Polygenic Disorders and Syndromes PDF

Polygenic diseases Multifactorial diseases occur as a result of complex actions of genetic and exogenous factors, which interact in different relationships and relationships and at different levels. The genetic component in the etiology of these diseases can be represented by A gene that creates a...

Polygenic diseases Multifactorial diseases occur as a result of complex actions of genetic and exogenous factors, which interact in different relationships and relationships and at different levels. The genetic component in the etiology of these diseases can be represented by A gene that creates a predisposition to monogenic disease on a multifactorial basis, A small number of mutated genes that underlie oligogenic diseases, or Many mutant genes associated with polygenic diseases Exogenous factors One locus several many loci Monogenic oligogenic polygenic Diseases with Diseasesmultifactorial basis 1. Schizophrenia 2. Affective diseases 3. Alzheimer's disease 4. Hypertension 5. Coronary heart disease 6. Familial hypertrophic cardiomyopathy 7. Bronchial asthma  Schizophrenia This disease has: Multifactorial basis where genetic and exogenous intertwine factors. In familial schizophrenia the first generation has 10% risk, 3% risk in the second generation. The frequency in adopted children who are related to the sick person is higher compared with the control groups of children of mentally healthy parents. Frequency in monozygotic twins is higher than in dizygotic twins Schizophrenia This disease does not have a specific type of inheritance and does not obey Mendel's laws. Candidate genes for schizophrenia are: Dopamine receptor gene, dopamine transporter, amyloid precursor gene, glutamate receptor gene, tyrosine dehydrogenase gene, serotonin receptor gene, 5-hydroxytryptamine receptor gene, etc.  Schizophrenia Dopamine (Hydroxythyramine; 3,4-dihydroxy-β-phenylethylamine) is a catecholamine from the group of biogenic amines with neurotransmitter and hormone functions produced by neurons in Substantia nigra. It produces the neurotransmitters norepinephrine (norepinephrine) and epinephrine (adrenaline). Arvid Carlson proves not only the essence of dopamine as a by-product in the synthesis of epinephrine, but also its function as a neurotransmitter, its significance for Parkinson's disease and offers dopamine as a drug in its treatment. He was awarded the Nobel Prize in Medicine and Physiology in 2000 for his research. Schizophrenia Candidate regions are: The long arm on chromosome 22 Хр21, Хq11.2-q12 15q21, 15q23-q24, 21q22.1-q22.2, DXYS1 локус Affective diseases These diseases are divided into: Manic-depressive (bipolar) Psychosis and depressive psychoses  Affective diseases These are multifactorial diseases associated with the candidate gene for tyrosine hydroxylase gene because it is associated with catecholamine synthesis. By alternative splicing, this gene produces four different mRNAs, which are different from their coding regions. It leads to protein synthesis with different characteristics brain regions. This gene is localized to 11 Chromosome adjacent to the insulin gene.  Alzheimer's disease This disease is the most common cause of 60-80% of dementia cases in the adult population over 65 years. The clinical picture is characterized with senile dementia, which progresses from 4 to 12 years and ends in death. In some Families The disease is transmitted by AD in the offspring, and in others it is not specified type of inheritance. All patients with Down syndrome develop brain changes, typical of Alzheimer’s disease. Because of this, scientists began searching for the gene responsible for this disease on chromosome 21. Other genes located on chromosome 14 and 1 have also been localized. Hypertension Hypertension is a multifactorial disease and involves participation as genetic factors well as exogenous factors. Candidate genes for hypertension are: The rhinine gene; angiotensinogen gene, genes that function in the endothelium Coronary heart disease The underlying pathogenetic mechanisms of the disease are related to A) disorders in the transport, metabolism or structure of lipoproteins in cholesterol; B) hypertension; C) thrombogenesis, thrombolysis and fibrinolysis; D) impaired blood flow through the coronary arteries as a result of the development of atherosclerotic plaques, regulatory disorders and congenital anomalies.  