Germline variant analysis from a cohort of patients with severe hypertriglyceridemia in Brazil.

Hypertriglyceridemia (HTG) is a common dyslipidemia associated with an increased risk of cardiovascular disease and pancreatitis. It is well stablished that the severe cases of disease often present with an underlying genetic cause. In this study, we determined the frequency and variation spectrum of genes involved in the triglyceride metabolism in a series of Brazilian patients with severe HTG. A total of 212 patients with very high HTG, defined with fasting triglycerides (TG) ≥ 880 mg/ dL, that underwent a multi-gene panel testing were included in this research. Germline deleterious variants (i.e. Pathogenic/Likely Pathogenic (P/LP) variants) were identified in 28 out of 212 patients, reflecting an overall diagnostic yield of 13% in our cohort. Variants of unknown significance (VUS) were identified in 87 patients, and represent 80% of detected variants in this dataset. We confirm the LPL as the most frequently mutated gene in patients with severe HTG, and we had only one suspected case of familial chylomicronemia syndrome, caused by a homozygous variant in LMF1, in our cohort. Notably, we report 16 distinct and novel variants (P/LP and VUS), each of them representing a single case, not previously reported in any public databases or other studies. Our data expand our knowledge of genetic variation spectrum in patients with severe HTG in the Brazilian population, often underrepresented in public genomic databases, being also a valuable clinical resource for genetic counseling and healthcare programs in the country.

Whole genome sequencing as a first-tier diagnostic test for infants in neonatal intensive care units: A pilot study in Brazil.

In this pilot study, we aimed to evaluate the feasibility of whole genome sequencing (WGS) as a first-tier diagnostic test for infants hospitalized in neonatal intensive care units in the Brazilian healthcare system. The cohort presented here results from a joint collaboration between private and public hospitals in Brazil considering the initiative of a clinical laboratory to provide timely diagnosis for critically ill infants. We performed trio (proband and parents) WGS in 21 infants suspected of a genetic disease with an urgent need for diagnosis to guide medical care. Overall, the primary indication for genetic testing was dysmorphic syndromes (n = 14, 67%) followed by inborn errors of metabolism (n = 6, 29%) and skeletal dysplasias (n = 1, 5%). The diagnostic yield in our cohort was 57% (12/21) based on cases that received a definitive or likely definitive diagnostic result from WGS analysis. A total of 16 pathogenic/likely pathogenic variants and 10 variants of unknown significance were detected, and in most cases inherited from an unaffected parent. In addition, the reported variants were of different types, but mainly missense (58%) and associated with autosomal diseases (19/26); only three were associated with X-linked diseases, detected in hemizygosity in the proband an inherited from an unaffected mother. Notably, we identified 10 novel variants, absent from public genomic databases, in our cohort. Considering the entire diagnostic process, the average turnaround time from enrollment to medical report in our study was 53 days. Our findings demonstrate the remarkable utility of WGS as a diagnostic tool, elevating the potential of transformative impact since it outperforms conventional genetic tests. Here, we address the main challenges associated with implementing WGS in the medical care system in Brazil, as well as discuss the potential benefits and limitations of WGS as a diagnostic tool in the neonatal care setting.

Utility of exome sequencing for the diagnosis of pediatric-onset neuromuscular diseases beyond diagnostic yield: a narrative review.

Diagnosis of neuromuscular diseases (NMD) can be challenging because of the heterogeneity of this group of diseases. This review aimed to describe the diagnostic yield of whole exome sequencing (WES) for pediatric-onset neuromuscular disease diagnosis, as well as other benefits of this approach in patient management since WES can contribute to appropriate treatment selection in NMD patients. WES increases the possibility of reaching a conclusive genetic diagnosis when other technologies have failed and even exploring new genes not previously associated with a specific NMD. Moreover, this strategy can be useful when a dual diagnosis is suspected in complex congenital anomalies and undiagnosed cases.

Stereotactic biopsy for intracranial space occupying lesions: Experience in a referral hospital in Mexico.

BACKGROUND: Stereotactic brain biopsy (SBB) is used for establishing the histological diagnosis of intracranial lesions that are not amenable for a direct surgical approach. OBJECTIVE: The objective of the study was to describe our experience having an evaluation of the biopsy sample by a neuropathologist during SBB. MATERIALS AND METHODS: Retrospective analysis of 140 consecutive patients who underwent SBB between 2014 and 2018 in whom trans-operatory analysis of the sample was performed. RESULTS: There were 56% men. The mean age was 45 years. Histological diagnosis was performed in 131 of 140 patients (94% overall diagnostic yield). The presurgical radiological diagnosis was correct in 39%. Neoplastic lesions were reported in 108 cases, and 32 were non-neoplastic. We performed craniotomy and resection after biopsy in 14%. We found complications in 6% of patients. CONCLUSIONS: SBB continues to be a safe, useful, and inexpensive procedure. The diagnostic performance of SBB increases when intraoperative cytological evaluation by a neuropathologist is included in the study.

