clinical genetics

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Slide 1: 

Clinical Genetics GUIDED BY : DR. JYOTI BHOJWANI PRESENTED BY : ASMITA GAUR

Medical Genetics : 

Medical Genetics Differs from human genetics Genetic medicine is a “newer” term Sub-specialties include Clinical genetics Genetic counseling Metabolic/biochemical genetics Cytogenetics Molecular genetics Mitochondrial genetics

Slide 3: 

Clinical Genetics Consultant Cytogenetics Lab Molecular Genetics Lab A Medical Genetics Unit Set-Up Clinical diagnosis Genetic counselling Risk assessment Prenatal & pre-symptomatic diagnosis Medical Genetics in Health Services

Types of Genetic Diseases : 

Types of Genetic Diseases Chromosomal disorders Single gene/ Multi gene diseases Inborn errors of Metabolism

When Meiosis Goes Wrong! : 

When Meiosis Goes Wrong! Genetic abnormalities Chromosomes Loose a piece (deletion) Recombine with a non-homologous chromosome (translocation) Separate incorrectly during anaphase Cytokinesis might not happen We can test for certain genetic abnormalities by monitoring a Karyotype

Karyotype of The Human Genome : 

Karyotype of The Human Genome Mitotic (doubled) chromosomes taken from a white blood cell (WBC) at metaphase 23 chromosome pairs = 46 total

Slide 7: 

Chromosomes are arranged by: size location of centromere Banding patterns also considerably help identify the chromosomes

Fetal Testing : 

Fetal Testing

Conducting a Karyotype Test : 

Conducting a Karyotype Test

Chromosome Abnormalities : 

Chromosome Abnormalities Changes in chromosome number Increase in entire chromosome sets (polyploidy) Reductions or increase in ONE chromosome (aneuploidy) Changes in chromosome structure Translocation/Chromosomal Breaks Deletions Fragile sites

Changes in chromosome number : 

Changes in chromosome number 1. Polyploidy – presence of additional sets of chromosomes Common in plants Lethal in most animals 2. Aneuploidy – presence of extra chromosome or an absence of one a. Trisomy – “three bodies” – having one extra chromosome b. Monosomy – missing a single chromosome

Polyploidy and Aneuploidy in Fruit Flies : 

Polyploidy and Aneuploidy in Fruit Flies

Meiotic nondisjunction causes either gain or loss of single chromosomes : 

Meiotic nondisjunction causes either gain or loss of single chromosomes

Polyploidy : 

Polyploidy Increase in the genome size Rare in animals In human, found in liver cells and cancer cells In plants, leads to ‘giantism’

Aneuploidy : 

Aneuploidy Monosomy: Results from fertilization between one normal gamete & one gamete that is missing a chromosome. In Humans: Autsosomal Monosomy extremely serious! Embryo usually ceases development very early. (considered lethal) Nullisomy: Loss of a chromosome pair

Slide 16: 

Trisomy: one normal gamete & one gamete that contains an extra chromosome. In Humans: Autosomal Trisomy usually results in spontaneous abortion. The only autosomal trisomies seen in live births are trisomy 13, 18 and 21. Trisomy 21 (Down’s Syndrome) is the only autosomal trisomy that allows survival until adult hood.

Slide 17: 

Down’s Syndrome

Down’s Syndrome : 

Down’s Syndrome Large tongue Flat face Slanted eyes Single crease across palm Mental retardation With exceptions!

Slide 19: 

Prognosis: Today many Down’s syndrome affected children reach adulthood. However, not many survive past 50. Risk Factor: Maternal Age Note: In Trisomy 21 that has occurred as a result of non-disjunction, the non-disjunction was maternal 94% of the time! (In other trisomies nondisjunction maternal 93% of time.)

Edward’s Syndrome: Trisomy 18 : 

Edward’s Syndrome: Trisomy 18 Infant with Edward’s Syndrome

Edward’s Syndrome : 

Edward’s Syndrome Heart defects Displaced liver Low-set ears Abnormal hands Severe retardation 98% abort Lifespan < 1 year

Patau Syndrome: Trisomy 13 : 

Patau Syndrome: Trisomy 13 Cleft lip and palate Extra fingers & toes polydactylism Defects Heart Brain Kidneys Most abort Live span < 1 month

Symptoms : 

Symptoms Cardiac defects occur in 80% of cases Holoprosencephaly the brain is not divided into halves, is often present and is generally signalled by the presence of midline facial defects absent or malformed nose severe clefting of the lip and/or palate polydactyly of the left hand

Sex Chromosome Aneuploidy : 

Sex Chromosome Aneuploidy Sex Chromosome Aneuploidy is more common than Autosome Aneuploidy! In order to survive and develop embryo needs at least one X chromosome. An individual who has an intact Y-chromosome will be male, regardless of the number of X chromosomes he possesses. In the absence of an intact Y;female.

