Genetic Disorders PDF

1/2567 GENETIC DISORDERS School of Allied Health Sciences Walailak University MTH65-204 Sec 1: Asst. Prof. Dr. Yanisa Rattanapan Sec 2: Asst. Prof. Dr. Wetpisit Chanmol Sec 3: Asst. Prof. Dr. Sirirat S...

1/2567 GENETIC DISORDERS School of Allied Health Sciences Walailak University MTH65-204 Sec 1: Asst. Prof. Dr. Yanisa Rattanapan Sec 2: Asst. Prof. Dr. Wetpisit Chanmol Sec 3: Asst. Prof. Dr. Sirirat Surinkaew MTH64-203E Asst. Prof. Dr. Sirirat Surinkaew LEARNING OBJECTIVES 1. Explain the meaning of mutations 2. Explain principles and give examples of ü Single-gene disorders, chromosomal disorders, and complex disorders ü Monogenic genetic diseases (eg. autosomal dominant, autosomal recessive and X-linked diseases) ü Chromosome abnormality genetic disease ü Multifactorial disorders 3. Explain type of genetic testing and indication MUTATION 3 A mutation is a change in the DNA sequence of an organism. Mutations can result from errors in DNA replication during cell division, exposure to mutagens or a viral infection. Germline mutations (occur in eggs and sperm) can be passed on to offspring. E.g., Sickle cell disease, cystic fibrosis, Tay Sachs disease, and Huntington's disease Somatic mutations (occur in body cells) are not passed on. E.g., Skin cancer, lung cancer, McCune-Albright syndrome, and Sturge-Weber syndrome Degree of mutations 1) Gene (DNA) mutation is a change in DNA molecules covers only 1 - 3 nucleotides. 2) Chromosomal mutation is a change related to the number or structure of a chromosome.  GENE (DNA) MUTATION 4 Gene (DNA) mutation is a change in DNA molecules covers only 1 - 3 nucleotides. Substitution – one base pair is replaced by a different base pair. Insertion – addition of one or more nucleotide base pairs into a DNA sequence Deletion – a nucleotide is removed from a DNA sequence. Nonsense mutation – base to convert to the genetic code, stop the polypeptide chain. https://saylordotorg.github.io/text_the-basics-of-general-organic-and-biological-chemistry/s22-05-mutations-and-genetic-diseases.html  PEDIGREE 5 NOMENCLATURE https://www.ncbi.nlm.nih.gov/books/NBK65817/figure/CDR 0000062865__1237/  TYPES OF GENETIC DISORDERS 6 Single-gene disorders – where a mutation affects one gene. Autosomal dominant Autosomal recessive X-linked dominant X-linked recessive Y-linked Chromosomal disorders – where chromosomes (or parts of chromosomes) are missing or changed. Complex disorders – where there are mutations in two or more genes. AUTOSOMAL DOMINANT Familial Hypercholesterolemia (FH) Hereditary Spherocytosis (HS) Marfan Syndrome (MFS)  AUTOSOMAL DOMINANT 8 Autosomal – gene in question is located on one of the non-sex chromosomes (autosomes). Dominant – a single copy of the mutated gene (from one parent) is enough to cause the disorder. Tobias ES, Connor M, Ferguson-Smith M. Essential medical genetics. John Wiley & Sons; 2011 Nov 15. Dowell DR. NextGen genealogy: The DNA connection. ABC-CLIO; 2014 Nov 25.  9 FAMILIAL HYPERCHOLESTEROLEMIA (FH) It is caused by a defect on chromosome 19. About 60-80% of people with FH have a mutation found in one of LDLR, APOB, and PCSK9 genes, which affect how your body regulates and removes cholesterol from your blood. Defect makes the body unable to remove low density lipoprotein (LDL, or bad) cholesterol from the blood. Results in a high level of LDL in the blood Narrowing of the arteries from atherosclerosis at an early age Increased risk of early onset of coronary artery disease (CAD), even in childhood https://medlineplus.gov/ency/article/000392.htm#:~:text=Familial%20hypercholesterolemia%20is%20a%20disorder,Familial%20combined%20hyperlipidemia