Medical genetics and genomics Toncheva 2020
Content
I. HUMAN GENETICS AND GENOMICS... 15
1. Place of genomics in personalized medicine - Draga Toncheva is
2. Organization of the nuclear and mitochondrial genome - Sena Karachanak 19
2.1. Structure and function of genes 21
2.2. Expression of genetic information through the genetic code and protein synthesis 22
2.2.1. Metabolism of mRNA 22
2.2.2. Regulation of gene activity 26
2.2.3. Epigeietics 26
2.3. Mitochondrial genome assembly 29
3. Microscopic and submicroscopic structure and function of chromosomes - Stoyan Lalchev.31
3.1. Chromosomal morphology 31
3.2. Submicroscopic organization and function of chromosomes 33
3.3. Normal human karyotype 37
3.4. Chromosomal heteromorphism 38
II. ETIOLOGY OF GENETIC DISEASES .42
4. Etiology of genetic diseases 42
4.1. Monogenic defects - Dragomira Nikolova 42
4.1.1. Mutagenesis 43
4.1.2. DNA damage repair mechanisms 43
4.1.2.1. Direct refund 43
4.1.2.2. Recovery by Excision 44
4.1.2.3. Single strand breakage repair (SSBR, single strand breakage repair) 46
4.1.2.4. Double strand breakage repair (DSBR, double strand breakage repair) 47
4.1.2.5. Translesion synthesis 48
4.1.3. Germline and somatic mutations 49
4.1.4. Gonadal and somatic mosaicism 50
4.1.5. Definition and classification of gene mutations in the human genome 50
4.1.6. Phenotypic expression of mutations 55
4.1.6.1. Loss-of-function (LOF) mutations 55
4.1.6.2. Mutations with acquisition of function (GOF, Gain-of-function) • 55
4.1.6.3. Dominant-negative mutations (antimorphic mutations) 55
4.2. Chromosome mutations - Vera Damyanova 56
4.2.1. Multiple chromosomal aberrations 56
4.2.2. Structural chromosome aberrations 57
4.2.3. Marker chromosomes J…..63
III. DIAGNOSIS OF GENETIC DISEASES 64
5. Methods of diagnosis of genetic diseases and hereditary predispositions .64
5.1. Molecular genetic methods - Dragomira Nikolova 64
5.1.1. Polymerase chain reaction (PCR) 64
5.1.2. Allele-specific polymerase chain reaction 64
5.1.3. Quantitative fluorescence polymerase chain reaction (QF-PCR) 64
5.1.4. Real time PCR (Real time PCR) 64
5.1.5. RFLP analysis of restriction fragment length 64 polymorphisms
5.1.6. Allele-specific oligonucleotides (ASOs) 64
5.1.8. Multiplex ligase-dependent amplification of samples (MLPA) 64
5.1.9. Next Generation Sequencing (NGS) 64
5.1.10. FISH (fluorescence in situ hybridization) 64
5.2. Methods for the diagnosis of chromosomal aberrations - Marta Mihailova 75
5.2.1. Molecular karyotyping (aCGH) 75
5.2.2. Cytogenetic methods 77
IV. TYPES OF INHERITANCE IN MONOGENEIC DISEASES - Stoyan Lalchev 82
6. Mendelian type of inheritance and genetic risk 82
6.1. Autosomal dominant type of inheritance 82
6.2. Autosomal recessive mode of inheritance 86
6.3. Sex-linked type of inheritance 89
6.3.1. X-recessive type of inheritance 89
6.3.2. X-dominant type of inheritance… 92
6.3.3. Y-linked type (Hollandric) inheritance 93
7. Sex-limited and sex-dependent type of inheritance 93
V. CLINICAL GENETICS – MONOGENIC AND CHROMOSOMAL DISEASES 94
8. Genetic hemolytic anemias - Rada Staneva 94
8.1. Thalassemias 97
8.1.1. p-thalassemia 97
8.1.2. P-thalassemia-like conditions 102
8.1.3. a-thalassemia 103
8.2. Abnormal hemoglobins 105
8.2.1 HbS-disorders 105
8.3. Anemias due to membrane defects 109
