Parental segregation study reveals rare benign and likely benign variants in a Brazilian cohort of rare diseases.

Genomic studies may generate massive amounts of data, bringing interpretation challenges. Efforts for the differentiation of benign and pathogenic variants gain importance. In this article, we used segregation analysis and other molecular data to reclassify to benign or likely benign several rare clinically curated variants of autosomal dominant inheritance from a cohort of 500 Brazilian patients with rare diseases. This study included only symptomatic patients who had undergone molecular investigation with exome sequencing for suspected diseases of genetic etiology. Variants clinically suspected as the causative etiology and harbored by genes associated with highly-penetrant conditions of autosomal dominant inheritance underwent Sanger confirmation in the proband and inheritance pattern determination because a "de novo" event was expected. Among all 327 variants studied, 321 variants were inherited from asymptomatic parents. Considering segregation analysis, we have reclassified 51 rare variants as benign and 211 as likely benign. In our study, the inheritance of a highly penetrant variant expected to be de novo for pathogenicity assumption was considered as a non-segregation and, therefore, a key step for benign or likely benign classification. Studies like ours may help to identify rare benign variants and improve the correct interpretation of genetic findings.

Frequency of carriers for rare metabolic diseases in a Brazilian cohort of 320 patients.

BACKGROUND: Several metabolic disorders follow an autosomal recessive inheritance pattern. Epidemiological information on these disorders is usually limited in developing countries. Our objective is to assess carrier frequencies of rare autosomal recessive metabolic diseases in a cohort of Brazilian patients that underwent molecular investigation with exome sequencing and estimate the overall frequency of these diseases using the Hardy-Weinberg equation. METHODS AND RESULTS: We reviewed the molecular findings of 320 symptomatic patients who had carrier status for recessive diseases actively searched. A total of 205 rare variants were reported in 138 different genes associated with metabolic diseases from 156 patients, which represents that almost half (48.8%) of the patients were carriers of at least one heterozygous pathogenic/likely pathogenic (P/LP) variant for rare metabolic disorders. Most of these variants are harbored by genes associated with multisystemic involvement. We estimated the overall frequency for rare recessive metabolic diseases to be 10.96/10,000 people, while the frequency of metabolic diseases potentially identified by newborn screening was estimated to be 2.93/10,000. CONCLUSIONS: This study shows the potential research utility of exome sequencing to determine carrier status for rare metabolic diseases, which may be a possible strategy to evaluate the clinical and social burden of these conditions at the population level and guide the optimization of health policies and newborn screening programs.

Exome sequencing and targeted gene panels: a simulated comparison of diagnostic yield using data from 158 patients with rare diseases.

Next-generation sequencing (NGS) has altered clinical genetic testing by widening the access to molecular diagnosis of genetically determined rare diseases. However, physicians may face difficulties selecting the best diagnostic approach. Our goal is to estimate the rate of possible molecular diagnoses missed by different targeted gene panels using data from a cohort of patients with rare genetic diseases diagnosed with exome sequencing (ES). For this purpose, we simulated a comparison between different targeted gene panels and ES: the list of genes harboring clinically relevant variants from 158 patients was used to estimate the theoretical rate of diagnoses missed by NGS panels from 53 different NGS panels from eight different laboratories. Panels presented a mean rate of missed diagnoses of 64% (range 14%-100%) compared to ES, representing an average predicted sensitivity of 36%. Metabolic abnormalities represented the group with highest mean of missed diagnoses (86%), while seizure represented the group with lowest mean (46%). Focused gene panels are restricted in covering select sets of genes implicated in specific diseases and they may miss molecular diagnoses of rare diseases compared to ES. However, their role in genetic diagnosis remains important especially for well-known genetic diseases with established genetic locus heterogeneity.

Frequency of carriers for rare recessive Mendelian diseases in a Brazilian cohort of 320 patients.

