Genetics

Question 1

What are the different types of congenital abnormalities?

Answer 1

Single: Malformation, Disruption, Deformation and Dysplasia.
Multiple: Sequence, Syndrome and Association.

Question 2

Define malformation.

Answer 2

A morphologic defect of an organ, part of an organ or larger region of the body resulting from an intrinsically abnormal development process (e.g. congenital heart defects).

Question 3

Define disruption.

Answer 3

A morphologic defect of an organ, part of an organ or larger region of the body resulting from the extrinsic breakdown of or interference with, an originally normal development.

Question 4

Define deformation.

Answer 4

Abnormal form, shape or position of a part of the body caused by mechanical forces.

Question 5

Define dysplasia.

Answer 5

An abnormal organisation of cells into tissues and its morphological results. For example: Thanatophoric dysplasia which is caused by a single gene (FGFR3) and leads to bowed long bones, narrow thorax and large skull.

Question 6

Define sequence.

Answer 6

A pattern of multiple anomalies derived from a single known or presumed prior anomaly or mechanical factor (e.g. Potter Sequence).

Question 7

Define syndrome.

Answer 7

Multiple anomalies thought to be pathogenetically related and not representing a sequence (e.g. Down Syndrome caused by Trisomy 21).

Question 8

Define association.

Answer 8

A nonrandom occurrence in two or more individuals of multiple congenital abnormalities not known to be polytopic defect, sequence or syndrome (e.g. VACTERL association).

Question 9

What are the three types of chromosomal abnormalities?

Answer 9

Structural (translocations, deletions, insertions); Numerical (aneuploidy - loss or gain); Mosaicism (different cell lineages).

Question 10

Why do some translocations have no effect?

Answer 10

Because the gene is still transcribed despite translocation. An effect is only seen if a gene is disrupted or a fusion product is formed.

Question 11

What is aneuploidy?

Answer 11

The loss or gain of one or more chromosomes.

Question 12

What are the different types of aneuploidy?

Answer 12

Monosomy: loss of single chromosome - almost always lethal.
Disomy: normal
Trisomy: gain of one chromosome - tolerated sometimes.
Tetrasomy: gain of two chromosomes - tolerated sometimes.

Question 13

What are the different forms of trisomy?

Answer 13

16 is most common but is fatal in utero. 13, 18 and 21 are viable.

13: Patau Syndrome - heart defects, cleft lip, mental retardation.
18: Edwards Syndrome - heart defects, kidney malformation, digestive tract defects, mental retardation.
21: Down Syndrome.

Question 14

What are the clinical features of Down Syndrome?

Answer 14

Newborn: hypotonia, lethargy, excess nuchal skin.
Craniofacial: macroglossia, small ears, epicanthic folds, sloping palpebral fissures, Brushfield spots.
Limbs: single palmar crease, sandal gap.
Cardiac: septa defects, atrioventricular canal.
Other: short stature, duodenal atresia.

Question 15

How does age effect risk of Down Syndrome?

Answer 15

The risk remains low until the maternal age of 32 and then increases exponentially up to 45.

Question 16

What are the different causes of Down Syndrome?

Answer 16

Trisomy 21 (95%), Translocations (4%) and Mosaicism (1%).

Question 17

How does trisomy 21 occur to cause Down Syndrome?

Answer 17

Nondisjunction during meiosis 1 (both chromosomes go into 1 copy during anaphase) leads to trisomy. The extra chromosome has a maternal origin 90% of the time.

Question 18

What is a Robertsonian translocation?

Answer 18

This is when the long arms of two chromosomes split at the centromere and join to form 1 long chromosome. The short arms are lost. 1/3 of parents are carriers. They lead to a high risk of Down Syndrome in the offspring.

Question 19

Define mosaicism.

Answer 19

This is when there are more than one cell lineages in a tissue due to mitotic nondisjunction. The earlier it happens during development, the larger the effect it has on the tissues.

Question 20

What is Turner Syndrome?

Answer 20

A condition caused by monosomy X 80% due loss of X or Y in paternal meiosis.

Question 21

What is Klinefelter’s Syndrome?

Answer 21

A sex chromosome aneuploidy where the person has XXY. They are phenotypically male and it leads to many defects such as learning disability and infertility.

Question 22

What is dosage compensation?

Answer 22

The process by which organisms ensure equivalent gene expression both sexes despite XX and XY.

Question 23

What are the mechanisms of dosage compensation?

