scholarly journals Interpreting Osteogenesis Imperfecta Variants of Uncertain Significance in the Context of Physical Abuse: A Case Series

2018 ◽  
Vol 08 (02) ◽  
pp. 063-068
Author(s):  
Jennifer Canter ◽  
Vinod Rao ◽  
Vincent Palusci ◽  
David Kronn ◽  
Michal Manaster ◽  
...  
Keyword(s):  
Child Abuse ◽  
Osteogenesis Imperfecta ◽  
Physical Abuse ◽  
Clinical Significance ◽  
Case Series ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
Potential Abuse ◽  
Uncertain Significance

AbstractUnexplained childhood fracture(s) warrant consideration of physical abuse and osteogenesis imperfecta (OI). Genetic OI testing may identify “variants of unknown significance (VUS).” Interpretation of VUS in context of potential abuse may have protective, criminal, and medical impacts. This case series explores practices regarding clinicians' interpretation of VUS during child abuse evaluations. Variability was noted regarding factors considered for interpreting clinical significance. Based on these cases, recommendations for careful and thorough evaluation are detailed, including proposed use of a limited follow-up skeletal survey in 3 months, as a consideration to assess healing of prior fractures and to look for any additional injuries.

scholarly journals Novel mutations in NOTCH2 gene in infants with neonatal cholestasis

2019 ◽  
Vol 11 (3) ◽  
Author(s):  
Eliana Shaul ◽  
Debora Kogan-Liberman ◽  
Stephanie Schuckalo ◽  
Dominique Jan ◽  
Michelle Ewart ◽  
...  
Keyword(s):  
Case Series ◽  
Alagille Syndrome ◽  
Notch Signaling Pathway ◽  
Clinical Approach ◽  
Neonatal Cholestasis ◽  
Retrospective Case ◽  
Variants Of Unknown Significance ◽  
Intrahepatic Bile Ducts ◽  
Sorting Intolerant From Tolerant ◽  
Unknown Significance

One cause of neonatal cholestasis (NC) is paucity of intrahepatic bile ducts which can be associated with Alagille syndrome or non- syndromic. Alagille syndrome is caused by autosomal dominant mutations in the Notch signaling pathway ligand Jagged1 in 94% of patients and mutations in the NOTCH2 receptor in <1% of patients. This is a retrospective case series studying infants with neonatal cholestasis found to have variants of unknown significance (VOUS) in NOTCH2. Sorting intolerant from tolerant (SIFT) and polymorphism phenotyping (PolyPhen) were utilized to predict a damaging effect. Five infants with NC without other features of Alagille syndrome were found to have one copy of a VOUS in NOTCH2, predicted to be damaging by SIFT and PolyPhen. Our cases support the notion that NOTCH2 mutations may result in hypoplastic biliary system. Further characterization of these variants is important to assist with our clinical approach to NC.

scholarly journals Next-generation sequencing approach to hyperCKemia

2019 ◽  
Vol 5 (5) ◽  
pp. e352 ◽  
Author(s):  
Anna Rubegni ◽  
Alessandro Malandrini ◽  
Claudia Dosi ◽  
Guja Astrea ◽  
Jacopo Baldacci ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Molecular Diagnosis ◽  
Diagnostic Yield ◽  
Clinical Neurology ◽  
Next Generation ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

ObjectiveNext-generation sequencing (NGS) was applied in molecularly undiagnosed asymptomatic or paucisymptomatic hyperCKemia to investigate whether this technique might allow detection of the genetic basis of the condition.MethodsSixty-six patients with undiagnosed asymptomatic or paucisymptomatic hyperCKemia, referred to tertiary neuromuscular centers over an approximately 2-year period, were analyzed using a customized, targeted sequencing panel able to investigate the coding exons and flanking intronic regions of 78 genes associated with limb-girdle muscular dystrophies, rhabdomyolysis, and metabolic and distal myopathies.ResultsA molecular diagnosis was reached in 33 cases, corresponding to a positive diagnostic yield of 50%. Variants of unknown significance were found in 17 patients (26%), whereas 16 cases (24%) remained molecularly undefined. The major features of the diagnosed cases were mild proximal muscle weakness (found in 27%) and myalgia (in 24%). Fourteen patients with a molecular diagnosis and mild myopathic features on muscle biopsy remained asymptomatic at a 24-month follow-up.ConclusionsThis study of patients with undiagnosed hyperCKemia, highlighting the advantages of NGS used as a first-tier diagnostic approach in genetically heterogeneous conditions, illustrates the ongoing evolution of molecular diagnosis in the field of clinical neurology. Isolated hyperCKemia can be the sole feature alerting to a progressive muscular disorder requiring careful surveillance.

