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Ophthalmic Genetics Apr 2022To investigate the penetrance of gene mutation in primary open-angle glaucoma (POAG) through systematic review and meta-analysis. To explore the factors affecting the... (Meta-Analysis)
Meta-Analysis
PURPOSE
To investigate the penetrance of gene mutation in primary open-angle glaucoma (POAG) through systematic review and meta-analysis. To explore the factors affecting the penetrance of and provide evidence-based medical evidence for clinical work.
METHODS
We searched all studies that reported the penetrance of mutation in PubMed, Embase, Web of Science, and Chinese databases including Wanfang, CNKI (China National Knowledge Infrastructure), and CBM (China Bio-Med). Random effects meta-analysis was conducted to estimate the penetrance of mutation in POAG.
RESULTS
Fifty-two studies were included in this analysis after screening. Meta-analysis of the penetrance of mutation showed that the penetrance of mutation in POAG was 60% (95% CI: 51.0% to 68.0%) and the penetrance of mutation in POAG and suspected POAG was 68% (95% CI: 60.0% to 75.0%). The penetrance of mutation increases with age. Among Caucasians, Asians, and Africans, the penetrance of mutation in POAG was 55%, 71%, 54%, respectively, and the penetrance of mutation in POAG and suspected POAG was 64%, 83%, and 57%, respectively. Besides, the penetrance of different mutation sites was significantly discrepant. The penetrance of mutation in POAG ranged from 10.3% to 100% depending on the mutation sites. Some mutation sites have a certain population specificity, which is only pathogenic in Caucasians or Asians.
CONCLUSIONS
The penetrance of mutation in POAG showed significant differences due to different mutation sites. The penetrance increased with the accrescent of age. Ethnic difference was an important factor affecting the penetrance of mutation. Knowing the rules and influencing factors of the penetrance of mutations is significant for the assessment of the risk of POAG in carriers with the mutation.
Topics: Cytoskeletal Proteins; DNA Mutational Analysis; Eye Proteins; Glaucoma, Open-Angle; Glycoproteins; Humans; Mutation; Penetrance
PubMed: 35014583
DOI: 10.1080/13816810.2021.2021427 -
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 -
European Journal of Endocrinology Dec 2021CYP24A1 encodes a 24-hydroxylase involved in vitamin D catabolism, whose loss-of-function results in vitamin D-dependent hypercalcemia. Since the identification of...
BACKGROUND AND OBJECTIVES
CYP24A1 encodes a 24-hydroxylase involved in vitamin D catabolism, whose loss-of-function results in vitamin D-dependent hypercalcemia. Since the identification of CYP24A1 variants as a cause of idiopathic infantile hypercalcemia, a large body of literature has emerged indicating heterogeneity in penetrance, symptoms, biochemistry, and treatments. The objectives of the present research work were to investigate the clinical heterogeneity of the disease, the possibility of a relevant phenotype for monoallelic carriers, and to compare the hypocalcemic effect of the available therapies.
METHODS
Two reviewers searched different databases for studies published between the identification of CYP24A1 variants and December 31, 2020. Eligible studies included clinical trials and reports describing carriers of CYP24A1 variants.
RESULTS
Fifty eligible studies were identified, accounting for 221 patients. Genetic data were retrieved and allele frequencies were calculated. Acute hypercalcemia was the typical presentation during the first year of life (76%, P = 0.0005), and nephrocalcinosis was more frequent in infancy (P < 0.0001). Pregnancy was associated with symptomatic hypercalcemia in 81.8% and high rates of obstetric complications. Monoallelic carriers displayed significant rates of nephrolithiasis (19.4%), nephrocalcinosis (4.9%), and symptomatic hypercalcemia (5.6%).
CONCLUSIONS
CYP24A1 loss-of-function results in an age-dependent phenotype, which can be exacerbated by triggering factors, such as pregnancy. Although biallelic carriers present more significant clinical and biochemical features, monoallelic carriers have an increased risk of calcium-related conditions. The highly variable tested therapeutic approaches did not allow to draw conclusions on preferable therapeutic regime.
Topics: Female; Genetic Variation; Heterozygote; Humans; Hypercalcemia; Mutation; Pregnancy; Pregnancy Complications; Vitamin D3 24-Hydroxylase
PubMed: 34735369
DOI: 10.1530/EJE-21-0713 -
Breast Cancer Research and Treatment Jan 2022Several male breast cancer (MBC) susceptibility genes have been identified, but the MBC risk for individuals with a pathogenic variant in each of these genes (i.e.,... (Review)
Review
PURPOSE
Several male breast cancer (MBC) susceptibility genes have been identified, but the MBC risk for individuals with a pathogenic variant in each of these genes (i.e., penetrance) remains unclear. We conducted a systematic review of studies reporting the penetrance of MBC susceptibility genes to better summarize current estimates of penetrance.
METHODS
A search query was developed to identify MBC-related papers indexed in PubMed/MEDLINE. A validated natural language processing method was applied to identify papers reporting penetrance estimates. These penetrance studies' bibliographies were reviewed to ensure comprehensiveness. We accessed the potential ascertainment bias for each enrolled study.
RESULTS
Fifteen penetrance studies were identified from 12,182 abstracts, covering five purported MBC susceptibility genes: ATM, BRCA1, BRCA2, CHEK2, and PALB2. Cohort (n = 6, 40%) and case-control (n = 5, 33%) studies were the two most common study designs, followed by family-based (n = 3, 20%), and a kin-cohort study (n = 1, 7%). Seven of the 15 studies (47%) adjusted for ascertainment adequately and therefore the MBC risks reported by these seven studies can be considered applicable to the general population. Based on these seven studies, we found pathogenic variants in ATM, BRCA2, CHEK2 c.1100delC, and PALB2 show an increased risk for MBC. The association between BRCA1 and MBC was not statistically significant.
