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Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive Total 2-10 2 1-2 5-12 Chromosomal changes 6-7 Disease with genetic base 7-10 Congenital malformations Total 20 38-51 History Gregor Mendel (1822-1884) The burden of Mendelian (single gene) disorders • Although individually rare, genetic diseases collectively constitute a major health problem. • About 5 - 8 % of admissions to a pediatric hospital and about 1 % of admissions to an adult hospital are for Mendelian disorders. • 9 % of pediatric deaths are due to Mendelian disorders • About 1- 2 % of the population has a Mendelian disorder. • Most Mendelian disorders are apparent by childhood. • Life span is reduced in about 60 % of these disorders. • Each person is estimated to have 1 - 5 lethal recessive alleles. Importance of recognizing Mendelian disorders Establishment of definitive diagnosis. Recognition of other relatives with disease or at risk for disease. More accurate prognosis can be given Anticipation/prevention of complications, both medical and emotional/psychological More informed family planning. Important definition Alleles: Alternative forms of a gene that can be distinguished by their alternate phenotypic effects or by molecular differences; a single allele for each locus is inherited separately from each parent. Autosome: One of chromosomes 1 – 22. Dominant allele: An allele whose phenotype is detectable (even if only weakly) in a single dose or copy. Recessive allele: An allele whose phenotype is apparent only in the homozygous or hemizygous state. Heterozygous: Having a normal allele on one chromosome and a mutant allele on the other. More terms to know Hemizygous: Having half the number of alleles (e.g. males are hemizygous for all X chromosome genes) Expressivity: The severity or intensity of the phenotype of an allele. Penetrance: The degree to which a gene expresses any observable phenotype Locus (pl. loci): The position on a chromosome of a gene or other chromosome marker; also, the DNA at that position. Proband: The first affected individual who comes to clinical genetic evaluation. Indicated by an arrow on Definition In normal human we have: 22 homologous pairs of chromosomes. Autosomal genes are present in pairs, one maternal and the other paternal. Homozygous: Both gene pair are identical. Heterozygous: Different. Trait: Gene-determind characteristic. Trait Definition Gene-determined characteristics. Types 1. Dominant trait Express in the heterozygote. 2. Recessive trait Express in the homozygote. 3. Codominant trait The effect of both alleles is seen in heterozygot. Modes of Inheritance Autosomal recessive. Autosomal dominant. X-linked dominant. X-linked recessive. Y-linked. Mitochondrial. Most genetic diseases manifest during childhood Distribution of Mendelian disorders 100 90 80 70 60 50 40 30 20 10 0 Autosomal dominant Autosomal recessive X-linked Frequency of Mendelian diseases by organ system Organ system Respiratory Endocrine Nails Immune Hair Teeth Circulatory Ear Gastrointestinal Limbs Blood Gentourinary Metabolic Craniofacial Skin Eye Musculoskeletal Nervous system Integument (includes skin, hair and nails) Percent of phenotypes with system affected 1 4 5 5 6 8 9 9 9 10 11 13 15 16 21 28 30 34 35 Recessive Allele 6 5 4 3 2 1 I have to be in charge now! Damaged Allele 6 5 4 3 2 1 4 4 3 3 2 2 1 1 1 1 2 2 3 3 1 1 2 2 3 3 4 4 5 5 6 6 Pedigree Marriage Unaffected Offspring illegitimate Affected Marriage consanguineous Propositus Twins dizygous Heterozygous gene carier Autosomal recessive Heterozygous gene carier X-Link recessive Twins monozygous Subject without offspring Deceased Sex unknown Abortion or stilbirth Pedigree symbols Clues that suggest a Mendelian disease • Positive family history. • Characteristic syndrome. • Unusual syndrome Progressive neurologic deterioration. Multiple organ system abnormalities. Intermittent neurologic symptoms. • Lack of environmental or other primary cause of symptoms and signs. Taking a family history • Inquire about the health of each family member through second degree relatives (grandparents, first cousins). • Pay special attention to any signs or symptoms related to your patient’s condition in relatives. • Inquire about causes of any deaths, including any stillbirths or early deaths, institutionalizations. • Obtain medical (and death) records of relatives as well as of proband. • Inquire about any possible consanguinity. • Recognize that false paternity does occur. Autosomal dominant disorders Dominant 6 5 2 Quit ! I will speak for both of us Normal 6 5 4 4 3 3 2 2 1 1 1 4 4 3 3 2 2 1 1 1 1 1 2 2 3 3 1 1 2 2 3 3 4 4 5 5 6 6 Autosomal dominant disorders Autosomal dominant disorders comprise the majority (about 68%) of known human Mendelian conditions. Clear evidence of transmission from one generation to the next. Genearl characteristics Generally there is a family histry of the same disorder. The phenotype appears in every generation. a. Each affected individual has an affected parent. b. Exceptions to this rule occur if: There is a new mutation. There is reduced penetrance of the phenotype. The age of onset varies. The severity of conditions is variable and diffeculte to predict. Autosomal dominant Phenotypically normal parents do not transmit the trait, unless there is lack of penetrance, or the apparently 'normal' parent has unrecognized signs. Affected people are heterozygous for the abnormal allele. Autosomal dominant traits Every affected individual should have at least 1 affected parent. Affects males and females equally. Homozygous dominant condition is often fatal. Difficult to determine with small families. Transmision A child of an affected parent has a 50% chance of inheriting the trait. Males and females are equally at risk. Affected individuals may have unaffected children. Males can transmit to males or femaless and vice versa. Unaffected persons do not transmit the condition. Male to male transmission occurs. Autosomal dominant disorder Parents Gametes A Offspring Aa aa Aa a Aa 1:1 a a aa aa Altered Dominant Genes Homozygosity for a dominant disorder Uncommon unless two people with the same disorder marry. The risk is 25% homozygous affected (lethal). 