Answer 23

Random inactivation of a single X chromosome in females (most mammals); increased expression of X chromosome in males; decreased expression of both X chromosomes in hermaphrodites.

Question 24

What is Di George Syndrome?

Answer 24

A genomic disorder caused by microdeletion in chromosome 22. Diagnostic features include cardiac anomalies, abnormal facies, cleft palate and learning difficulties.

Question 25

What is Charcot-Marie-Tooth Disease 1A?

Answer 25

A genomic disorder caused by microduplication in chromosome 17. Diagnostic features include foot drop, distal muscle wasting, absent reflexes etc.

Question 26

What are the two types of genetic diseases?

Answer 26

Monogenic: Clear inheritance, no environment, individually rare. E.g. Huntington's disease, cystic fibrosis. Complex disorders: no clear inheritance, environment essential, common. E.g. type 2 diabetes, Crohn's disease.

Question 27

Define Mendelian inheritance.

Answer 27

The process whereby individuals inherit and transmit to their offspring one of two alleles present in homologous chromosomes.

Question 28

Define allele.

Answer 28

Alternate forms of a gene or DNA sequence at the same chromosome location.

Question 29

Define homologous chromosomes.

Answer 29

A matching but non-identical pair of chromosomes, one inherited from each parent.

Question 30

What is the difference between a mutation and a polymorphism?

Answer 30

A mutation is any inheritable change in the DNA sequence that causes monogenic diseases while polymorphisms are mutations present in >1% of the population and contributes to complex diseases.

Question 31

What are the two types of point mutations?

Answer 31

Missense mutations leads to a change in a single amino acid in a sequence while nonsense mutations causes shortening of the peptide chain due to a stop codon.

Question 32

What are the two types of frameshift mutations?

Answer 32

Insertion (adding a single nucleotide) and deletion (removing a single nucleotide). Both lead to an incorrect amino acid sequence.

Question 33

What are the rules of drawing a family pedigree?

Answer 33

Build up the tree from the bottom; record names and date of births. Square = male; circle = female; filled in shape = affected individual. Lines link related individuals. Draw sloping line through shape if individual has died.

Question 34

What are the characteristics of Autosomal dominant inheritance?

Answer 34

At least one parent would be affected (M or F); transmitted by M or F vertically; 50% risk of each child being affected.

Question 35

Describe an example of an autosomal dominant disease.

Answer 35

Huntington's Disease is usually onset between 35 - 44 years and the median survival age is 15 - 18 years. It causes motor, cognitive and psychiatric dysfunction and there is no cure. Age of onset decreases down the generations and severity increases.

Question 36

What is the cause of Huntington's disease?

Answer 36

Patients inherit a mutated version of a gene coding for protein called Huntingtin on chromosome 4. the mutation involves repeats of an unstable CAG triplet. A toxic form of the protein forms clumps in the basal ganglia leading to cell death. Number of CAG repeats increases down the generations.

Question 37

What are the features of Autosomal recessive inheritance?

Answer 37

No parents affected; can affect M or F; transmitted by M or F; usually no family history; 25% risk of offspring affected and 50% risk of offspring carrier.

Question 38

Describe an example of an autosomal recessive condition.

Answer 38

Cystic fibrosis is a life-threatening condition which affects 1 in 22 in the UK. Thick mucus in lungs causes breathing problems and blocked pancreas affect digestive system. Daily enzyme and physiotherapy treatment required.

Question 39

What are the characteristics of X-linked recessive inheritance?

Answer 39

Parents aren't affected; transmitted by F and affects M; 50% risk of affected sons; 50% risk of carrier daughters.

Question 40

Describe an example of a X-linked recessive condition.

Answer 40

Haemophilia is blood clotting disorder that affects about 6500 people in the UK. It causes easy bruising and excessive bleeding. It can be successfully treated with injections of clotting factors.

Question 41

What causes Haemophilia A?

Answer 41

Mutation in F8 gene in chromosome 10 produces a mutated form of the protein called Coagulation factor VIII. The lack of functioning protein leads to ineffective clotting.

Question 42

Define incomplete penetrance.

Answer 42

Symptoms aren't always present in an individual with disease causing mutations (only seen in dominant inheritance).

Question 43

Define variable expressivity.

Answer 43

Disease severity may vary between individuals with the same disease causing mutations (only seen in dominant inheritance).

Question 44

Define phenocopy.

Answer 44

Having the same disease but with a different underlying cause.

Question 45

Define epistasis.

Answer 45

Interaction between disease gene mutations and other modifier genes can affect phenotype.

