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Genetic Diseases 1 Dr. Nabila Hamdi MD, PhD Topics Genetic Diseases Hemodynamic Disorders Cardiovascular Diseases CNS Liver Hematopoietic System Assessments Student assessment methods Quizzes Assignments Mid-term exam Final exam Assessment weight 20% 5% 30% 45% Course materials Will be posted on PBT website: http://pbt.guc.edu.eg Course instructor: Dr. Nabila Hamdi [email protected] B3.114 2 ILOs • • • • • • • • • • • • Define and use in proper context the genetic terminology. Be able to describe the main modes of Mendelian and non-Mendelian inheritance. Given a family history or pedigree, indicate the most likely mode of inheritance. Understand the clinical implications of incomplete penetrance and variable expressivity Appreciate the risk of individuals suffering simple Mendelian disorders. Be able to describe clinical features of common Mendelian diseases. Be able to describe clinical features of common chromosomal disorders. Understand the principles of cytogenetics and analysis of karyotypes. Recall major types of structural chromosome abnormalities and their basic implications. Discuss and contrast examples of diseases following an atypical pattern of inheritance. Recognize the genetic and environmental contribution to multi-factorial conditions. To have a clinical knowledge of several Mendelian and chromosomal conditions. 3 Outline I. II. NATURE OF GENETIC ABNORMALITIES CONTRIBUTING TO HUMAN DISEASE MENDELIAN DISORDERS: DISEASES CAUSED BY SINGLE-GENE DEFECTS 1. 2. 3. 4. 5. Transmission Patterns Diseases Caused by Mutations in Genes Encoding Structural Proteins Diseases Caused by Mutations in Genes Encoding Receptor Proteins Diseases Caused by Mutations in Genes Encoding Channels Diseases Caused by Mutations in Genes Encoding Enzyme Proteins III. IV. COMPLEX MULTIGENIC DISORDERS CYTOGENETIC DISORDERS 1. 2. 3. Chromosomal Abnormalities Cytogenetic Disorders Involving Autosomes Cytogenetic Disorders Involving Sex Chromosomes IV. SINGLE-GENE DISORDERS WITH ATYPICAL PATTERNS OF INHERITANCE 1. 2. Triplet Repeat Mutations Diseases Caused by Mutations in Mitochondrial Genes 4 General Organization of the Human Genome Humans have only about 30,000 protein-coding genes, far fewer than the 100,000 previously estimated and almost half the number in the lowly rice plant!! 5 Phenotypic Diversity “Polymorphisms” Single Nucleotide Polymorphisms (SNPs) Copy Number Variations (CNVs) CNVs are responsible for 5 to 24 million base pairs of sequence difference between any two individuals Less than 1% of SNPs occurs in coding regions http://www.wadsworth.org/events/genetics/ Any two individuals share greater than 99.5% of their DNA sequences. Thus, the remarkable diversity of humans is encoded in less than 0.5% of our DNA. 6 Genetic Abnormalities Contributing to Human Diseases Mutations (SNPs) CNVs Protein-Coding Genes Amplification Deletion 50% CNVs encompass gene coding sequences leading to dosage imbalances (phenotypic diversity, susceptibility to diseases) Alterations in ncRNA Long non-coding RNAs (lncRNAs) MicroRNAs (miRNAs) Epigenetic Changes Modulation of gene expression in the absence of alterations in DNA sequence Hypermethylation Histone modifications 7 Genetic Abnormalities Contributing to Human Diseases Mutations Point mutations (substitution of a single nucleotide base by a different base) “Missense” mutations (sickle cell anemia) “Nonsense” mutations (Thalassemia) 8 Genetic Abnormalities Contributing to Human Diseases Frameshift mutations (addition or deletion of one or two base pairs) No shift!! Trinucleotide repeat mutations Cystic Fibrosis • Fragile X syndrome: Increased tandem repeats of CGG within FMR1 gene. • Huntington disease: Increased tandem repeats of CAG in a gene located on 4p16.3. 9 Mendelian Disorders Diseases Caused by Single Gene Defects (Anemia) (Anemia) (Anemia) *Some variants of Ehlers-Danlos syndrome have an autosomal recessive inheritance pattern. Biochemical Basis and Inheritance Pattern for Selected Mendelian Disorders 10 Mendelian Transmission Patterns ?? Recurrence?? 11 Human Genetics https://www.uic.edu/classes/bms/bms655/lesson4.html/ http://www.biologie.uni-hamburg.de/b-online/library/cat-removed/u4aos1p5.html Mendelian Transmission Patterns Recurrence?? 12 Human Genetics https://www.uic.edu/classes/bms/bms655/lesson4.html/ http://www.biologie.uni-hamburg.de/b-online/library/cat-removed/u4aos1p5.html Mendelian Transmission Patterns Disorders of Autosomal Dominant Inheritance • Manifested in the heterozygous state. • Both males and females are affected, and both can transmit the condition (50% chance). • Reduced penetrance: some persons inherit the mutant gene but are phenotypically normal. • Variable expressivity: a trait is consistently associated with a mutant gene but is expressed differently among persons carrying the gene. • The age at onset is delayed, and symptoms and signs do not appear until adulthood. • Proteins involved in regulation of complex metabolic pathways (LDL receptors) and key structural proteins (collagen, fibrillin). 