Several Mendelian disorders follow an autosomal recessive inheritance pattern. Epidemiological information on many inherited disorders may be useful to guide health policies for rare diseases, but it is often inadequate, particularly in developing countries. We aimed to calculate the carrier frequencies of rare autosomal recessive Mendelian diseases in a cohort of Brazilian patients using whole exome sequencing (WES). We reviewed the molecular findings of WES from 320 symptomatic patients who had carrier status for recessive diseases. Using the Hardy-Weinberg equation, we estimated recessive disease frequencies (q2 ) considering the respective carrier frequencies (2pq) observed in our study. We calculated the sensitivity of carrier screening tests based on lists of genes from five different clinical laboratories that offer them in Brazil. A total of 425 occurrences of 351 rare variants were reported in 278 different genes from 230 patients (71.9%). Almost half (48.8%) were carriers of at least one heterozygous pathogenic/likely pathogenic variant for rare metabolic disorders, while 25.9% of epilepsy, 18.1% of intellectual disabilities, 15.6% of skeletal disorders, 10.9% immune disorders, and 9.1% of hearing loss. We estimated that an average of 67% of the variants would not have been detected by carrier screening panels. The combined frequencies of autosomal recessive diseases were estimated to be 26.39/10,000 (or ~0.26%). This study shows the potential research utility of WES to determine carrier status, which may be a possible strategy to evaluate the clinical and social burden of recessive diseases at the population level and guide the optimization of carrier screening panels.

Diagnostic power and clinical impact of exome sequencing in a cohort of 500 patients with rare diseases.

Rare diseases comprise a diverse group of conditions, most of which involve genetic causes. We describe the variable spectrum of findings and clinical impacts of exome sequencing (ES) in a cohort of 500 patients with rare diseases. In total, 164 primary findings were reported in 158 patients, representing an overall diagnostic yield of 31.6%. Most of the findings (61.6%) corresponded to autosomal dominant conditions, followed by autosomal recessive (25.6%) and X-linked (12.8%) conditions. These patients harbored 195 variants, among which 43.6% are novel in the literature. The rate of molecular diagnosis was considerably higher for prenatal samples (67%; 4/6), younger children (44%; 24/55), consanguinity (50%; 3/6), gastrointestinal/liver disease (44%; 16/36) and syndromic/malformative conditions (41%; 72/175). For 15.6% of the cohort patients, we observed a direct potential for the redirection of care with targeted therapy, tumor screening, medication adjustment and monitoring for disease-specific complications. Secondary findings were reported in 37 patients (7.4%). Based on cost-effectiveness studies in the literature, we speculate that the reports of secondary findings may influence an increase of 123.2 years in the life expectancy for our cohort, or 0.246 years/cohort patient. ES is a powerful method to identify the molecular bases of monogenic disorders and redirect clinical care.

Cognitive function and carotid stenosis: review of the literature / Funções cognitivas e estenose de artéria carótida: revisão da literatura

Stroke is a known cause of cognitive impairment but the relationship between asymptomatic carotid artery stenosis and cognitive function is not clear. The main risk factors for vascular disease are also related to carotid stenosis and cognitive impairment. The association of high-grade stenosis of the internal carotid artery with cognitive impairmentis related to silent embolization and hypoperfusion, but it may also be present without evidence of infarction on magnetic resonance imaging. Carotid stenosis treatment may lead to a decline in cognitive function due to complications related to the procedures (endarterectomy or stenting). On the other hand, reperfusion may improve cognitive impairment. The best treatment choice is unclear, considering possible deterioration of cognitive function related to carotid artery stenosis. There is insufficient evidence to consider cognitive impairment an important factor in determining the therapy for carotid stenosis.

O acidente vascular cerebral é uma doença que pode levar ao declínio cognitivo, mas a relação entre a estenose carotídea e as funções cognitivas não são bem esclarecidas. Os fatores de risco para doenças vasculares estão também relacionados à estenose de carótida e ao declínio cognitivo. A associação da estenose grave de carótida interna com o declínio cognitivo está relacionada a embolia silenciosa e hipoperfusão, mas pode também estar presente sem a evidência de lesão isquêmica pela ressonância. O tratamento da estenose carotídea pode levar ao declínio cognitivo devido acomplicações relacionadas aos procedimentos (endarterectomia ou stent). Por outro lado a reperfusão pode melhorar o declínio cognitivo. Não está claro qual a melhor decisão terapêutica considerando a possível deterioração cognitiva relacionada à estenose carotídea. Não existe evidência suficiente para considerar o declínio cognitivo um fator importante na decisão terapêutica para estenose de carótida.

