Medical Genetics

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A 7-year-old child with Down syndrome is admitted to the paediatric ward.

What is the genetic basis of the disorder?

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Down syndrome results when abnormal cell division involving chromosome 21 occurs. These cell division abnormalities result in extra genetic material from chromosome 21, which is responsible for the characteristic features and developmental problems of Down syndrome. Any one of three genetic variations can cause Down syndrome:

Trisomy 21. About 95 percent of the time, Down syndrome is caused by trisomy 21 — the child has three copies of chromosome 21 (instead of the usual two copies) in all cells. This is caused by abnormal cell division during the development of the sperm cell or the egg cell.

Mosaic Down syndrome. In this rare form of Down syndrome, children have some cells with an extra copy of chromosome 21. This mosaic of normal and abnormal cells is caused by abnormal cell division after fertilization.

Translocation Down syndrome. Down syndrome can also occur when part of chromosome 21 becomes attached (translocated) onto another chromosome, before or at conception. These children have the usual two copies of chromosome 21, but they also have additional material from chromosome 21 attached to the translocated chromosome.

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How would the diagnosis have been made?

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After birth, the initial diagnosis of Down syndrome is often based on the baby's appearance. But the features associated with Down syndrome can be found in babies without Down syndrome, so your health care provider will likely order a test called a chromosomal karyotype. Using a sample of blood, this test analyzes your child's chromosomes. If there's an extra chromosome 21 present in all or some cells, the diagnosis is Down syndrome.

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Diagnostic tests that can identify Down syndrome include:

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Amniocentesis. A sample of the amniotic fluid surrounding the fetus is withdrawn through a needle inserted into the mother's uterus. This sample is then used to analyze the chromosomes of the fetus. Doctors usually perform this test in the second trimester, after 15 weeks of pregnancy. The test carries a slight risk of miscarriage, but risk increases if it's done before 15 weeks.

Chorionic villus sampling (CVS). In CVS, cells are taken from the placenta and used to analyze the fetal chromosomes. Typically performed in the first trimester, after 10 weeks of pregnancy, this test appears to carry a somewhat higher risk of miscarriage than second trimester amniocentesis.

Cordocentesis. In this test, also known as percutaneous umbilical blood sampling or PUBS, fetal blood is taken from a vein in the umbilical cord and examined for chromosomal defects. Doctors can perform this test between 18 and 22 weeks of pregnancy. This test carries a significantly greater risk of miscarriage than does amniocentesis or CVS, so it's only offered when results of other tests are unclear and the desired information can't be obtained any other way.

Front 4

What is the normal male chromosome complement?

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The normal male chromosome complement is 46 chromosomes, including the sex chromosomes XY.

Front 5

Name a factor that increases the risk of a mother having a child with Down syndrome

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Age (over 40 increased risk)

Front 6

Name a human genetic disease where ethnic differences in disease prevalence are notable. For the example you have chosen, discuss briefly relevant selective pressure(s).

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Thelassemia - a blood related genetic disorder which involves the absence of (or errors in) genes responsible for the production of haemaglobin (alpha (chromosome 16) or beta subunits (chromosome 11) can be affected)

There can be various gradations of the disease depending on the gene and the type of mutations.

Prevalence: the alpha and beta thalassaemias are the most common inherited single-gene disorders in the world with the highest prevalence in areas where malaria was or still is endemic.

The burden of this disorder in many regions is of such a magnitude that it represents a major public health concern. For example in Iran, it is estimated that about 8,000 pregnancies are at risk each year. In some endemic countries in the Mediterranean region, long-established control programs have achieved 80-100% prevention of newly affected births.

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Genetic testing and counselling, and prenatal diagnosis

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play an increasingly important role in informing individual as well as professional decisions around the prevention, management and treatment of this disease.

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Haemophilia

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Haemophilia is a hereditary (sex-linked recessive disorder) bleeding disorder, in which there is a partial or total lack of an essential blood clotting factor. It is a lifelong disorder, that results in excessive bleeding, and many times spontaneous bleeding, which, very often , is internal.

Haemophilia A is the most common form, referred to as classical haemophilia. It is the result of a deficiency in clotting factor 8, while haemophilia B (Christmas Disease) is a deficiency in clotting factor 9.

