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Heart (British Cardiac Society) Jun 2022Bicuspid aortic valve (BAV) affects 1% of the general population. was the first gene associated with BAV. The proportion of familial and sporadic BAV disease attributed...
INTRODUCTION
Bicuspid aortic valve (BAV) affects 1% of the general population. was the first gene associated with BAV. The proportion of familial and sporadic BAV disease attributed to mutations has not been estimated.
AIM
The aim of our study was to provide an estimate of familial and sporadic BAV disease attributable to mutations.
METHODS
The population of our study consisted of participants of the University of Leicester Bicuspid aoRtic vAlVe gEnetic research-8 pedigrees with multiple affected family members and 381 sporadic patients. All subjects underwent sequencing. A systematic literature search was performed in the NCBI PubMed database to identify publications reporting sequencing in context of congenital heart disease.
RESULTS
sequencing in 36 subjects from 8 pedigrees identified one variant c.873C>G/p.Tyr291* meeting the American College of Medical Genetics and Genomics criteria for pathogenicity. No pathogenic or likely pathogenic variants were identified in 381 sporadic patients. Literature review identified 64 relevant publication reporting sequencing in 528 pedigrees and 9449 sporadic subjects. After excluding families with syndromic disease pathogenic and likely pathogenic variants were detected in 9/435 (2.1%; 95% CI: 0.7% to 3.4%) of pedigrees and between 0.05% (95% CI: 0.005% to 0.10%) and 0.08% (95% CI: 0.02% to 0.13%) of sporadic patients. Incomplete penetrance of definitely pathogenic mutations was observed in almost half of reported pedigrees.
CONCLUSIONS
Pathogenic and likely pathogenic genetic variants explain 2% of familial and <0.1% of sporadic BAV disease and are more likely to associate with tetralogy of Fallot and hypoplastic left heart.
Topics: Aortic Valve; Bicuspid Aortic Valve Disease; Heart Valve Diseases; Humans; Mutation; Pedigree; Receptor, Notch1
PubMed: 35288444
DOI: 10.1136/heartjnl-2021-320428 -
Journal of Community Genetics Feb 2022Preimplantation genetic testing (PGT) involves testing embryos created through in vitro fertilization for the presence of hereditary genetic disorders and chromosome... (Review)
Review
Preimplantation genetic testing (PGT) involves testing embryos created through in vitro fertilization for the presence of hereditary genetic disorders and chromosome abnormalities. PGT for monogenic conditions (PGT-M) is generally performed for childhood-onset, lethal disorders, but is increasingly accepted for certain adult-onset conditions, conditions with available treatment options or conditions with lower penetrance. Furthermore, the development of PGT for polygenic conditions (PGT-P) makes ethical questions regarding PGT indications imperative. A systematic review was therefore performed to gather and analyse studies on the perspectives of healthcare professionals on the appropriate scope of PGT, with the aim of getting insights into the concerns about the scope of PGT now and in the near future. PRISMA guidelines were followed. Twelve qualitative articles were included. The main themes extracted were the scope of PGT and decision-making about PGT. Defining 'a serious genetic condition' was seen as complex, but severity, high penetrance and absence of treatability and patients' experience were seen as relevant indications to determine the appropriateness of PGT. In navigating the decision-making processes with patients, professionals experienced friction between setting limits and respecting patients' autonomy. Such friction and ethical dilemmas around seriousness, informed decision-making and preventative medicine show that while expanding the list of possible PGT indications and the development of PGT-P could augment patients' reproductive autonomy, it could also lead to an increased reproductive 'burden' for patients. These insights are crucial for establishing guidelines that help healthcare professionals navigate ethical tensions associated with PGT.
PubMed: 35028914
DOI: 10.1007/s12687-021-00573-w -
European Journal of Medical Genetics Feb 2022The 22q11 region is prone to generating recurring Copy Number Variations (CNVs) as a result of the large numbers of Low Copy Repeats (LCRs). Typical duplications... (Review)
Review
The 22q11 region is prone to generating recurring Copy Number Variations (CNVs) as a result of the large numbers of Low Copy Repeats (LCRs). Typical duplications encompass the LCR-A-to-D region but atypical duplications of various sizes have also been reported. These duplications are responsible for highly variable phenotypes with incomplete penetrance and expressivity, which is challenging for adequate genetic counselling, especially in the prenatal period. To better delineate prenatal phenotypes associated with these CNVs, we report here a clinical and molecular description of twelve cases (9 foetuses and 3 deceased new-borns babies) carrying recurrent 22q11 duplications (diagnosed via aCGH), along with a review of the existing literature. 22q11 duplications were inherited from an apparently healthy parent in almost 60% of the cases. Other CNVs were diagnosed for 8% of the cases. Increased nuchal translucency and cardiac anomalies (CHD) were the most prominent phenotypes observed, along with mild renal and skeletal anomalies. Duplications encompassing the LCR-C-to-D region (and the CRKL gene) seemed more likely to generate CHDs and renal malformations. Cleft lip/palate were observed in foetuses with duplications encompassing the LCR-A-to-B region or the SPECC1L gene, as previously suggested. However, genotype-phenotype correlations remain difficult to ascertain. Second-hit point variants, epigenetic or environmental variations could play a role in the phenotypic variability of 22q11 duplications, but remain a challenge for assessment in the short period of pregnancy.