ANTECEDENTES: la biopsia cerebral por estereotaxia (SBB) se utiliza para establecer el diagnóstico histológico de lesiones intracraneales que no son susceptibles de un abordaje quirúrgico directo. OBJETIVO: describir nuestra experiencia de tener una evaluación de la muestra de biopsia por un neuropatólogo durante el procedimiento. MATERIAL Y MÉTODOS: análisis retrospectivo de 140 pacientes consecutivos sometidos a SBB entre 2014-2018 en los que se realizó análisis transoperatorio de la muestra. RESULTADOS: El 56% fueron hombres. La edad promedio fue de 45 años. El diagnóstico histológico se realizó en 131 de 140 pacientes (rendimiento diagnóstico global del 94%). El diagnóstico radiológico prequirúrgico fue correcto solo en el 39%. Se identificaron lesiones neoplásicas en 108 casos, y en 32 se documentaron lesiones no neoplásicas. En el 14% de los casos se realizó posterior a la biospia craneotomía y resección de la lesión. Encontramos complicaciones en el 6% de los pacientes. CONCLUSIONES: SBB sigue siendo un procedimiento seguro, útil y económico. El rendimiento diagnóstico de SBB aumenta cuando se incluye la evaluación citológica intraoperatoria por un neuropatólogo.

Clinical utility of the small bowel capsule endoscopy in the study of small bowel diseases in Colombia: Results of a national registry. / Utilidad clínica de la videocápsula endoscópica en el estudio de patologías de intestino delgado en Colombia: resultados de un registro nacional.

INTRODUCTION: The small bowel capsule endoscopy (SBCE) has revolutionised the study of small bowel diseases. The objective of this study is to determine the indications, findings and diagnostic yield of SBCE in a national registry. PATIENTS AND METHODS: An observational, analytical cross-sectional study was carried out, analysing the SBCE records at seven centres in the country, where different variables were collected. RESULTS: 1,883 SBCEs were evaluated. The average age was 55.4 years (5.6-94.2). The most frequent indications were suspicion of small bowel bleeding (SBB) (64.4%), study of Crohn's disease (15.2%) and chronic diarrhoea (11.2%). 54.3% were prepared with laxatives. The most frequent lesions found were erosions/ulcers (31.6%), angioectasias (25.7%) and parasitosis (2.7%). The diagnostic yield (P1+P2, Saurin classification) of SBCE in SBB was 60.6%, being higher in overt SBB (66.0%) compared to occult SBB (56.0%) (P=.003). The studies with better preparation showed higher detection of lesions (93.8% vs. 89.4%) (OR=1.8, CI: 95%: 1.2-2.6; P=.004). The SBCE complication rate was 3.1%, with complete SB visualisation at 96.6% and SB retention rate of 0.7%. 81.5% of SBCEs were performed on an outpatient basis, and presented a greater complete SB visualisation than hospital ones (97.1% vs. 94.3%) (OR=2.1, CI: 95%, 1.2-3.5; P=.008). CONCLUSIONS: The indications, findings and diagnostic performance of SBCEs in Colombia are similar to those reported in the literature, with a high percentage of complete studies and a low rate of complications.

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.

Capsule endoscopy for the study of small bowel disorders: Experience at a private institution in Mexico. / Cápsula endoscópica para el estudio de patologías de intestino delgado: experiencia en una institución privada en México.

INTRODUCTION AND AIMS: Capsule endoscopy has revolutionized the study of small bowel disorders. Its diagnostic yield, reasons for referral, and frequency of significant endoscopic findings at our institution are unknown. The aims of our study were to describe the reasons for referral, the frequency of significant endoscopic findings, and the diagnostic yield of capsule endoscopy in patients that underwent the procedure for the study of small bowel disorders. MATERIAL AND METHODS: A retrospective study was conducted that included all patients that underwent capsule endoscopy for small bowel disorder evaluation at our institution. The diagnostic yield for significant endoscopic findings, the frequency of significant endoscopic findings, and the reasons for referral for capsule endoscopy were determined. RESULTS: A total of 134 patients were included in the study and 143 capsule endoscopies were performed. Women made up 48.5% of the sample and the mean patient age was 63 years (18.7 standard deviation). The main reasons for referral were suspicion of overt small bowel bleeding (55.9%) and suspicion of occult small bowel bleeding (28.6%). The overall diagnostic yield was 66.4%. The most common significant findings were small bowel angioectasias (52.6%) and small bowel ulcers (38.9%). There were two adverse events (1.3%): one capsule retention that required enteroscopic removal and one asymptomatic bronchoaspiration of the capsule that resolved spontaneously. CONCLUSIONS: The frequency of significant endoscopic findings with capsule endoscopy at our institution was different from that reported in other Mexican studies, but the reasons for referral and the diagnostic yield were similar.