8.3.1 Hereditary spherocytosis 109
8.4. Anemias due to enzyme defects 111
8.4.1 Pyruvate Kinase Deficiency 111
8.4.2 Glucose-6-phosphate dehydrogenase deficiency 112
9. Congenital metabolic diseases - Olga Antonova 115
9.1. Diseases with disorders of amino acid metabolism 117
9.1.1. Aminoacidopathies 117
9.1.2. Organic acidopathies 122
9.1.3. Defects of the urea cycle 122
9.2. Diseases with disorders of carbohydrate metabolism 123
9.2.1. Galactosemia 123
9.2.2. Disrupted fructose metabolism. 126
9.2.3. Diseases of glycogen storage 127
9.3. Diseases with disorders in lipoprotein exchange 129
9.3.1. Familial hypercholesterolemia (FH) 129
9.4. Diseases of lysosomes - Olga Antonova, Radka Tincheva 133
9.4.1. Mucopolysaccharidoses 134
9.4.2. Bfingoliidoses 135
9.4.3. Mucolipidoses 138
10. Hereditary diseases of the connective tissue and bone system - Victoria Spasova ¡39
10.1. Brittle bone disease (Osteogenesis imperfecta) 140
10.2. Marfan 143 syndrome
10.3. Ehlers-Danlos syndrome 145
I. Congenital immunodeficiency diseases – Draeoma ¿¡¡Kl Nikolovi ]4~
11.1 Combined immunodeficiencies affecting cellular and humoral immunity ¡49
11.1.1. Severe combined immunodeficiency (TK11D, SC.ID) 149
11.1.2 Adenosine deaminase deficiency (ADD) 150
11.1.3 Omen syndrome 152
11.1.4 Combined immunodeficiencies (CIDs) "Jewish T lymphocyte syndrome" (BLS) 153
11.2. Combined syndromic and nodeficiencies 154
11.2.1. Wiskott-Aldrich syndrome (WAS) 154
11.3. Primarily antibody deficiencies 156
11.3.1. X-linked agammaglobulinemia (XLA) 156
11.3.2. General variable immune deficiency (OVID, CVID) 158
11.4. Diseases of impaired immune regulation 159
11.4.1.Shediac-Higashi syndrome (CHS) 159
11.5. Congenital defects of phagocyte number, function, or both 160
11.5.1. Chronic granulomatous disease (CGD) 162
11.6 Defects of innate immunity 164
11.7 Autoinflammatory diseases 164
11.8 Complement defects 164
11.8.1. Hereditary angioedema (HAE) 165
11.9. Phenocopy of primary immunodeficiencies 166
12. Neuromuscular diseases - Gada Staneva 16Я
12. 1 Spinal muscular atrophy (SMA) 169
12.2 Hereditary motor-sensory neuropathies (HMSN). Charcol-Marie-Tooth disease (CMT)… 173
12.2.1. CMT1- demyelinating neuropathies 175
12.2.2. CMT 2- neuropathies with axonal damage 177
12.3 Congenital myasthenic syndromes (CMS) 178
12.4. Muscular dystrophies (MD) 180
12.4.1 Dystrophinopathies 180
12.4.2 Limb-girdle muscular dystrophy (LGMD) 185
12.4.3 Emery-Dreifuss muscular dystrophy (EDMD) 190
12.4.4. Facio-scapulo-humeral muscular dystrophy (FSHD) 191
13. Monogenic diseases with pulmonary manifestations - Gada Staneva 195
13.1 Cystic fibrosis (MB) 195
13.2 Alpha-1-antitrypsin deficiency (AATD) 200
14. Hereditary deafness - Raba Staneva 203
14.1 Non-syndromic deafness 203
14.1.1 Autosomal recessive non-syndromic deafness (ARNH) 204
14.1.2 Autosomal dominant non-syndromic deafness (ADND) 205
14.1.3 X-linked non-syndromic deafness (HNH) 205
14.1.4 Mitochondrial non-syndromic deafness (MND) 06
14.2 Deafness syndrome |….207
15. Monogenic SKIN diseases - Rada Staneva 10
15.1. Epidermodisis bullosa 210
15.2 Ichthyosis 213
15.2.1. Ichthyosis vulgaris 213
15.2.2 X-linked ichthyosis 214
X 7 .■ BpiojcHu AP-nxi io ,a 215
16. , ' I.ill night. Л 1, ГЯ • "L SHII WITH DISORDER IN HEMOSTASIS - ¡'ada Staneva 21?
