GENETIC ASSESSMENT AND COUNSELING

Genetic counseling is the communication of information and advice about inherited conditions. To provide accurate information regarding the natural history and the recurrence risk of a disease to the family seeking counseling, a precise diagnosis is needed Proband : a person seeking such advise

Stages of genetic counseling

1. 2. 3. 4. 5.

Five stages can be identified in this communication process: History and pedigree construction Examination Diagnosis Counseling Follow-up.

HISTORY and PEDIGREE CONSTRUCTION

A standard medical history is required for the proband and for any other affected persons in the family; information written out in narrative form may be difficult to interpret. Pedigree is constructed using common symbols and may demonstrate patterns of transmission of familial disorders. Provides a graphic record of the family health history.

Pedigree charts

Used to show how a particular trait is passed from one generation to the next in a family

Pedigree Analysis is an Essential Tool of Human Genetics

Pedigree analysis allows deduction of modes of inheritance and prediction of probably outcomes.

Pedigree

For each individual on the diagram record information about them on the FAMILY NAMES LIST

List their name and date of birth List all serious, chronic, or recurrent illnesses or abnormalities such as:
- birth defects (specify); miscarriage/stillbirth - development delay/short stature - deafness/hearing impairment; eye problems; - muscle disease; bone or joint problems; - kidney, endocrine problems, diabetes - mental disorders, heart defects (specify) - cancer or tumors (list type, location, age diagnosed)

List all causes of death, if known and age at time of death.

Factual and health information to include in a pedigree

Age/birth date Age of death; cause of death Pregnancy complications ( e.g., miscarriage, stillbirth, pregnancy termination) Infertility vs. no children by choice Neonatal deaths, mental retardation or malformed children Relevant health information Affected/unaffected status (defined by shading of symbols in legend) Ethnic background Consanguinity Date pedigree was drawn

Autosomal dominant inheritance disease (2)

Family History Diagram (pedigree)

Draw 3 generation; indicate the proband with an arrow and use common symbols in pedigree construction. All members of the same generation are placed on the same horizontal level; roman numerals are used for each generation, starting with the earliest; Arabic numerals are used to indicate each individual within a generation (numbering for the left) When drawing a pedigree it is advisable to start at the bottom of the page with the most recent generation and work upwards.

Human monogenic disorders (Mendelian inheritance disorders) 3

symbols used in pedigree

Symbols Used in Pedigree Analysis

FOUR MAIN TYPES OF GENETIC DISEASE

Mendelian - determined by single major gene multiple genetic and non-genetic factors involved

Multifactorial Chromosomal -

visible chromosomal abnormality Mitochondrial disease

MENDELIAN AND NON-MENDELIAN DISORDERS

Mendelian Specific patterns of inheritance Rules apply even for isolated case Patterns apply universally Non Mendelian (multifactorial) No specific patterns Risk estimates vary with individual family Variation with different populations

Human monogenic disorders (Mendelian inheritance disorders) 1

disease of autosomal dominant, AD disease of autosomal recessive, AR disease of X-linked dominant inheritance, XD disease of X-linked recessive inheritance, XR disease of Y-linked inheritance

Autosomal dominant disorders

These disorders are expressed when the dominant allele is present in the genotype.

AUTOSOMAL DOMINANT INHERITANCE

Risk of transmission by affected person = 50% Risk of transmission by unaffected person = 0% (in theory) Both sexes can transmit equally

Autosomal dominant pedigree chart

A pedigree analysis shows that:

Every affected person has an affected parent. About half of the offspring of an affected person are also affected (assuming only one parent is affected). The phenotype occurs equally in both sexes.

Figure 10.10 Pedigree Analysis and Dominant Inheritance

Characteristic features of an autosomal dominant pedigree

Vertical pattern of transmission 50% chance of affected heterozygote passing gene to children Either sex can be affected in equal numbers. A new mutation in the gene resulting in the offspring being first affected and then may be inherited in a dominant fashion. Isolated cases of dominant disorders may be the result of a new mutation. Some autosomal dominant disorders exhibit reduced penetrance or appear to skip generations because the disorders is not expressed in some individuals who inherit the gene May show variable expressivity with different family members showing different manifestations of the trait. Severely affected offspring may be born to minimally affected adults. Some dominant genes code for late onset disorders.

Dominant Lethal Alleles

Dominant alleles that are lethal are much less common than lethal recessives because:

Dominant lethal allele cannot be carried by heterozygotes w/o affecting them and The afflicted individuals usually die before passing on the lethal allele

-They can escape elimination if it does not cause death until a relatively advanced age ex. Huntington disease: degeneration of the nervous system that doesnt begin until middle age.