Klinefelter’s Syndrome : 

Klinefelter’s Syndrome Male,( 47 total chromosomes, 3 sex chromosomes XXY) May have some learning difficulties but usually not mentally retarded Affected male may not develop normally at puberty In severe cases: rudimentary testes & prostate gland, sparse facial and pubic hair, long arms and legs, breast development may occur Infertility (in mild cases man may not discover disorder until he experiences infertility)

Turner’s Syndrome : 

Turner’s Syndrome Female (45 total chromosomes, 1 sex chromosome (X)) Only monosomy that is Not lethal Abnormalities: don’t develop normal at time of puberty, underdeveloped breasts, rudimentary ovaries Infertile: Do not ovulate or menstruate Treatment: Hormone supplements can help these women lead normal lives

Changes in chromosome structure : 

Changes in chromosome structure Errors during recombination (Meiosis I) can result in some chromosomal abnormalities. Chromosomal aberrations fall into following general categories: Change in number of genes a) Loss : deletion b)Addition : Duplication Change in gene arrangement a) Inversion b)Translocation

Chromosomal duplication : 

Chromosomal duplication A duplication occurs when part of a chromosome is copied (duplicated) abnormally, resulting in extra genetic material from the duplicated segment.

Chromosomal deletion : 

Chromosomal deletion A deletion occurs when a chromosome breaks and some genetic material is lost. E.g. Autism

Cri-du-chat Syndrome : 

Cri-du-chat Syndrome Low birth weight and poor growth. Feeding problems because of difficulty swallowing and sucking. Hyperactivity, aggression, repetitive movements. Unusual facial features Excessive dribbling. Constipation. CTNND2 gene is involved

Translocations : 

Translocations Simple translocation: Broken chromosome fragment becomes attached to a nonhomologous chromosome Reciprocal translocation: Broken chromosome fragments become exchanged between nonhomologous chromosomes

Burkitt’s lymphoma : 

Burkitt’s lymphoma Burkitt's lymphoma is a solid tumour of B lymphocytes usually at (8;14) translocation About 25% of Burkitt lymphomas contain Epstein-Barr virus genomes The long (q) arm of the resulting chromosome 8 is shorter (8q−) than its normal homologue; the long arm of translocated chromosome 14 longer(14q+).

Philadelphia Chromosome : 

Philadelphia Chromosome This abnormality is a reciprocal translocation between one chromosome 9 and one chromosome 22. This translocation is designated t(9;22). It results in one chromosome 9 longer than normal and one chromosome 22 shorter than normal. The latter is called the Philadelphia chromosome The DNA removed from chromosome 9 contains most of the proto-oncogene designated c-ABL Leading to leukaemia.

Chromosomal inversion : 

Chromosomal inversion An inversion is a chromosome rearrangement in which a segment of a chromosome is reversed end to end. Inversions are of two types:- paracentric and pericentric.

Fragile Sites : 

Fragile Sites Fragile X Syndrome: normally CGG is repeated 50 times; in fragile X, up to 1000 times Results in range of mental retardation and behavioral problems Occurs in both sexes; most females with fragile X are heterozygous

Slide 36: 

Single gene disorders Single mutant gene has a large effect on the patient Transmitted in a Mendelian fashion Autosomal dominant, autosomal recessive, X-linked & Y-linked

Slide 37: 

Standard pedigree symbols Male, affected Female, unaffected Male, deceased Mating Consanguineous mating Pregnancy Male, heterozygous for autosomal recessive trait Female, heterozygous for Autosomal or X-linked recessive trait Dizygotic (non-identical) twins Monozygotic (identical) twins Spontaneous abortion or still birth

Slide 38: 

Autosomal dominant trait Aa aa A a a Phenotype Genotype Gametes a A a a Zygote Phenotype

Slide 39: 