17. Monogenic Ophthalmology – Olga Antonova 224
17.1 Blindness and low vision 224
17.1.1. Retinitis pigmentosa (PR) 224
17.1.2. Retinoblastoma 226
17.1.3. Leber Hereditary Optic Neuropathy (LHON) ;…. 226
17.2. Congenital disorders of color vision. 226
P.Z. Cataract 228
17.4. Aniridia 229
18. Monogenic kidney diseases - Olga Antonova 232
18.1. Autosomal dominant polycystic kidney disease (ADPCD) 232
18.2. Autosomal recessive polycystic kidney disease (ARPCK) 235
19. Monogenic diseases with defects in reparation – Mihail Ganev 237
19.1. Ataxia-telangiectasia (Louis-Bar syndrome) 237
19.2. Xeroderma pigmentosum 240
19.3. Fanconi 243 anemia
19.4. Bloom 248 syndrome
20. Monogenic endocrine diseases - Mihail Ganev 252
20.1. Congenital adrenal hyperplasia (CAH) 252
20.1.1. 21 -hydroxylase deficiency 252
20.1.2. Rarer forms of VNH 257
20.2. Pituitary dwarfism 260
20.2.1. HN within syndromes with congenital anomalies 261
20.2.2. HN in combined DRH (affecting at least 2 pituitary hormones) 261
20.2.3. XN when affecting the effector pathway of PX 262
2.0.3. Congenital hypothyroidism 268
21. Hereditary diseases with dynamic mutations - Dragomira Nikolova 276
21.1. Huntington's disease (HD or Huntington's chorea). 276
21.2. Myotonic dystrophy 279
21.3. Fragile X chromosome 282 syndrome
22. Mitochondrial diseases - Vera Damyanova 285
22.1. General characteristics of mitochondrial diseases 285
22.2. Leber optic neuropathy (LHON) 289
22.3. MERRF 290 syndrome
22.4. MELAS 291 syndrome
22.5. NARP 292 syndrome
22.6. Leigh 292 syndrome
22.7. Kearns-Sayre 294 syndrome
23. Prion diseases - Draga Toncheva ..296
23.1. Definition 296
23.2. Molecular Pathogenesis 296
23.3. Genetic factors associated with prion diseases 298
23.4. Prion Disease Clinic 300
23.5. Treatment of prion diseases 302
24. Chromosomal diseases - Marta Mihailova JO i
24.1. General characteristics and diagnostics 303
24.2. Chromosomal diseases due to mutations in sex chromosomes 305
24.2.1 Klinefelter syndrome 305
24.2.2. Fraccaro syndrome (Fraccaro) 308
24.2.3 Polysomy Y (47.XYY) 309
24.2.4 Monosomy X (Turner's syndrome) ZY
24.2.5 Trisomy X (Syndrome of "super female") 312
24.3, Chromosomal diseases associated with autosomal aberrations 313
24.3.1. Chromosomal diseases associated with number aberrations of autosomes 313
24.3.2. Chromosomal diseases associated with structural aberrations of autosomes 324
25. Microdeletion AND microduplication syndromes - Savana Hadjidskopa 330
25.1. Prader-Willi syndrome 330
25.2. Angelman syndrome (happy doll syndrome) 336
26.3. 22ql 1.2 deletion syndrome (DiGeorge syndrome) 340
25.4. Williams-Beuren 344 syndrome
25.5. Smith-Magenis 347 syndrome
25.6. Miller-Dieker syndrome (Miller-Dieker syndrome) 351
25.7. Other less common microdeletion/microduplication syndromes 354 syndromes
VI. GENETIC PREDISPOSITION TO MULTIFACTOR DISEASES -357
