MEDICAL GENETICS & MENDELIAN INHERITANCE MOHAMED FAKHRY 2015 1

MEDICAL GENETICSMEDICAL GENETICS&&

MENDELIAN INHERITANCEMENDELIAN INHERITANCE

MOHAMED FAKHRY 20151

GENETICS GENETICS HeredityHeredity & its variation

HUMAN GENETICS HUMAN GENETICS It is the science of heredity & its variation in humanhuman

MEDICAL GENETICSMEDICAL GENETICSItIt deals with human genetic variations of medicalmedical

relevance and/or significance .


Subgroups of Medical GeneticsSubgroups of Medical GeneticsMolecular & Biochemical GeneticsMolecular & Biochemical Genetics The study of the structure and function of individual genesgenes

Cytogenetics Cytogenetics The study of the structure of chromosomeschromosomes

Immunogenetics Immunogenetics The study of the genetics of the immuneimmune system

Clinical GeneticsClinical Genetics It concerned with clinical manifestation clinical manifestation of genetic diseases

Genetic EpidemiologyGenetic EpidemiologyThe study of epidemiologyepidemiology of genetic diseaseEpidemiology = The branch of medicine that deals with the incidence, distribution, and possible control of diseases and other factors relating to health

Population GeneticsPopulation Genetics The study of genetics of populationspopulations

3

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.


CYTOGENETICS It 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 analysisA. Postnatal 1) Newborn infant with birth defect2) Children with learning disability3) Children with dysmorphic features4) Recurrent miscarriage

B. Prenatal 1) Abnormalities on ultrasound scan2) Increased risk of Down syndrome (↑maternal age)3) Previous child with a chromosomal abnormality4) One parent carries a structural chromosomal abnormality 5

MOLECULAR GENETICSIs 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 analysis1)Cystic fibrosis2)Haemoglobinopathies3)Duchenne and Becker muscular dystrophy4)Myotonic dystrophy5)Spinal muscular atrophy6)Hereditary neuropathy7)Familial breast cancer

6


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

GENETIC REGISTERS None has his/her details included on a register without giving informed consent ل = المسبقة الموافقة

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


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

AllelesAlleles

10

HeterozygousHeterozygousHomozygousHomozygous

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 symptoms

2. -----→Autosomal Dominant Inheritance

Variable expressivity = التعبير في اختالفMany 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



New MutationNew 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

2. -----→Autosomal Dominant Inheritance

General Characteristics Of Autosomal Dominant Inheritance General Characteristics Of Autosomal Dominant Inheritance

1. Males and females are equally affected2. Disorder are transmitted by both sexes3. Successive generations will be affected4. Male to male transmission occurs

Examples of Autosomal Dominant DisordersExamples of Autosomal Dominant Disorders

1) Acute intermittent porphyria2) Facioscapulohumeral dystrophy3) Familial breast cancer4) Familial hypercholesterolaemia5) Myotonic dystrophy6) Spinocerebellar ataxia


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


-----→ 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 disorders1) Haemoglobinopathies are the most common autosomal recessive disorder

worldwide; 1in 6 or 1 in 10 are carriers2) Cystic fibrosis is the commonest autosomal recessive disorder in children of

Europeans; 1 in 25 of the population are carriers3) Deafness (some forms) 4) Phenylketonurea5) Sickle cell disease6) Thalassaeemia

Uniparental disomyChild 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)

-----→ 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 affected2. Both parents are unaffected carriers3. Two out of three unaffected siblings are carriers4. Parental consanguinity increased the incidence of autosomal recessive

disorders


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

Examples of X Linked Recessive Disorders

1. Becker muscular dystrophy2. Duchenne muscular dystrophy3. Colour blindness4. G-6P-D deficiency5. Haemophilia A, B6. Ocular Albinism7. Retinitis pigmentosa

Charateristics of X Linked Recessive Inheritance

1) Males are almost affected2) Transmission occurred through carrier females3) Males to males does not occur4) All daughters of affected males are carrier


20

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


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


MENDELMENDEL''S LAWS OF INHERITANCES LAWS OF INHERITANCE

Three Laws of InheritanceThree Laws of Inheritance

The Law of Unit Inheritance The Law of Segregation The Law of Independent Assortment


The Law of Unit InheritanceThe 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 2nd (As t is recessive & does not appear) generation (T= Tall, dominant gene; t = Short, recessive gene)


The Law of SegregationThe Law of SegregationThe 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

GAMETE

25

The Law of Independent AssortmentMembers 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

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

Documents

MEDICAL GENETICS & MENDELIAN INHERITANCE MOHAMED FAKHRY 2015 1