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MEDICAL GENETICS & MENDELIAN INHERITANCE MOHAMED FAKHRY 2015 1.

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Presentation on theme: "MEDICAL GENETICS & MENDELIAN INHERITANCE MOHAMED FAKHRY 2015 1."— Presentation transcript:

1 MEDICAL GENETICS & MENDELIAN INHERITANCE MOHAMED FAKHRY

2 GENETICS Heredity Heredity & its variation HUMAN GENETICS human It is the science of heredity & its variation in human MEDICAL GENETICS Itmedical It deals with human genetic variations of medical relevance and/or significance. MOHAMED FAKHRY

3 Subgroups of Medical Genetics Molecular & Biochemical Genetics genes The study of the structure and function of individual genesCytogenetics chromosomes The study of the structure of chromosomes Immunogenetics Immunogenetics immune The study of the genetics of the immune system Clinical Genetics clinical manifestation It concerned with clinical manifestation of genetic diseases Genetic Epidemiology epidemiology The study of epidemiology of genetic disease Epidemiology = The branch of medicine that deals with the incidence, distribution, and possible control of diseases and other factors relating to health Population Genetics populations The study of genetics of populations 3

4 Common Reasons For Referral To Genetic Clinic 1.Children with congenital abnormalities (birth defects), learning disability dysmorphic features. 2.Couples who have lost a child or stillborn baby with a congenital abnormality. 3.Couples who have reproductive loss as termination of pregnancy due to fetal abnormality or recurrent miscarriage (recurrent abortion). 4.Children and adults when a family history of known genetic disorder. 5.Individuals with a family history of a common condition with a strong genetic component, including familial cancers. MOHAMED FAKHRY

5 CYTOGENETICS  I t concerned with analysis of chromosomes on a variety of samples including whole blood, amniotic fluid, placental samples, cultures of solid tissues and bone marrow aspirates  Routine chromosomal analysis requires the study of metaphase chromosome in cells  Common reasons for cytogenetic analysis A.Postnatal 1)Newborn infant with birth defect 2)Children with learning disability 3)Children with dysmorphic features 4)Recurrent miscarriage B.Prenatal 1)Abnormalities on ultrasound scan 2)Increased risk of Down syndrome (↑maternal age) 3)Previous child with a chromosomal abnormality 4)One parent carries a structural chromosomal abnormality 5

6 MOLECULAR GENETICS  Is the study of structure and function of individual genes  DNA can be extracted from any tissue containing nucleated cells including stored tissue blocks  Tissues include; whole blood collected into EDTA anticoagulant, buccal samples obtained by scraping the inside of the cheek or by mouth wash  After the extraction of DNA, frozen DNA samples can be stored to be used in the future  Some common reasons for molecular genetic analysis 1)Cystic fibrosis 2)Haemoglobinopathies 3)Duchenne and Becker muscular dystrophy 4)Myotonic dystrophy 5)Spinal muscular atrophy 6)Hereditary neuropathy 7)Familial breast cancer 6

7 MOHAMED FAKHRY BIOCHEMICAL GENETICS Routine neonatal screening for conditions such as phenylketonurea (PKU; due to deficiency of phenylalanine hydroxylase ) and congenital hypothyroidism are done on neonatal blood samples taken from all newborn babies

8 GENETIC REGISTERS  None has his/her details included on a register without giving informed consent = الموافقة المسبقة ل  The register functions as a reference list of cases for diagnostic information and also to facilitate patient management  Registers are particularly useful for disorders amenable = liable to DNA analysis including dominant disorder with late onset (such as myotonic dystrophy), X-linked disorder (such as Duchenne and Becker muscular dystrophy where carrier testing is done to female relatives) and chromosomal translocations where relatives are offered carrier testing  Registers can also provide data on the incidence and natural course of disease as well as used to monitor the control and effectiveness of services MOHAMED FAKHRY

9 MENDELIAN INHERITANCE I.Original Principle Of Mendelian Inheritance  Genes are represented in pairs, one inherited from each parent  Each individual gene have two different alleles which can act in dominant or recessive way  During meiosis =, segregation of alleles occurs so that each gamete receive one allele  Alleles at different loci segregate independently 9

10 Alleles 10 Heterozygous Homozygous

11 11 2.Autosomal Dominant Inheritance  The autosomal dominant disorders affect both males and females  The affected people are heterozygous for the abnormal alleles (one allele is abnormal and the other allele is normal) and transmit this disorder to half of their offspring (males or females)  Dominant disorder may have a late or variable onset of signs and sym ptoms

12 →Autosomal Dominant Inheritance  Variable expressivity = اختلاف في التعبير Many of autosomal dominant conditions varies between different affected individual within the same family and this called variable expressivity due to instability of underlying mutation or due to unexplained cause  Lack of penetrance 1.Few dominant disorders who inherits the gene does not develop the disorder; this phenomenon has been shown in retinoblastoma, otosclerosis and hereditary pancreatitis. Retinoblastoma; the person need a second somatic mutation to occur before the person develops an eye tumor 2.Non genetic factors may also influence the expression and penetrance of dominant gene for example diet in hypercholesterolemia, drugs in porphyria and anesthetic drugs in malignant hyperthermia MOHAMED FAKHRY

13 MOHAMED FAKHRY  New Mutation New mutation lead to presence of a dominant disorder in a person who does not have a family history of the disease before  Homozygosity Homozygosity for dominant genes is uncommon, it is happening only when two parents with the same disorder have children. This lead to two out of three surviving children will be affected →Autosomal Dominant Inheritance