Huntingtons Disease

Huntington's disease (HD) is an inherited, degenerative brain disorder which results in an eventual loss of both mental and physical control. The disease is also known as Huntington's chorea. Chorea means "dance-like movements" and refers to the uncontrolled motions often associated with the disease.

Huntingtons Disease
dominant progressive disorder of the nervous system that usually appears in adults 35-45 years old symptoms include involuntary movements, loss of motor control, and decline in cognitive abilities mutant alleles of HD gene contain 36 CAG repeats, compared to 26 in normal alleles
Neuropathology

Achondroplasia

A form of dwarfism Only heterozygotes have the disorder The torso is of normal size, but arms and legs are very short. Average adult height of 4 feet. 1 in 25,000 births. Gene is found on chromosome 4

Dominant Disorders

Many are non-lethal (ex. Polydactyly) Achondroplasia is a form of dwarfism

Figure 9.17

Osteogenesis Imperfecta

Characterized by bone fragility, blue sclera, conductive, mixed, or sensorineural hearing loss, and hyperelasticity of joints and ligaments Transmitted AD with variable expressivity and incomplete penetrance Two genes have been identified: COLIA1 on chromosome 17q and COLIA2 on chromosome 7q

Polydactyl

Autosomal Dominant Disorders

Neurofibromatosis Small benign tumors, made up largely of nerve cells, occur under skin or on various organs. The effects can range from mild to severe, and some neurological impairment is possible; this disorder is variably expressive. The gene for this trait is on chromosome 17.

AUTOSOMAL RECESSIVE INHERITANCE

Affected individuals homozygotes Heterozygotes essentially healthy Increased consanguinity

Autosomal recessive inherited disease 1

Characteristic features of pedigree

Both parents of the patients are generally disease-free, but are carriers . They are not aware that they carry a recessive gene until after the birth of an affected child. When both parents are carriers, there is a 25% chance with each pregnancy of having un affected child. The onset chance is equal in male and female It is unusual to find other affected individuals in preceding or succeding generations. The disorders is generally found only in sibs, thus resulting in a horizontal pattern of inheritance. There is no patient in the children of patients. This disease dont transmit continuously. It is often sporadic. Disease risk in the children of consanguineous mating is higher than the children of non-consanguineous mating

Autosomal recessive inherited disease 2

CONSANGUINITY AND RECESSIVE DISORDERS

Consanguinity is note more often among the parents of individuals with rare recessive disorders. Without family history, increased risk small With recessive disorder, risk may be high Risks fall off rapidly with genetic distance

Autosomal recessive inherited disease 4

figure 10-11.jpg

Figure 10.11

Figure 10.11

Sickle Cell Anemia

An inherited, chronic disease in which the red blood cells, normally discshaped, become crescent shaped. As a result, they function abnormally and cause small blood clots. These clots give rise to recurrent painful episodes called "sickle cell pain crises".

Testing for PKU (Phenylketonuria)

PKU results from the absence of an enzyme required to metabolize excess amounts of the amino acid phenylalanine high levels of phenylalanine in the blood cause brain damage, seizures and mental retardation damage in newborns can begin within weeks after starting to drink breast milk and formula the blood test for newborns 2-3 days after birth measures the levels of phenylalanine babies with PKU have to stay on a low-protein diet

PKU (phenylketonuria)

The body cannot break down the amino acid phenylalanine If not detected early, or if a specific diet is not followed, serious brain damage can occur. 1 in 60 Caucasians are carriers of the gene that causes PKU. The gene is found on chromosome 12

PKU

Phenylalanine is an essential amino acid and is found in nearly all foods which contain protein, dairy products, nuts, beans, tofu etc. A low protein diet must be followed. Brain damage can result if the diet is not followed causing mental retardationand mousy body odor (phenylacetic acid is in sweat).

Tay-Sachs disease

Monogenic, autosomal recessive Central nervous system degrades, ultimately causing death. Most common among people of Jewish, eastern Europe descent.

Incomplete Dominance

Persons with Tay Sachs lack a crucial enzyme to metabolize a type of lipid. The lipids accumulate in the brain interfering with normal function. Causes regression of nervous system, - blind, deaf, bedridden, inability to move limbs Cherry red spot in retina Heterozygotes have an intermediate level of the lipid metabolizing enzyme

Patients are unable to produce skin or eye pigments, and thus are light-sensitive Autosomal recessive

Albinism

Albinism

1. 2.

Lack of pigment in skin, hair, and eyes. Approx. 1 in 17,000 people Dangers: Eye problems Severe sensitivity to sunburn.

A Heterogeneous Trait/Disease is One That May be Caused by Mutations in More Than One Gene
Human deafness is one example of a heterogeneous trait: mutations in any of at least 50 genes lead to deafness. How can one tell if two deaf individuals carry mutations in the same gene or mutations in different genes?