CONCLUSION
This work supports the conclusion that pathogenic variants in ATM, BRCA2, CHEK2 c.1100delC, and PALB2 increase the risk of MBC, whereas pathogenic variants in BRCA1 may not be associated with increased MBC risk.
Topics: Ataxia Telangiectasia Mutated Proteins; Breast Neoplasms, Male; Checkpoint Kinase 2; Cohort Studies; Fanconi Anemia Complementation Group N Protein; Genes, BRCA2; Genetic Predisposition to Disease; Humans; Male; Penetrance
PubMed: 34642874
DOI: 10.1007/s10549-021-06413-2 -
Laboratory Medicine Mar 2022The advent of next generation sequencing has revolutionized diagnostic approaches to hereditary polyneuropathies. Recently, mutations on the membrane...
The advent of next generation sequencing has revolutionized diagnostic approaches to hereditary polyneuropathies. Recently, mutations on the membrane metallo-endopeptidase (MME) gene, encoding neprilysin, have been related to the development of late-onset Charcot-Marie-Tooth disease type 2 (CMT2). Here, we report the first Greek patient presenting with a slowly progressive late-onset axonal polyneuropathy and a novel, likely pathogenic, heterozygous variant in the MME gene. In addition, we have performed a systematic review of all published case reports of patients with MME mutations. The results of the studies show that MME variants can be inherited as both fully penetrant autosomal-recessive and incompletely penetrant autosomal-dominant traits. A number of heterozygous variants characterized as incompletely penetrant impose an increased risk of developing a CMT2-like phenotype late in life, identical to the case study described here. Greater mutation numbers in different populations and mutation-specific functional studies will be essential to identify the pathogenicity and inheritance of more MME variants.
Topics: Charcot-Marie-Tooth Disease; Humans; Mutation; Neprilysin; Phenotype; Polyneuropathies
PubMed: 34480178
DOI: 10.1093/labmed/lmab060 -
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 -
Expert Review of Clinical Immunology Aug 2021: Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a rare inborn immune error characterized by a triad of chronic mucocutaneous candidiasis...
: Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a rare inborn immune error characterized by a triad of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism (HP), and adrenal insufficiency (ADI).: Literature search was conducted in PubMed, Web of Science, and Scopus databases using related keywords, and included studies were systematically evaluated.: We reviewed 938 APECED patients and the classic triad of APECED was detected in 57.3% (460 of 803) of patients. CMC (82.5%) was reported as the earliest, HP (84.2%) as the most prevalent, and ADI (72.2%) as the latest presentation within the classic triad. A broad spectrum of non-triad involvements has also been reported; mainly included ectodermal dystrophy (64.5%), infections (58.7%), gastrointestinal disorders (52.0%), gonadal failure (42.0%), neurologic involvements (36.4%), and ocular manifestations (34.3%). A significant positive correlation was detected between certain tissue-specific autoantibodies and particular manifestations including ADI and HP. Neutralizing autoantibodies were detected in at least 60.0% of patients. Nonsense and/or frameshift insertion-deletion mutations were detected in 73.8% of patients with CMC, 70.9% of patients with HP, and 74.6% of patients with primary ADI.: Besides penetrance diversity, our review revealed a diverse affected ethnicity (mainly from Italy followed by Finland and Ireland). APECED can initially present in adolescence as 5.2% of the patients were older than 18 years at the disease onset. According to the variety of clinical conditions, which in the majority of patients appear gradually over time, clinical management deserves a separate analysis.
Topics: Adolescent; Autoantibodies; Frameshift Mutation; Humans; Mutation; Polyendocrinopathies, Autoimmune; Transcription Factors
PubMed: 33957837
DOI: 10.1080/1744666X.2021.1925543 -
Journal of Clinical Neuroscience :... Apr 2021Acute brain injury is a leading cause of morbidity and mortality worldwide. The term is inclusive of traumatic brain injury, cerebral ischemia, subarachnoid hemorrhage,...
Acute brain injury is a leading cause of morbidity and mortality worldwide. The term is inclusive of traumatic brain injury, cerebral ischemia, subarachnoid hemorrhage, and intracerebral hemorrhage. Current pharmacologic treatments have had minimal effect on improving neurological outcomes leading to a significant interest in the development neuroprotective agents. Minocycline is a second-generation tetracycline with high blood brain barrier penetrance due to its lipophilic properties. It functions across multiple molecular pathways involved in secondary-injury cascades following acute brain injury. Animal model studies suggest that minocycline might lead to improved neurologic outcomes, but few such trials exist in humans. Clinical investigations have been limited to small randomized trials in ischemic stroke patients which have not demonstrated a clear advantage in neurologic outcomes, but also have not been sufficiently powered to draw definitive conclusions. The potential neuroprotective effect of minocycline in the setting of traumatic brain injury, subarachnoid hemorrhage, and intracerebral hemorrhage have all been limited to pilot studies with phase II/III investigations pending. The authors aim to synthesize what is currently known about minocycline as a neuroprotective agent against acute brain injury in humans.
Topics: Animals; Brain Injuries; Humans; Minocycline; Neuroprotective Agents
PubMed: 33775346
DOI: 10.1016/j.jocn.2021.01.005 -
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