The mechanisms responsible for the determination and fine-tuning of phenotypes are still not well understood, albeit it is widely accepted that the specific disease genotype, epigenetic factors, and environmental influences are significantly involved. However, it has become increasingly apparent that modifier genes must play a considerable role in the phenotypic heterogeneity of Mendelian disorders, reflected for instance by intrafamilial variations, incomplete penetrance, and varying severity of the clinical course. New genetic technologies and advances in molecular medicine allow huge amounts of information to be generated from individual samples in the form of genomic, transcriptomic, and pro- teomic data. However, analysis and interpretation of this flood of findings, most notably putting them into the right biological context, represents one of the main challenges for research and medicine today. The purpose of this review is to provide insight into the role of modifier genes as an important source of phenotypic variability in so-called monogenicdisorders, using the example of cystic fibrosis (CF). Further, it discusses the benefits and limitations of the actual knowledge as well as future technical and strategic approaches. However, since a comprehensive discussion of all modifier gene studies is beyond the scope of this review, the main focus will rather be on recent progress made in the field.
Complex genetic diseases (Polygenic disorders) This is more prevalent than monogenicdisorders occurring in more than 1% of the population. They are a result of genetic alterations at multiple areas of the genes and are influenced by environmental and behavioral factors. These qualitative trait disorders are regulated by several genes, associated with variations in multiple genes, each with a small contribution and is called polymorphisms. When a specific allele occurs, in at least 1% of the population, it is said to be genetic polymorphism. The simplest type of polymorphism results from a single base mutation which substitutes one nucleotide for another, and has recently been termed as a single nucleotide polymorphism (SNP). Other types of polymorphism are restriction fragment length polymorphism (RFLP) and simple tandem repeats (STRs), consisting of relevant allele or nucleotide repetition. 3
although their pace of implementation may perhaps be better described as a slow revolution in health care. There are signifi- cant challenges in moving from traditional genetics, with its focus on monogenicdisorders with significant implications for health of a very small proportion of the population, to the development of genetic profiling approaches which are useful for screening, risk assessment, disease prevention, and health promotion. The idea of personalized medicine as fully individualized medicine has still to be realized, and is likely unrealistic. 140 However, the application of genetics in strati-
Multifactorial diseases such as type 2 diabetes, osteoporosis, and cardiovascular disease are caused by a complex interplay of many genetic and nongenetic factors, each of which conveys a minor increase in the risk of disease. Unraveling the genetic origins of these diseases is expected to lead to individualized medicine, in which the prevention and treatment strategies are personalized on the basis of the results of predictive genetic tests. This great optimism is counterbalanced by concerns about the ethical, legal, and social implications of genomic medicine, such as the protection of privacy and autonomy, stigmatization, discrimination, and the psychological burden of genetic testing. These concerns are translated from genetic testing in monogenicdisorders, but this translation may not be appropriate. Multiple genetic testing (genomic profiling) has essential differences from genetic testing in monogenicdisorders. The differences lie in the lower predictive value of the test results, the pleiotropic effects of susceptibility genes, and the low inheritance of genomic profiles. For these reasons, genomic profiling may be more similar to nongenetic tests than to predictive tests for monogenic diseases. Therefore, ethical, legal, and social issues that apply to predictive genetic testing for monogenic diseases may not be relevant for the prediction of multifactorial disorders in genomic medicine.
Next-generation sequencing also enables whole-exome sequencing. The exome makes up only 1.5% of the whole genome, but it contains all protein-coding genes. It has been estimated that more than 10,000 monogenicdisorders affect around one percent of humans at birth, and about two percent of couples carry a single gene variation that could result in a child with a severe genetic disorder (Aslamkhan, 2015; Babar, 2017; Nuffield Council on Bioethics, 2018). However, the detection pace of new monogenicdisorders is declining while, in contrast, detection pace of polygenic disorders and multifactorial traits, which affect a much larger share of the population, is increasing (Nuffield Council on Bioethics, 2018; Second International Summit on Human Genome Editing, 2018a). It means that, with further developments in genomics, we may expect a higher utility of PGD, although according to experts, it will primarily be related to elderly diseases which are mainly multifactorial (Alon et al., 2019).