Topics: Abnormalities, Multiple; Adaptor Proteins, Signal Transducing; Chromosome Duplication; Chromosomes, Human, Pair 22; DiGeorge Syndrome; Female; Fetus; Humans; Infant, Newborn; Male; Phenotype; Phosphoproteins
PubMed: 35026468
DOI: 10.1016/j.ejmg.2022.104422 -
Frontiers in Pediatrics 2021Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by fibrofatty infiltration of predominantly the right ventricular...
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by fibrofatty infiltration of predominantly the right ventricular (RV) myocardium. Affected patients typically present as young adults with hemodynamically stable ventricular tachycardia, although pediatric cases are increasingly recognized. These young subjects often have a more severe phenotype with a high risk of sudden cardiac death (SCD) and progression toward heart failure. Diagnosis of ARVC is made by combining multiple sources of information as prescribed by the consensus-based Task Force Criteria. The description of Naxos disease, a fully penetrant autosomal recessive disorder that is associated with ARVC and a cutaneous phenotype of palmoplantar keratoderma and wooly hair facilitated the identification of the genetic cause of ARVC. At present, approximately 60% of patients are found to carry a pathogenic variant in one of five genes associated with the cardiac desmosome. The incomplete penetrance and variable expressivity of these variants however implies an important role for environmental factors, of which participation in endurance exercise is a strong risk factor. Since there currently is no definite cure for ARVC, disease management is directed toward symptom reduction, delay of disease progression, and prevention of SCD. This clinically focused review describes the spectrum of ARVC among children and adolescents, the genetic architecture underlying this disease, the cardio-cutaneous syndromes that led to its identification, and current diagnostic and therapeutic strategies in pediatric ARVC subjects.
PubMed: 34926342
DOI: 10.3389/fped.2021.750916 -
Circulation. Genomic and Precision... Oct 2021The p.Val142Ile variant, predominantly found among people of African descent, is the most common cause of variant transthyretin amyloidosis and carriers predominantly...
BACKGROUND
The p.Val142Ile variant, predominantly found among people of African descent, is the most common cause of variant transthyretin amyloidosis and carriers predominantly develop a cardiomyopathy (variant transthyretin amyloidosis cardiomyopathy) phenotype. Yet, there are conflicting data on the prevalence and outcomes of p.Val142Ile variant carriers.
METHODS
We performed a systematic review of the prevalence and outcomes of p.Val142Ile variant transthyretin amyloidosis cardiomyopathy among subjects of African descent. We found 62 relevant articles after searching the MEDLINE databases from 1980 to 2020 that reported data for ≈150 000 subjects.
RESULTS
The reported worldwide prevalence of the p.Val142Ile variant is 0.3% to 1.6% in the general population. Among people of African descent, the reported prevalence from all studies ranges from 1.1% to 9.8%, but for studies with >1000 subjects, it is 3% to 3.5%. The prevalence of the p.Val142Ile variant in a region is dependent on the reported percentage of subjects who are of African descent in that region. p.Val142Ile variant transthyretin amyloidosis cardiomyopathy typically presents in the seventh to eighth decade of life and the majority of cases reported were male, with 25% to 38% diagnosed with atrial fibrillation. It was associated with a longitudinally worse quality of life and a lower adjusted survival compared with other types of transthyretin amyloidosis cardiomyopathy.
CONCLUSIONS
The p.Val142Ile variant is the most common variant of the transthyretin gene with most carriers being of African descent. The true penetrance is unknown but the p.Val142Ile variant is associated with increased rates of incident heart failure and portends a lower overall survival. Increased awareness could lead to earlier diagnosis and improved heart failure outcomes among those of African descent, which is of increasing importance given the advent of novel therapeutics for this disease.