Prevalence: Due to the sex-linkage of the disorder, there is a greater prominence in males than in females. About a third of new diagnoses are where there is no previous family history. It appears world-wide and occurs in all racial groups. About 6,000 people are affected with haemophilia in the UK. There are about 5400 people in the UK with haemophilia A and about 1100 with haemophilia B.

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Cystic fibrosis diagnosis

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The sweat test - measures the amount of salt in sweat

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Cystic Fibrosis

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Cystic fibrosis is a genetic disorder that affects the respiratory and digestive systems.People with cystic fibrosis inherit a defective gene on chromosome 7 called CFTR (cystic fibrosis transmembrane conductance regulator).

The protein produced by this gene normally helps salt (sodium chloride) move in and out of cells. Chloride channel.

More than 1,000 different mutations in the CFTR gene have been identified in cystic fibrosis patients. The most common mutation (in 70% of cystic fibrosis patients) is a three-base deletion in the DNA sequence, causing an absence of a single amino acid in the protein product.

If the protein doesn't work correctly, that movement is blocked and an abnormally thick sticky mucus is produced on the outside of the cell. The cells most seriously affected by this are the lung cells. This mucus clogs the airways in the lungs, and increases the risk of infection by bacteria.The thick mucus also blocks ducts in the pancreas, so digestive enzymes can't get into the intestines. Without these enzymes, the intestines cannot properly digest food.

People who have the disorder often do not get the nutrition they need to grow normally.

Finally, cystic fibrosis affects the sweat glands. Too much salt is lost through sweat, which can disrupt the delicate balance of minerals in the body.

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Tay Sachs disease

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Tay-Sachs disease is a fatal genetic disorder in which harmful quantities of a fatty substance called Ganglioside GM2 accumulate in the nerve cells in the brain. This is caused by a decrease in the functioning of the Hexosaminidase A enzyme.

Abnormal Hexosaminidase A enzyme activity causes an accumulation of fat in nerve cells, leading to paralysis, dementia, blindness, psychoses, and even death.

Though the degradation of the central nervous system begins at the fetal stage, observations such as loss of peripheral vision and motor co-ordination are not seen until about 6 months of age.

This disease is autosomal recessive which means that an individual must inherit two defective genes, one from each parent, to inherit this disease.

According to the age of onset there are two existing forms of Tay-Sachs disease.

1. Infantile Tay-Sachs disease; and

2. Late onset Tay-Sachs disease (chronic GM2-gangliosidosis).

The frequency of the condition is much higher in in Ashkenazi Jews of Eastern European origin than in others.

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Amniocentesis

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Amniocentesis (also referred to as amniotic fluid test or AFT) is a medical procedure used in prenatal diagnosis of chromosomal abnormalities and fetal infections, and also used for sex determination in which a small amount of amniotic fluid, which contains fetal tissues, is sampled from the amniotic sac surrounding a developing fetus, and the fetal DNA is examined for genetic abnormalities. The most common reason to have an "amnio" is to determine whether a baby has certain genetic disorders or a chromosomal abnormality, such as Down syndrome.

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Chorionic villus sampling

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Chorionic villus sampling (CVS) is a form ofprenatal diagnosis to determine chromosomal or genetic disorders in the fetus. It entails sampling of the chorionic villus (placental tissue) and testing it for chromosomal abnormalities, usually with FISH or PCR.

CVS usually takes place at 10–12 weeks' gestation, earlier than amniocentesis or percutaneous umbilical cord blood sampling. It is the preferred technique before 15 weeks

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Three sex chromosomes

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Front 15

Huntington’s disease

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Huntington’s disease is a degenerative brain disorder, in which afflicted individuals lose their ability to walk, talk, think, and reason. They easily become depressed, and lose their short-term memory capacity. They may also experience a lack of concentration and focus. This disease begins between ages 30-45, and every individual with the gene for the disease will eventually develop the disease.

Huntington's is an autosomal dominant genetic disorder which means that if one parent carriers the defective Huntington's gene, his/her offspring have a 50/50 chance of inheriting the disease.

Huntington's disease was originally called Huntington's chorea ("chorea" is the Greek word for dancing). This is because the involuntary movements associated with the condition can look like jerky dancing. However, "disease" is now the preferred term, because the condition involves a lot more than just abnormal movements.

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The chance that a mutant genotype will be expressed as the corresponding mutant phenotype is referred to as the

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Concordance

Heritability

Molecular inheritance

Penetrance

Relative risk

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Penetrance

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Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene (allele or genotype) that also expresses an associated trait (phenotype). In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms.

