1 Introduction to Clinical Genetics

Question 1

How many DNA helices are there in the nucleus of every somatic cell?

Answer 1

46, every chromosome is one DNA double helix and on that DNA double helix, certain regions are the genes

Question 2

What is a karyotype?

Answer 2

the number and appearance of chromosomes in the nucleus of an eukaryotic cell, take a blood sample and look at the B cells - the chromosomes are in metaphase

Question 3

What are the different types of genetic diseases?

Answer 3

chromosome disorders (less than 1%), single gene disorders (2%), mitochondrial disorders (1:5,000), multifactorial disorders (common)

Question 4

What are chromosomal disorders?

Answer 4

abnormalities in number or structure of chromsomes (alterations affect the genes - too many genes, too few genes, altered genes)

Question 5

What is the difference between polyploidy and aneuploidy?

Answer 5

Polyploidy is a multiple of 23 (haploid =23, diploid = 46, triploid = 69) and not common except in miscarried baby or cancer cells. Aneuploidy is not a multiple (i.e. having an extra chromosome like 47)

Question 6

What are single gene disorders?

Answer 6

Genes code for a protein or RNA. Alterations in the coding sequence produce effects on the function of the protein (loss (typical, gain or alternation of function). Single gene disorders are the basis of Mendelian inheritance (autossomal disorders and sex-linked disorders)

Question 7

How many genes does the mitochondrial genome contain and what biochemical process do they code for?

Answer 7

The mitochondrial genome contains 13 genes and they code for the Electron Transport Chain

Question 8

What are mitochondrial disorders?

Answer 8

Mitochondria are organelles responsible for a variety of biochemical functions, but most importantly ATP generation. They have there own genome that can be disrupted by the same mutational mechanisms as the nuclear DNA

Question 9

What kind of inheritance do mitochondrial disorders follow?

Answer 9

Generally non-mendial inheritance. Maternal inheritance for mutations in the mitochondrial DNA and Mendelian inheritance for mitochondrial gens on the nuclear DNA

Question 10

What are multifactorial disorders?

Answer 10

These are the most common of the genetic disorders and likely the basis for many common diseases. They are a combination of both genes and environment (polygenic - many genes acting together, teratogenic - primarily environmental based (i.e chemicals, alchohol), multifactorial - combination of both genes and environment).

Question 11

What are the four tools used for genetic diagnosis?

Answer 11

inheritance patterns, chromosome analysis, biochemical tests, DNA diagnostic tests

Question 12

What are the classes for inheritance patterns?

Answer 12

autosomal dominant, recessive, sex-linked (always construct a pedigree as part fo the medical history)

Question 13

What are tools for analyzing chromosomes?

Answer 13

Chromosome analysis can be done with Karyotypes, FISH, Comparative Genomic Hybridization

Question 14

What are biochemical tests done for genetic diagnosis?

Answer 14

Plasma amino acids, urine organic acids

Question 15

What DNA diagnostic tests are there for genetic diagnosis?

Answer 15

sequencing

Question 16

How are the sex indicated on a genetic pedigree?

Answer 16

Squares are males, Circles are females

Question 17

What can a karyotype detect?

Answer 17

Detects alterations in number, large duplications/deletions, translocations

Question 18

What can Fluorescent in-situ hybridization (FISH) and comparative genomic hybridization (CGH) detect?

Answer 18

FISH can detect small deletions, and CGH can detect duplications and deletions

Question 19

Down syndrome is an example of what class of genetic disorders?

Answer 19

Chromosomal disorder, aneuploidy = abnormal number of chromosomes, dosage of 3 on chromosome 21

Question 20

What is fluorescetn in-situ hybridization (FISH)?

Answer 20

amolecular cytogenetictechnique that usesfluorescent probesthat bind to only those parts of the chromosome with a high degree of sequencecomplementarity, used to detect and localize the presence or absence of specific DNA sequences on chromosomes

Question 21

When is the DNA sequence present with FISH?

Answer 21

The DNA sequence is present when the probe hybridizes to the sample

Question 22

When would you use FISH?

Answer 22

You have to know what you are looking for, know the DNA sequence assocaited with gene

Question 23

What does comparative genomic hybridization test for?

Answer 23

Deletions/duplications

Question 24

What is comparative genomic hybridization?