Autosomal dominant trait Male to female and female to male transmittance Affected individuals have an affected parent One copy of mutant allele = disease 50% risk to offspring of affected parent 50% of protein function insufficient for normal phenotype Neurofibromatosis: nerve tissue grows to tumors,neurofibromas Marfan’s syndrome: gene FBN1,encodes a connective protein fibrillin

Osteogenesis imperfecta (OI) - an autosomal dominant disease : 

Osteogenesis imperfecta (OI) - an autosomal dominant disease Caused by mutation in one of the two genes encoding type I collagen COL1A1 - chromosome 17q COL1A2 - chromosome 7q Incidence: 1/20,000 births Type I collagen is an essential structural component of the extracellular matrix of many tissues including bone, tendon and skin Clinical symptoms include fragile bones, fractures, deformity, deafness and blue sclerae

Slide 41: 

Aa Aa A a a Phenotype Genotype Gametes a A A A Zygote Phenotype A a a A a Autosomal recessive

Slide 42: 

Autosomal recessive Male to female and female to male transmittance Two copies of a mutant allele = disease 50% offspring carriers & 25% offspring affected Consanguinity increases frequency of affecteds 50% of protein function sufficient for normal phenotype Cystic fibrosis CF conductance regulator Sickle-cell disease -globin

Slide 43: 

CFTR function Regulates the flow of chloride ions across the cell membrane

Sickle Cell Anemia : 

Sickle Cell Anemia an autosomal recessive mutation in the β-globin gene RBCs sickle shaped Anemia Pain, Stroke Leg ulcers Jaundice Gall stones

Slide 45: 

a Aa a a Phenotype Genotype Gametes Phenotype A Female Zygotes Male Zygotes XY XX X-linked recessive

Slide 46: 

X-linked recessive Females are carriers, males are affected Carrier female will transmit to 50% of sons (affected) and to 50% of daughters (carriers) Affected male cannot transmit to sons but will transmit to 100% of daughters (carriers) 50% function sufficient for normal phenotype Duchenne muscular dystrophy Dystrophin Haemophilia A Factor VIII

Hemophilia : 

Hemophilia Blood clotting impaired Recessive allele X-linked recessive trait More common in males

Slide 48: 

X-linked dominant Males and females are affected Affected female will transmit to 50% of sons and to 50% of daughters Affected male cannot transmit to sons but will transmit to 100% of daughters klinefelter syndrome,hypophosphatemic ricketts

Slide 49: 

Y-linked Only males are affected Affected males always have an affected father All sons of an affected man are affected male infertility,hypertrichosis pinnae

Inborn Errors of Metabolism : 

IEM as a group are not rare: occur 1 in 5000 births collectively Often treatable if diagnosed Most difficult task for clinician is to know when to consider IEM and which tests to order for evaluation Due to defects in single gene Inborn Errors of Metabolism

Slide 51: 

Autosomal dominant disorders (neurofibromatosis, tuberous sclerosis, polycystic kidney disease, familiar polyposis coli, hereditary spherocytosis, Marfan syndrome, osteogenesis imperfecta, achondroplasia, familiar hypercholesterolemia) Autosomal recessive disorders (cystic fibrosis, phenylketonuria, homocystinuria, hemochromatosis, sickle cell anemia, thalassemias, alkaptonuria, neurogenic muscular atrophies) X-linked disorders:(glucose-6-phosphate dehydrogenase deficiency)

Biochemical and molecular basis of single-gene disorders : 

Biochemical and molecular basis of single-gene disorders Enzyme defects and their consequences Defects in receptors and transport systems Alterations in structure, function or quantity of nonenzyme proteins Genetically determined adverse reactions to drugs.

Slide 53: 

The “sick” newborn infant Eye anomalies / Gastrointestinal abnormalities Hair and skin abnormalities Hematological / Hepatic dysfunction Sepsis Unusual odor PKU mousy smell Cystiurea sulfourus smell Clinical presentations

Slide 54: 

defective enzyme Substrate (increased) Product (decreased) action Metabolites (increased) Co-factor A Co-factor B other enzymes Metabolites (decreased) EFFECT ON OTHER METABOLIC ACTIVITY e.g., activation, inhibition, competition Theoretical consequences of an enzyme deficiency.

