scholarly journals Phenotypic Variability of a Pathogenic PKP2 Mutation in an Italian Family Affected by Arrhythmogenic Cardiomyopathy and Juvenile Sudden Death: Considerations From Molecular Autopsy to Sport Restriction

2021 ◽  
Vol 8 ◽  
Author(s):  
Maria Pia Leone ◽  
Pietro Palumbo ◽  
Johan Saenen ◽  
Sandra Mastroianno ◽  
Stefano Castellana ◽  
...  
Keyword(s):  
Task Force ◽  
Phenotypic Variability ◽  
Genetic Disorder ◽  
Physical Exertion ◽  
Dominant Mode ◽  
Specific Gene ◽  
Incomplete Penetrance ◽  
Arrhythmogenic Cardiomyopathy ◽  
Cascade Screening ◽  
Molecular Autopsy

Background: Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder with an estimated prevalence between 1:2,000 and 1:5,000 and is characterized by the fibrofatty replacement of cardiomyocytes that predisposes to malignant arrhythmias, heart failure, and sudden cardiac death. The diagnosis is based on the 2010 Task Force Criteria including family history, electrocardiographic traits and arrhythmogenic pattern, specific gene mutations, and structural and/or histological abnormalities. Most ACMs display an autosomal dominant mode of inheritance often with incomplete penetrance and variable expressivity. Genetic screening of patients with ACM identifies pathogenic or likely pathogenic variants, prevalently in genes encoding the cardiac desmosome (PKP2, DSP, DSC2, DSG2, and JUP) or less frequently in non-desmosomal genes (CTNNA3, PLN, TMEM43, RYR2, SCN5A, CDH2, and DES).Methods: In the present study, we performed molecular autopsy in a boy who died suddenly during physical exertion. In addition to post-mortem examination, a DNA sample was analyzed with next-generation sequencing (NGS).Results: The genetic analysis revealed the presence of pathogenic heterozygous c.314del (p.Pro105Leufs*7) frameshift variant in the PKP2 gene. Cascade screening of family members allowed us to identify 12 mutation carriers and to intervene on subjects at risk, many of whom were athletes.Conclusions: Molecular autopsy can establish cardiogenetic diagnosis and allow appropriate preventative measures in high-risk relatives.

scholarly journals P3686A novel desmin gene variant as an important cause of biventricular arrhythmogenic cardiomyopathy

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A Protonotarios ◽  
E Quinn ◽  
C Dalageorgou ◽  
M Futema ◽  
M M Akhtar ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Task Force ◽  
Research Training ◽  
Gene Mutations ◽  
Clinical Information ◽  
Holter Monitoring ◽  
Definite Diagnosis ◽  
Arrhythmogenic Cardiomyopathy ◽  
Cascade Screening ◽  
Mutation Carriers

Abstract Introduction Arrhythmogenic Cardiomyopathy (AC) is typically caused by mutations in the desmosomal genes, however non-desmosomal genes have been increasingly implicated. Desmin gene (DES) mutations have been previously reported in AC, but in many cases there are insufficient data to support their pathogenicity. Purpose We assessed our AC cohort for DES gene mutations and describe the clinical phenotype associated with a recurring variant present in 3 unrelated families. Methods Genetic testing was performed using next-generation sequencing for 41 genes in a total of 138 AC probands with a definite diagnosis of AC based on the revised 2010 Task Force diagnostic criteria. All candidate variants were confirmed using Sanger sequencing. Clinical and genetic cascade screening were expanded to the first-degree relatives of the probands. Retained tissue from deceased individuals was used for genetic testing. All living mutation carriers underwent clinical assessment including physical examination, 12-lead ECG, signal-averaged ECG, echocardiography, cardiac magnetic resonance imaging (MRI) and 24h Holter-monitoring. Results Two DES gene variants, p.Ser298Leu (n=1) and p.Leu115Ile (n=3), were identified in 4 out of the 138 probands (3%). The former coexisted with a pathogenic DSP gene mutation and has not been further evaluated. The latter is a novel variant, absent in control databases (gnomAD) and was the only variant present in 3 unrelated families (see figure). One carrier required heart transplant (A-II-1), two died suddenly (A-III-1, B-II-1) and one died of non-cardiac causes (B-I-2). Detailed clinical information was present in 8 mutation carriers (2 male, age 45±19 years). Seven (88%) had a definite diagnosis and one had a borderline diagnosis of AC. All cases (100%) had right ventricular (RV) wall motion abnormalities, 6 (75%) had a dilated RV, 6 (75%) a dilated LV and 6 (75%) had LV dysfunction (mild in 5 and severe in 1). LV late gadolinium enhancement (LGE) was present in all 6 carriers that had a cardiac MRI with a circumferential sub-epicardial distribution (see figure, case A-III-2). Non-sustained ventricular tachycardia (VT) was present in 7 (88%) and sustained VT in 2 cases (25%). The ventricular ectopic burden per 24h ranged from 426 to 10583 with a median value of 820. Figure 1 Conclusion Variants of the DES gene are rare causes of AC. The novel p.Leu115Ile variant seems to be prevalent in a large UK-based cohort and it causes a biventricular form of AC, with a characteristic scar pattern on MRI and severe outcomes. Acknowledgement/Funding Alexandros Protonotarios is supported by a BHF Clinical Research Training Fellowship no. FS/18/82/34024

