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 Stakeholder Views on Active Cascade Screening for Familial Hypercholesterolemia

Healthcare ◽  
2018 ◽  
Vol 6 (3) ◽  
pp. 108 ◽  
Author(s):  
Carla van El ◽  
Valentina Baccolini ◽  
Peter Piko ◽  
Martina Cornel
Keyword(s):  
The Netherlands ◽  
Familial Hypercholesterolemia ◽  
Screening Program ◽  
Family Members ◽  
Preventive Strategy ◽  
Cascade Screening ◽  
Privacy Regulation ◽  
Psychological Burden ◽  
Roles And Responsibilities ◽  
Screening Programs

In familial hypercholesterolemia (FH), carriers profit from presymptomatic diagnosis and early treatment. Due to the autosomal dominant pattern of inheritance, first degree relatives of patients are at 50% risk. A program to identify healthy relatives at risk of premature cardiovascular problems, funded by the Netherlands government until 2014, raised questions on privacy and autonomy in view of the chosen active approach of family members. Several countries are building cascade screening programs inspired by Dutch experience, but meanwhile, the Netherlands’ screening program itself is in transition. Insight in stakeholders’ views on approaching family members is lacking. Literature and policy documents were studied, and stakeholders were interviewed on pros and cons of actively approaching healthy relatives. Sociotechnical analysis explored new roles and responsibilities, with uptake, privacy, autonomy, psychological burden, resources, and awareness as relevant themes. Stakeholders agree on the importance of early diagnosis and informing the family. Dutch healthcare typically focuses on cure, rather than prevention. Barriers to cascade screening are paying an own financial contribution, limited resources for informing relatives, and privacy regulation. To benefit from predictive, personalized, and preventive medicine, the roles and responsibilities of stakeholders in genetic testing as a preventive strategy, and informing family members, need to be carefully realigned.

scholarly journals Analysis of the mutational spectrum of the SLC26A4 gene and its contribution to the etiology of inherited hearing loss in the indigenous population of Southern Siberia

2020 ◽  
pp. 43-45
Author(s):  
В.Ю. Данильченко ◽  
М.В. Зыцарь ◽  
Е.А. Маслова ◽  
М.С. Бады-Хоо ◽  
И.В. Морозов ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Unknown Etiology ◽  
Southern Siberia ◽  
Pathogenic Variants ◽  
Slc26a4 Gene ◽  
Wide Range ◽  
Polymorphic Variants ◽  
Tyva Republic

Мутации в гене SLC26A4 являются частой причиной потери слуха во многих регионах мира. В работе приводятся результаты молекулярно-генетического анализа (с использованием секвенирования по Сэнгеру) последовательности гена SLC26A4, впервые проведенного в выборке пациентов с потерей слуха неустановленной этиологии (n=232) из Республик Тыва и Алтай. Установлены контрастные различия патогенетического вклада мутаций в гене SLC26A4 в этиологию нарушения слуха у коренных жителей этих географически близких регионов: 28,2% - для тувинцев и 4,3% - для алтайцев. Выявлены как уже известные, так и новые патогенные варианты, а также широкий спектр полиморфных вариантов гена SLC26A4. Mutations in the SLC26A4 gene are a common cause of hearing loss in many regions of the world. This paper presents the results of molecular genetic analysis (by Sanger sequencing) of the SLC26A4 sequence, first performed in the sample of patients with hearing loss of unknown etiology (n=232) from the Tyva Republic and the Altai Republic. Contrast differences of the pathogenic contribution of SLC26A4 mutations to the etiology of hearing impairment were revealed in the indigenous peoples of these geographically close regions: 28.2% for Tuvinians and 4.3% for Altaians. Both known and novel pathogenic variants as well as a wide range of polymorphic variants were found in the SLC26A4 gene sequence.

scholarly journals Characterization of a novel CSF1R mutation causing hereditary diffuse leukoencephalopathy with spheroids in a case presenting with young-onset dementia

BJPsych Open ◽  
2021 ◽  
Vol 7 (S1) ◽  
pp. S118-S118
Author(s):  
Walid Nasr ◽  
Mahmoud Gad ◽  
Tareq Qassem
Keyword(s):  
Novel Mutation ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Insertion Mutation ◽  
Heterozygous Deletion ◽  
Young Onset ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Young Onset Dementia ◽  
Rapid Cognitive Decline

ObjectiveThis poster aims to report an unregistered mutation CSF1R gene in a patient presenting young-onset dementia.Hypothesis: Novel heterozygous deletion–insertion mutation in the Colony-Stimulating Factor 1 Receptor (CSF1R) gene is linked to a case of hereditary diffuse leukoencephalopathy with spheroids (HDLS), presenting with young-onset dementia.BackgroundCSF1R mediates proliferation, differentiation, and survival of monocytes/ macrophages and microglia. Pathogenic variants in the CSF1R gene cause autosomal dominant diffuse hereditary leukoencephalopathy with spheroids characterized by variable behavioural, cognitive, and motor changes, usually presenting with young-onset dementia. The average lifespan after the start of the symptoms is often 6 years.Case reportMolecular genetic analysis of whole-exome sequencing (WES) was carried out for a 49-year-old male patient presenting with rapid cognitive decline, behavioural symptoms and impaired sphincteric control.DiscussionWES identified the heterozygous deletion–insertion variant c.2356_2357delinsAC p.(Leu786Thr) (chr5:149435867-49435868; hg19) in the CSF1R gene. To the best of our knowledge the variant has not been described in the literature so far (HGMD 2019.3). No allele frequencies in the general population have been documented.ConclusionWe believe that we have identified a novel mutation in the CSF1R gene. This mutation is likely to be linked to this patient presenting with young-onset dementia.

