoimmune, multisystem disease presenting with recurrent oral and genital ulceration as well as ocular involvement. Aneurysmal degeneration of coronary arteries remains a rare phenomenon in Behçet's disease. The case of a patient with Behçet's disease who presented with severe stenosis of the left anterior descending artery associated with a giant aneurysm of the proximal segment is described. Surgical revascularization was proposed, followed by percutaneous embolization of the aneurysm.

Síndrome de Behçet/complicações , Aneurisma Coronário/complicações , Estenose Coronária/etiologia , Adulto , Síndrome de Behçet/diagnóstico por imagem , Aneurisma Coronário/diagnóstico por imagem , Aneurisma Coronário/terapia , Angiografia Coronária , Estenose Coronária/diagnóstico por imagem , Estenose Coronária/cirurgia , Diagnóstico Diferencial , Embolização Terapêutica , Humanos , Masculino , Revascularização Miocárdica , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X