FAMILIAL HYPERCHOLESTEROLEMIA (FH) 10 Physical signs of FH Xanthomas – fatty skin deposits Hands Elbows Knees Ankles https://webeye.ophth.uiowa.edu/eyeforum/atlas/pages/xanthelasma.html Eyelids à Xanthelasmas Angina – chest pain Sudden stroke-like symptoms Trouble speaking Drooping on one side of the face Weakness of an arm or leg Loss of balance http://thnm.adam.com/content.aspx?productid=117&isarticlelink=false&pid=2&gid=2490  HEREDITARY SPHEROCYTOSIS (HS) 11 Erythrocytes is loss of membrane surface area relative HS Normal RBC to intracellular volume, which leads to spherically shaped erythrocytes with decreased deformability. Abnormalities in erythrocyte membrane proteins, particularly ankyrin, α- and β-spectrin, band 3, and protein 4.2 Increased erythrocyte fragility leads to vesiculation and membrane loss. Characteristic symptoms of HS Hemolytic anemia – destruction of RBC in the spleen and their removal from the blood stream Jaundice – a yellow tone to the skin Splenomegaly – enlarged spleen, splenic destruction of poorly deformable HS erythrocytes https://medizzy.com/feed/24694563  MARFAN SYNDROME (MFS) 12 Tall and Thin MFS is a spectrum of disorders caused by a heritable genetic defect of connective tissue Defect FBN1 gene on chromosome 15, which codes Finger Length for the connective tissue protein fibrillin. Physical signs of MFS Tall and thin with disproportionately long arms, legs, fingers and toes Longer Arms Breastbone that protrudes outward or dips inward Flat feet Flat feet If aorta is affected, the condition can become life-threatening Extreme nearsightedness https://www.mayoclinic.org/diseases-conditions/marfan- syndrome/symptoms-causes/syc-20350782 AUTOSOMAL RECESSIVE Cystic Fibrosis (CF) Phenylketonuria (PKU) Galactosemia Lysosomal Storage Diseases (LSDs)  AUTOSOMAL RECESSIVE 14 A genetic condition can occur when the child inherits one copy of a mutated (changed) gene from each parent (2 mutated genes). Parents of a child with an autosomal recessive condition usually do not have the condition. Tobias ES, Connor M, Ferguson-Smith M. Essential medical genetics. John Wiley & Sons; 2011 Nov 15. Dowell DR. NextGen genealogy: The DNA connection. ABC-CLIO; 2014 Nov 25.  CYSTIC FIBROSIS (CF) 15 CF affects the cells that produce mucus, sweat and digestive juices. 1:2000 live births – most common lethal genetic disease in white population CF is abnormal function of an epithelial chloride channel protein encoded by CF transmembrane conductance regulator (CFTR) gene at 7q31.2. Defect in the transport of chloride ions across epithelial Defect in the exocrine glands – abnormally viscid mucous secretions Blockage of airways, pancreatic ducts, and biliary ducts https://www.yourgenome.org/facts/what-is-cystic-fibrosis/  CYSTIC FIBROSIS (CF) 16 Respiratory signs and symptoms A persistent cough that produces thick mucus (sputum) Wheezing Exercise intolerance Repeated lung infections Inflamed nasal passages or a stuffy nose Recurrent sinusitis Digestive signs and symptoms Foul-smelling, greasy stools Poor weight gain and growth Intestinal blockage, particularly in newborns (meconium ileus) Chronic or severe constipation, which may include frequent straining while trying to pass stool, eventually causing part of the rectum to protrude outside the anus (rectal prolapse) https://en.wikipedia.org/wiki/Cystic_fibrosis  PHENYLKETONURIA (PKU) 17 PKU is caused by an absence phenylalanine hydroxylase (PAH) gene PAH helps create the enzyme needed to break down phenylalanine (Phe à Tyr), PKU causes an amino acid called phenylalanine to build up in