Familial hypertrophic cardiomyopathy This disease is polygenic, has a heterogeneous characteristic and is the result of mutations in different genes. Genetic products are sarcoma proteins. The clinical spectrum includes asymptomatic forms, synocopy, myocardial ischaemia, Heart failure and sudden death. This is the most common "cardiac" cause of death in humans up to 35 years of age. The genetic risk is 50% for the offspring of the patient due to AD type of inheritance. Children may have a more severe clinical picture than their parents  Bronchial asthma A common heterogeneous disease in childhood. Allergic asthma (atopic type) is the most common form of this disease. Atopy is characterized by IgE reaction to inhalation of protein allergens such as familial accumulation of cases with allergic manifestations such as bronchial asthma, seasonal rhinitis and childhood eczema. Candidate genes are over 20. Diseases associated with somatic mutations The mutation process disrupts the structure and function of DNA in somatic cells with a frequency of 10-6 per gene / cell. Due to the low frequency of the various mutations, they do not reach a phenotypic statement. Under certain conditions, these mutations may have clinical significance. If they occur in dividing embryonic cells. If they increase cell proliferation, to form a fast-growing cancer cell clone. Mosaicism is due to post-zygomatic mutations that determine the origin of two or more genetically distinct cell lines. According to the type of mutation are divided into: Chromosomal mosaicism Mosaicism of gene mutations Gonadal mosaicism (healthy parents and children with AD disease)  Chromosomal diseases Etiology Chromosomal diseases occur as a result of chromosomal mutations, which disrupt the number of chromosomal (numerous) aberrations or cause an unbalanced type of structural change (structural aberrations). Clinical symptoms are due to a change in the amount (surplus or loss) of hereditary material. Classification The classification of inherited diseases is built on different principles - Inherited and non-inherited chromosomal diseases according to whether chromosomal aberration is inherited - full and polar forms according to the time of occurrence of the mutation - chromosomal diseases with aberrations of autosomes or sex chromosomes according to the place of mutation - chromosomal diseases with full aberration that affects the whole chromosome- monosomy, trisomy  Peculiarities of inherited chromosomal diseases Inherited chromosomal In the first case In the second case diseases Karyotype of parents Normal karyotype Normal karyotype Parents' health condition Clinically healthy parents Clinically healthy parents (normal phenotype) (normal phenotype) Karyotype of the sick child Mosaic form - numerical Full form - numerical chromosomal aberration or chromosomal aberration or unbalanced structural Time of occurrence of the unbalanced structural reorganization during mutation change during embryogenesis Clinical picture of gametogenesis, full Partial clinical chromosomal disease manifestation of the manifestation of the Genetic risk of recurrence disease, depends on the disease of the disease in the family age of the mother in some Low (equal to the chromosomal diseases population frequency of the disease)  Differences between solid and mosaic forms of chromosomal diseases Chromosomal diseases Full form Mosaic form Karyotype of parents Normal karyotype Normal karyotype Carrying a balanced structural chromosomal Parents' health condition mutation Mosaic karyotype Clinically healthy parents Clinically healthy parents (normal phenotype) (normal phenotype) Karyotype of the sick Partial clinical child manifestation Mosaic form - part of the full form - all cells with cells are numerical or Time of occurrence of the structural or numerical unbalanced structural mutation aberration inherited or aberration Clinical picture precursor mutation full A more rigid mutation clinical manifestation of Partial clinical disease manifestation of the disease  Genomic imprinting This phenomenon is characterized by sex-linked expression of only one of the two alleles (maternal or paternal) of a single genetic locus. Gene activity is known to depend on cytosine methylation, in areas rich in CG sequences located in or close to gene regulatory sites. Genes are active in hypomethylation and are inactive in hypermethylation of these regions. Genetic imprinting is accomplished by methylation of only one allele of the allelic pair. The genes that are expressed depending on the sex have short tandem