Human genome sequencing and genotypic- phenotypic studies are now focusing more on the treatment of genetic diseases other than identification strategies . During pre-genetic medicine era, metabolic manipulation and protein augmentation have been considered as extraordinarily effective for the treatment of various monogenicdisorders including phenylketonuria, sickle cell anemia, thalassemia and endocrine disorders respectively . Many of the innate metabolic disorders have been cured with gene therapy and manipulation of genome codes for the defective enzymes and proteins in the metabolic trails .
Hereditary recurrent fevers, as well as Majeed syn- drome, Blau syndrome, and Pyogenic sterile Arthritis, Pyoderma gangrenosum and Acne (PAPA) syndrome, have been extensively reviewed since the concept of autoinflammation was created in 1999 . However, very little information has been assembled regarding the phenotype, genetics and epidemiology of the more re- cently discovered autoinflammatory disorders. Here in this review, we aimed to offer novel diagnostic options to those patients for whom a genetic link could not be established. More than 25 autoinflammatory genes were listed during the last international conference on auto- inflammation, Lausanne, 23-26 May, 2013, including at least five to six new ones in the pipeline. Both pheno- type and genotype heterogeneity have been described which further hinders correct diagnosis and highlights the necessity for a gene and disease nomenclature con- sensus. A systematic in-depth description of the clinical features of these patients has been undertaken thanks to the Eurofever initiative [59,60]. Massively parallel sequen- cing approaches should help in identifying the causative gene among those already known or novel genes through whole exome or genome sequencing. Development of such innovative genetic diagnostic tools is in progress
able to identify, among patients who meet PFAPA syndrome diagnostic cri- teria, those with a low probability of carrying one of the mutations associ- ated with monogenic periodic fever. In this study, we analyzed the main clin- ical features that could distinguish pa- tients who meet current PFAPA syn- drome criteria with negative versus positive genetic testing results. Fur- thermore, we tested the accuracy of a set of variables in identifying patients with higher probability of carrying rel- evant mutations of genes associated with monogenic periodic fever (the Gaslini diagnostic score). 10
hypercholesterolemia to atherosclerosis. Elucidation of gene defects that cause severe hypercholesterolemia has provided molecular entrées into the biosynthetic and regulatory pathways that produce and eliminate cholesterol and has led to the development of potent pharmacological agents that dramatically reduce circulating levels of cholesterol. The last decade of the twentieth century culminated in the demonstration that pharmacological reductions in plasma cholesterol levels result in fewer cardiovascular events and reduce total mortality. This review will summarize recent developments in our understanding of the molecular pathogenesis and treatment of monogenic forms of severe hypercholesterolemia, and some implications that these findings have for the management of common forms of hypercholesterolemia. General overview of LDL metabolism. Cholesterol is a rigid, hydrophobic molecule that confers structural integrity to plasma membranes of vertebrate cells. Excess cellular cholesterol is esterified with fatty acids to form cholesteryl esters, which are either stored as lipid droplets in cells or packaged with other apolipoproteins to form VLDL in the liver and and chylomicrons in the intestine (Figure 1). The two major cholesterol-carrying lipoproteins in humans are LDL and HDL. Approximately 70% of circulating cholesterol is transported as LDL. LDL is formed in the circulation from VLDL (Figure 1). […]
Remark 2.7. Every finite monogenic ternary semigroup T = hai is homomorphic image of an infinite monogenic ternary semigroup (consider the epimorphism ϕ : O −→ T by ϕ(k) = a k for every k ∈ O ). Also it is easy to see that all the homomorphic images of an infinite monogenic ternary semigroup, which are not isomorphic to it, will be finite monogenic ternary semigroup.
A b s t r ac t . A family L of subsets of a set X is called linked if A ∩ B 6 = ∅ for any A, B ∈ L . A linked family M of subsets of X is maximal linked if M coincides with each linked family L on X that contains M . The superextension λ(X ) of X consists of all maximal linked families on X . Any associative binary operation ∗ : X × X → X can be extended to an associative binary operation ∗ : λ(X ) × λ(X ) → λ(X ). In the paper we study automorphisms of the superextensions of finite monogenic semigroups and charac- teristic ideals in such semigroups. In particular, we describe the automorphism groups of the superextensions of finite monogenic semigroups of cardinality 6 5.