the body. Hyperphenylalaninemia since birth – impairs brain development Most profound symptom Learning difficulties – after 6 months, severe mental retardation, IQ under 50 Behavioral disorders, such as hyperactivity, self-harm, and epilepsy Decreased pigmentation of hair and skin – absence of tyrosine Early screening test – blood test given to newborns 24 - 72 hours after birth. Main treatment for PKU is a low-protein diet that completely avoids high-protein foods (such as meat, eggs, dairy products, potatoes, and cereals. https://app.healthand.com/th/topic/general-  GALACTOSEMIA 18 Galactose is a sugar contained in milk, including in both human breast milk and cow's milk–based. Galactosemia is the inability to metabolize the milk sugar component galactose to glucose. Caused by deficiency of galactose-1-phosphate uridyltransferase (GALT or G1PUT) Symptoms of galactosemia Convulsions Irritability Lethargy Poor feeding -- baby refuses to eat formula containing milk Poor weight gain Yellow skin and whites of the eyes (jaundice) Vomiting Treated by completely eliminating milk and milk products – the main source of galactose Infants are typically fed a soy-based infant formula after diagnosis. https://www.andersondiagnostics.com/newbornscreening/galactosemia/  LYSOSOMAL STORAGE DISEASES (LSDS) 19 Lysosomes contain a variety of hydrolytic enzymes, involved in the breakdown of complex substrates (sphingolipids and mucopolysaccharides, etc.) into soluble end products. Lack of a lysosomal enzyme, catabolism of its substrate remains incomplete, leading to accumulation of substrates in excess within the lysosomes. At present, more than 50 LSDs are known. Symptoms of LSDs Developmental delay Movement disorders Seizures Dementia Deafness http://storagewaribun.blogspot.com/2016/12/lysosomal-storage-disease.html Blindness  X-LINKED RECESSIVE Duchenne Muscular Dystrophy (DMD) Color Blindness  X-LINKED RECESSIVE 21 Mutations in genes on the X chromosome. Male carrying such a mutation will be affected, because he carries only one X chromosome. Female carrying a mutation in one gene, with a normal gene on the other X chromosome, is generally unaffected. Tobias ES, Connor M, Ferguson-Smith M. Essential medical genetics. John Wiley & Sons; 2011 Nov 15. Dowell DR. NextGen genealogy: The DNA connection. ABC-CLIO; 2014 Nov 25.  DUCHENNE MUSCULAR DYSTROPHY (DMD) 22 Caused by mutations in the dystrophin gene located on the short arm of the X chromosome (Xp21), resulting in progressive muscle wasting. Severe type of muscular dystrophy that primarily affects boys. Muscle weakness usually begins around the age of four and worsens quickly. Muscle loss typically occurs first in the thighs and pelvis followed by the arms, result in trouble standing up. Dystrophin is expressed in a wide variety of tissues, Brain Peripheral nerves Skeletal Cardiac myocytes https://naqiffabeauty123.wixsite.com/mysite/single-post/2016/03/15/duchenne-muscular-dystrophy-dmd  DUCHENNE MUSCULAR DYSTROPHY (DMD) 23 Clinical Features Boys with DMD are normal at birth, and early motor milestones are met on time. Walking, is often delayed, and the first indications of muscle weakness are clumsiness and inability to keep up with peers. Enlargement of the calf muscles associated with weakness, a phenomenon termed pseudohypertrophy, is an important clinical finding. Lordosis Gowers sign: the child uses hands to rise from the floor, bend its trunk, leans with hands on knees, climbing himself, due to lumbar and proximal extremity muscles weakness. Respiratory and cardiac muscles are often affected, respiratory failure or cardiac decompensation