Question 46

What is the difference between the molecular mechanisms in dominant, recessive and co-dominant inheritance?

Answer 46

Dominant: usually codes for a toxic protein masking the normal copy. Recessive: usually due to a missing protein and only expressed because normal copy is absent. Co-dominant: effect of both mutated and normal genes apparent.

Question 47

What are the therapeutical implications of dominant and recessive inheritance?

Answer 47

Dominant: treatment must neutralise the toxic protein or switch off the mutant gene. Recessive: need to restore activity of the missing protein by replacing the gene or protein product.

Question 48

What is genomic imprinting?

Answer 48

It is a form of non-mendelian inheritance that doesn't affect the genetic sequence.

Question 49

How many human genes show are affected by genomic imprinting?

Answer 49

Affects approximately 75 known genes in humans.

Question 50

How does genomic imprinting affect inheritance and gene expression?

Answer 50

Some genes are maternally or paternally inherited. Those genes have markers which identify them based on parental origin. Some genes are only expressed if inherited from the mother and some only from the father. If a maternally dominant gene is inherited by a male, it will be expressed in the male but in that male's germ cells, the markers are wiped and redone so those genes become paternal in origin. So the gene won't be expressed in the male's offspring.

Question 51

How are genes imprinted?

Answer 51

Genomic imprinting occurs via DNA methylation when a methyl group is added to the 5 position of a pyrimidine ring of cytosine. It happens at CG dinucleotides.

Question 52

Name two disorders caused Chromosome 15 imprinting disorders.

Answer 52

Paternal chromosome loss of function: Prader-Willi Syndrome. | Maternal chromosome loss of function: Angelman Syndrome.

Question 53

What are the symptoms of Prader-Willi Syndrome?

Answer 53

Behavioral problems; Obesity (Hyperphagia); Mental impairment (IQ 60-70); Infertility; Muscle hypotonia; Short stature with small hands and feet.

Question 54

What are the ways of managing Prader-Willi Syndrome?

Answer 54

Puberty: hormone treatments Obesity: diet restriction Short stature: growth hormone treatment. Hypotonia: exercise to increase muscle mass.

Question 55

What are the consistent symptoms of Angelman Syndrome?