repeats, rich in CG sequences, that determine the mono-parental character of the inheritance. Chromosomal diseases in structural or numerical aberrations of sex chromosomes The X chromosome is a large submetacentric chromosome. Contains over 50 genes. More than 100 diseases are due to mutations in this chromosome. A small acrocentric chromosome is on the chromosome. It has 2 genes. Chromosomal diseases in structural or numerical aberrations of sex chromosomes Klinefelter syndrome Population frequency 1: 1000 live births. This syndrome is due to an extra X chromosome in the genomic complex of males. The karyotype of the full form of the disease contains an additional X chromosome 47, XXY. Some patients have been diagnosed with three X's (48, XXXY) or four X's (49, XXXY). The structure of the extra X chromosome can be changed: 47, Xi (Xq) Y; 47 Xdel (X) (q13q21) Y; 47, Xr (X) Y Mosaicism 46XY / 47, XXY; 46ХУ / 48, ХХХУ; 46ХУ / 47, ХХУ / 48, ХХХУ..  Chromosomal diseases in structural or numerical aberrations of sex chromosomes Klinefelter syndrome Hypogonadism Aspermia or azoospermia, Male sterility Initial marks small testicles, normal penis Secondary signs of weak hair of female type, developed mammary glands-gynecomastia Tall height, long limbs, eunuchoid physique, narrow shoulders.  Chromosomal diseases in structural or numerical aberrations of sex chromosomes Superman Syndrome 47, XYY Population frequency 1: 1000 live births. The karyotype of the full form of the disease contains an additional U chromosome 47, XXY. The structure of the extra U chromosome can be changed: 47, Xi (Uq) i (Uq) Y; Mosaicism 46XY / 47, XYY; 46XY / 48, XYYY; 46XY / 47, XYY / 48, XYYY. Clinical picture of the full form: discrete facial dysmorphism, high growth, normal intellect, or slight mental retardation, antisocial behavior - impulsivity, aggression, predisposition to psychopathy, reduced fertility, etc.  Chromosomal diseases in structural or numerical aberrations of sex chromosomes 46,ХХ in men Population frequency 1:20 000 live births. Clinical picture: short stature, normal intellect, impaired reproduction  Chromosomal diseases in structural or numerical aberrations of sex chromosomes Turner syndrome 45 X Population frequency 1: 2500 live births. Clinical picture: short stature, slow physical development, short neck, ptosis of the eyelids, epicanth, brachydactyly, lymphedema of the extremities in newcomers that disappears over time.  Chromosomal diseases in structural or numerical aberrations of sex chromosomes Turner syndrome 45 X Tooth problems. Poor or abnormal tooth development can lead to a higher risk of tooth loss. The shape of the roof of the mouth and lower jaw often results in crowded teeth and poorly aligned jaws.  Chromosomal diseases in structural or numerical aberrations of sex chromosomes Polysomy X The disease develops in the presence of an additional X chromosome. Patients usually have trisomy 47, XXX and much less often tetrasomy 48 XXXX, pentasomy 49, XXXXXX. Mosaicism 46XX / 47, XXX; 46ХХ / 48, ХХХХ; 46ХХ / 47, ХХХ / 48, ХХХХ. In a woman with trisomy 47, XXX has no clinical features, with increasing number of chromosomes the clinical picture increases, problems with psychomotor development, dysmorphic and malformative manifestations - hypertelorism, flattened base of the nose, strabismus, clinodactyly, low mood ears, hypo renal malformations. The expressionless face of the sick mentions Down syndrome.  Chromosomal diseases in structural or numerical aberrations of sex chromosomes Morris Syndrome (46, XY) The disease develops in women but who have a male karyotype. Patients most commonly have trisomy 47, XXX, and much less frequently tetrasomy 48 XXXX, a mutation of the TFM testosterone receptor located on the X chromosome. The disease is inherited by AR. Patients are perceived as women, have female genitals, mammary glands are normal, low hair, pubic lips are hypoplastic, the placenta is short and ends blindly, there is aplasia of the uterus and ovaries, amenorrhea, intra-abdominal testes, which develop at puberty, cryptorchidism, aspermia, and normal estrogen production.  