Topics: Amino Acid Substitution; Amyloid Neuropathies, Familial; Cardiomyopathies; Female; Humans; Male; Mutation, Missense; Prealbumin; Prevalence; Risk Factors; Sex Factors
PubMed: 34461737
DOI: 10.1161/CIRCGEN.121.003356 -
European Journal of Human Genetics :... Nov 2021Individuals with Birt-Hogg-Dubé syndrome (BHDS) may develop fibrofolliculomas, pneumothorax and/or renal cell carcinoma (RCC). Currently, all patients with pathogenic...
Individuals with Birt-Hogg-Dubé syndrome (BHDS) may develop fibrofolliculomas, pneumothorax and/or renal cell carcinoma (RCC). Currently, all patients with pathogenic FLCN variants are recommended to have renal surveillance. It has however been suggested that some FLCN variants only cause pneumothorax, which would make surveillance unnecessary in certain cases. This review assesses this possibility. We provide an up-to-date analysis of clinical and genetic features of BHDS. The PUBMED database was systematically searched to find all articles describing patients with pathogenic FLCN variants. The relevant clinical and genetic features of these patients were recorded and analysed. The prevalence of pneumothorax, pulmonary cysts, RCC and characteristic skin lesions in BHDS were 50.9% (n = 1038), 91.9% (n = 720), 22.5% (n = 929) and 47.9% (n = 989), respectively. There was a higher prevalence of pneumothoraces (p < 0.0001) but lower prevalence of dermatological findings (p < 0.0001) in patients from East Asia compared to North America or Europe. Of the 194 pathogenic FLCN variants, 76 could be defined as 'pneumothorax-only'. Pneumothorax only pathogenic variants (POPVs) were distributed throughout the gene, and there were no statistical differences in variant type. The majority of POPVs (65/76) affected no more than three individuals. Individuals with 'POPVs' also tended to be younger (45 vs. 47 years, p < 0.05). Many apparent POPVs in the literature could result from variable expressivity, age-related penetrance and other confounding factors. We therefore recommend that all individuals found to carry a pathogenic FLCN variant be enroled in lifelong surveillance for RCC.
Topics: Birt-Hogg-Dube Syndrome; Humans; Kidney Neoplasms; Mutation; Phenotype; Pneumothorax; Proto-Oncogene Proteins; Tumor Suppressor Proteins
PubMed: 34267338
DOI: 10.1038/s41431-021-00921-x -
Dermatology (Basel, Switzerland) 2021Increasing availability of panel testing for known high-penetrance familial melanoma genes has made it possible to improve risk awareness in those at greatest risk....
BACKGROUND
Increasing availability of panel testing for known high-penetrance familial melanoma genes has made it possible to improve risk awareness in those at greatest risk. Prior to wider implementation, the role of genetic testing in preventing melanoma, through influencing primary and secondary preventative behaviours, requires clarification.
METHODS
Database searches of PubMed, Embase, CINAHL, PsycINFO and the Cochrane Library were conducted for studies describing preventative behaviour outcomes in response to genetic testing for melanoma risk. Publications describing original research of any study type were screened for eligibility.
RESULTS
Eighteen publications describing 11 unique studies were reviewed. Outcomes assessed are based on health behaviour recommendations for those at increased risk: adherence to sun-protective behaviour (SPB); clinical skin examinations (CSE); skin self-examinations (SSE); and family discussion of risk. Overall, modest increases in adherence to primary prevention strategies of SPB were observed following genetic testing. Importantly, there were no net decreases in SPB found amongst non-carriers. For secondary preventative behaviour outcomes, including CSE and SSE, increases in post-test intentions and long-term adherence were reported across several subgroups in approximately half of the studies. While this increase reached significance in mutation carriers in some studies, one study reported a significant decline in annual CSE adherence of non-mutation carriers.
CONCLUSIONS
Evidence reviewed suggests that genetic testing has a modestly positive impact on preventative behaviour in high-risk individuals. Furthermore, improvements are observed regardless of mutation carrier status, although greater adherence is found in carriers. While additional studies of more diverse cohorts would be needed to inform clinical recommendations, the findings are encouraging and suggest that genetic testing for melanoma has a positive impact on preventative behaviours.
Topics: Genetic Testing; Health Behavior; Humans; Melanoma; Patient Compliance; Primary Prevention; Secondary Prevention; Self-Examination; Skin Neoplasms; Melanoma, Cutaneous Malignant
PubMed: 33588421
DOI: 10.1159/000513919 -
Journal of Neurochemistry Mar 2021The liver-derived, circulating transport protein transthyretin (TTR) is the cause of systemic hereditary (ATTRv) and wild-type (ATTRwt) amyloidosis. TTR stabilization...