are common causes of death. https://www.viquepedia.com/archive/Duchenne-muscular-dystrophy  COLOR BLINDNESS 24 Inability to see the difference between certain colors. Usually people have three types of cone cell in the eye Red Green Blue Color blindness – one type of cone cell is defect with the gene that produce photopigment. Genes that can give you red-green color blindness are passed down on the X chromosome – more common in men. https://www.bekirsitkiaslan.net/en/colour-blindness-a CHROMOSOMAL DISORDERS Down syndrome (Trisomy 21) Edward Syndrome (Trisomy 18) Patau syndrome (Trisomy 13) Klinefelter Syndrome (XXY) Turner Syndrome (TS) (Monosomy with X0) Supermale (XYY) Superfemale (XXX) Cri du chat syndrome (Del5p)  CHROMOSOME 26 Chromosome is a long DNA molecule with part or all of the genetic material of an organism. https://www.coolaboo.com/biology/chromosomes/ CHROMOSOME STRUCTURE 27 https://thebiologynotes.com/chromosomes/ https://opengenetics.pressbooks.tru.ca/chapter/cytogenetic-map/  KARYOTYPE 28 Karyotype is an individual's complete set of chromosomes. Laboratory-produced image of a person's chromosomes isolated from an individual cell and arranged in numerical order. Karyotype may be used to look for abnormalities in chromosome number or structure. Normal results – 22 pairs of autosomes and two sex chromosomes Euploidy à 46 chromosomes (2n) Females: 44 autosomes and 2 sex chromosomes (XX), written as 46, XX Males: 44 autosomes and 2 sex chromosomes (XY), written as 46, XY Abnormal results 47, XY, +21 à Down syndrome (Trisomy 21) 47, XXY à Klinefelter syndrome t(9;22) à Philadelphia (Ph) chromosome 47, XY, +18 à Edward Syndrome (Trisomy 18) 45, X, or 45, X0 à Turner syndrome (TS) https://www.ucsfbenioffchildrens.org/medical-tests/karyotyping  CYTOGENETIC DISORDERS Genome abnormalities – loss or gain of whole chromosomes: monosomy (n) and trisomy (3n) Chromosome abnormalities 1. Number (sex chromosomes or autosomes): gain or loss of whole chromosomes in the human cell Aneuploidy Polyploidy Mixoploidy 2. Structure Deletion Duplication Inversion Translocation, etc.  NUMERICAL CHROMOSOMAL ABERRATIONS 30 1. Aneuploidy – having missing or extra chromosomes Human cell having 45 or 47 chromosomes instead of the usual 46 Trisomy is the most common aneuploidy. 2. Polyploidy – more than two complete sets of chromosomes, common among plants, as well as among certain groups of fish and amphibians. E.g., some salamanders, frogs, and leeches Two types of polyploidy 1. Triploidy (3n) – additional set of chromosomes in the cell for a total of 69 chromosomes, very seldom survive to term 2. Tetraploidy (4n) – four copies of each chromosome 3. Mixoploidy – a mixture of cell populations whose component cells differ in their chromosome numbers à 46, XY/ 69,XXY Mosaicism – having 2 or more genetically different sets of cells in body, all derived from a single zygote Chimerism – having 2 or more genetically different cell lines originating from different zygotes  MOSAICISM VS CHIMERISM 31 Mosaicism Chimerism Mosaicism is similar to chimerism in that it is defined by the presence of two genetically distinct cell lines; however, in the case of chimerism there is fusion of two different zygotes within a single embryo. https://www.alhakam.org/the-virgin-birth-scientific-plausibility/ https://www.quora.com/Whats-the-difference-between-a-mosaic-and-a-chimera https://www.livescience.com/61890-what-is-chimerism-fused-twin.html https://www.biologyonline.com/dictionary/mosaicism  STRUCTURAL CHROMOSOMAL MUTATION 32 Chromosomal mutation is a change related to the number or structure of a chromosome. Deletion – loss of part of chromosome Duplication – extra copy made of part of chromosome Inversion – reverses direction of part of chromosome Translocation – part of one attaches to another chromosome https://www.quora.com/What-are-the-four-types-of-chromosomal-mutations  CHROMOSOME STRUCTURE: DELETIONS 33 Deletions (del) – a portion of the chromosome is missing or has been deleted. Loss of chromosomal material Large-scale deletions are lethal. http://www.csun.edu/~cmalone/pdf360/Ch08-1%20struct.pdf  34 CHROMOSOME STRUCTURE: DUPLICATIONS Duplications (dup) – a portion of the chromosome has been duplicated, resulting in extra genetic material. http://www.csun.edu/~cmalone/pdf360/Ch08-1%20struct.pdf  35 CHROMOSOME STRUCTURE: INVERSIONS Inversions (inv) – a portion of the chromosome has broken off, turned upside down, and reattached, therefore the genetic material is inverted. http://www.csun.edu/~cmalone/pdf360/Ch08-1%20struct.pdf  36 CHROMOSOME STRUCTURE: TRANSLOCATIONS Exchange of chromosomal segments between nonhomologous chromosomes Two major types 1. Reciprocal translocation (arm) 2. Robertsonian translocation (centromere) 1. 2. Chronic Myeloid Leukemia (CML), translocation, t(9;22)(q34;q11), of genetic material between chromosome 9 and 22, and contains a fusion gene called BCR-ABL. https://ph.parkwaycancercentre.com/learn-about-cancer/types-of-cancer/chronic-myeloid-leukaemia-cml/ http://www.csun.edu/~cmalone/pdf360/Ch08-1%20struct.pdf  37 NUMERICAL CHROMOSOME ABERRATIONS Autosomal aneuploidy Down syndrome (Trisomy 21), 1:1000 Edward Syndrome (Trisomy 18), 1:3000 Patau syndrome (Trisomy 13), 1:16000 Sex chromosome aneuploidies (SCA) Klinefelter Syndrome (XXY), 1 - 2.5:1000 Turner Syndrome (TS) (Monosomy with X0), 1:2000 - 2500 Supermale (XYY), 1:1000 Superfemale (XXX), 1:1000 STRUCTURAL CHROMOSOME ABERRATIONS Cri-du-chat syndrome (del5p), 1:15,000 to 1:50,000  Autosomal Aneuploidy 38 DOWN SYNDROME (TRISOMY 21) http://www.learningaboutelectronics.com/Articles/Karyotype-profile-of-chromosomes.php https://nursingcrib.com/nursing-notes-reviewer/down-syndrome/  Autosomal Aneuploidy 39 EDWARD SYNDROME (TRISOMY 18) http://www.learningaboutelectronics.com/Articles/Karyotype-profile-of- chromosomes.php  Autosomal Aneuploidy 40 PATAU SYNDROME (TRISOMY 13) http://www.learningaboutelectronics.com/Articles/Karyotype-profile-of-chromosomes.php  Sex Chromosome Aneuploidies (SCA) 41 KLINEFELTER SYNDROME (XXY) http://www.learningaboutelectronics.com/Articles/Karyotype-profile-of-chromosomes.php  Sex Chromosome Aneuploidies (SCA) 42 TURNER SYNDROME (TS) (MONOSOMY WITH X0) http://www.learningaboutelectronics.com/Articles/Karyotype-profile-of-chromosomes.php  Sex Chromosome Aneuploidies (SCA) 43 SUPERMALE (XYY) Extra Y chromosome Called the super-male disease, also known as Jacobs syndrome Sign Acne Tall stature (excessively tall) Superior muscle strength Reduced muscle coordination Overly-aggressive Lacking in empathy IQ around 80 – most people (about 68%) have an IQ between 85 and 115. http://www.learningaboutelectronics.com/Articles/Karyotype-profile-of- chromosomes.php  Sex Chromosome Aneuploidies (SCA) 44 SUPERFEMALE (XXX) Usually there are no other physical differences and normal fertility Cannot be distinguished from XX females Often taller than average Normal IQ Increasing numbers cause mental deficiency http://www.learningaboutelectronics.com/Articles/Karyotype-profile-of-chromosomes.php  Structural Abnormalities 45 CRI DU CHAT SYNDROME (DEL5P) Caused by a partial deletion (monosomy) of a varying length of the short arm (p) of chromosome 5 Characterized at birth High pitched cry à