Answer 55

``` Developmental delay and speech impairment; Movement disorder; Behavioural uniqueness (happy, excitable, short attention span) ```

Question 56

What are the frequent symptoms of Angelman Syndrome?

Answer 56

Microcephaly; Seizures onset before 3 years of age.

Question 57

What are the treatments for Angelman Syndrome?

Answer 57

Treatment is symptomatic. Anticonvulsant for seizures, physio and communication therapies for movement and speech.

Question 58

What is the karyotype of the mitochondrial genome?

Answer 58

Mitochondria contain 37 genes and 2-10 copies of those genes per mitochondria.

Question 59

What is MELAS?

Answer 59

Mitochondrial Encephalomyopathy with Lactic Acidosis and Strobe-like episodes.

Question 60

What are the symptoms of MELAS?

Answer 60

The symptoms are progressive and fatal. | Muscle weakness; vomiting; episodic seizures; headache; hemiparesis; dementia.

Question 61

What gene mutations cause MELAS?

Answer 61

Single base mutations in tRNA codon translations and NADH dehydrogenase subunits 1 and 5.

Question 62

What is LHON?

Answer 62

Leber's Hereditary Optic Neuropathy. A condition more common in males that causes degeneration of retinal ganglion cells.

Question 63

What are the symptoms of LHON?

Answer 63

Bilateral and painless loss of central vision, optic atrophy. Age of onset between 6 and 60 (average 20).

Question 64

How is LHON diagnosed and treated?

Answer 64

LHON is diagnosed based on ophthalmological findings and blood tests. The treatment is symptomatic.

Question 65

How is MELAS diagnosed and treated?

Answer 65

MELAS is diagnosed by doing a muscle biopsy. The treatment is symptomatic.

Question 66

What mutations cause LHON?

Answer 66

NADH dehydrogenase subunits 1, 4, 5 and 6; cytochrome B.

Question 67

What is heteroplasmy?

Answer 67

It is the presence of more than one organellar genome such as in mitochondria. It determines the severity of mitochondrial disorders.

Question 68

What is PKU?

Answer 68

Phenylketonuria is a condition caused by a deficiency in Phenylalanine hydroxylase.

Question 69

What are the symptoms of PKU?

Answer 69

Blond hair and blue eyes caused by lack of melanin; eczema and musty odour caused by excess phenylacetate; seizures and severe mental retardation if untreated.

Question 70

How is PKU treated?

Answer 70

The condition needs to be detected early during newborn screening. To treat, remove phenylalanine from diet and provide protein supplements for other proteins.

Question 71

What is MCAD Deficiency?

Answer 71

Medium Chain Acyl-CoA Dehydrogenase deficiency is the most common disorder of fatty acid oxidation.

Question 72

What are symptoms of MCAD Deficiency?

Answer 72

Episodic hypoketotic hypoglycemia; vomiting; encephalopathy; metabolic acidosis; coma.

Question 73

What are the treatments for MCAD deficiency?

Answer 73

Avoid fasting and use nutritional supplements in times of increased stress.

Question 74

What are the characteristics of malignant tumours?

Answer 74

Dysregulated growth; evasion of apoptosis; limitless replication; sustained angiogenesis; metastasis; dysregulation of energy metabolism; promotion of inflammation; genome instability and mutations; evasion of immune system.

Question 75

What are driver mutations in cancer?

Answer 75

A mutation that gives a selective growth advantage, thus promoting cancer development.

Question 76

What are Tumour Suppressor (TS) genes?

Answer 76

they regulate cell division by working at the DNA damage checkpoints in the cell cycle. They also affect apoptosis and DNA repair. They cause the loss of a function which prevents cells becoming cancerous.

Question 77

What are Proto-oncogenes?

Answer 77

They are genes that promote growth and proliferation of cells through growth factors, transcription factors and tyrosine kinases. They only form tumours if there are too many copies which means it is permanently activated.

Question 78

What is Knudson's two-hit hypothesis?

Answer 78

Most TS genes require two mutations to become faulty. The first hit is usually a point mutation that reduces transcription levels but doesn't have a phenotypic effect. The second hit is usually a deletion that causes total loss of transcription.

Question 79

What is familial and sporadic cancer?

Answer 79

Familial cancers have an inherited germline component (1%). Sporadic are the non-inherited.

Question 80

What are the effects of germline mutations of BRCA1 and BRCA2?

Answer 80

It impairs the process that repairs DNA breaks and stimulates faulty repair. So, they create a 60% risk of developing breast cancer by age 90 with an earlier average age of onset. Also increases risk of ovarian cancer. BRCA2 mutations predispose men to breast cancer.

Question 81

What are BRCA genes?

Answer 81

BRCA1 and BRCA2 are tumour suppressor genes found on chromosome 17 and 13 respectively. They help to repair broken DNA through homologous recombination.

Question 82

What is homologous recombination?

Answer 82

It is a method of genetic recombination where nucleotide sequences are exchanged between homologous chromosome as a way to accurately repair broken DNA.

Question 83

What are two of the main forms of colorectal cancer caused by gene mutations?

Answer 83

Familial Adenomatous Polyposis (FAP); Lynch Syndrome or Hereditary Non-Polyposis Colon Cancer (HNPCC).

Question 84

How does genetic mutation cause FAP?

Answer 84

APC is a negative regulator protein that controls cell division. Muation to the APC gene in chromosome 5 causes uncontrolled cell division and polyp formation in colon leading to cancer.

Question 85

What are the effects of FAP?

Answer 85

It makes up 1% of colorectal cancers. Hundreds of polyps form in the colon and there is a 100% chance of some of them becoming cancerous.