The liver-derived, circulating transport protein transthyretin (TTR) is the cause of systemic hereditary (ATTRv) and wild-type (ATTRwt) amyloidosis. TTR stabilization and knockdown are approved therapies to mitigate the otherwise lethal disease course. To date, the variety in phenotypic penetrance is not fully understood. This systematic review summarizes the current literature on TTR pathophysiology with its therapeutic implications. Tetramer dissociation is the rate-limiting step of amyloidogenesis. Besides destabilizing TTR mutations, other genetic (RBP4, APCS, AR, ATX2, C1q, C3) and external (extracellular matrix, Schwann cell interaction) factors influence the type of onset and organ tropism. The approved small molecule tafamidis stabilizes the tetramer and significantly decelerates the clinical course. By sequence-specific mRNA knockdown, the approved small interfering RNA (siRNA) patisiran and antisense oligonucleotide (ASO) inotersen both significantly reduce plasma TTR levels and improve neuropathy and quality of life compared to placebo. With enhanced hepatic targeting capabilities, GalNac-conjugated siRNA and ASOs have recently entered phase III clinical trials. Bivalent TTR stabilizers occupy both binding groves in vitro, but have not been tested in trials so far. Tolcapone is another stabilizer with the potential to cross the blood-brain barrier, but its half-life is short and liver failure a potential side effect. Amyloid-directed antibodies and substances like doxycycline aim at reducing the amyloid load, however, none of the yet developed antibodies has successfully passed clinical trials. ATTR-amyloidosis has become a model disease for pathophysiology-based treatment. Further understanding of disease mechanisms will help to overcome the remaining limitations, including application burden, side effects, and blood-brain barrier permeability.
Topics: Amyloid; Amyloidosis, Familial; Animals; Gene Knockdown Techniques; Humans; Prealbumin
PubMed: 33155274
DOI: 10.1111/jnc.15233 -
European Respiratory Review : An... Sep 2020The percentage of α-antitrypsin protease inhibitor ZZ (PiZZ) genotypes in patients with COPD is controversial, with large differences among various studies. We aimed to...
The percentage of α-antitrypsin protease inhibitor ZZ (PiZZ) genotypes in patients with COPD is controversial, with large differences among various studies. We aimed to estimate the prevalence of PiZZ in COPD patients from 20 European countries with available data, according to the number of PiZZ and COPD individuals in each country.A systematic review was conducted to select European countries with reliable data on the prevalence of PiZZ and COPD. We created a database with the following data: 1) total population and population aged ≥40 years according to the Eurostat database; 2) number and 95% CI of PiZZ patients aged ≥40 years; 3) application of a conversion factor of genetic penetrance of 60%; 4) number of COPD individuals, with 95% CI, aged ≥40 years; and 5) calculation of the PiZZ/COPD ratio. Finally, results were presented using an Inverse Distance Weighted Interpolation map.We found 36 298 (95% CI 23 643-56 594) PiZZ individuals at high risk and 30 849 709 (95% CI 21 411 293-40 344 496) COPD patients, with a PiZZ/COPD ratio of 0.12% (range 0.08-0.24%), and a prevalence of 1 out of 408 in Northern, 1 out of 944 in Western, 1 out of 1051 in Central, 1 out of 711 in Southern, and 1 out of 1274 in Eastern Europe.These data may be useful to plan strategies for future research and diagnosis, and to rationalise the available therapeutic resources.
Topics: Europe; Genotype; Humans; Prevalence; Pulmonary Disease, Chronic Obstructive; alpha 1-Antitrypsin Deficiency
PubMed: 32699024
DOI: 10.1183/16000617.0014-2020 -
European Journal of Human Genetics :... May 2020Family-based penetrance is frequently cited as a major challenge for translating penetrance estimates from familial populations to asymptomatic populations. A systematic...
Family-based penetrance is frequently cited as a major challenge for translating penetrance estimates from familial populations to asymptomatic populations. A systematic review was performed to assess the literature evidencing penetrance estimates in patients without a family history of disease, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework. Initially 1592 papers were identified, which were filtered to a final nine, through application of inclusion and exclusion criteria. Fundamental differences in the identified papers prevented combination of papers using meta-analysis, so thematic analysis to produce a narrative synthesis was performed. Key themes included disease risk modifiers, evidence, study limitations and bias. A methodological appraisal too was used to assess quality of included studies. It is evident from the findings that the evidence base for penetrance estimates in individuals without a family history of disease is limited. Future work is needed to refine design of penetrance studies and the impact of incorrect estimates.
Topics: Genetic Diseases, Inborn; Genetic Testing; Humans; Medical History Taking; Pedigree; Penetrance
PubMed: 31937893
DOI: 10.1038/s41431-019-0556-5