Friedreich Ataxia: Diagnostic Yield and Minimal Frequency in South Brazil.

Friedreich ataxia (FRDA) is an autosomal recessive disorder due to mutations in the FXN gene. FRDA is characterized by the classical triad of ataxia, absent reflexes, and Babinski sign, but atypical presentations might also occur. Our aims were to describe the proportion of FRDA diagnoses in suspected families living in Rio Grande do Sul, South Brazil, and to estimate a minimum frequency of symptomatic subjects. Subjects that were evaluated by molecular analysis for FRDA at the Hospital de Clínicas de Porto Alegre were identified in our files. Patients' clinical manifestation and phenotypes were described and compared. The number of FRDA subjects alive in the last 5 years was determined. One hundred fifty-six index cases (families) were submitted to evaluation of GAA repeats at FXN since 1997: 27 were confirmed as FRDA patients. Therefore, the diagnostic yield was 17.3%. Proportion of classical, late onset, and retained reflexes subphenotypes were similar to those described by other studies. A minimum prevalence was estimated as 0.20:100.000 inhabitants. In conclusion, we verified that this FRDA population displayed the usual clinical characteristics, but with a lower period prevalence than those obtained in populations from Europe.

Percutaneous computed tomography-guided biopsy performed by thoracic surgeons in 955 patients: A paradigm shift in image-guided thoracic procedures.

OBJECTIVES: Computed tomography-guided fine needle aspiration (CT-FNA) biopsy is a well-established diagnostic technique in the evaluation of lung nodules that is performed by radiologists in most centers. In this series, we analyzed the diagnostic and perioperative outcomes following CT-FNA performed by a dedicated group of thoracic surgeons. METHODS: We conducted a retrospective analysis of 955 patients undergoing CT-FNA by the thoracic surgery service. Primary outcome variables included diagnostic yield and accuracy, number of needle passes, complication rates, and adequacy of specimen for molecular testing. RESULTS: A satisfactory diagnostic specimen was obtained in 94.1% of cases. The average number of needle passes was 3.2 ± 1.5 (range, 1-10 passes). Diagnostic yield was significantly improved by increasing the number of passes from 1 to 2 to 3 passes (P = .0003). CT-FNA diagnostic accuracy was 88.8%. Diagnostic accuracy did not significantly improve with ≥4 passes (P = .20). Molecular testing was successful in 43.1%, and did not improve with ≥4 passes (P = .5). Molecular testing success did improve with the addition of core needle biopsy (P = .005). The pneumothorax rate for CT-FNA alone was 26.4%, and increased with ≥4 passes (P = .009). The median length of stay for CT-FNA alone was 0 days (range, 0-74 days), with same-day discharge in 67.5% of patients. CONCLUSIONS: Thoracic surgeons can perform CT-FNA with excellent diagnostic yield and accuracy. Diagnostic yield, accuracy, and success in molecular testing do not improve with ≥4 CT-FNA passes. Pneumothorax rates do increase with ≥4 passes. The addition of core needle biopsy enhances success with molecular testing.

Diagnostic Yield of Pulmonary CT Angiography in the Evaluation of Pulmonary Embolisms Treated at the Puerto Rico Medical Center from 2008 to 2012.

OBJECTIVE: The objective of this study was to determine the diagnostic yield of pulmonary CT angiography (PCTA) in the evaluation of pulmonary embolisms treated at the Puerto Rico Medical Center from 2008 to 2012. METHODS: A total of 1,004 CT angiograms were reviewed in the evaluation of pulmonary embolisms. Patient records covering from 2008 to 2012 were obtained from the picture archiving and communication system (PACS) of the Puerto Rico Medical Center. Follow-up studies and those of pediatric patients were excluded from the study. The results were recorded as either positive or negative for pulmonary embolism, according to the final report rendered by board-certified radiologists. RESULTS: Of the 1,004 patient records reviewed, 964 were included in the study. Forty-six out of the total studies reviewed were positive, while a total of 918 studies were negative. A mean diagnostic yield of 4.8% (SD = 0.63) was obtained. CONCLUSION: At the Puerto Rico Medical Center, the mean diagnostic yield in the evaluation of pulmonary embolism using PCTA was 4.8%, which is in concordance with those of several previous studies, all of which had similar low yields. New diagnostic algorithms for efficiently employing PCTA for the evaluation of pulmonary embolisms are discussed herein.