Chromosomal diseases in structural or numerical aberrations of autosomes Chromosomal diseases in structural or numerical aberrations of autosomes Down syndrome This syndrome is the leading cause of mental retardation and congenital heart disease. The frequency is 1: 900 -1: 700 live births. The disease develops when an additional or partial 21 chromosome appears, in all cells of the body (full form) or in part of them (mosaic form). Chromosome 21 is one of the smallest in our body, contains 1500 genes, including the gene for Alzheimer's disease, the gene for amyloid precursor, the gene for superoxide dismutase-1, genes for purine enzymes, gene for alpha A crystalline, human oncogenes and others. An extra copy of 1/3 of the long shoulder of this chromosome is enough to develop the disease. Chromosomal diseases in structural or numerical aberrations of autosomes Down syndrome 47,ХУ+21 In the full form of this disease, the extra chromosome 21 may be in free form or it may be attached or translocated to one of the group D chromosomes (13,14,15). In families of clinically healthy parents, sick children with an inherited form of this syndrome are born. The mutation occurs during meiosis in gametogenesis or during mitosis in embryogenesis. Analyses have shown that in 80% of patients the homologous 21 chromosomes did not segregate in the first meiotic division. In ¾ of the cases the disorder occurs in the gametogenesis of the mother and in ¼ in the gametogenesis of the father Chromosomal diseases in structural or numerical aberrations of autosomes Down syndrome 47, ХХ+21; 47,ХУ+21 The full form includes: Dysmorphism Malformations Mental retardation Facial dysmorphism: flat face, slanted eyes, epicant, wide nose, large serrated tongue, improperly shaped teeth, small ears. Chromosomal diseases in structural or numerical aberrations of autosomes Down syndrome 47, ХХ+21; 47,ХУ+21 Monkey furrow and brachydactyly Malformations Microcephaly, brachiocephaly, Congenital heart disease, Malformations of the digestive tract On food. Chromosomal diseases in structural or numerical aberrations of autosomes Down syndrome 47,ХХ+21; 47,ХУ+21 Mental development is affected differently, but most often the sick are oligophrenic, children are born with short stature and muscle hypotension. Reduced resistance to infections. They develop Alzheimer's disease early, increased purine synthesis, they have predisposition to acute leukemia, acute myelocytic leukemia, retinoblastoma, and often develop cataracts. The average lifespan of these patients is 30 g.. Mosaic forms have a lighter clinical picture Chromosomal diseases in structural or numerical aberrations of autosomes Edwards syndrome 47,ХХ+18; 47ХУ+18 The frequency of this disease is 1: 11000 live births. The clinical picture develops on an additional 18 chromosomes. The full form is with karyotype 47, XX + 18; 47ХУ + 18; much rarer the disease is due to more complex karyotype changes, which usually combine numerical aberrations of chromosome 18 with sex chromosomes: 48, XXX + 18, 48, XYY + 18 and so on. In mosaicism: 46XX / 47XX + 18; 46XY / 47XY + 18 This disease is inherited and is usually due to a mutation in parents with normal karyotype either during gametogenesis or during embryogenesis Chromosomal diseases in structural or numerical aberrations of autosomes Edwards syndrome 47,ХХ+18; 47ХУ+18 The clinical picture is characterized by a wide range of dysmorphic symptoms and severe malformations, severe disturbances in psychomotor development Bone abnormalities, short chest and sternum, narrow and asymmetrical tendon, hypoplasia of male organs, cryptorchidism in female genitalia - prominent clitoris, malformations of internal organs. Malformations affect: brain (poorly developed brain, corpus callosum deficiency), heart (valvular abnormalities, coronary atresia), kidneys (hypoplasia, cystic kidneys, hydronephrosis), digestive organs (oesophageal atresia, pyloric stenosis, pyloric stenosis) diaphragmatic hypoplasia) Chromosomal diseases in structural or numerical aberrations of autosomes Edwards syndrome 47,ХХ+18; 47ХУ+18 Facial dysmorphism, small lower segment wide and high forehead, small nose, small mouth, poorly modeled and low set ears, rabbit mouth and so on. flexion of the hands second and fifth fingers cover the third and fourth, radius aplasia and hexadactyly. This syndrome has a subtle character in 80-90% of cases die in the first week of life. Chromosomal diseases in structural or numerical aberrations of autosomes Partial monosomy 18q- This is the most common partial deletion chromosome syndrome, the pathology developing in long shoulder deletions on chromosome 18. The segments that are deleted vary in length depending on the breaking points of the chromosome: terminal deletions, interstitial deletions. The disease is most often due to a daytime mutation in the gametogenesis of parents with a normal karyotype. The disease is inherited when we have a balanced translocation in one of the parents. Children are born with low weight, specific facial dysmorphia, skull and ear abnormalities, ptosis of the eyelids, malformations of various organs. Mandatory prenatal diagnosis for a second child.  