50% heterozygous affected. 25% homozygous normal. Homozygosity for a dominant disorder Homozygous affected Heterozygous affected Dominant disorder with lack of penetrance Seen in person who inherits the gene but he does not devolop the disorder. The risk of such people to transmit the disorder to their children is about 10%. Non-genetic factor favor the expresion of dominant genes. Example: Drug in porphyria. Diet in hypercholesterlaemia. Example of autosomal dominant disorder • Achondroplasia. • Mytonic dystrophy. • Tuberous sclerosis. • Noonan’s syndrome. • Huntington’s disease. • Epidermolysis bullosa. • Adult polycystic kidney. • Familial hypercholesterolaemia. • Familial adenomatous polyposis. Autosomal recessive disorder Autosomal Recessive Trait (e.g. disease) due to absence of normal gene, since autosomal (and therefore two copies of each chromosome) requires two abnormal gene copies (i.e. alleles). Therefore, abnormal gene must come from both parents. Autosomal recessive traits • Males and females equally affected. • 1/4 of offspring will be affected. • Trait typically found in siblings, not parents. • Parents of affected children may be related. • Trait may appear as isolated event in small families. Inheritance Recognized by: a. 1/4 th of offspring affected b. males = females among affected. c. In general, parents unaffected. d. For rare disorders, increased consanguinity. Autosomal recessive inheritance • The risk to each sib of an affected individual of showing the phenotype is 25 %. • Consanguinity significantly increases the risk of manifesting a recessive phenotype. • Males and females are equally likely to be affected. • Ethnicity and geographic isolation may affect the frequency of recessive conditions in a population. Autosomal recessive disorder • Occur in the offspring of a carrier parents. • The risk for the offspring is 25%. • There is no family history in general. • Commonly severe. • Prenatal diagnosis for recessive disorder is indicated after the 1st affected child. Consanguinity parents are more likely to carry the increases the risk of a recessive disorder (both same defective gene). How did they get this frequent? Two mechanisms: 1) Selection, e.g. heterozygote advantage against malaria in sickle cell disease. 2) Genetic drift, founder population of relatively small sample size. Autosomal recessive disorders Examples of autosomal recessive disorder • Thalassaemia. • Cystic fibrosis. • Galactosaemia. • Sickle cell disease. • Hurler’s syndrome. • Haemochromatosis. • Congenital adrenal hyperplasia. Consanguinity and autosomal recessive inheritance Disease Ethnic Group Frequency • Sickle cell disease African-American 1/600 • Beta-thalassemia Italians, Greeks 1/3600 • Alpha-thalassemia Southeast Asians 1/2500 • Familial mediterranean fever Armenians/N. African Jews 1/200 Sickle cell • Sickle trait (the presence of any HbS) is dominant, but is generally asymptomatic unless extremely hypoxic (e.g. unpressurized at high altitude) • Sickle cell anemia is recessive • Clinical syndrome: – Painful abdominal and bone crises brought out especially by hypoxia, but often unpredictable – Complications include infarcts of internal organs and joints – May autosplenectomize, leading to predisposition to infections X-linked inheritance Menelian Inheritance X-link dominant disorder • Incontinentia pigmenti. • Rickets resistant to vitamin D. X-link recessive disorder • Glucose-6-phosphate dehydrogenase. • Duchenne muscular dystrophy. • Haemophilia A, B. • Ocular albinism. • Color blindness. Affected male and a normal female The trait is never passed to son, all female affected X Healthy X X Healthy Healthy Normal male and affected female 1/2 the sons affected and 1/2 the daughters affected Affected Healthy Healthy Affected Hypophosphatemia Autosomal recessive disorder Aa Aa A a AA 1 25% Aa : 2 25% A a Aa aa : 1 25% Trait • Males are usually more severely affected than females. • The trait may be lethal in males. • In the general population, females are more likely to be affected than males Why? X-Linked Recessive Inheritance • Trait is more common in males than females. • An affected man passes the gene to all of his daughters. • A son of a carrier mother has a 50 % chance of inheriting the trait. • Male-to-male transmission never occurs. • Carrier females are usually asymptomatic, but some may express the condition with variable severity because of Xinactivation. X-link recessive • As with any X-linked trait, the disease is never passed from father to son. • Males are much more likely to be affected than females. If affected males cannot reproduce, only males will be affected. • All affected males in a family are related through their mothers. • Trait or disease is typically passed from an affected grandfather, through his carrier daughters, to half of his grandsons. X-linked recessive, affected father Never any Male-to-Male transmission! Normal Female Parents Gametes Offspring XX X X Affected Male XhY Xh Y hX XhX X XY XY 2 carrier daughters : 2 normal sons: X linked recessive, normal father, carrier mother 1 carrier daughter 1 normal daughter 1 affected son 1 normal son A typical X-linked recessive pedigree