infant cry resembles a meowing cat Small head Flattened bridge of the nose Low birth weight Poor muscle tone Microcephaly Potential medical complications https://healthjade.com/cri-du-chat-syndrome/  GENETIC TESTING 46 FISH NIP KARYOTYPE (FLUORESCENCE IN SITU (NONINVASIVE PRENATAL TESTING) HYBRIDIZATION) Look for abnormalities in Fluorescent DNA probes to target chromosome number or structure specific chromosomal locations within Determining the risk that the fetus will be Large deletions and duplications the nucleus, resulting in colored signals born with certain genetic abnormalities. Balanced rearrangements that can be detected using a fluorescent Analyzes small fragments of DNA that are (translocations, inversions, and microscope. circulating in a pregnant woman's blood. insertions) Gestational age after 9-10 weeks will be Deletions Duplications performed. Translocations Al Shakaki A. Bioethical Deliberation on Genomic Testing: Islamic Perspectives (Doctoral dissertation, Hamad Bin Khalifa University (Qatar)). Asif M, et al. A novel four-way complex variant translocation involving chromosome 46, XY, t (4; 9; 19; 22)(q25: q34; p13. 3; q11. 2) in a chronic myeloid leukemia patient. Frontiers in Oncology. 2016 May 30;6:124. https://www.quantumdxs.com/patients/nipt  47 INDICATIONS FOR GENETIC TESTING Prenatal genetic analysis Postnatal genetic analysis Mother >35 years is an Multiple congenital anomalies increased risk of trisomy. Unexplained mental retardation and/or developmental delay Parent who is a carrier of a Suspected aneuploidy balanced reciprocal E.g., Down syndrome translocation, Robertsonian Suspected unbalanced autosome translocation or inversion. Suspected sex chromosomal abnormality Parent with a previous child E.g., Turner syndrome with a chromosomal Infertility (to rule out sex abnormality. chromosomal abnormality) Multiple spontaneous abortion Parent who is a carrier of an (to rule out the parents as X-linked genetic disorder. carriers of balanced translocation COMPLEX DISORDERS  COMPLEX DISORDERS 49 Complex diseases are also called multifactorial diseases. Caused by a combination of genetic, environmental, and lifestyle factors, most of which have not yet been identified. Main factor is genes but the cause includes other factors that aren’t genes, such as Nutrition, lifestyle, alcohol and tobacco, some medicines, an illness, and pollution The vast majority of diseases fall into this category, including several congenital defects and a number of adult-onset diseases. Symptoms expressed are proportional to the number of genes that have mutated. https://www.nationwidechildrens.org/conditions/health-library/medical- genetics-multifactorial-inheritance  MULTIFACTORIAL DISEASES 50 Common examples Heart disease Diabetes mellitus Hypertension Cancer e.g., breast and colon Some cases of cleft lip and palate Neural tube defects https://clinicalgate.com/polygenic-and-multifactorial-inheritance/  ASSIGNMENT FOR ACTIVE LEARNING (10 POINTS) 51 Students were divided into 3 groups, 12-13 each. Student Number Group Topic 1 - 12 1 Mutation and complex disorders 13 - 25 2 Single-gene disorders 25 - 37 3 Chromosomal disorders Each group sets multiple choice questions (5 choices) with answer from the assigned topic, 5 items. Please! submit the assignment on eLearning with file name as “Topic Name”.  REFERENCES 1. Robbins SL, Kumar V, Cotran RS. Hemodynamic, thrombosis and shock in Robbins pathologic basic of disease, 8th ed. Philadelphia: W.B. Saunder, 2010. 2. Schneider AS, Szanto PA. Pathology, 4th ed. Philadelphia: Lippincott Williams & Wilkins, a Wolters Kluwer besiness, 2009