Complementation Tests Reveal Whether Individuals Expressing a Recessive Trait Carry Mutations in the Same or Different Genes

Two deaf parents produce all normal hearing offspring.

Although illustrated for a human recessive trait, realize that controlled complementation tests are not carried out in humans but only in experimental organisms.

Complementation Tests Reveal Whether Individuals Expressing a Recessive Trait Carry Mutations in the Same or Different Genes

Two deaf parents produce all deaf offspring.

Although illustrated for a human recessive trait, realize that controlled complementation tests are not carried out in humans but only in experimental organisms.

Another Inadvertent Complementation Test

A cross between two albino parents reveals that at least two genes can be mutated to generate albinism.

X-LINKED INHERITANCE

Many important genes on X c.500 known diseases or characteristics Mostly recessive - so usually only seen in males Dominants lethal in male

X-linked genes are never passed from father to son. The Y chromosome is the only sex chromosome that passes from father to son. Males are never carriers if they have a mutated gene on the X chromosome, it will be expressed. Males are termed hemizygous for genes on the X chromosome.

X-linked dominant

X-linked dominant diseases are those that are expressed in females when only a single copy of the mutated gene is pres ent . Very few X-linked dominant diseases have been identified (e.g. hypophosphatemic rickets, Alport syndrome, diabetes insipidus) hypophosphatemic rickets or vitamin D resistant rickets >>>low serum phosphorus, skeletal abnormalities Alport syndrome, which involves progressive hearing loss and progressive kidney problems.

hypophosphatemic rickets

Pattern for inheritance

Mating A

Mating B

Characteristics of X-linked dominant diseases include:

Never passed from father to son. Affected males produce only affected females. An affected male only has one X chromosome to pass on to his daughte rs Affected females produce 50% normal and 50% affected offspring.. >>>> heterozygous Males are usually more severely affected than females. Some X-linked dominant traits may even be lethal to males . Females are more likely to be affected. Since females have 2 X chromosomes, they have 2 chances to inherit the mut ated allele.

The pattern for the pedigree of Xlinked dominant inheritance

Amelogenesis Imperfecta-1

a-s.clayton.edu/hampikian/ b4201/reportsChap6.html

: X-linked dominant Gene name: Amelogenin, Chromosome location: Xp22.3-p22.1 Altered Cellular function: Abnormal tooth enamel Symptoms: Very hard enamel, thin enamel, small teeth, and/or rough teeth Incidence: Rare

X-linked recessive

hereditary pattern in which a recessive gene on the X chromosome results in the manifest ation of characteristics in male offspring and a carrier state in female offspring X-linked recessive diseases are those in which a female must have two copies of the mutant allele in order for the mutant phenoty pe to develop.

X-Linked Recessive Inheritance

Disorders more commonly affect males Heterozygote female will pass the gene to 50% of her sons who will express the trait, and to 50% of her daughters who will be carriers for the trait Affected males pass the gene to all of their daughters and none of their sons Hallmark is absence of male to male transmission

X-Linked Disorders

In pedigree charts that show the inheritance pattern for X-linked recessive disorders, more males than females have the trait because recessive alleles on the X chromosome are expressed in males. A grandfather passes an X-linked recessive disorder to a grandson through a carrier daughter. X-linked recessive disorders include red-green color blindness, muscular dystrophy, and hemophilia.

X-linked recessive pedigree chart

The pattern for the pedigree of Xlinked recessive inheritance

Pedigree analysis of X-linked recessive phenotypes:

The phenotype appears much more often in males than in females. A male with the mutation can pass it only to his daughters. Daughters who receive one mutant X are heterozygous carriers. The mutant phenotype can skip a generation if the mutation is passed from a male to his daughter and then to her son.

X-LINKED INHERITANCE Some important examples

Duchenne muscular dystrophy Haemophilia (A and B) Fragile X mental retardation X-linked immune deficiencies Colour blindness

Hemophilia

A disorder in which a persons blood does not clot properly. Gene found on X chromosome. 1 in 10,000 males born are afflicted.

Hemophilia, the royal disease

Hemophilia is the oldest known hereditary bleeding disorder. Caused by a recessive gene on the X chromosome. There are about 20,000 hemophilia patients in the United States. One can bleed to death with small cuts.

The severity of hemophilia is related to the amount of the clotting factor in the blood. About 70% of hemophilia patients have less than one percent of the normal amount and, thus, have severe hemophilia.

Hemophilia

Hemophilia refers to the lack of one of several clotting factors that leads to excessive bleeding in affected individuals. Hemophiliacs bleed externally after injury, but also bleed internally around joints. Hemorrhages can be stopped with blood transfusions or a biotechnology clotting factor.

