Primary immunodeficiency diseases(PIDs)refer to a heterogenous group of disorders characterized clinically by increased susceptibility to infections,autoimmunity and increased risk of malignancies.These group of disor...Primary immunodeficiency diseases(PIDs)refer to a heterogenous group of disorders characterized clinically by increased susceptibility to infections,autoimmunity and increased risk of malignancies.These group of disorders present with clinical manifestations similar to PIDs with known genetic defects but have either no genetic defect or have a somatic mutation and thus have been labelled as“Phenocopies of PIDs”.These diseases have been further subdivided into those associated with somatic mutations and those associated with presence of auto-antibodies against various cytokines.In this review,we provide an update on clinical manifestations,diagnosis and management of these diseases.展开更多
Brugada phenocopies(BrP) are clinical entities that are etiologically distinct from true congenital Brugada syndrome. BrP are characterized by type 1 or type 2 Brugada electrocardiogram(ECG) patterns in precordial lea...Brugada phenocopies(BrP) are clinical entities that are etiologically distinct from true congenital Brugada syndrome. BrP are characterized by type 1 or type 2 Brugada electrocardiogram(ECG) patterns in precordial leads V1-V3. However, BrP are elicited by various un-derlying clinical conditions such as myocardial ischemia, pulmonary embolism, electrolyte abnormalities, or poor ECG filters. Upon resolution of the inciting underlying pathological condition, the BrP ECG subsequently nor-malizes. To date, reports have documented BrP in the context of singular clinical events. More recently, recur-rent BrP has been demonstrated in the context of re-current hypokalemia. This demonstrates clinical repro-ducibility, thereby advancing the concept of this new ECG phenomenon. The key to further understanding the pathophysiological mechanisms behind BrP requires experimental model validation in which these phenom-ena are reproduced under strictly controlled environ-mental conditions. The development of these validation models will help us determine whether BrP are tran-sient alterations of sodium channels that are not repro-ducible with a sodium channel provocative test or al-ternatively, a malfunction of other ion channels. In this editorial, we discuss the conceptual emergence of BrP as a new ECG phenomenon, review the progress made to date and identify opportunities for further investiga-tion. In addition, we also encourage investigators that are currently reporting on these cases to use the term BrP in order to facilitate literature searches and to help establish this emerging concept.展开更多
Objectives To formulate an equation for fine mapping of disease loci under complex conditions and determine the marker-disease distance in a specific case using this equation. Methods Lewontin’s linkage disequi...Objectives To formulate an equation for fine mapping of disease loci under complex conditions and determine the marker-disease distance in a specific case using this equation. Methods Lewontin’s linkage disequilibrium (LD) measure D’ was used to formulate an equation for mapping disease genes in the presence of phenocopies, locus heterogeneity, gene-gene and gene-environment interactions, incomplete penetrance, uncertain liability and threshold, incomplete initial LD, natural selection, recurrent mutation, high disease allele frequency and unknown mode of inheritance. This equation was then used to determine the distance between a marker (ε4 within the apolipoprotein E gene, APOE) and Alzheimer’s disease (AD) loci using published data.Results An equation was formulated for mapping disease genes under the above conditions. If these conditions are present but ignored, then recombination fraction θ between marker and disease loci will be either overestimated or estimated with little bias. Therefore, an upper limit of θ can be obtained. AD has been found to be associated with the marker allele ε4 in Africans, Asians, and Caucasians. This suggests that the AD-ε4 allelic LD predates the divergence of peoples occurring 100?000 years ago. With the age of AD-ε4 allelic LD so estimated, the maximal distance was calculated to be 23.2 kb (mean 5.8 kb). Conclusions (1) A method is developed for LD mapping of susceptibility genes. (2) A mutation within the APOE gene itself, among others, is responsible for the susceptibility to AD, which is supported by recent evidence from studies using transgenic mice.展开更多
文摘Primary immunodeficiency diseases(PIDs)refer to a heterogenous group of disorders characterized clinically by increased susceptibility to infections,autoimmunity and increased risk of malignancies.These group of disorders present with clinical manifestations similar to PIDs with known genetic defects but have either no genetic defect or have a somatic mutation and thus have been labelled as“Phenocopies of PIDs”.These diseases have been further subdivided into those associated with somatic mutations and those associated with presence of auto-antibodies against various cytokines.In this review,we provide an update on clinical manifestations,diagnosis and management of these diseases.
文摘Brugada phenocopies(BrP) are clinical entities that are etiologically distinct from true congenital Brugada syndrome. BrP are characterized by type 1 or type 2 Brugada electrocardiogram(ECG) patterns in precordial leads V1-V3. However, BrP are elicited by various un-derlying clinical conditions such as myocardial ischemia, pulmonary embolism, electrolyte abnormalities, or poor ECG filters. Upon resolution of the inciting underlying pathological condition, the BrP ECG subsequently nor-malizes. To date, reports have documented BrP in the context of singular clinical events. More recently, recur-rent BrP has been demonstrated in the context of re-current hypokalemia. This demonstrates clinical repro-ducibility, thereby advancing the concept of this new ECG phenomenon. The key to further understanding the pathophysiological mechanisms behind BrP requires experimental model validation in which these phenom-ena are reproduced under strictly controlled environ-mental conditions. The development of these validation models will help us determine whether BrP are tran-sient alterations of sodium channels that are not repro-ducible with a sodium channel provocative test or al-ternatively, a malfunction of other ion channels. In this editorial, we discuss the conceptual emergence of BrP as a new ECG phenomenon, review the progress made to date and identify opportunities for further investiga-tion. In addition, we also encourage investigators that are currently reporting on these cases to use the term BrP in order to facilitate literature searches and to help establish this emerging concept.
文摘Objectives To formulate an equation for fine mapping of disease loci under complex conditions and determine the marker-disease distance in a specific case using this equation. Methods Lewontin’s linkage disequilibrium (LD) measure D’ was used to formulate an equation for mapping disease genes in the presence of phenocopies, locus heterogeneity, gene-gene and gene-environment interactions, incomplete penetrance, uncertain liability and threshold, incomplete initial LD, natural selection, recurrent mutation, high disease allele frequency and unknown mode of inheritance. This equation was then used to determine the distance between a marker (ε4 within the apolipoprotein E gene, APOE) and Alzheimer’s disease (AD) loci using published data.Results An equation was formulated for mapping disease genes under the above conditions. If these conditions are present but ignored, then recombination fraction θ between marker and disease loci will be either overestimated or estimated with little bias. Therefore, an upper limit of θ can be obtained. AD has been found to be associated with the marker allele ε4 in Africans, Asians, and Caucasians. This suggests that the AD-ε4 allelic LD predates the divergence of peoples occurring 100?000 years ago. With the age of AD-ε4 allelic LD so estimated, the maximal distance was calculated to be 23.2 kb (mean 5.8 kb). Conclusions (1) A method is developed for LD mapping of susceptibility genes. (2) A mutation within the APOE gene itself, among others, is responsible for the susceptibility to AD, which is supported by recent evidence from studies using transgenic mice.