13 Mendelian Transmission Patterns Disorders of Autosomal Recessive Inheritance • Manifested in the homozygous state: when both of the alleles at a given gene locus are mutants. • There are skipped generations. • The trait does not usually affect the parents, but siblings may show the disease (consanguineous marriage!) • The recurrence risk is 25% for each birth. • Complete penetrance is common. • Onset is frequently early in life. • Enzyme proteins are affected: 50% loss of enzyme activity can be compensated 14 for. Mendelian Transmission Patterns X-linked Disorders • All sex-linked disorders are X-linked. • Most X-linked disorders are X-linked recessive • Transmitted by heterozygous female carriers only to sons. • Heterozygous females rarely express the full phenotypic change. • Sons of heterozygous women have one chance in two of receiving the mutant gene (50%). • An affected male does not transmit the disorder to sons, but all daughters are carriers. 15 Mendelian Disorders 1. Diseases Caused by Mutations in Genes Encoding Structural Proteins Marfan Syndrome Ehlers-Danlos Syndromes 16 Marfan Syndrome http://quizlet.com/2752374/connective-tissue-flash-cards/ • Mutation affecting fibrillin: glycoprotein, secreted by fibroblasts, is the major component of microfibrils found in the extracellular matrix. • Microfibrils serve as scaffolding for the deposition of tropoelastin, an integral component of elastic fibers. • Microfibrils are particularly abundant in the aorta, ligaments, and the ciliary zonules that 17 support the ocular lens. Marfan Syndrome • Fibrillin is encoded by the FBN1 gene, which maps to chromosomal locus 15q21. • Molecular diagnosis of Marfan syndrome is not yet feasible: more than 600 distinct causative mutations in the very large FBN1 gene have been found. • Autosomal dominant with variable expressivity (it is believed to be related to different allelic mutations in the FBN1 gene. • The prevalence of Marfan syndrome is estimated to be 1 per 5000. • Approximately 70% to 85% of cases are familial. • The rest are sporadic, arising from de novo FBN1 mutations in the germ cells of parents. 18 “Spider fingers” http://www.handresearch.com/diagnostics/marfan-syndrome-hand-test.htm http://ratedmedicine.wordpress.com/high-arched-palate/ High-arched palate http://www.hughston.com/hha/a_12_2_4.htm http://temasek68.blogspot.com/2009_06_01_archive.html Marfan Syndrome: Skeletal abnormalities 19 Marfan Syndrome http://www.cardiachealth.org/mitral-valve-prolapse-mvp Nucleus Medical Media, Inc. http://www.hughston.com/hha/a_12_2_4.htm Aortic aneurysm Mitral valve prolapse Aortic incompetence Cardiovascular abnormalities 20 Marfan Syndrome http://quizlet.com/3969760/3-orbit-and-eyeball-flash-cards/ Chapter 73 Cataract: Clinical Types MANUEL B. DATILES III and BENJAMIN V. MAGNO Bilateral dislocation, or subluxation, of the lens secondary to weakness of its suspensory ligaments. Occular problems 21 Marfan Syndrome Skeletal abnormalities • • • • Elongated habitus with abnormally long legs, arms, and fingers. High-arched palate and hyperextensible joints. Spinal deformities, such as severe kyphoscoliosis. Chest is deformed (deeply depressed or pigeon-breast) Ocular changes Bilateral dislocation, or subluxation, of the lens secondary to weakness of its suspensory ligaments. Cardiovascular system • • • • Fragmentation of the elastic fibers in the tunica media of the aorta predisposes to aneurysmal dilation and aortic dissection. Dilation of the aortic valve ring, giving rise to aortic incompetence. The cardiac valves, especially the mitral valve, may be excessively distensible and regurgitant (floppy valve syndrome), giving rise to mitral valve prolapse and congestive cardiac failure. Aortic rupture is the most common cause of death. Ehlers-Danlos Syndromes http://quizlet.com/2752374/connective-tissue-flash-cards/ • (EDSs) are a group of diseases characterized by defects in collagen synthesis or structure. • The mode of inheritance encompasses both autosomal dominant and recessive patterns. • There are approximately 30 distinct types of collagen which are the products of different genes. 23 Elastic Man: Garry Turner sets stretchiest skin record! 24 http://strange-wonders.blogspot.com/2012/05/elastic-man-garry-turner sets_10.html Firestein: Kelley's Textbook of Rheumatology, 8th ed. http://www.pregnancy-bliss.co.uk/ehlers-danlos-syndrome.html 25 Ehlers-Danlos Syndromes • Tissues rich in collagen, such as skin, ligaments, and joints, frequently are involved. • The abnormal collagen fibers lack adequate tensile strength. • Skin is hyperextensible and joints are hypermobile. • The skin is extraordinarily stretchable, extremely fragile, and vulnerable to trauma. • Minor injuries produce gaping defects, and surgical repair or any surgical intervention is accomplished only with great difficulty. • Wound healing is poor. 26 Ehlers-Danlos Syndromes There are at least six clinical and genetic variants of EDS, among them: Kyphoscoliotic EDS (AR): Ocular fragility with rupture of the cornea and retinal detachment, deficiency of the enzyme lysyl hydroxylase affects crosslinks among collagen molecules. Vascular EDS (AD): Rupture of the colon and large arteries, deficient synthesis of type III collagen resulting from mutations affecting collagen III gene. Classical EDS (AD): Diaphragmatic hernias, deficient synthesis of type V collagen resulting from mutations affecting collagen V gene. 27 References ROBBINS Basic Pathology 9th Edition ROBBINS Basic Pathology 8th Edition Source of the cover image: http://www.biologyreference.com/Fo-Gr/Genetic-Diseases.html 28 Thank you… 29