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Concordance

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Concordance, as used in genetics, usually means the presence of the same trait in both members of a pair of twins.

However, the strict definition is the probability that a pair of individuals will both have a certain characteristic, given that one of the pair has the characteristic

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Heritability

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Heritability is a statistic used in breeding and genetics works that estimates how much variation in a phenotypic trait in a population is due to genetic variation among individuals in that population.

Some humans in a population are taller than others; heritability attempts to identify how much genetics play a role in part of the population being taller.

Heritability is estimated by comparing individual phenotypic variation among differently related individuals in a population.

Heritability is an important concept in quantitative genetics, particularly inselective breeding and behavior genetics (for instance, twin studies), but is less widely used in population genetics.

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Down syndrome is an example of a

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Balanced translocation

Frame shift

Monosomy

Polymorphism

Trisomy

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Trisomy

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A condition in which an extra copy of a chromosome is present in the cell nuclei, causing developmental abnormalities.

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Monosomy

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Monosomy is a form of aneuploidy with the presence of only one chromosome from a pair. Partial monosomy occurs when only a portion of the chromosome has one copy, while the rest has two copies

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Polymorphism

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The occurrence of two or more clearly different morphs or forms, also referred to as alternativephenotypes, in the population of a specie

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Frame shift

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A frameshift mutation (also called a framing error or a reading frame shift) is a genetic mutation caused by indels (insertions or deletions) of a number of nucleotides in a DNA sequence that is not divisible by three.

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Translocations

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Translocations can be balanced (in an even exchange of material with no genetic information extra or missing, and ideally full functionality) or unbalanced (where the exchange of chromosome material is unequal resulting in extra or missing genes).

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The subcellular location where growth hormone mRNA is translated is

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At the cis face of the golgi apparatus

on free ribosomes in the cytoplasm

at lysosomes

in the nucleus

at the rough endoplasmic reticulum (RER)

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Free vs. Bound ribosomes

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Free ribosomes produce proteins that are used by the cell. This includes proteins that are used for the metabolism of food. The free ribosomes produce enzymes involved in the metabolism of glucose.

Bound ribosomes produce proteins that are transported out of the cell. This includes proteins that are required for a specific function, such as digestive enzymes.

Bound ribosomes also produce polypeptide hormones. A few proteins produced by bound ribosomes are used in the cell membrane and on the outer surface of the cell. Surface receptors and cell signaling proteins are produced by bound ribosomes.

Front 28

The development potential of embryonic stem cells is

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Pluripotent

Quiescent

Terminally differentiated

Totipotent

Unipotent

Front 29

What type of inheritance does this family tree indicate? (check this)

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Autosomal recessive

Dominant with poor penetrance

Mitochondrial

Sex-linked

Dominant

Front 30

Which of the following shows polygenic inheritance?

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Androgen insensitivity

Down syndrome

Haemophilia B

Huntington's chorea

Type II diabetes

(Polygenic inheritance are those whose exact gene have not been identified or there are many genes which are implicated in the causation of the disease. Like for example, Diabetis mellitus)

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Polygenic traits

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Polygenic traits are due to the actions of more than one gene and often, their interaction with the environment. These usually result in a measurable range in phenotype, such as height, eyecolor or skin color. These are known as multifactoral or quantitative characteristics. Polygenic inheritance results in an additive effect of the genes on a single phenotype.

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Trisomy table

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Front 33

Which is true of chromosome condensation and gene expression?

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All regulatory sequences for a gene are present upstream of its TATA initiation site

Gene expression requires increased chromosome condensation around histone proteins

In genetic cloning the polymerase chain reaction is used to amplify a short sequence of mRNA

In spermatozoa chromatin is condensed around protamines

Polyadenylation of a gene silences its activity

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In transcription and translation

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Actively transcribed genes are located in heterochromatin

Membrane proteins are translated on free cytosolic ribosomes

Messenger RNA is produced in the nucleolus

Ribosomal RNA is produced in the nucleolus

The 5' end of the mRNA codes for the C-terminal of the protein

Front 35

Concerning genetic regulation

What is meant by the term "to clone a DNA sequence"?

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DNA cloning either through the use of cloning vectors or the polymerase chain reaction, whereby a single DNA molecule can be copied to generate many billions of identical molecules.

