scholarly journals Introduction of a Variant Classification System for Analysis of Genotype-Phenotype Relationships in Heritable Retinoblastoma

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1605
Author(s):  
Isabel Hülsenbeck ◽  
Mirjam Frank ◽  
Eva Biewald ◽  
Deniz Kanber ◽  
Dietmar R. Lohmann ◽  
...  
Keyword(s):  
Classification System ◽  
Phenotypic Expression ◽  
Complete Loss ◽  
Variant Classification ◽  
Rb1 Gene ◽  
Screening Programs ◽  
Pathogenic Variants ◽  
Classification Framework ◽  
Age Of Diagnosis ◽  
The Common

Constitutional haploinsufficiency of the RB1 gene causes heritable retinoblastoma, a tumor predisposition syndrome. Patients with heritable retinoblastoma develop multiple retinoblastomas early in childhood and other extraocular tumors later in life. Constitutional pathogenic variants in RB1 are heterogeneous, and a few genotype-phenotype correlations have been described. To identify further genotype-phenotype relationships, we developed the retinoblastoma variant effect classification (REC), which considers each variant’s predicted effects on the common causal mediator, RB1 protein pRB. For validation, the RB1 variants of 287 patients were grouped according to REC. Multiple aspects of phenotypic expression were analyzed, known genotype-phenotype associations were revised, and new relationships were explored. Phenotypic expression of patients with REC-I, -II, and -III was distinct. Remarkably, the phenotype of patients with variants causing residual amounts of truncated pRB (REC-I) was more severe than patients with complete loss of RB1 (REC-II). The age of diagnosis of REC-I variants appeared to be distinct depending on truncation’s localization relative to pRB structure domains. REC classes identify genotype-phenotype relationships and, therefore, this classification framework may serve as a tool to develop tailored tumor screening programs depending on the type of RB1 variant.

scholarly journals Prevalent Pathogenic Variants of ATP7B in Chinese Patients with Wilson’s Disease: Geographical Distribution and Founder Effect

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 336
Author(s):  
Guo-Min Yang ◽  
Rou-Min Wang ◽  
Nan Xia ◽  
Zi-Wei Zheng ◽  
Yi Dong ◽  
...  
Keyword(s):  
Geographical Distribution ◽  
Founder Effect ◽  
Wilson’S Disease ◽  
Autosomal Recessive Disorder ◽  
Wilson's Disease ◽  
Chinese Patients ◽  
Mainland Chinese ◽  
Pathogenic Variants ◽  
Specific Distribution ◽  
The Common

Wilson’s disease (WD) is an autosomal recessive disorder caused by ATP7B pathogenic variants. This study aimed to show the geographical distribution and haplotype spectrum of three prevalent pathogenic variants (p.R778L, p.P992L, p.T935M) in mainland Chinese population and clarify whether the founder effect may account for their origins. We firstly summarized the frequency and geographical distribution of p.R778L, p.P992L and p.T935M in 715 WD patients. Then, to construct haplotypes associated with the three variants, Sanger sequencing and microsatellite typing at three dinucleotide-repeat markers (D13S314, D13S301, D13S316) flanking the ATP7B gene were performed in 102 WD families. An obvious regional-specific distribution feature was found in p.T935M. Linkage disequilibrium at the three markers was shown in all the three variants and we found the common haplotypes specific for p.R778L, p.P992L and p.T935M respectively, represented successively by 10-7-7, 10-9-5 and 12-4-8, which all exhibited great significance vs. the control chromosomes (p < 0.01). Meanwhile, haplotypes for the three variants differed from the studies in other regions to some extent. The common haplotypes we found indicate that three prevalent pathogenic variants emerge due to the founder effect. Furthermore, the study contributes to expand our knowledge of the genetic diversity of WD from a cross-regional perspective.

scholarly journals Assessment of genetic referrals and outcomes for women with triple negative breast cancer in regional cancer centres in Australia

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Lucie G. Hallenstein ◽  
Carol Sorensen ◽  
Lorraine Hodgson ◽  
Shelly Wen ◽  
Justin Westhuyzen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Genetic Testing ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cancer Genetics ◽  
Eligibility Criteria ◽  
Pathogenic Variants ◽  
Genetics Services ◽  
Age Of Diagnosis ◽  
Over Time