Cascade screening program for familial hypercholesterolemia

2018 ◽  
Vol 65 (5) ◽  
pp. 280-286
Author(s):  
Patricia Rubio-Marín ◽  
Alfredo Michán-Doña ◽  
Juan Maraver-Delgado ◽  
Raquel Arroyo-Olivares ◽  
Rosalía Barrado Varea ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Screening Program ◽  
Cascade Screening

Cervical cancer screening information flow in Northern regional administrative service in Portugal

2020 ◽  
Vol 30 (Supplement_5) ◽  
Author(s):  
D Portela ◽  
V Cruz ◽  
H Monteiro ◽  
F Tavares
Keyword(s):  
Cervical Cancer ◽  
Cancer Screening ◽  
Cervical Cancer Screening ◽  
Information Flow ◽  
Screening Program ◽  
Population Based ◽  
Health Administration ◽  
Screening Programs ◽  
Longitudinal Data Collection ◽  
Northern Regional

Abstract Management of a population-based screening program circuit depends on characteristics and technical barriers of its application and implementation. The aim is to clarify the information flow, to understand and build a vision of cervical screening information flows in Northern Regional Health Administration Portuguese Public System and to identify the constraints among them. A total of 5 cluster meetings were presented and two expert interviews were conducted allowing to present an informational flow and its constraints. Aims addressed in each interview where based on the expertise of the interviewed. Cervical cancer screening program depends on the use of SiiMA application. This is an information system for the management of population-based screening program which involves mainly 3 entities and allows a longitudinal data collection and study. Three main constraints were reported. The time for updating data for the list of eligible women was bigger than accorded reaching up to 3 months delay. A duplicate of records and discharges in hospital care since the discharge was done both in the hospital system and the SiiMA platform manually in order to the woman re-enter the screening program. Pendencies were seen due to other screening programs running in parallel which had to be sorted out manually in the regional level or by the entity involved. The existence of a screening application is vital for the implementation purposes of a screening program. The lack of integration of the systems increases bureaucratic work, costs and causes time delay. To improve the efficiency of digital transformation ensuring the quality of the process it is necessary to adapt the design of the health informatic systems to the daily practice and its wants and needs. The strategies of forcing an ever-increasing number of frameworks have demonstrated not to be so effective. Therefore, it is a cornerstone to understand these flows in order to improve its structure, intervention and optimization. Key messages The existence of a screening digital application is vital but its expanding use arises constraints. Due to the complexity of such programs, a digital strategy is crucial for management and monitoring of the screening at this scale.

Abstract 15779: Quality of Life in a Cohort of Familial Hypercholesterolemia Patients Undergoing Molecular Cascade Screening in Brazil

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Ana Cristina Souto ◽  
Alexandre Pereira ◽  
Cinthia E Jannes ◽  
Julia Fukushima ◽  
Jose E Krieger ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Familial Hypercholesterolemia ◽  
Linear Models ◽  
Screening Program ◽  
Short Form ◽  
Smoking Habit ◽  
Genetic Diagnosis ◽  
Cascade Screening ◽  
Social Demographic

Introduction:: Familial hypercholesterolemia (FH) is an underdiagnosed and undertreated disease associated with elevated risk of early cardiovascular disease (CVD) and thus can reduce quality of life. The present health related quality of life (HRQL) investigation, evaluated patients personal interpretation of morbidity burden in daily life. Methods: The study included a total of 1,032 adult individuals participating in a FH molecular cascade-screening program. The involved individuals were index cases (IC n=363), with genetic diagnosis or FH and their first-degree relatives (FDR, n=669). All patients were evaluated at the first session of the molecular diagnosis process. HRQL measurements, mental (MCS) and physical (PCS) component scores, was carried out with the Medical Outcomes Study (MOS) 12-Item Short-Form Health Survey (SF-12) questionnaire. Results: IC were older (52±13.1 vs. 46±16.2 years, P<0.05) and presented lower PCS than FDR (44.7±9.3 vs. 49.2±8.4, P<0.05). No differences were seen on the MCS component. Overall, generalized linear models showed that smoking habit (11.9% prevalence, P=0.006), previous diagnosis of hyperlipidemia (78.6%, P=0.020) and depression (13.5% prevalence, P<0.000) were significant predictors of MCS. The presence of heart failure (6.5%, P=0.018), angina pectoris (12.9%, P=0.005), previous myocardial infarction (12.3%, P=0.012), hypertension (33.9%, P=0.018) and obesity (12.8%, P<0.000) were all predictors of PCS. The presence of arrhythmias (10.7% prevalence) predicted both MCS and PCS (P=0.042 and P=0.00, respectively). Male gender (42.4%, P<0.000) and education level (< 9 years of background, 28% P<0.000) were social-demographic aspects predictive of differences in MCS and PCS, respectively. Conclusions: Reductions in the individuals’ reported quality of life were explained by differences in social-demographic characteristics but mainly by inadequate health/disease status, such as risk factors and previous CVD. Active FH genetic cascade diagnosis by promoting early and adequate medical care and thus preventing early CVD, may improve substantially the subjective appraisal of HRQL.