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How might the size and identity of the cloned DNA sequence be determined

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Size - gel electrophoresis

Identity - Nucleic acid hybridization, which makes it possible to find a specific sequence of DNA or RNA with great accuracy and sensitivity on the basis of its ability to bind a complementary nucleic acid sequence.

Front 37

Give three types of DNA polymorphisms that occur in humans

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RFLP:restriction fragment length polymorphisms

VNTR:variable number tandem repeats (8 to >50 base pairs)

STR: short tandem repeats (1–8base pairs)

SNP: single-nucleotide polymorphisms

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SNPS

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SNPs underlie differences in our susceptibility to disease; a wide range ofhuman diseases, e.g. sickle-cell anemia, β-thalassemia and cystic fibrosis result from SNPs

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Restriction fragment length polymorphism

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In molecular biology, restriction fragment length polymorphism, or RFLP, is a technique that exploits variations in homologous DNA sequences. It refers to a difference between samples of homologous DNA molecules from differing locations of restriction enzyme sites, and to a related laboratory technique by which these segments can be illustrated.

In RFLP analysis, the DNA sample is broken into pieces and (digested) by restriction enzymesand the resulting restriction fragments are separated according to their lengths by gel electrophoresis. Although now largely obsolete due to the rise of inexpensive DNA sequencing technologies, RFLP analysis was the firstDNA profiling technique inexpensive enough to see widespread application.

RFLP analysis was an important tool in genome mapping, localization of genes for genetic disorders, determination of risk for disease, and paternity testing.

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DNA Polymorphism

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A DNA polymorphism is any difference in the nucleotide sequence between individuals. These differences can be single base pair changes, deletions, insertions, or even changes in the number of copies of a given DNA sequence.

SNPs (single nucleotide polymorphisms) are the most common type of DNA polymorphism in humans. An example of an SNP would be if a cytosine (C) nucleotide is present at a particular locus in one person’s DNA but a thymine (T) nucleotide occurs at the same locus in another person’s DNA.

You might be surprised to learn that around 90% of all human genetic variation is due to SNPs!

polymorphisms are used for humanidentification and parentage testing.

Front 41

Give an example of an autosomal dominant and an X-linked condition

Back 41

Autosomal dominant - Huntington's disease

X-linked condition - haemophilia (X-linked recessive; factor VIII or IX deficiency)

Front 42

What can you deduces about the mode of inheritance from pedigrees A and B?

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A. X-linked recessive (only boys affected through maternal line)

Front 43

What can you deduces about the mode of inheritance from pedigrees A and B?

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B. Autosomal recessive

Front 44

In molecular genetics:

What are the two main properties of a restrictive enzyme as exploited by molecular biologists?

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1. Sequence-specific recognition of DNA

2. Cleavage activity (a distance away from recognised site)

Front 45

Give one application of restriction enzymes in molecular genetics

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DNA cloning

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What is a restriction fragment length polymorphism (RFLP)?

Back 46

A restriction fragment length polymorphism is defined by the existence of alternative alleles associated with restriction fragments that differ in size from each other.

A difference in homologous DNA sequence (of variable length).

Front 47

Name one other type of DNA polymorphism amenable to molecular genetic analysis.

Back 47

SNP (single nucleotide polymorphism)

Front 48

Cystic fibrosis (CF) is inherited as an autosomal recessive disorder. The gene is present in about 1/30 of the population.

What is the frequency of the disease per thousand births in this population? Show your working

Back 48

1/30 * 1/4 = 1/120

1 in every 120 births affected, i.e. 8 in every 1000.

Front 49

If a person has a sibling with CF, what is the theoretical chance of that person having a CF child?

Back 49

2/3 (chance that she is a carrier) * (1/4 if partner a carrier) * 1/30 gene present in population) = 1/180

Front 50

What is the underlying defect in cystic fibrosis?

Back 50

A mutation in the CFTR gene; which encodes for NaCl transporter/Cl- channel.

Front 51

Name two organs usually affected in cystic fibrosis

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Lungs and Pancreas

Front 52

Define genetic linkage

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Genetic linkage is the tendency of alleles that are close together on a chromosome to be inherited together during the meiosis phase of sexual reproduction.

Linked genes sit close together on a chromosome, making them likely to be inherited together. Genes on separate chromosomes are never linked. But not all genes on a chromosome are linked.

Front 53

Give three examples of genetic markers suitable for the study of linkage with human disease loci.

