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Disease-associated mosaic variation in clinical exome sequencing: a two-year pediatric tertiary care experience.

ABSTRACT: Exome sequencing (ES) has become an important tool in pediatric genomic medicine, improving identification of disease-associated variation due to assay breadth. Depth is also afforded by ES, enabling detection of lower-frequency mosaic variation compared to Sanger sequencing in the studied tissue, thus enhancing diagnostic yield. Within a pediatric tertiary-care hospital, we report two years of clinical ES data from probands evaluated for genetic disease to assess diagnostic yield, characteristics of causal variants, and prevalence of mosaicism among disease-causing variants. Exome-derived, phenotype-driven variant data from 357 probands was analyzed concurrent with parental ES data, when available. Blood was the source of nucleic acid. Sequence read alignments were manually reviewed for all assessed variants. Sanger sequencing was used for suspected de novo or mosaic variation. Clinical provider notes were reviewed to determine concordance between laboratory-reported data and the ordering provider's interpretation of variant-associated disease causality. Laboratory-derived diagnostic yield and provider-substantiated diagnoses had 91.4% concordance. The cohort returned 117 provider-substantiated diagnoses among 115 probands for a diagnostic yield of 32.2%. De novo variants represented 64.9% of disease-associated variation within trio analyses. Among the 115 probands, five harbored disease-associated somatic mosaic variation. Two additional probands were observed to inherit a disease-associated variant from an unaffected mosaic parent. Among inheritance patterns, de novo variation was the most frequent disease etiology. Somatic mosaicism is increasingly recognized as a significant contributor to genetic disease, particularly with increased sequence depth attainable from ES. This report highlights the potential and importance of detecting mosaicism in ES.

SUBMITTER: Miller CR

PROVIDER: S-EPMC7304353 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Disease-associated mosaic variation in clinical exome sequencing: a two-year pediatric tertiary care experience.

Miller Cecelia R CR Lee Kristy K Pfau Ruthann B RB Reshmi Shalini C SC Corsmeier Donald J DJ Hashimoto Sayaka S Dave-Wala Ashita A Jayaraman Vijayakumar V Koboldt Daniel D Matthews Theodora T Mouhlas Danielle D Stein Maggie M McKinney Aimee A Grossman Tom T Kelly Benjamin J BJ White Peter P Magrini Vincent V Wilson Richard K RK Mardis Elaine R ER Cottrell Catherine E CE

Cold Spring Harbor molecular case studies 20200612 3

Exome sequencing (ES) has become an important tool in pediatric genomic medicine, improving identification of disease-associated variation due to assay breadth. Depth is also afforded by ES, enabling detection of lower-frequency mosaic variation compared to Sanger sequencing in the studied tissue, thus enhancing diagnostic yield. Within a pediatric tertiary-care hospital, we report two years of clinical ES data from probands evaluated for genetic disease to assess diagnostic yield, characteristi ...[more]

PMID: 32371413

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Project description:IntroductionWhipple procedure is one of the major surgeries performed in tertiary care centers. Once considered a high mortality procedure is now being practicing with mortality declining to less than 5%. This study describes our five-year experience of the Whipple procedure in terms of preoperative, operative, and postoperative parameters of patients undergoing surgery in a local tertiary care setting.Material and methodsThis was a non-randomized interventional study that was conducted at the Surgical Department of Services Hospital Lahore from January 2014 to December 2018. A total of 57 Whipple procedures were performed during this period. Demographic data, presenting symptoms, physical signs, past medical history, preoperative stenting details, intra-operative duration of surgery, postoperative course and complications, pathology, and causes of postoperative death were collected on a pre-designed questionnaire. Data were entered and analyzed by using SPSS 22 (IBM Corp., Armonk, USA).ResultsOut of 57 patients, 19 were females and 38 were males. The mean age of patients was 53±05 years. The most common presenting symptom was jaundice 39 (68.4%), followed by abdominal pain 32 (56.1%). The mean size of the tumor on CT-scan was 2.8±1.4 cm, the mean operation time was 315±38.3 min, mean blood loss during surgery was 500±130 ml, and mean hospital stay was 10±6 days. The major postoperative complication was the pancreatic fistula (12%). Twenty-one out of 39 patients presented with jaundice had undergone preoperative biliary stenting by endoscopic retrograde biliary stenting. The most common histological diagnosis was adenocarcinoma of pancreas 19 (33.3%). Out of 57 patients, nine (15.8%) patients expired in the first 30 days and the most frequent cause of mortality was septic shock.ConclusionIn this study, the most common presentation of patients undergoing Whipple procedure was obstructive jaundice, the most frequent operative complication was pancreatic fistula, and the most prevalent histopathology was carcinoma of the pancreas. Perioperative parameters such as mean operative time, mean blood loss during surgery, and mean length of hospital stay were comparable with other studies. However, mortality in this study was slightly higher. It can be concluded that with meticulous surgical technique, securing hemostasis strictly and standard critical care postoperatively can decrease morbidity and mortality after the Whipple procedure.