Slide 55: 

PROTEIN GLYCOGEN FAT AMINO ACIDS FRUCTOSE GALACTOSE FREE FATTY ACIDS AMMONIA UREA UREA CYCLE ORGANIC ACIDS GLUCOSE PYRUVATE ACETYL CoA KREBS CYCLE NADH KETONES ATP LACTATE An integrated view of the metabolic pathways

Disorders of carbohydrate metabolism : 

Disorders of carbohydrate metabolism Glycogen storage disease due to ‘glycogen synthase’ deficiency GSD type VIII : X-linked recessive Other enzyme deficiency like ‘glu-6-phos’ , ‘pyruvate carboxylase’ leads to severe liver disease

Amino-acid metabolism : 

Amino-acid metabolism PKU(phenylketonuria) : defective enzyme is ‘phenylalanine hydroxylase’ Autosomal recessive Causes mental retardation, brain damage Maple syrup urine disease(MSUD) : also called branched chain ketoaciduria Autosomal recessive Deficiency of α -ketoacid dehydrogenase complex Causes brain damage, eventually die

Organic acid metabolism : 

Organic acid metabolism Alkaptonuria(black urine disease) : defect in enzyme ‘homogentisate 1,2-dioxygenase’ Autosomal recessive ‘alkapton’ accumulates in blood Causes damage to cartilages, heart valves, forms kidney stones

Fatty acid oxidation : 

Fatty acid oxidation Glutaric acidemia : defect in enzyme complex ‘medium chain acyl dehydrogenase(MCAD)’ Recognized as ‘SIDS’ (sudden infant death syndrome)

Porphyrin metabolism : 

Porphyrin metabolism Acute intermittent porphyria : autosomal dominant Deficient enzyme is ‘porphobilinogen deaminase’ Causes abdominal pain, constipation and muscle weakness

Purine or pyrimidine metabolism : 

Purine or pyrimidine metabolism Lesch-nyhan syndrome : X-linked recessive Deficient enzyme is ‘HGPRT’ (hypoxanthine guanine phosphoribosyl transferase) Causes severe gout, kidney problem, poor muscle control, mental retardation

Peroximal function disorder : 

Peroximal function disorder Zellweger syndrome : also called cerebrohepatorenal syndrome Reduction or absence of peroxisomes in the cells of liver, kidneys and brain Death occurs in 6 months of age, respiratory distress, gastrointestinal bleeding, liver failure

Lysosomal storage disorders : 

Lysosomal storage disorders Niemann pick disease : autosomal recessive Deficiency of ‘sphingomylinase’ Gaucher’s disease : deficiency of enzyme ‘glucocerebrosidase’ Defects in house keeping genes Autosomal recessive

Mitochondria and Disease : 

Mitochondria and Disease Mitochondria are known as "the powerhouse" of the cell because of the ATP they produce Because of their bacterial origin, mitochondria are the only organelle to contain DNA (apart from the nucleus). It is circular, contains 37 genes,13 genes encodes for respiratory chain proteins.

Leber's hereditary optic neuropathy : 

Leber's hereditary optic neuropathy (LHON) is a maternally inherited cause of blindness. LHON was the first disease to be associated with mutations of mitochondrial DNA (mtDNA). LHON is only transmitted through the mother as it is primarily due to mutations in the mitochondrial (not nuclear) genome and only the egg contributes mitochondria to the embryo. Men cannot pass on the disease to their offspring This affects predominantly young adult males.

Myoclonic Epilepsy with Ragged Red Fibers (MERRF) : 

Myoclonic Epilepsy with Ragged Red Fibers (MERRF) It is extremely rare, with an estimated prevalence 1/400,000 in Europe Symptoms "Ragged Red Fibers" - clumps of diseased mitochondria accumulate in the subsarcolemmal region of the muscle fibres and appear as "Ragged Red Fibers" when muscle is stained with modified Gomori trichrome stain short stature hearing loss lactic acidosis exercise intolerance

Other diseases associated with mitochondria : 

Other diseases associated with mitochondria Diabetes mellitus and deafness (DAD) this combination at an early age can be due to mitochondrial disease Leigh syndrome, subacute sclerosing encephalopathy after normal development the disease usually begins late in the first year of life, although onset may occur in adulthood a rapid decline in function occurs and is marked by seizures, altered states of consciousness, ventilatory failure Neuropathy, ataxia, retinitis pigmentosa, and ptosis (NARP) progressive symptoms as described in the acronym Myoneurogenic gastrointestinal encephalopathy (MNGIE) gastrointestinal pseudo-obstruction ,neuropathy Mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like symptoms (MELAS)

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