14  General Characteristics Of Autosomal Dominant Inheritance 1.Males and females are equally affected 2.Disorder are transmitted by both sexes 3.Successive generations will be affected 4.Male to male transmission occurs  Examples of Autosomal Dominant Disorders 1)Acute intermittent porphyria 2)Facioscapulohumeral dystrophy 3)Familial breast cancer 4)Familial hypercholesterolaemia 5)Myotonic dystrophy 6)Spinocerebellar ataxia MOHAMED FAKHRY

15 3.Autosomal Recessive Inheritance  Most mutations inactivate genes and act recessively. Autosomal recessive disorders occur in individuals who are homozygous for a particular recessive genes ( have two abnormal alleles of that gene), inherited from parents that carry the mutant genes in the heterozygous state  Autosomal recessive disorders are commonly sever, and many of the inborn errors of metabolism are of autosomal recessive inheritance MOHAMED FAKHRY

16 -----→ Autosomal Recessive Inheritance  Many complex malformations syndromes are also due to autosomal recessive disorders and their detection in the first affected children in the family is important because of high risk recurrence rate  Prenatal diagnosis of recessive disorders can be done by biochemical assays, DNA analysis and ultrasound scanning to recognize any abnormalities  Examples of autosomal recessive disorders 1)Haemoglobinopathies are the most common autosomal recessive disorder worldwide; 1in 6 or 1 in 10 are carriers 2)Cystic fibrosis is the commonest autosomal recessive disorder in children of Europeans; 1 in 25 of the population are carriers 3)Deafness (some forms) 4)Phenylketonurea 5)Sickle cell disease 6)Thalassaeemia  Uniparental disomy Child can inherits two copies of a particular chromosome (carries an autosomal recessive genes) from one parent and none from the other parent → Affected homozygote (carry two affected recessive genes)

17 -----→ Autosomal Recessive Inheritance  Consanguinity Consanguinity increase the risk of a recessive disorder because both parents more likely to carry the same defective gene that has been inherited from a common ancestor. It increase the risk of severe abnormalities including recessive disorder is about 3% above the risk in the general population  Characteristics of autosomal recessive inheritance 1.Males and females are equally affected 2.Both parents are unaffected carriers 3.Two out of three unaffected siblings are carriers 4.Parental consanguinity increased the incidence of autosomal recessive disorders MOHAMED FAKHRY

18 4.X Linked Recessive Inheritance  In X linked recessive conditions, males are affected because they have only a single copy of gene carried by the X chromosome (hemizygosity) but the disorder can be transmitted through female carrier  The absence of male to male transmission is a hallmark of X linked inheritance  Many X linked recessive disorder are severe and some are fatal during early life so that the affected male do not reproduce 18

19 Examples of X Linked Recessive Disorders 1.Becker muscular dystrophy 2.Duchenne muscular dystrophy 3.Colour blindness 4.G-6P-D deficiency 5.Haemophilia A, B 6.Ocular Albinism 7.Retinitis pigmentosa Charateristics of X Linked Recessive Inheritance 1)Males are almost affected 2)Transmission occurred through carrier females 3)Males to males does not occur 4)All daughters of affected males are carrier MOHAMED FAKHRY

20 20

21 5. X Linked Dominant Inheritance  The X linked dominant gene will lead to disorder that affects both males (hemizygous) and heterozygous females  The genes are transmitted in the same way as in X linked recessive genes; females transmit the mutant gene to half of their sons and half of their daughters, while males transmit the mutant gene to all their daughters and no one of their males MOHAMED FAKHRY

22 6.Y Linked Inheritance  In Y linked inheritance, males are only affected, and the transmission is from a father to all his sons through the Y chromosome  Y liked inheritance is probably autosomal dominant  Genes involved in male development and spermatogenesis are carried by the Y chromosome MOHAMED FAKHRY

23 MENDEL ' S LAWS OF INHERITANCE Three Laws of Inheritance  The Law of Unit Inheritance  The Law of Segregation  The Law of Independent Assortment MOHAMED FAKHRY

24 The Law of Unit Inheritance The characteristics (traits i.e. genes) do not blend (mix), but are inherited as units, which might not be expressed in the first generation offsprings, but may appear unaltered in later generations. First Generation Second Generation TT t t Tt Tt Tt Tt Tt Tt TT Tt Tt tt All tall in the first generation 75% Tall and 25% short in 2 nd (As t is recessive & does not appear) generation (T= Tall, dominant gene; t = Short, recessive gene) MOHAMED FAKHRY

25 The Law of Segregation The two members of a single trait (gene) i.e. alleles, are never found in the same gamete, but always segregate and pass to different gametes The failure of two alleles to segregate due to chromosome non-disjunction give rise to genetic defects (e.g. in Down’s syndrome) Germ line cell GAMETE 25

26 The Law of Independent Assortment Members of different gene pairs assort to the gametes independently of one another i.e. random recombination of maternal and paternal chromosomes occur in gametes. Maternal Paternal Crossing-over Gametes Maternal Paternal Crossing-over Gametes 26

27 The exceptions to Law of Independent Assortment (not recognized by Mendel) are closely "linked“ genes on the same chromosome, which do not assort independently Maternal Paternal Crossing-over Gametes 27


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