scholarly journals A137 COLONOSCOPY RELATED ADVERSE EVENTS IN A POPULATION-BASED COLON SCREENING PROGRAM

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. 158-159
Author(s):  
M Tomaszewski ◽  
D Sanders ◽  
R A Enns ◽  
L Gentile ◽  
C Nash ◽  
...  
Keyword(s):  
Adverse Events ◽  
Chart Review ◽  
Screening Program ◽  
Population Based ◽  
Serious Adverse Events ◽  
Screening Programs ◽  
Medical Visits ◽  
Admission Data ◽  
Respiratory Event ◽  
Event Rates

Abstract Background The British Columbia Colon Screening Program (BCCSP) is a population-based program enrolling 50–74 year old individuals for biennial FIT (OC-Sensor, cut-off 10 mcg/g) with follow-up colonoscopy for positive FIT. The neoplasia detection rate is 50–55% and over 75% of colonoscopies have a specimen taken. Previously reported colonoscopy adverse event rates for FIT based screening programs vary widely: 0.03–6.2% and 0–2.7% for bleeding and perforation, respectively. Mortality as a result of colonoscopy is rare but has been reported in 0.0004%-0.0074% of colonoscopies. The rate of colonoscopy related adverse events in BCCSP participants is unknown. Aims To determine the rate of colonoscopy related serious adverse events within the BCCSP. Methods This is a retrospective cohort study of all participants undergoing colonoscopy in BCCSP from November 15, 2013 to December 31, 2017. BCCSP contacts screening participants by phone 14 days post colonoscopy to determine unplanned medical visits the day prior (during bowel preparation) or following the colonoscopy. Unplanned events underwent chart review if the event was a perforation, cardiovascular or respiratory event, or resulted in death, hospitalization, or significant intervention including repeat colonoscopy, interventional radiology, surgery, blood transfusion, cardioversion, casting of a fracture or suturing of a laceration. Chart review was conducted by a Colonoscopy Lead and reviewed by BCCSP Quality Committee. Unplanned events were defined as serious adverse events (SAE) if they resulted in death, hospitalization or significant intervention and further classified as probably, possibly, or unlikely related to the colonoscopy. Results A total of 108,004 colonoscopies were performed. Unplanned events were reported in 1753 participants, of which 586 met criteria for review. Of these, 578 were confirmed unplanned events and 409 were SAEs of which 367 (89.7%) were probably, 22 (5.4%) possibly and 20 (4.9%) unlikely associated with colonoscopy. 36/10,000 colonoscopies were associated with a SAE that was probably or possibly related: perforation in 5/10,000, bleeding 22/10,000. Three deaths occurred in the 14 days following colonoscopy that were probably (2 perforations) or possibly related to the colonoscopy (0.3/10,000). Conclusions The BCCSP has a colonoscopy SAE rate in keeping with previous publications, particularly in the context of a very high proportion of procedures associated with polypectomy, a known risk factor for perforation and bleeding. This study will help inform screening participants about the risks of colonoscopy in the BC program. Future studies are required to confirm these rates using hospital admission data. Funding Agencies None

scholarly journals Complex Transposon Insertion as a Novel Cause of Pompe Disease

2021 ◽  
Vol 22 (19) ◽  
pp. 10887
Author(s):  
Igor Bychkov ◽  
Galina Baydakova ◽  
Alexandra Filatova ◽  
Ochir Migiaev ◽  
Andrey Marakhonov ◽  
...  
Keyword(s):  
Pompe Disease ◽  
Autosomal Recessive ◽  
Mobile Genetic Element ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Lysosomal Storage ◽  
Pathogenic Variants ◽  
Transposon Insertion ◽  
Gaa Gene ◽  
Mutation Databases

Pompe disease (OMIM#232300) is an autosomal recessive lysosomal storage disorder caused by mutations in the GAA gene. According to public mutation databases, more than 679 pathogenic variants have been described in GAA, none of which are associated with mobile genetic elements. In this article, we report a novel molecular genetic cause of Pompe disease, which could be hardly detected using routine molecular genetic analysis. Whole genome sequencing followed by comprehensive functional analysis allowed us to discover and characterize a complex mobile genetic element insertion deep in the intron 15 of the GAA gene in a patient with infantile onset Pompe disease.

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