Answer 24

a molecular cytogenetic method for analysing copy number variations (CNVs) relative to ploidy level in the DNA of a test sample compared to a reference sample, without the need for culturing cells. The aim of this technique is to quickly and efficiently compare two genomic DNA samples arising from two sources, which are most often closely related, because it is suspected that they contain differences in terms of either gains or losses of either whole chromosomes or subchromosomal regions (a portion of a whole chromosome)

Question 25

When do you want to use FISH over CGH?

Answer 25

FISH you really have to know what you are looking for, CGH gives you more broad spectrum

Question 26

What is exome sequencing?

Answer 26

Determination of the sequence of the coding portion of the human genome, most mutations that casue disease will alter this coding sequence

Question 27

What is whole genome sequencing?

Answer 27

Sequence everything, will pick up mutations in promoter regions, introns, 3’-untranslated regions

Question 28

How is phenylketonuria (PKU) characterized?

Answer 28

Loss of phenylalanine hydroxylase (PAH) activity with accumulation of phenylalanine

Question 29

What is mosaicism?

Answer 29

Mosaicism is more than one genotype in a person

Question 30

What is mitochondrial inheritance?

Answer 30

Mitochondrial inheritance is abnormal mitochondria passed on in the cytoplasm of an ovum from mother

Question 31

What is genetic imprinting?

Answer 31

Parent of origin difference in gene expression. Imprinted genes are genes whose expression is determined by the parent that contributed them. Imprinted genes violate the usual rule of inheritance that both alleles in a heterozygote are equally expressed

Question 32

What is uniparental disomy?

Answer 32

Both chromosomes of a pair inherited from one parent

Question 33

What are unstable triplet repeat mutations?

Answer 33

These develop by expansion of normally present trinucleotide repeats

Question 34

What is presymptomatic genetic testing?

Answer 34

testing a person for genetic mutation wthat will certainly cause disease later in life (testing for a fully penetrant genes - you have the gene and you will develop the disorder, gives a definite answer for the patient)

Question 35

What is predisposition genetic testing?

Answer 35

Testing a person for a genetic mutation which will possibly cause disease later in life (tests are problematic because prediction of disease occurrence is very inexact)

Question 36

What are the risks of genetic testing?

Answer 36

Detection of false paternity, stigmatization - including survivor guilt, loss of employment or insurance, psychological harm

Question 37

What are ethical principles which apply to medical genetics?

Answer 37

Autonomy, Beneficence, Justice, Nonmaleficence, Veracity (tell the truth), Fidelity (keeping all contracts and promises)

Question 38

What is the most common class of genetic disorder?

Answer 38

Multifactorial, 60% (single gene - 2%, mitochondrial 1:5K, chromosomal - 1%)

Question 39

Imprinted genes are geneswhose expression is determined by the parent that contributed them.Imprinted genesviolate the usual rule of inheritance that both alleles in a heterozygoteareequally expressed

Answer 39

The answer is autosomal dominant. Autosomal recessive inheritance usually does not show affected individuals in every generation; X-linked recessive shows mostly males; X-lined dominant will have more females and mitochondrial disease shows maternal transmission. A key factor to look for is male-to-male transmission as this must be autosomal dominant

Question 40

Which of the following is a major ethical issue when mutation analysis by DNA sequence is performed on a child and parents?

Answer 40

Detection of false paternity is the biggest ethical issue. This can cause significant family issues, obviously.

Question 41

A newborn has dysmorphic features consisting of up-slanting palpebral fissures, a flat nasal bridge, large tongue, and single transverse palmar creases. The infant is also hypotonic. Which of the following is an appropriate genetic test to order?

Answer 41

The diagnosis is Down syndrome or Trisomy 21. This chromosomal anomaly can easily be detected by a routine karyotype. FISH is useful for detection deletions of small regions of DNA (and sometimes duplications) but as the probe is targeted to a region, a suspected deletion is usually needed to properly pick a probe (such as the elastin gene for William’s syndrome on chromosome 7). Comparative genomic hybridization would identify the extra chromosome 21, but it is expensive and not the most appropriate test at this time (although this may be changing in the very near future!). There is no need to perform DNA sequencing of chromosome 21 as this will identify DNA changes, but these changes are not what causes Trisomy 21. Plasma amino acids would not provide any diagnostic information as amino acid metabolism is not affected in Trisomy 21