scholarly journals Histopathological Features and Protein Markers of Arrhythmogenic Cardiomyopathy

2021 ◽  
Vol 8 ◽  
Author(s):  
Carlos Bueno-Beti ◽  
Angeliki Asimaki
Keyword(s):  
Cardiac Myocytes ◽  
Left Ventricular ◽  
Muscle Disease ◽  
Incomplete Penetrance ◽  
Protein Markers ◽  
Cell Coupling ◽  
Arrhythmogenic Cardiomyopathy ◽  
Right Ventricular Free Wall ◽  
Cascade Screening ◽  
Age Related

Arrhythmogenic cardiomyopathy (ACM) is a heritable heart muscle disease characterized by syncope, palpitations, ventricular arrhythmias and sudden cardiac death (SCD) especially in young individuals. It is estimated to affect 1:5,000 individuals in the general population, with >60% of patients bearing one or more mutations in genes coding for desmosomal proteins. Desmosomes are intercellular adhesion junctions, which in cardiac myocytes reside within the intercalated disks (IDs), the areas of mechanical and electrical cell-cell coupling. Histologically, ACM is characterized by fibrofatty replacement of cardiac myocytes predominantly in the right ventricular free wall though left ventricular and biventricular forms have also been described. The disease is characterized by age-related progression, vast phenotypic manifestation and incomplete penetrance, making proband diagnosis and risk stratification of family members particularly challenging. Key protein redistribution at the IDs may represent a specific diagnostic marker but its applicability is still limited by the need for a myocardial sample. Specific markers of ACM in surrogate tissues, such as the blood and the buccal epithelium, may represent a non-invasive, safe and inexpensive alternative for diagnosis and cascade screening. In this review, we shall cover the most relevant biomarkers so far reported and discuss their potential impact on the diagnosis, prognosis and management of ACM.

scholarly journals The Role of MicroRNAs in Arrhythmogenic Cardiomyopathy: Biomarkers or Innocent Bystanders of Disease Progression?

2020 ◽  
Vol 21 (17) ◽  
pp. 6434
Author(s):  
Maria Bueno Marinas ◽  
Rudy Celeghin ◽  
Marco Cason ◽  
Gaetano Thiene ◽  
Cristina Basso ◽  
...  
Keyword(s):  
Gene Expression Regulation ◽  
Phenotypic Variability ◽  
Incomplete Penetrance ◽  
Primary Role ◽  
Arrhythmogenic Cardiomyopathy ◽  
Small Noncoding Rnas ◽  
Early Disease Detection ◽  
Pathogenic Variants ◽  
Fatty Replacement ◽  
Genes Encoding