Abstract Background Guidelines for referral to cancer genetics service for women diagnosed with triple negative breast cancer have changed over time. This study was conducted to assess the changing referral patterns and outcomes for women diagnosed with triple negative breast cancer across three regional cancer centres during the years 2014–2018. Methods Following ethical approval, a retrospective electronic medical record review was performed to identify those women diagnosed with triple negative breast cancer, and whether they were referred to a genetics service and if so, the outcome of that genetics assessment and/or genetic testing. Results There were 2441 women with newly diagnosed breast cancer seen at our cancer services during the years 2014–2018, of whom 237 women were diagnosed with triple negative breast cancer. Based on age of diagnosis criteria alone, 13% (31/237) of our cohort fulfilled criteria for genetic testing, with 81% (25/31) being referred to a cancer genetics service. Of this group 68% (21/31) were referred to genetics services within our regions and went on to have genetic testing with 10 pathogenic variants identified; 5x BRCA1, 4x BRCA2 and × 1 ATM:c.7271 T > G. Conclusions Referral pathways for women diagnosed with TNBC to cancer genetics services are performing well across our cancer centres. We identified a group of women who did not meet eligibility criteria for referral at their time of diagnosis, but would now be eligible, as guidelines have changed. The use of cross-discipline retrospective data reviews is a useful tool to identify patients who could benefit from being re-contacted over time for an updated cancer genetics assessment.

Population-Based Screening in Children For Early Diagnosis and Treatment of Familial Hypercholesterolemia: Design of The VRONI Study

2021 ◽  
Author(s):  
Veronika Sanin ◽  
Raphael Schmieder ◽  
Sara Ates ◽  
Lea Dewi Schlieben ◽  
Jens Wiehler ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Screening Program ◽  
Molecular Genetic ◽  
Population Based ◽  
Molecular Genetic Analysis ◽  
Cascade Screening ◽  
Screening Programs ◽  
Pathogenic Variants ◽  
Risk Indices ◽  
Training Courses

Abstract Background: Heterozygous Familial Hypercholesterolemia (FH) represents the most frequent monogenic disorder with an estimated prevalence of 1:250 in the general population. Diagnosis during childhood enables early initiation of preventive measures, reducing the risk of severe consecutive atherosclerotic manifestations. Nevertheless, population-based screening programs for FH are scarce.Methods: In the VRONI study children aged 5 to 14 years in Bavaria are invited to participate in a FH screening program during regular pediatric visits. The screening is based on LDL-C measurements from capillary blood. If exceeding 130 mg/dl (3.34 mmol/l), i.e. the expected 95th percentile in this age group, subsequent molecular genetic analysis for FH is performed. Children with FH pathogenic variants enter a registry and are treated by specialized pediatricians. Furthermore, qualified training centers offer FH-focused training courses to affected families. For first degree relatives, reverse cascade screening is recommended to identify and treat affected family members.Results: Implementation of VRONI required intensive prearrangements for addressing ethical, educational, data-safety, legal and organisational aspects, which will be outlined in this paper. Recruitment started in January of 2021, within two months more than 280 pediatricians screened over 1,150 children. Approximately 60,000 children are expected to be enrolled in the VRONI study until 2024. Conclusion: VRONI aims to test the feasibility of a population-based screening for FH in children in Bavaria, intending to set the stage for a nation-wide FH screening infrastructure. Further we aim to validate genetic variants of unclear significance, detect novel causative mutations, and contribute to polygenic risk indices. (German Clinical Trials Register: DRKS00022140; registered August 21st2020.)

scholarly journals Towards an automatic classification system for supporting the development of critical reflective skills in L2 learning

2016 ◽  
Author(s):  
Gary Cheng
Keyword(s):  
Undergraduate Students ◽  
Classification System ◽  
Automatic Classification ◽  
Structured Interview ◽  
Active System ◽  
Online Questionnaire ◽  
Classification Framework ◽  
L2 Learning ◽  
Students Attitudes ◽  
Reflective Skills

This study aimed to develop an automatic classification system, namely ACTIVE, for generating immediate and individualised feedback on students’ reflective entries about their second language (L2) learning experiences. It also aimed to explore students’ attitudes towards using the system to support the development of their reflective skills in L2 learning. A total of 466 undergraduate students took part in the study. One hundred and twenty-seven participants were involved in the development phase, where their reflective entries were manually annotated according to a classification framework for critical reflection on L2 learning, and the annotated entries were then used to develop the ACTIVE system. The remaining participants were asked to generate automated feedback reports on their reflective entries for improvement by using the system. To solicit their views towards the system, the participants were administered an online questionnaire and some of them were also invited to attend a semi-structured interview. The overall results indicate that the classification accuracy of the system is comparable to that of human annotators. They also suggest that both teacher and machine feedback types have strengths and limitations, highlighting the need to further explore the use of multi-channel, multi-layer feedback in improving students’ reflective skills in L2 learning.