26. General characteristics – Vera Damyanova Z..:…..: 357
26.1. Genetic risk 359
26.2. Study the etiological role of genetic factors 361
26.2.1. Family Studies .362
26.2.2. Twin studies 362
26.2.3. Adoptive Research 363
27. Genetic predisposition to some of the most common multifactorial diseases 364
27.1 Alzheimer's disease - Marta Mihailova, Draga Toncheva 364
27.2 Diabetes – Marta Mihailova 370
27.2.1. General characteristic 370
27.2.2. Diabetes mellitus type 1 373
27.2.3. Diabetes mellitus type II 376
27.2.4. Gestational diabetes 378
27.2.6. Genetic defects related to the action of insulin 379
27.2.7. Other reasons for the development of diabetes 380
27.3. Nutrigenomic aspects of obesity - Marta Mihailova 381
27.3.1. Monogenic forms of obesity 383
27.3.2. Syndromic obesity 386
28.3.3. Polygenic obesity 387
28. Genetics of CANCER - Draga Toncheva ¡90
28.1. General cellular and molecular characterization of cancer syndromes.
Characteristics of cancer cells 390
28.2, Driver Mutations 392
28.2.1. Activated oncogenes 392
28.2.2. Inactivated tumor suppressor genes (TSG) j- 398
28.1.2. Other mechanisms, beyond mutations in cancer genes, that alter gene activity | 404
28.4. Hereditary cancer syndromes 1,405
28.5. Syndromes with genetic predisposition to colorectal carcinoma (CRC) 408
28.5.1. Hereditary polyposis colorectal carcinomas 408
28.5.2. Hereditary nonpolyposis colorectal carcinomas (HNPCC) 411
28.6. Syndromes with genetic predisposition to breast and ovarian cancer 414
28.6.1. Hereditary breast and ovarian cancer 414
28.6.2. Li-Fraumeni syndrome l 4/7
28.6.3. Cowden syndrome 417
28.7. Familial melanoma 418
28.8. Multiple endocrine neoplasia (MEN) 419
28.9. Retinoblastoma -421
29. Dysmorphoiagia in the neonatal period - Radka 'Gincheva 423
29.1. Cornelia de Lange syndrome 425
29.2. Zellweger 425 syndrome
29.3. Goldenhar 427 syndrome
29.4. Syndromes with craniostenosis 427
29.4.1. Crouzon 427 syndrome
29.4.2. Apert syndrome (acrocephalosyndactyly syndrome) 428
30. Genetics of autism spectrum disorders - Marta Mihailova 430
30.1. Monogenic syndromes associated with ASD 434
30.1.1. Fragile X syndrome (FXS) 434
30.1.2. Tuberous sclerosis (TS) 434
30.1.3. Rett 435 syndrome
30.2. Other diseases associated with ASD 435
VII. REPRODUCTIVE GENETICS – Savina Hadzydekova, Georgi Stamenov 441
31. Reproductive Genetics 441
32. Genetic causes of infertility 441
32.1. Male infertility 443
32.2. Female infertiles
Medical Genetics and Genomics is a highly specialized and authoritative textbook designed for medical students, geneticists, graduate students, and anyone interested in the study of genetics in the context of medicine and genomics. The authors of the textbook are well-known specialists in the field of medical genetics, which confirms its authority and relevance in the relevant field.
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