Arrhythmogenic cardiomyopathy (AC) is an inherited cardiac disease characterized by a progressive fibro-fatty replacement of the working myocardium and by life-threatening arrhythmias and risk of sudden cardiac death. Pathogenic variants are identified in nearly 50% of affected patients mostly in genes encoding for desmosomal proteins. AC incomplete penetrance and phenotypic variability advocate that other factors than genetics may modulate the disease, such as microRNAs (miRNAs). MiRNAs are small noncoding RNAs with a primary role in gene expression regulation and network of cellular processes. The implication of miRNAs in AC pathogenesis and their role as biomarkers for early disease detection or differential diagnosis has been the objective of multiple studies employing diverse designs and methodologies to detect miRNAs and measure their expression levels. Here we summarize experiments, evidence, and flaws of the different studies and hitherto knowledge of the implication of miRNAs in AC pathogenesis and diagnosis.

scholarly journals A rare cause of sudden unexpected death syndrome (SUDS) in the first year of life: endomyocardial fibroelastosis (EFE) due to two compound heterozygous MYBPC3 mutations

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Benno Hartung ◽  
Anne Tank ◽  
Sven Dittmann ◽  
Stefanie Ritz-Timme ◽  
Eric Schulze-Bahr
Keyword(s):  
Genetic Disorder ◽  
Gene Mutations ◽  
First Year ◽  
Molecular Testing ◽  
Compound Heterozygous ◽  
Cascade Screening ◽  
Unexpected Death ◽  
Molecular Autopsy ◽  
Deceased Child ◽  
First Year Of Life

Abstract Background Autopsies regularly aim to clarify the cause of death; however, relatives may directly benefit from autopsy results in the setting of heritable traits (“mortui vivos docent”). Case presentation A case of a sudden unexpected cardiac death of a 5.5-months-old child is presented. Autopsy and thorough postmortem cardiac examinations revealed a massively enlarged heart with endomyocardial fibroelastosis. Postmortem molecular testing (molecular autopsy) revealed an unusual combination of two biparental MYBPC3 gene mutations likely to underlie the cardiac abnormalities. Thus, the molecular autoptic findings also had consequences for the relatives of the deceased child and impact on further family planning. Conclusions The presented case highlights the need for clinical autopsies including cardiac examinations and postmortem molecular testing; it also paves the way for further cascade screening of family members for cardiac disease, if a distinct genetic disorder is suspected.

scholarly journals The 2020 “Padua Criteria” for Diagnosis and Phenotype Characterization of Arrhythmogenic Cardiomyopathy in Clinical Practice

2022 ◽  
Vol 11 (1) ◽  
pp. 279
Author(s):  
Francesca Graziano ◽  
Alessandro Zorzi ◽  
Alberto Cipriani ◽  
Manuel De Lazzari ◽  
Barbara Bauce ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Diagnostic Criteria ◽  
Tissue Characterization ◽  
Task Force ◽  
Positive Family History ◽  
Standard Test ◽  
Arrhythmogenic Cardiomyopathy ◽  
Increased Risk ◽  
Criteria For Diagnosis ◽  
The Right

Arrhythmogenic Cardiomyopathy (ACM) is a heredo-familial cardiac disease characterized by fibro-fatty myocardial replacement and increased risk of sudden cardiac death. The diagnosis of ACM can be challenging due to the lack of a single gold-standard test: for this reason, it is required to satisfy a combination of multiple criteria from different categories including ventricular morpho-functional abnormalities, repolarization and depolarization ECG changes, ventricular arrhythmias, tissue characterization findings and positive family history/molecular genetics. The first diagnostic criteria were published by an International Task Force (ITF) of experts in 1994 and revised in 2010 with the aim to increase sensitivity for early diagnosis. Limitations of the 2010 ITF criteria include the absence of specific criteria for left ventricle (LV) involvement and the limited role of cardiac magnetic resonance (CMR) as the use of the late gadolinium enhancement technique for tissue characterization was not considered. In 2020, new diagnostic criteria (“the Padua criteria”) were proposed. The traditional organization in six categories of major/minor criteria was maintained. The criteria for identifying the right ventricular involvement were modified and a specific set of criteria for identifying LV involvement was created. Depending on the combination of criteria for right and LV involvement, a diagnosis of classic (right dominant) ACM, biventricular ACM or left-dominant ACM is then made. The article reviews the rationale of the Padua criteria, summarizes the main modifications compared to the previous 2010 ITF criteria and provides three examples of the application of the Padua criteria in clinical practice.

scholarly journals Prevalence of Sickle Cell Disease and Other Haemoglobin Variants in Calabar, Cross River State, Nigeria