Hemophilia

www.pathguy.com/ lectures/hemophilia.jpg

www.thecrookstoncollection.com/ Collection/med

Hemophilia

The blood fails to clot normally Lacking a blood clotting factor VIII(antihemophilic globulin, AHG),IX bleeding from even minor cuts in 1,500 newborn males. Most (75%) have hemophilia A, a lack of clotting factor VIII. Hemophilia B- "Christmas Disease" is a defect in clotting factor IX. Transfusions of fresh whole blood or plasma or factor concentrates control bleeding

X linkage recessive inherited disease 2

Britain's Queen Victoria has the hemophilia gene, and passed on to her children. Hemophilia is a hereditary coagulation disorder disease, the patient may be death due to the small wound and unremit bleeding. Queen Victoria's granddaughter, Alexandra (21) marrid with the Russian Czar Nicholas II, leading to their son with hemophilia.

A Pedigree of Hemophilia in the Royal Families of Europe

www.people.virginia.edu/ ~rjh9u/gif/roylhema.gif

Muscular Dystrophy

Muscular dystrophy is characterized by the wasting of muscles. The most common form is Duchenne muscular dystrophy; this is an X-linked disorder, occurring in 1 of 3,600 males. Muscles weaken, frequent falls and difficulty in rising occur early; death occurs by age 20.

Duchenne muscular dystrophy involves the absence of a protein called dystrophin that is involved in the release of calcium from the sarcoplasmic reticulum of muscle cells. The lack of dystrophin causes calcium to leak into the cell, which promotes the action of an enzyme that dissolves muscle fibers. A test is now available to determine the carriers of Duchenne muscular dystrophy.

Duchene muscular dystrophy

Color Blindness

Three types of cones are in the retina detecting red, green, or blue. Genes for blue cones are autosomal; those for red and green cones are on the X chromosome. Males are much more likely to have red-green color blindness than females. About 8% of Caucasian men have red-green color blindness.

Color Blindness

Cause: x-linked recessive 1/10 males have, 1/100 females have. Why the difference? Individuals are unable to distinguish shades of red-green. Are you color blind?

Figure 10.24 Red-Green Color Blindness Is a Sex-Linked Trait in Humans

X-Linked Alleles

The key for an X-linked problem shows the allele attached to the X as in: XB = normal vision Xb = color blindness. Females with the genotype XBXb are carriers because they appear to be normal but each son has a 50% chance of being color blind depending on which allele the son receives. XbXb and XbY are both colorblind.

Y linkage genetic disorder

All male genetic
Testicular determinig factor (TDF) and azoospermia factor(AZF)

The very tragic disease hairy ears

Y-linked trait, which are rare symptomshairy ears

Beyond Simple Inheritance Patterns

Polygenic Inheritance

Several pairs of genes may be involved in determining the phenotype in interaction with environmental factors Individuals who have a first or second degree relative with such a polygenic multifactorial disorder should be referred for counseling, given that their risk of having an affected child. The recurrence risk to sibs or the offspring of an affected individual is ~ 3-5%. The recurrence risk increases when more family members are affected or the parents are related

Polygene Inheritance

Depends on several different gene pairs at different loci acting in tandem Results in continuous phenotypic variation between two extremes Examples: skin color, eye color, and height Examples of multifactorial disorders include cleft lip and palate, neural tube defect, mental disorders, pyloric stenosis, diabetes.

Extrachromosomal (Mitochondrial) Inheritance

All mitochondrial genes are transmitted by the mother Unusual muscle disorders and neurological problems have been linked to these genes

Mitochondrial disease

Caused by a mutation in the small amount of DNA present in the mitochondria of cells Inherited only from the mother because sperm do not transmit mitochondria to the offspring Expression of disease varies between affected people because only a fraction of the mitochondria harbor the mutation Typical mitochondrial disorders gradually worsen

Mitochondrial Inheritance

ANALYSIS OF THE PEDIGREE - CONCLUSIONS

Detecting pattern depends on accurate information Identifying inheritance pattern greatly affects risk estimates Important decisions people make will depend on accuracy of your knowledge

Recurrence Risk

AD: can range from 50% to less depending on the gene's penetrance AR: children of heterozygotes have 25% chance of having the disorder and 50% chance of being a carrier

Recurrence risk for carriers depends on the status of their mate

X-linked: male offspring of maternal carrier of recessive trait are at 50% risk of being affected; female offspring are at 50% risk of being a carrier Mitochondrial disorder: depends on whether mother is homoplasmic or heteroplasmic

Analysis of the pedigree: Carrier Recognition in the Autosomal Recessive Disease

Identification of the heterozygote unaffected carriers Two major avenues are used to identify carriers: pedigrees and blood tests Pedigrees trace a particular genetic trait through several generations; helps to predict the future Blood tests and DNA probes can detect the presence of unexpressed recessive genes