The Value of Next-Generation Sequencing in the Screening and Evaluation of Hematologic Neoplasms in Clinical Practice

2019 ◽  
Vol 153 (5) ◽  
pp. 639-645 ◽  
Author(s):  
Victoria Northrup ◽  
Allison Maybank ◽  
Nancy Carson ◽  
Tarek Rahmeh
Keyword(s):  
Next Generation Sequencing ◽  
Next Generation ◽  
Hematologic Neoplasms ◽  
Clinical Value ◽  
Variants Of Unknown Significance ◽  
Myeloid Neoplasms ◽  
Unknown Significance ◽  
Conventional Cytogenetics ◽  
Generation Sequencing

Abstract Objectives The implementation of next-generation sequencing (NGS) in routine clinical hematology practice remains limited. We evaluate the clinical value of NGS in the screening, diagnosis, and follow-up in hematologic neoplasms. Methods A targeted NGS panel was used to assess a total of 178 patients for questionable or previously diagnosed myeloid neoplasms. Results Gene variants were identified in 53% of patients. Novel variants were identified in 29% of patients and variants of unknown significance in 34%. Bone marrow samples yielded a higher number of variants than in peripheral blood. NGS is a more sensitive test than conventional cytogenetics. In several cases, NGS played a key role in the screening, diagnostics, prognostic stratification, and the clinical follow-up of a wide variety of myeloid neoplasms. Conclusions NGS is an effective tool in the evaluation of suspected and confirmed hematologic neoplasms and could become part of the routine workup of patients.

scholarly journals Predicting ovarian/breast cancer pathogenic risks of BRCA1 gene variants of unknown significance

2020 ◽  
Author(s):  
Hui-Heng Lin ◽  
Hongyan Xu ◽  
Hongbo Hu ◽  
Zhanzhong Ma ◽  
Jie Zhou ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Random Forest ◽  
Clinical Significance ◽  
Brca1 Gene ◽  
Gene Variants ◽  
Sequencing Data ◽  
Forest Model ◽  
Variants Of Unknown Significance ◽  
Sequencing Technologies ◽  
Unknown Significance

AbstractThe difficulty of early diagnosis for ovarian cancer is an important cause of the high mortal rates of ovarian cancer patients. Instead of symptom-based diagnostic methods, modern sequencing technologies enable the access of human’s genetic information via reading DNA/RNA molecules’ nucleotide base sequences. In such way, genes’ mutations and variants could be identified and hence a better clinical diagnosis in molecular level could be expected. However, as sequencing technologies gain more popularity, novel gene variants with unknown clinical significance are found, giving difficulties to interpretations of patients’ genetic data, precise disease diagnoses as well as the making of therapeutic strategies and decisions. In order to solve these issues, it is of critical importance to figure out ways to analyze and interpret such variants. In this work, BRCA1 gene variants with unknown clinical significance were identified from clinical sequencing data, and then we developed machine learning models so as to predict the pathogenicity for variants with unknown clinical significance. Amongst, in performance benchmarking, our optimized random forest model scored 0.85 in area under receiver-operating characteristic curve, which outperformed other models. Finally, we applied the optimized random forest model to predict the pathogenic risks of 7 BRCA1 variants of unknown clinical significances identified from our sequencing data, and 6315 variants of unknown clinical significance in ClinVar database. As a result, our model predicted 4724 benign and 1591 pathogenic variants, which helped the interpretation of these variants of unknown significance and diagnosis.

scholarly journals PRPH2 mutation update: In silico assessment of 245 reported and 7 novel variants in patients with retinal disease

2021 ◽  
Author(s):  
Manon H.C.A Peeters ◽  
Mubeen Khan ◽  
Anoek A.M.B Rooijakkers ◽  
Timo Mulders ◽  
Lonneke Haer-Wigman ◽  
...  
Keyword(s):  
Retinal Disease ◽  
Variants Of Unknown Significance ◽  
Novel Variants ◽  
Unknown Significance ◽  
Uncertain Significance ◽  
Variation Database ◽  
The Many ◽  
Source Variation ◽  
Additional Index