Cognitive function and carotid stenosis: Review of the literature.

Stroke is a known cause of cognitive impairment but the relationship between asymptomatic carotid artery stenosis and cognitive function is not clear. The main risk factors for vascular disease are also related to carotid stenosis and cognitive impairment. The association of high-grade stenosis of the internal carotid artery with cognitive impairment is related to silent embolization and hypoperfusion, but it may also be present without evidence of infarction on magnetic resonance imaging. Carotid stenosis treatment may lead to a decline in cognitive function due to complications related to the procedures (endarterectomy or stenting). On the other hand, reperfusion may improve cognitive impairment. The best treatment choice is unclear, considering possible deterioration of cognitive function related to carotid artery stenosis. There is insufficient evidence to consider cognitive impairment an important factor in determining the therapy for carotid stenosis.

O acidente vascular cerebral é uma doença que pode levar ao declínio cognitivo, mas a relação entre a estenose carotídea e as funções cognitivas não são bem esclarecidas. Os fatores de risco para doenças vasculares estão também relacionados à estenose de carótida e ao declínio cognitivo. A associação da estenose grave de carótida interna com o declínio cognitivo está relacionada a embolia silenciosa e hipoperfusão, mas pode também estar presente sem a evidência de lesão isquêmica pela ressonância. O tratamento da estenose carotídea pode levar ao declínio cognitivo devido a complicações relacionadas aos procedimentos (endarterectomia ou stent). Por outro lado a reperfusão pode melhorar o declínio cognitivo. Não está claro qual a melhor decisão terapêutica considerando a possível deterioração cognitiva relacionada à estenose carotídea. Não existe evidência suficiente para considerar o declínio cognitivo um fator importante na decisão terapêutica para estenose de carótida.

Risk score to predict the outcome of patients with cerebral vein and dural sinus thrombosis.

BACKGROUND: Around 15% of patients die or become dependent after cerebral vein and dural sinus thrombosis (CVT). METHOD: We used the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) sample (624 patients, with a median follow-up time of 478 days) to develop a Cox proportional hazards regression model to predict outcome, dichotomised by a modified Rankin Scale score >2. From the model hazard ratios, a risk score was derived and a cut-off point selected. The model and the score were tested in 2 validation samples: (1) the prospective Cerebral Venous Thrombosis Portuguese Collaborative Study Group (VENOPORT) sample with 91 patients; (2) a sample of 169 consecutive CVT patients admitted to 5 ISCVT centres after the end of the ISCVT recruitment period. Sensitivity, specificity, c statistics and overall efficiency to predict outcome at 6 months were calculated. RESULTS: The model (hazard ratios: malignancy 4.53; coma 4.19; thrombosis of the deep venous system 3.03; mental status disturbance 2.18; male gender 1.60; intracranial haemorrhage 1.42) had overall efficiencies of 85.1, 84.4 and 90.0%, in the derivation sample and validation samples 1 and 2, respectively. Using the risk score (range from 0 to 9) with a cut-off of >or=3 points, overall efficiency was 85.4, 84.4 and 90.1% in the derivation sample and validation samples 1 and 2, respectively. Sensitivity and specificity in the combined samples were 96.1 and 13.6%, respectively. CONCLUSIONS: The CVT risk score has a good estimated overall rate of correct classifications in both validation samples, but its specificity is low. It can be used to avoid unnecessary or dangerous interventions in low-risk patients, and may help to identify high-risk CVT patients.

Transient global amnesia as a manifestation of acute myocardial infarction: a case of missed sudden cardiac death?

Acute myocardial infarction may lead to several clinical manifestations and many times this diagnosis is missed. Transient global amnesia (TGA) is a well-defined clinical syndrome of unknown etiology. Several mechanisms have been proposed but only trigger events have been clearly associated with the attack. We describe a case of acute myocardial infarction manifestated by TGA.