Chromosomal diseases in structural or numerical aberrations of autosomes Patau syndrome The frequency of this disease is 1: 12000- 1: 8000 live births. The clinical picture develops on an additional 13 chromosomes. The full form is with karyotype 47, XX + 13; 47ХУ + 13; the disease is due to more complex changes in the karyotype, in which numerical aberrations of chromosome 13 are most often combined with sex chromosomes, 48, XXX + 13, 48, XYY + 13, and so on. translocations in group D (13,14,15) Patients are born with low birth weight, microcephaly, microphthalmia, arinecephaly, rabbit mouth, and severe mental retardation. Children rarely reach the age of one.  Chromosomal diseases in structural or numerical aberrations of autosomes Cri-du-chat syndrome, 5p- The frequency of this disease is 1: 50,000 live births. The clinical picture develops when the short shoulder is divided into 5 chromosomes. Patients are born with low birth weight, microcephaly, lunar face, specific crying such as cat meowing, flat nose, short fingers, clinodactyly of the little finger, muscular hypotension, congenital heart disease, spina bifida, severe mental retardation, and etc.  Chromosomal diseases in structural or numerical aberrations of autosomes Syndrome Wolf-Hirschhorn (4p-) The frequency of this disease is 1: 50,000 live births. the deletion is in the distal part of chromosome 4. A syndrome can be a newly formed defect or an inherited one if we have balanced chromosomal aberration. Severely retarded and physically absent (children are born with low birth weight and short stature) Dysmorphia - high frontal hairline, hemangioma of the forehead, hyperthermia, ptosis of the eyelids, wide beak- shaped nose, short distance between nose and lips, small mandible, poorly modeled ears, large clitoris in female children, small scrotum, cryptorchidism hypo in boys. Additional clinic: malformations of the heart, brain, kidneys and eyes.  Chromosomal diseases in structural or numerical aberrations of autosomes Syndrome Prader-Willi The syndrome is the result of interstitial microdeletion - del (15) (q11-q13) in the proximal part of chromosome 15. Structural aberration in a child affects the paternal chromosome; Monoparental dysomy - the homologous chromosomes on chromosome 15 are from the mother defects, changes in genetic immunization.  Chromosomal diseases in structural or numerical aberrations of autosomes Syndrome Prader-Willi Clinical picture Absence in physical development, behavioral problems, characteristic person, hyperphagia, obesity, hypogonadism, tendency to diabetes, hypopigmentation  Chromosomal diseases in structural or numerical aberrations of autosomes Angelman Syndrome (Happy Doll Syndrome) In 70% of cases there is interstitial micro-deletion del (15) (q11-q13) of the maternal chromosome. in 3-5% mono-parental disomy of paternal origin. In 4% defects in the imprinting processes Rare cytogenic conversions affecting the 15q11- q13 region In 20% mutations in the ubiquitin-protein ligase gene..  Chromosomal diseases in structural or numerical aberrations of autosomes Angelman Syndrome (Happy Doll Syndrome) symptoms Severe absence of psychomotor development. Characteristic facies, jagged tongue and unmotivated laughter, interrupted movements, hyperactive behavior, EEG changes, hypo- pigmentation.  Chromosomal diseases in structural or numerical aberrations of autosomes Williams syndrome The frequency of this disease is 1: 20000; 1: 7500 according to new data live births. Spontaneous deletion of region q11.23 on chromosome 7. This region region contains more than 25 genes, and researchers believe that the loss of several of these genes probably contributes to the characteristic traits of this disorder. Connective tissue abnormalities and cardiovascular disease (aortic stenosis and pulmonary stenosis). Insufficient elastin production can be the cause of hoarseness, hernias and diverticula of the bladder. Difficulties with visual-spatial tasks, unique behavioral characteristics, learning difficulties and other cognitive difficulties.  Chromosomal diseases in structural or numerical aberrations of autosomes Williams syndrome