2019 ◽  
pp. 1-6
Author(s):  
Akaba Kingsley ◽  
Ofem Enang ◽  
Ofonime Essien ◽  
Annette Legogie ◽  
Omini Cletus ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Genetic Disorder ◽  
Globin Gene ◽  
Specific Gene ◽  
Cell Disease ◽  
Cellulose Acetate Electrophoresis ◽  
Genetic Changes ◽  
Female Ratio ◽  
Cross River State

Background: Sickle cell disease (SCD) is the commonest genetic disorder worldwide with a global prevalence of 20-25 million. About 12-15 million affected persons are in Sub-Sahara Africa with Nigeria bearing the highest burden of people living with sickle cell disease. SCD is a disease characterized as an autosomal, recessive, heterogeneous, and a monogenetic disorder caused by an A-to-T point mutation in the β-globin gene responsible for the production of abnormal hemoglobin S (HbS), which polymerizes in the deoxygenated state and results in the sickling of erythrocytes.  Haemoglobin variants are mutant forms of haemoglobin in a population usually occurring as a result of genetic changes in specific genes, or globins that causes change on alterations in the amino acid. They could affect the structure, behavior, the production rate and the stability of the specific gene. Well-known haemoglobin variants such as sick-cell anaemia are responsible for diseases and are considered haemoglobinopathies. Other variants cause no detectable pathology and are thus considered as non-pathological variants. Aim: The study is aimed at evaluating the burden of sickle cell disease and other haemoglobin variants in Calabar, South-South Nigeria. Methods: This is a retrospective study done at the haematology laboratory of University of Calabar Teaching Hospital, Calabar. Cellulose acetate electrophoresis at alkaline pH was used for the evaluation of haemoglobinopathies. The data were entered into Microsoft Excel 2016 spreadsheet and analysed with the IBM SPSS Version 22. Data were summarized into percentage of different phenotypes. Results: Results of the total 3648 haemoglobin electrophoresis recorded, 1368 (37.50%) were male while the remaining 2280 (62.5%) females given a male to female ratio of 1:1.7. Five haemoglobin phenotypes were identified as HbAA, HbAS, HbAC, HbSC and HbSS. The overall average values of their prevalence were HbAA 64.78%, HbAS 32.62%, HbSS 2.14%, HbAC 0.33%, HbSC 0.14%. Thus, the prevalence of SCD (Prevalence of HbSS+HbSC) was 2.28%. The highest proportion of SCD was observed in 2011 with least in 2016 and 2017 respectively. Conclusion: The prevalence of SCD and other haemoglobin variants in Calabar is similar to that of the national prevalence rate. There is need for continuous enlightenment and premarital counselling on the pattern of inheritance of SCD most especially with the increased burden of sickle traits in the environment has reported in this study.

scholarly journals Mitochondrial tRNA mutations in Chinese children with tic disorders

2020 ◽  
Vol 40 (12) ◽  
Author(s):  
Peifang Jiang ◽  
Yinjie Ling ◽  
Tao Zhu ◽  
Xiaoying Luo ◽  
Yilin Tao ◽  
...  
Keyword(s):  
Mutational Analysis ◽  
Phenotypic Variability ◽  
Han Chinese ◽  
Tic Disorders ◽  
Trna Genes ◽  
Incomplete Penetrance ◽  
Mitochondrial Trna ◽  
Pathogenic Potential ◽  
Total Prevalence ◽  
Chinese Subjects

Abstract Aim: To conduct the clinical, genetic, and molecular characterization of 494 Han Chinese subjects with tic disorders (TD). Methods: In the present study, we performed the mutational analysis of 22 mitochondrial tRNA genes in a large cohort of 494 Han Chinese subjects with TD via Sanger sequencing. These variants were then assessed for their pathogenic potential via phylogenetic, functional, and structural analyses. Results: A total of 73 tRNA gene variants (49 known and 24 novel) on 22 tRNA genes were identified. Among these, 18 tRNA variants that were absent or present in <1% of 485 Chinese control patient samples were localized to highly conserved nucleotides, or changed the modified nucleotides, and had the potential structural to alter tRNA structure and function. These variants were thus considered to be TD-associated mutations. In total, 25 subjects carried one of these 18 putative TD-associated tRNA variants with the total prevalence of 4.96%. Limitations: The phenotypic variability and incomplete penetrance of tic disorders in pedigrees carrying these tRNA mutations suggested the involvement of modifier factors, such as nuclear encoded genes associated mitochondrion, mitochondrial haplotypes, epigenetic, and environmental factors. Conclusion: Our data provide the evidence that mitochondrial tRNA mutations are the important causes of tic disorders among Chinese population. These findings also advance current understanding regarding the clinical relevance of tRNA mutations, and will guide future studies aimed at elucidating the pathophysiology of maternal tic disorders.