Mutations in PRPH2, encoding peripherin-2, are associated with the development of a wide variety of inherited retinal diseases (IRDs). To determine the causality of the many PRPH2 variants that have been discovered over the last decades, we surveyed all published PRPH2 variants up to July 2020, describing 720 index patients that in total carried 245 unique variants. In addition, we identified seven novel PRPH2 variants in eight additional index patients. The pathogenicity of all variants was determined using the ACMG guidelines. With this, 107 variants were classified as pathogenic, 92 as likely pathogenic, one as benign, and two as likely benign. The remaining 50 variants were classified as variants of uncertain significance. Interestingly, of the in total 252 PRPH2 variants, more than half (n=137) were missense variants. All variants were uploaded into the Leiden Open source Variation Database. Our study underscores the need of experimental assays for variants of unknown significance to improve pathogenicity classification, which is needed to better understand genotype-phenotype correlations, and in the long-term, hopefully also support the development of therapeutic strategies for patients with PRPH2-associated IRD.

scholarly journals Predicting Ovarian/Breast Cancer Pathogenic Risks of Human BRCA1 Gene Variants of Unknown Significance

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Hui-Heng Lin ◽  
Hongyan Xu ◽  
Hongbo Hu ◽  
Zhanzhong Ma ◽  
Jie Zhou ◽  
...  
Keyword(s):  
Random Forest ◽  
Clinical Significance ◽  
High Throughput Sequencing ◽  
Brca1 Gene ◽  
Random Forest Model ◽  
Gene Variants ◽  
Sequencing Data ◽  
Forest Model ◽  
Variants Of Unknown Significance ◽  
Unknown Significance

High-throughput sequencing is gaining popularity in clinical diagnoses, but more and more novel gene variants with unknown clinical significance are being found, giving difficulties to interpretations of people’s genetic data, precise disease diagnoses, and the making of therapeutic strategies and decisions. In order to solve these issues, it is of critical importance to figure out ways to analyze and interpret such variants. In this work, BRCA1 gene variants with unknown clinical significance were identified from clinical sequencing data, and then, we developed machine learning models so as to predict the pathogenicity for variants with unknown clinical significance. Through performance benchmarking, we found that the optimized random forest model scored 0.85 in area under receiver operating characteristic curve, which outperformed other models. Finally, we applied the best random forest model to predict the pathogenicity of 6321 BRCA1 variants from both sequencing data and ClinVar database. As a result, we obtained the predictive pathogenic risks of BRCA1 variants of unknown significance.

scholarly journals Leukocytosis Associated with Clozapine Treatment: A Case Series and Systematic Review of the Literature

Medicina ◽  
2021 ◽  
Vol 57 (8) ◽  
pp. 816
Author(s):  
Pasquale Paribello ◽  
Mirko Manchia ◽  
Massimo Zedda ◽  
Federica Pinna ◽  
Bernardo Carpiniello
Keyword(s):  
Systematic Review ◽  
Clinical Significance ◽  
Case Series ◽  
Treatment Interruption ◽  
Psychiatric Clinic ◽  
Review Of The Literature ◽  
Benign Condition ◽  
Clozapine Treatment ◽  
Selection Of

Background and Objectives: Clozapine is the only antipsychotic approved for treatment-resistant schizophrenia. Despite its superior efficacy profile as compared with other antipsychotics, clozapine remains underutilized. Clozapine monitoring systems clearly describe the proposed management of clozapine-induced neutropenia; however, no specific mention is made of how to interpret neutrophilic leukocytosis, despite that being a relatively frequent finding. Prescribers unfamiliar with this molecule may misjudge its clinical significance, potentially leading to untimely treatment interruption. Here, we systematically review the literature on the risk of neutrophilic leukocytosis during clozapine treatment, and describe eight additional cases among our patient cohort. Materials and Methods: We performed a systematic review of the literature on PubMed and Embase using the PRISMA 2020 guidelines, and selected all original reports describing either (1) the prevalence of neutrophilic leukocytosis during clozapine treatment, or (2) the clinical significance of neutrophilic leukocytosis. We described eight additional cases of neutrophilic leukocytosis during clozapine treatment while attending an outpatient psychiatric clinic. Results: Our research ultimately yielded the selection of 13 articles included in this systematic review. The case series highlighted the presence of stable and clinically unremarkable neutrophilia during a follow-up ranging from one to ten years. Conclusions: Existing evidence indicates that leukocytosis associated with clozapine treatment can be considered as an asymptomatic and benign condition, suggesting that no change in clozapine treatment is needed upon its detection.

scholarly journals Diagnostic Yield of Genetic Testing in Sudden Cardiac Death with Autopsy Findings of Uncertain Significance