Trombose venosa cerebral: evolução clínica e fatores prognósticos em 111 pacientes / Cerebral venous thrombosis: clinical outcome and prognostic factors in 111 patients

Introdução: A evolução clínica da trombose venosa cerebral (TVC) pode variar desde a recuperação completa ao óbito. Séries européias e um estudo multicêntrico identificaram alguns fatores indicativos de prognóstico da TVC, dado importante na decisão da melhor terapêutica para os pacientes. Este estudo busca identificar, a partir do seguimento prospectivo de cento e onze pacientes com TVC, os fatores prognósticos envolvidos na evolução clínica durante o período de 2 anos. Pacientes Métodos: Foram acompanhados prospectivamente 111 pacientes com diagnóstico de TVC desde a fase aguda do diagnóstico, confirmado por meio de RM de encéfalo e/ou angiografia cerebral (ARM, ATC ou angiografia digital). Obtidos dados do quadro clínico e seguimento por um protocolo clínico. 96% dos pacientes foram anticoagulados na fase aguda com heparina e seguida de anticoagulação com warfarina. Submetidos a investigação para os fatores predisponentes para TVC. A evolução clínica foi quantificada por meio da escala modificada de Rankin (EMR) após 3, 6, 12 e 24 meses, definindo os pacientes de bom prognóstico EMR 1, e mau prognóstico EMR 2. Comparamos dados clínicos da fase aguda e resultados encontrados nos exames de imagem e laboratoriais como possíveis fatores prognósticos, através da análise univariada pelo teste 2 e os fatores de significância estatística (p<0,1), foram analisados com regressão logística ajustada e cálculo da razão de chances (RC), (intervalo de confiança IC=95%). Resultados: A média da idade dos pacientes foi de 35 anos, 72% mulheres, 40% afro-brasileiros. As principais manifestações clínicas foram: cefaléia 97%, déficit focal 47%, crise epiléptica 40%, alteração da consciência 28%, síndrome de HIC (SHIC) isolada 40%. Quanto aos fatores predisponentes; 75% das mulheres usavam anticoncepcional, 31% dos pacientes apresentavam trombofilia hereditária, 13% SAAF, 6% eram portadores de vasculites, 25% outros estados pro trombóticos, 7 % apresentavam fatores...

Introduction: The cerebral venous thrombosis (CVT) clinical evolution is quite variable from complete recovery to death. Some European series and a multicenter study had identified prognostic factors related to CVT prognosis. The identification of these factors is important for the best therapeutic decision to patients. This study aims to identify the prognostic factors enrolled in clinical evolution of 111 patients with CVT in a prospective outcome clinical trial during two years. Subjects and Methods: One hundred and eleven patients were prospective followed with the diagnosis of CVT since acute phase diagnosis, confirmed by brain MRI and/or brain angiography (MRA , CTA or digital angiography). Information about clinical features and follow-up were filled on a clinical form. 96% of the patients were anticoagulated on heparin followed by warfarin treatment. The patients were investigated to predisposing factors to CVT. The clinical evaluation was accessed by the modified Rakin scale (mRs) after 3, 6, 12 and 24 months, considering patients with good outcome when mRs < 1 and poor outcome when mRs > 2. The acute phase clinical features, laboratory and imaging data were compared as possible prognosis factors beyond univariate 2 test and the factors with statistical significance (p<0,1) and then analyzed by logistic regression adjusted and Odds Ratio values (confidence interval CI=95%). Results: The mean age of the patients was 35 years, 72% were women, and 40% were African Brazilian. The main clinical features observed were: headache 97%, focal sign 47%, epileptic seizure 40%, isolated ICH syndrome 40% and altered mental status 28%. All the patients were investigated to predisposing factors; 75% of the women were on oral contraceptive, 31% of the patients presented hereditary thrombophilia, 13 % antiphospholipid syndrome, 6% presented vasculitis, 25% other protrhrombotic state, 7% presented some local feature (arterialvenous malformation or infection) and 5%...