Abstract 13296: Risk Loci of Hypertrophic Cardiomyopathy Identified via the UK Biobank

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Alex Gyftopoulos ◽  
Yi-Ju Chen ◽  
Libin Wang ◽  
Charles H Williams ◽  
Young Wook Chun ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Large Population ◽  
Phenotypic Expression ◽  
Coiled Coil ◽  
Intraflagellar Transport ◽  
Genetic Profile ◽  
Uk Biobank ◽  
Disease Manifestation ◽  
Pathogenic Variants ◽  
The Uk

Introduction: Hypertrophic cardiomyopathy (HCM) is the most commonly inherited cardiac disease affecting 1:500 to 1:200 individuals worldwide. HCM has a heterogeneous genetic profile and phenotypic expression. More than 1400 known pathogenic variants have been identified in 11 sarcomere genes. In about 40% of HCM patients, the genetic cause may not be identified. The same mutation may lead to different phenotypes and severity in different individuals. Identification of novel HCM genes and modifiers will expand our understanding of the signaling pathways that are responsible for phenotypic expression of HCM. Methods: The UK Biobank comprises clinical and genetic data for greater than 500,000 individuals. We used OASIS, an information system for analyzing, searching, and visualizing associations between phenotype and genotype data to analyze this data. We compared control individuals to HCM individuals identified by ICD-10 code (I42.1 and I42.2) in a 20-to-1 fashion. Related individuals and those with confounding diagnoses were excluded. Results: The analysis was performed with Plink’s GLM option, and we identified 84 variants with a minor allele frequency of 0.5% or greater in 65 genes associated with HCM with a p < 1x10 -6 , including 4 with p < 5x10 -8 . The identified genes encode lncRNAs, miRNAs, and membrane proteins. Variants with high significance were identified in the genes encoding putative ciliary components DNAL4 (dynein axonemal light chain 4; p = 2.9x10 -8 ), MYO1D (unconventional myosin 1D; p = 3.1x10 -8 ), ITFAP (intraflagellar transport associated protein; p = 9.5x10 -8 ), CABCOCO1 (ciliary associated calcium biding coiled-coil 1; p = 3.7x 10 -7 ), EVL (Enah-Vasp-like; p = 4.4x 10 -7 ) and IFT122 (intraflagellar transport 122; p = 8.0 x10 -7 ). Conclusion: While none of these have previously associated with HCM, our findings suggest ciliary structure and function may play a role in disease manifestation. Our method is unique by pooling individuals in a large population set to identify potential causative or contributing mutations. Bioinformatic tools, such as OASIS, allow for the identification of previously unrecognized variants that may play a role in the development of HCM. This approach has identified numerous novel genes as possible risk loci.

The Utility and Validity of Current Diagnostic Procedures for Defining Temporomandibular Disorder Patients

1993 ◽  
Vol 7 (2) ◽  
pp. 97-112 ◽  
Author(s):  
G.T. Clark ◽  
R.E. Delcanho ◽  
J.-P. Goulet
Keyword(s):  
Classification System ◽  
Temporomandibular Disorders ◽  
Temporomandibular Disorder ◽  
Diagnostic Procedures ◽  
The Common ◽  
Definition Of ◽  
Patient Subgroups ◽  
Ideal Method ◽  
Over Time ◽  
Research Classification

This paper describes the evolution of different concepts of classifying and defining Temporomandibular Disorders (TMD) for both clinical and research settings. The literature is reviewed with respect to the utility and validity of the different questionnaire and examination procedures that have been used to assess TMD patients. The presented view is that many of these procedures have not been validated, that there is a lack of standardization in the use of the procedures themselves, and that an ideal method of classifying this broad group of patients into better-defined subgroups has not yet been developed. More standardized and better-defined research by trained and calibrated researchers is needed worldwide to elucidate these subgroups so that a better and widely agreed upon research classification system can be developed for widespread use. It also seems clear that as research requirements for defining TMD patient subgroups become more stringent over time, it may not be practical for the clinician to implement them on a day-to-day basis in his or her practice. As such, a practical utilitarian definition of the common subtype of TMD patients is also needed which parallels any research grouping, so that data from research are valuable and generalizable to the practicing clinician.

scholarly journals Clinical Utility of a Phenotype-Enhanced MYH7 -Specific Variant Classification Framework in Hypertrophic Cardiomyopathy Genetic Testing

2020 ◽  
Vol 13 (5) ◽  
pp. 453-459
Author(s):  
Connor L. Mattivi ◽  
J. Martijn Bos ◽  
Richard D. Bagnall ◽  
Natalie Nowak ◽  
John R. Giudicessi ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Hypertrophic Cardiomyopathy ◽  
Mayo Clinic ◽  
Clinical Utility ◽  
Similar Distribution ◽  
Variant Classification ◽  
Classification Framework ◽  
Uncertain Significance ◽  
Genetics And Genomics ◽  
Independent Cohort