Neonatal Screening for Cystic Fibrosis: Position Paper

PEDIATRICS ◽  
1983 ◽  
Vol 72 (5) ◽  
pp. 741-745 ◽  
Author(s):  
◽  
Lynn M. Taussig ◽  
Thomas F. Boat ◽  
Delbert Dayton ◽  
Norman Fost ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Newborn Screening ◽  
Neonatal Screening ◽  
Task Force ◽  
Genetic Disorder ◽  
Clinical Manifestations ◽  
Screening Tests ◽  
Current Status ◽  
Screening Methods ◽  
Asymptomatic Patients

Neonatal screening represents the search for a disorder in a general newborn population. The purpose of screening may be to improve the health of the affected infant, to provide counseling, or for research. Screening tests have been widely accepted for conditions such as phenylketonuria, hypothyroidism, and other metabolic conditions. Cystic fibrosis (CF) is the most common lethal genetic disorder among the white population (with a lower incidence among blacks), and thus there has been interest in screening newborns for CF1 However, proposals emanating from this interest have remained controversial.2-4 The recent development of a relatively simple test—the dried blood immuno-reactive trypsinogen (IRT) assay—has increased this interest.5-12 Besides considering technical reliability and validity of newborn screening methods, it is crucial that all other aspects of screening (including medical, ethical, psychosocial, and economic aspects) be rigorously examined before implementing mass screening.13-15 To address these issues the Cystic Fibrosis Foundation convened a Task Force on Neonatal Screening. Although the Task Force considered the current status of the IRT test, it focused on the generally accepted criteria for newborn screening, summarized in the Table,14 and the relationship of these criteria to the present state of knowledge related to CF. The issues identified by the Task Force, are summarized in this paper, and recommendations are presented at the conclusion. EFFECTIVENESS OF PRESYMPTOMATIC TREATMENT Evidence suggesting that the initiation of treatment before clinical manifestations of CF first appear improves prognosis has been controversial. Whereas some studies have yielded supportive data,16 others have not.4 There are no generally accepted treatment protocols for use in symptomatic or asymptomatic patients.

scholarly journals Case report: targeted whole exome sequencing enables the first prenatal diagnosis of the lethal skeletal dysplasia Osteocraniostenosis

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Lara Pemberton ◽  
Robert Barker ◽  
Anna Cockell ◽  
Vijaya Ramachandran ◽  
Andrea Haworth ◽  
...  
Keyword(s):  
Case Report ◽  
Prenatal Diagnosis ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Skeletal Dysplasia ◽  
Genetic Disorder ◽  
Specific Gene ◽  
Ultrasound Images ◽  
Whole Exome ◽  
Lethal Skeletal Dysplasia

Abstract Background Osteocraniostenosis (OCS) is a rare genetic disorder characterised by premature closure of cranial sutures, gracile bones and perinatal lethality. Previously, diagnosis has only been possible postnatally on clinical and radiological features. This study describes the first prenatal diagnosis of OCS. Case presentation In this case prenatal ultrasound images were suggestive of a serious but non-lethal skeletal dysplasia. Due to the uncertain prognosis the parents were offered Whole Exome Sequencing (WES), which identified a specific gene mutation in the FAMIIIa gene. This mutation had previously been detected in two cases and was lethal in both perinatally. This established the diagnosis, a clear prognosis and allowed informed parental choice regarding ongoing pregnancy management. Conclusions This case report supports the use of targeted WES prenatally to confirm the underlying cause and prognosis of sonographically suspected abnormalities.

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