called Dirac operator. Null solutions of this operator are called monogenic functions, which may be regarded as a natural generalization to a higher-dimensional setting of the holomorphic functions of one complex variable see 6, 7. A function f continuously diﬀerentiable in an open set Ω of R 2n and taking value in C
Short-chain 3-hydroxyacyl-CoA (SCHAD) deficiency leads to an autosomal recessive form of HI. SCHAD, encoded by HADH, catalyzes a step in the fatty acid oxi- dation (FAO) cycle . Although FAO defects are well known to cause hypoglycemia, the connection between an enzyme in the FAO cycle and HI was unclear. Subse- quently, it was shown that SCHAD is an inhibitory regulator of GDH, the enzyme involved in amino-acid stimulated insulin secretion, and loss of GDH’s inhib- ition due to SCHAD deficiency results in insulin dysre- gulation . Children with SCHAD-HI have fasting and protein-induced hypoglycemia and similar to patients with HI/HA, they respond well to diazoxide therapy. Biochemical markers of SCHAD-HI include increased concentration of 3-hydroxybutyrylcarnitine in plasma and 3-hydroxyglutaric acid in urine. These chil- dren do not exhibit the cardiac, skeletal or hepatic dys- function associated with FAO disorders.
and right monogenic. It is not clear whether the second term in the decomposition (5.2) for a ball is indeed (the conjugate of) a right monogenic function (the classi- cal Leibniz rule does not extend to monogenic functions). Even though balls and half spaces are known to be conformally equivalent, we do not yet know whether the point- wise multiplication of a Szeg˝ o projection by the outward normal unit vector satisﬁes some type of conformal invariance (see [7, 22] and, for the conformal invariance of Cauchy integrals on manifold, [6, 24]). Indeed, we believe this would be an interesting problem to be studied.
Some cases of canine diabetes share several similarities with the monogenic forms of human diabetes, known as maturity onset diabetes of the young (MODY). To date, however, there is no reported evidence of monogenic diabetes association studies in dogs. We identified six ca- nine allelic associations to genes that are causative for human monogenic forms of diabetes, but none of these associations can fully explain diabetes risk in any given dog breed. One gene ( ZFP57 ) was associated with two dif- ferent SNPs in two disparate breeds (Bichon Frise and Samoyed) and one breed (Cocker Spaniel) had an associ- ation with three SNPs from three different genes ( MTTL1, PAX4, INS ). The allele and genotype frequencies do not indicate that these associations explain the full susceptibil- ity to canine breed-related diabetes and suggest that Table 1 Breeds used in the study and overview of SNP
Abstract. The direct product N × N of two free monogenic semigroups contains uncountably many pairwise non-isomorphic subdirect products. Furthermore, the fol- lowing hold for N × S, where S is a finite semigroup. It contains only countably many pairwise non-isomorphic subsemigroups if and only if S is a union of groups. And it contains only countably many pairwise non-isomorphic subdirect products if and only if every element of S has a relative left- or right identity element.
Here, we reported on an auto- in ﬂ ammatory syndrome in a patient carrying a homozygous missense mu- tation in the SLC29A3 gene. The syn- drome was characterized by recurrent episodes of fever and in ﬂ ammation, to- gether with pericarditis, abdominal pain, and diarrhea. These observations suggest that SLC29A3-related disorders could be added to the ever-expanding list of monogenic periodic fever syn- dromes. A large number of clinically identi ﬁ able autoin ﬂ ammatory disorders have been genetically characterized over the last decade. 2 SLC29A3-related
In the vast majority of obese children, no syndromal or monogenic cause for the obese state can be diagnosed and therefore a polygenic cause is suggested. Generally, monogenic forms of childhood obesity are very rare . Mutations in only a few genes are known to cause the development of severe obesity in early childhood . Most of these genes are involved in the central nervous regulation of hunger and satiety where the leptin/leptin receptor system plays a pivotal role . Of all mono- genic forms of obesity, the only one causally treatable is congenital leptin deficiency caused by homozygous mu- tations of the leptin gene . Leptin is a protein secreted mainly by adipocytes, and its circulating levels correlate positively with the body mass index and the body fat mass. By central as well as peripheral action, leptin im- pacts diverse physiological processes including energy balance, metabolism, endocrine regulation, and immune function . One of the main functions of leptin is to control the body fat mass by inhibiting food intake via the central nervous system. Recombinant human