Question 86

How does genetic mutation causes Lynch Syndrome?

Answer 86

MSH2 and MLH1 are genes found on chromosomes 2 and 3 respectively. They code for proteins that repair DNA errors from the cell division stage. So, mutations to those genes causes faulty DNA repair and thus cancer.

Question 87

What are the prenatal testing steps in a normal pregnancy?

Answer 87

After a positive pregnancy test, book into antenatal care and see a midwife. Two ultrasound scans conducted: an ultrasound nuchal scan at 10-14 weeks and a high level anomaly scan at mid-trimester anomaly scan at 20-22 weeks.

Question 88

What are the aims of the 12 week scan?

Answer 88

To accurately date the pregnancy; diagnose multiple pregnancies; diagnose major fetal abnormalities; diagnose early miscarriage; assess risk of Down Syndrome and other chromosomal abnormalities.

Question 89

What is Nuchal Translucency?

Answer 89

It is a measure of the thickness of fluid at the back of the fetal neck. The test is conducted with the dating scan at 12 weeks.

Question 90

What does Nuchal Translucency (NT) indicate?

Answer 90

An NT of more than 3 mm at 12 weeks indicates chromosomal abnormalities such as Downs, Edwards, Patau and Turners. It can also indicate birth defects such as cardiac anomalies, pulmonary defects, renal defects, abdominal wall defects and skeletal dysplasias.

Question 91

What is the purpose of the mid-trimester scan?

Answer 91

The scan looks for structural anomalies, specifically for the heart, brain, spinal cord, face, kidneys and abdomen. The length of the bones is also measured.

Question 92

What is the purpose of the combined test?

Answer 92

Along with NT, the test looks at levels of free beta-hCG and PAPP-A. Down's babies have high levels of hCG and low PAPP-A.

Question 93

When is extra prenatal testing offered?

Answer 93

Abnormal findings at 12 or 20 week scan; after combined test shows increased risk of DS; if previous pregnancy affected with the DS or CF; if parents are carriers of chromosome.

Question 94

What are the aims of the prenatal testing?

Answer 94

Inform and prepare parent; allow in utero treatment; manage the rest of the pregnancy; be prepared for complications; allow termination of fetus.

Question 95

What are two minimally invasive methods of prenatal testing?

Answer 95

Maternal serum screening and Non-invasive Prenatal Diagnosis (using cell-free fetal DNA).

Question 96

What are the factors thats affect the values from minimally invasive testing?

Answer 96

The gestational age of the fetus, maternal age, weight, ethnicity, diabetes, possible genetic predisposition and multiple pregnancies.

Question 97

What is maternal serum screening?

Answer 97

The mother's blood is taken to test for markers of increased risk of trisomy 21 and 18 and/or neural tube defects.

Question 98

What are the markers tested in the two maternal serum screenings?

Answer 98

1st trimester screening at 11-14 weeks: hCG, PAPP-A. | 2nd trimester screening at 16-20 weeks: AFP, uE3, hCG.

Question 99

What is Non-invasive Prenatal Diagnosis (NIPT)?

Answer 99

NIPD works by analysing free DNA fragments from the mother's blood. 10-20% of this comes from the placenta and represents the fetal DNA. It is accurately detectable from 9 weeks.

Question 100

What are the uses of NIPD?

Answer 100

It tests for trisomy-21 because the amount of cfDNA for chromosome 21 will be higher. It is also used for achondroplasia (prevents cartilage turning to bone), thanatophoric dysplasia (extremely short bones) and apert syndrome (premature fusion of skull bones.

Question 101

What are the limitations of NIPD vs invasive methods?

Answer 101

Not able to distinguish between DNA from different fetuses during multiple pregnancies; relative proportion of cffDNA is lower in women with high BMI; invasive test may be required to confirm diagnosis.

Question 102

What are the benefits of NIPD vs invasive methods?

Answer 102

Reduced risk of miscarriage; less expertise required to perform blood test; can be offered earlier so result would be obtained sooner.

Question 103

What are the two types of invasive tests offered for a known risk?

Answer 103

Chorionic villus sampling (CVS) and amniocentesis.

Question 104

What is chorionic villus sampling (CVS)?

Answer 104

Chorionic villi are on the outermost layer of the placenta. A sample of it is taken transabdominally or transvaginally at 11-14 weeks. There is a 1-2% risk of miscarriage.

Question 105

What is amniocentesis?

Answer 105

A sample of amniotic fluid containing fetal cells is taken using a needle through the abdomen from 16 weeks. There is upto 1% risk of miscarriage and infection.

Question 106

What are the reproductive options available when there is a known risk?

Answer 106

Conceive naturally with or without prenatal testing; use donors; adopt; choose not to have children; Preimplantation genetic diagnosis.

Question 107

What is Preimplantation genetic diagnosis (PGD)?

Answer 107

It's an extra step during IVF a single cell is removed at the 8 cell stage and tested for genetic disorders.

Question 108

What is intracytoplasmic sperm injection (ICSI)?

Answer 108

A single sperm is injected into the egg during IVF, usually used for condition caused by a single faulty gene.

Question 109

What are the main eligibility criteria for PGD?

Answer 109

No other healthy children from the relationship and the female partner under 40.

Question 110

What are the downsides of PGD?

Answer 110

Emotionally distressing for the couple; lengthy process; success rate is 30% per cycle.

Question 111

What is role of genetic counselling in prenatal testing?

Answer 111

Arrange and explain all tests; facilitate decision making; give results; arrange termination if needed; discuss recurrence risks and plans for future pregnancies.