2021 ◽  
Vol 10 (9) ◽  
pp. 1806
Author(s):  
Mercedes Iglesias ◽  
Tomas Ripoll-Vera ◽  
Consuelo Perez-Luengo ◽  
Ana Belen García ◽  
Susana Moyano ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Ventricular Hypertrophy ◽  
Diagnostic Yield ◽  
Left Ventricular ◽  
Molecular Autopsy ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Unknown Significance ◽  
Uncertain Significance ◽  
Frequent Variant

Background: Sudden death (SD) in the young usually has an underlying genetic cause. In many cases, autopsy reveals unspecific and inconclusive results, like idiopathic left ventricular hypertrophy (LVH), nonsignificant coronary atherosclerosis (CA), and primary myocardial fibrosis (PMF). Their pathogenicity and their relation to SD cause is unknown. This study aims to evaluate the diagnostic yield of genetic testing in these cases. Methods: SD cases, between 1 and 50 years old, with findings of uncertain significance (idiopathic LVH, nonsignificant CA and PMF) on autopsy were evaluated prospectively, including information about medical and family history and circumstances of death. Genetic testing was performed. Results: In a series of 195 SD cases, we selected 31 cases presenting idiopathic LVH (n = 16, 51.61%), nonsignificant CA (n = 17, 54.84%), and/or PMF (n = 24, 77.42%) in the autopsy. Mean age was 41 ± 7.2 years. Diagnostic yield of genetic test was 67.74%, considering variants of unknown significance (VUS), pathogenic variants (PV) and likely pathogenic variants (LPV); 6.45% including only PV and LPV. Structural genes represented 41,93% (n = 13) of cases, while 38,7% (n = 12) were related to channelopathies. Conclusion: Molecular autopsy in SD cases between 1 and 50 years old, with findings of uncertain significance, has a low diagnostic yield, being VUS the most frequent variant observed.

Follow-up of carriers of BRCA1 and BRCA2 variants of unknown significance: Variant reclassification and surgical decisions

2011 ◽  
Vol 13 (12) ◽  
pp. 998-1005 ◽  
Author(s):  
Mitzi L. Murray ◽  
Felecia Cerrato ◽  
Robin L. Bennett ◽  
Gail P. Jarvik
Keyword(s):  
Brca1 And Brca2 ◽  
Variants Of Unknown Significance ◽  
Unknown Significance

scholarly journals Prevalence and clinical significance of esophageal abnormalities in children with celiac disease

2020 ◽  
Vol 33 (11) ◽  
Author(s):  
Meri Smolander ◽  
Samuli Nurminen ◽  
Marleena Repo ◽  
Laura Kivelä ◽  
Juho E Kivistö ◽  
...  
Keyword(s):  
Celiac Disease ◽  
Clinical Significance ◽  
Villous Atrophy ◽  
Demographic Data ◽  
Upper Gastrointestinal Endoscopy ◽  
High Power Field ◽  
Unknown Significance ◽  
Long Term Follow Up ◽  
Histological Results

Summary Variable endoscopic and histological findings of esophageal lining are often detected in celiac disease, with unknown significance. We investigated the frequency and significance of such abnormalities in children. Macroscopic esophageal findings as reported by endoscopist and histological results by pathologist were compared between 316 celiac disease patients and 378 disease controls who had undergone upper gastrointestinal endoscopy with systematic esophageal biopsy sampling. Association between esophageal abnormalities and other clinical and histological characteristics of the disease was evaluated in celiac disease patients. Endoscopic esophageal findings were reported least often (3.8%) of all diseases in celiac disease, whereas histopathologic abnormalities were frequent (16.8%, n = 53). Children with celiac disease and esophageal histopathology reported more reflux than those with normal esophagus (5.7 vs. 0.8%, P = 0.032), whereas the groups were comparable in the frequency and severity of other symptoms, demographic data, prevalence of celiac disease-associated and other coexisting chronic conditions, family history of celiac disease, anthropometric and laboratory parameters, and degree of villous atrophy. Only 2 (3.7%) out of the 53 children with histologic findings had esophageal symptoms at diagnosis, and altogether seven were treated with acid blockers. Four children had increased number (≥15 eosinophils per high-power field) of esophageal eosinophils, but none of them had definite eosinophilic esophagitis. The remaining 45 children had only unspecific inflammation in the esophagus and reported no esophageal problems during a median of 6.9 years follow-up. To conclude, although relatively common, histopathological esophageal findings in celiac disease are mostly unspecific and without major clinical significance even in a long-term follow-up.

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