Project description:BackgroundThe value of early integration of palliative care has been demonstrated increasingly for the past years in both oncological and nononcological diseases. Outpatient palliative care services might represent a feasible approach to implement supportive care in early disease. In this study, we aimed at evaluating which patients use and benefit from outpatient palliative care services, which symptoms are addressed most, and which support services are installed in this early phase of disease.MethodsWe retrospectively analyzed the entire patient collective of a recently developed palliative care outpatient clinic within the leading university hospital in Switzerland for a period of five years. Sociodemographics, symptoms, and information on disease as well as patient-reported outcomes were retrieved from the electronic patient files. Demographic and clinical data were analyzed by descriptive statistics between groups and survival was analyzed by means of Kaplan-Meier estimates and log-rank test.ResultsWe report on 642 consultations of 363 patients between 2016 and 2020. Patients had a mean of 1.8 visits (range 1-10), with n = 340 patients (93.7%) of patients suffering from an oncological disease. Overall symptom load was high, with n = 401 (73.7%) of patient-reported outcomes reporting two or more symptoms. Distress levels of 5 or higher were reported in n = 78 (30.4%) of available patient-reported outcomes. Independent of the origin of primary disease and the length of the disease trajectory, patients were referred to the palliative care service in median only four months before death.ConclusionWe identify high symptom load and distress in the outpatient palliative patient population. Patients benefitted from supportive medication, improvement of ambulatory support systems and advance care planning, and more than one-third of patients remained in follow-up, indicating a good acceptance of the service. Overcoming the overall late referral could, however, further increase the quality of life at earlier stages of disease.

Project description:ObjectiveTo present the clinical characteristics and outcome of transplant and nontransplant patients with invasive nocardiosis.Patients and methodsWe conducted a retrospective chart review of 110 patients 18 years and older diagnosed with culture-proven invasive nocardiosis (defined as the presence of clinical signs and/or radiographic abnormalities) between August 1, 1998, and November 30, 2018. Information on demographic, clinical, radiographic, and microbiological characteristics as well as mortality was collected.ResultsOne hundred ten individuals with invasive nocardiosis were identified, of whom 54 (49%) were transplant and 56 nontransplant (51%) patients. Most transplant patients were kidney and lung recipients. The overall mean age was 64.9 years, and transplant patients had a higher prevalence of diabetes and chronic kidney disease. A substantial proportion of nontransplant patients were receiving corticosteroids (39%), immunosuppressive medications (16%), and chemotherapy (9%) and had chronic obstructive pulmonary disease (20%), rheumatologic conditions (18%), and malignant neoplasia (18%). A higher proportion of transplant patients (28%) than nontransplant patients (4%) received trimethoprim-sulfamethoxazole prophylaxis. In both groups, the lung was the most common site of infection. Seventy percent of all Nocardia species isolated were present in almost equal proportion: N brasiliensis (16%), N farcinica (16%), N nova (15%), N cyriacigeorgia (13%), and N asteroides (11%). More than 90% of isolates were susceptible to trimethoprim-sulfamethoxazole, linezolid, and amikacin. There was no significant difference in mortality between the 2 groups at 1, 6, and 12 months after the initial diagnosis.ConclusionThe frequency of invasive Nocardia infection was similar in transplant and nontransplant patients and mortality at 1, 6, and 12 months was similar in both groups. Trimethoprim-sulfamethoxazole prophylaxis failed to prevent Nocardia infection.

Dataset Information

Disease-associated mosaic variation in clinical exome sequencing: a two-year pediatric tertiary care experience.

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Disease-associated mosaic variation in clinical exome sequencing: a two-year pediatric tertiary care experience.

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