Background: Missense variants in the MYH7 -encoded MYH7 (beta myosin heavy chain 7) represent a leading cause of hypertrophic cardiomyopathy (HCM). MYH7 -specific American College of Medical Genetics and Genomics (ACMG) variant classification guidelines were released recently but have yet to be assessed independently. We set out to assess the performance of the MYH7 -specific ACMG guidelines and determine if the addition of phenotype-enhanced criteria (PE-ACMG) using the HCM Genotype Predictor Score can further reduce the burden of variants of uncertain significance (VUS). Methods: Re-assessment was performed on 70 MYH7 -variants in 121 unique patients from Mayo Clinic, and an independent cohort of 54 variants in 70 patients from Royal Prince Alfred Hospital (Australia). Qualifying variants were re-adjudicated using both standard ACMG and MYH7 -ACMG guidelines, and HCM Genotype Predictor Score was used to provide a validated measure of strength of clinical phenotype to be incorporated into the MYH7 -ACMG framework. Results: Among Mayo Clinic identified variants, 11/70 (16%) were classified as pathogenic (P), 10/70 (14%) as likely pathogenic, and 49/70 (70%) as a VUS. A similar distribution was seen in the Australian patients (12/54 [22%] P, 12/54 [22%] likely pathogenic, and 30/54 [56%] VUS; P =not significant). Application of the MYH7 -ACMG resulted in a nonsignificant reduction of the VUS burden in both cohorts from 49/70 to 39/70 (56%; P =0.1; Mayo Clinic) and from 30/54 to 20/54 (37%; P =0.1; Australia). Using the combined PE-MYH7-ACMG framework, the VUS decreased significantly from 49 to 27 ( P <0.001, Mayo Clinic) and from 30 to 16 ( P <0.001; Australia). Conclusions: Use of the MYH7 -specific guidelines alone failed to significantly decrease VUS burden in 2 independent cohorts. However, a significant reduction in VUS burden was observed after the addition of phenotypic criteria. Using a patient’s strength of sarcomeric HCM phenotype for variant adjudication can increase significantly the clinical utility of genetic testing for patients with HCM.

Dewey and the visual arts: some thoughts on the scheme and its application

2011 ◽  
Vol 36 (4) ◽  
pp. 5-12
Author(s):  
Jill Cripps
Keyword(s):  
Visual Arts ◽  
Classification System ◽  
User Perspective ◽  
Library Users ◽  
The Common ◽  
Decimal Classification ◽  
Common Perception ◽  
Better Than ◽  
Library Collections

The Dewey Decimal Classification system, frequently used to arrange arts collections, has a number of commendable aspects but also some significant shortcomings. Evidence suggests that visual arts library users can further their creative ideas by browsing library shelves, and the author considers this should inform classification practice. Dewey, approached from a user perspective and applied with attention to the scheme’s potential, can provide a shelf order that promotes browsing. The common perception that Dewey is most suited to general library collections is perhaps not entirely justified. Within the visual arts, it possibly accommodates specialist resources rather better than is sometimes imagined, particularly with judicious adaptation. A number of modifications are easy enough to achieve and may be applied across a range of visual arts resources.

scholarly journals The Comprehensive AOCMF Classification System: Midface Fractures - Level 2 Tutorial

2014 ◽  
Vol 7 (1_suppl) ◽  
pp. 59-67 ◽  
Author(s):  
Christoph Kunz ◽  
Laurent Audigé ◽  
Carl-Peter Cornelius ◽  
Carlos H. Buitrago-Téllez ◽  
John Frodel ◽  
...  
Keyword(s):  
Classification System ◽  
En Bloc ◽  
Case Examples ◽  
Fracture Location ◽  
Midface Fracture ◽  
Level 3 ◽  
The Common ◽  
Fracture Mapping ◽  
Le Fort Classification ◽  
Level 2

The AOCMF Classification Group developed a hierarchical three-level craniomaxillofacial classification system with increasing level of complexity and details. The highest level 1 system distinguish four major anatomical units including the mandible (code 91), midface (code 92), skull base (code 93), and cranial vault (code 94). This tutorial presents the level 2 system for the midface unit that concentrates on the location of the fractures within defined regions in the central (upper, intermediate, and lower) and lateral (zygoma, pterygoid) midface, as well as the internal orbit and palate. The level 2 midface fracture location outlines the topographic boundaries of the anatomical regions. The common nasoorbitoethmoidal and zygoma en bloc fracture patterns, as well as the time-honored Le Fort classification are taken into account. This tutorial is organized in a sequence of sections dealing with the description of the classification system with illustrations of the topographical cranial midface regions along with rules for fracture location and coding, a series of case examples with clinical imaging and a general discussion on the design of this classification. Individual fracture mapping in these regions regarding severity, fragmentation, displacement of the fragment or bone defect is addressed in a more detailed level 3 system in the subsequent articles.

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