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1. Short tandem repeat (STR)

2. Single nucleotide polymorphism (SNP)

3. Restriction fragment length polymorphism (RFLP).

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What is a restriction enzyme?

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A protein produced by bacteria that cleaves DNA at specific sites along the molecule .

An endonuclease which recognizes a specific DNA sequence (restriction sites) and cleaves it at or a (variable) length away.

DNA cutting enzymes

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Give one use of restriction enzymes in molecular genetics

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DNA (gene) cloning

To digest genomic DNA for gene analysis by Southern blot.

Front 56

What is a restriction fragment length polymorphism?

Back 56

Refers to a difference between samples of homologous DNA molecules from differing locations of restriction enzyme sites, and to a related laboratory technique by which these segments can be illustrated.

In RFLP analysis, the DNA sample is broken into pieces and (digested) by restriction enzymes and the resulting restriction fragments are separated according to their lengths by gel electrophoresis.

Although now largely obsolete due to the rise of inexpensive DNA sequencing technologies, RFLP analysis was the first DNA profiling technique inexpensive enough to see widespread application.

RFLP analysis was an important tool in genome mapping, localization of genes for genetic disorders, determination of risk for disease, and paternity testing.

RFLP, as a molecular marker, is specific to a single clone/restriction enzyme combination.

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How are RFLPs identified

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By gel electrophoresis (and hybridization for sequence)

Front 58

Give one use of RFLPs in human genetics

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Mapping genes - the human genome project

Front 59

Red-green colour blindness is X-linked in humans. If a man is red-green colour blind, and both parents have normal colour vision, which of the man's grandparents is most likely to be red-green colour blind?

Back 59

Maternal grandmother

Maternal grandfather

Paternal grandmother

Paternal grandfather

Either grandfather is equally likely

Front 60

A couple has a daughter with Tay Sachs disease (metabolic disorder of the Hexosaminidase-A (Hex-A) gene), and three unaffected children. Neither parent nor any of the four biological grandparents of the affected child has had this disease. The most likely genetic explanation is the Tay Sachs disease inheritance is:

Back 60

Autosomal dominant

Autosomal recessive

Sex-linked recessive

Sex-linked dominant

Cannot make a reasonable guess from this information

Front 61

In a family, prominent ears are an inherited trait due to a single genetic locus. The man's mother and one sister also had prominent ears, but his father, his brother, and two other sisters had normal ears. The man and his normal-eared wife had seven children, including four boys and three girls. Two girls and two boys had prominent ears. The trait is most probably:

Back 61

Autosomal dominant

Autosomal recessive

Sex-linked recessive

Sex-linked dominant

Cannot make a reasonable guess from this information

Front 62

Klinefelter's syndrome (XXY) is an example of chromosomal aneuploidy that can be readily diagnosed by:

Back 62

Behavioural analysis

Somatic cell genetics

Karyotyping

Biochemical analysis

Pedigree analysis

Front 63

What mode of inheritance is shown below and why does it appear in the fifth generation (TBC)

Back 63

Autosomal recessive

Inbreeding? Tay Sachs?

Front 64

List three key features of the structure of DNA

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1. Double helix

2. Phosphate-sugar (deoxyribose) backbone

3. Nitrogenouse bases; Pyrimidines and Purines (4 bases; adenine, thymine, guanine, cytosine)

Front 65

Why is the stability of a DNA molecule related particularly to the G-C content?

Back 65

3 hydrogen bonds; as opposed to 2 between A-T

The GC pair is bound by three hydrogen bonds, while AT pairs are bound by two hydrogen bonds. To emphasize this difference in the number of hydrogen bonds, the base pairings can be represented as G≡C versus A=T. DNA with high GC-content is more stable than DNA with low GC-content; however, the hydrogen bonds do not stabilize the DNA significantly, and stabilization is due mainly to stacking interactions

Front 66

What are the substrates used by DNA polymerases for DNA replication?

Back 66

The strand of DNA and the nucleotides (A, T, G, C)

Front 67

Name two common patterns of Mandelian inheritance in human single gene disorders, and for each, give one example of a condition inherited this way

Back 67

Autosomal Dominant - Huntington's disease

Autosomal recessive - Tay Sach's disease

Front 68

Name any two non-genetic other factors which might influence the expression of a polygenic disease

Back 68

Environment

Diet

Physical activity

Alcohol and tabacco use.