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MCD Year 1 > Genetics > Flashcards

Genetics Flashcards

1
Q

What are the different types of congenital abnormalities?

A

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

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2
Q

Define malformation.

A

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).

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3
Q

Define disruption.

A

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.

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4
Q

Define deformation.

A

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

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5
Q

Define dysplasia.

A

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.

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6
Q

Define sequence.

A

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

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7
Q

Define syndrome.

A

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

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8
Q

Define association.

A

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).

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9
Q

What are the three types of chromosomal abnormalities?

A

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

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10
Q

Why do some translocations have no effect?

A

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

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11
Q

What is aneuploidy?

A

The loss or gain of one or more chromosomes.

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12
Q

What are the different types of aneuploidy?

A

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

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13
Q

What are the different forms of trisomy?

A

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.

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14
Q

What are the clinical features of Down Syndrome?

A

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.

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15
Q

How does age effect risk of Down Syndrome?

A

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

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16
Q

What are the different causes of Down Syndrome?

A

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

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17
Q

How does trisomy 21 occur to cause Down Syndrome?

A

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.

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18
Q

What is a Robertsonian translocation?

A

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.

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19
Q

Define mosaicism.

A

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.

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20
Q

What is Turner Syndrome?

A

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

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21
Q

What is Klinefelter’s Syndrome?

A

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.

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22
Q

What is dosage compensation?

A

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

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23
Q

What are the mechanisms of dosage compensation?

A

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.

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24
Q

What is Di George Syndrome?

A

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

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25
Q

What is Charcot-Marie-Tooth Disease 1A?

A

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

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26
Q

What are the two types of genetic diseases?

A

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.

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27
Q

Define Mendelian inheritance.

A

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

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28
Q

Define allele.

A

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

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29
Q

Define homologous chromosomes.

A

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

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30
Q

What is the difference between a mutation and a polymorphism?

A

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.

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31
Q

What are the two types of point mutations?

A

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.

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32
Q

What are the two types of frameshift mutations?

A

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

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33
Q

What are the rules of drawing a family pedigree?

A

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.

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34
Q

What are the characteristics of Autosomal dominant inheritance?

A

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

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35
Q

Describe an example of an autosomal dominant disease.

A

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.

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36
Q

What is the cause of Huntington’s disease?

A

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.

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37
Q

What are the features of Autosomal recessive inheritance?

A

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.

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38
Q

Describe an example of an autosomal recessive condition.

A

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.

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39
Q

What are the characteristics of X-linked recessive inheritance?

A

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

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40
Q

Describe an example of a X-linked recessive condition.

A

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.

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41
Q

What causes Haemophilia A?

A

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.

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42
Q

Define incomplete penetrance.

A

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

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43
Q

Define variable expressivity.

A

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

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44
Q

Define phenocopy.

A

Having the same disease but with a different underlying cause.

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45
Q

Define epistasis.

A

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

46
Q

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

A

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.

47
Q

What are the therapeutical implications of dominant and recessive inheritance?

A

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.

48
Q

What is genomic imprinting?

A

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

49
Q

How many human genes show are affected by genomic imprinting?

A

Affects approximately 75 known genes in humans.

50
Q

How does genomic imprinting affect inheritance and gene expression?

A

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.

51
Q

How are genes imprinted?

A

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.

52
Q

Name two disorders caused Chromosome 15 imprinting disorders.

A

Paternal chromosome loss of function: Prader-Willi Syndrome.

Maternal chromosome loss of function: Angelman Syndrome.

53
Q

What are the symptoms of Prader-Willi Syndrome?

A

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

54
Q

What are the ways of managing Prader-Willi Syndrome?

A

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

55
Q

What are the consistent symptoms of Angelman Syndrome?

A 
Developmental delay and speech impairment;
Movement disorder;
Behavioural uniqueness (happy, excitable, short attention span)
56
Q

What are the frequent symptoms of Angelman Syndrome?

A

Microcephaly; Seizures onset before 3 years of age.

57
Q

What are the treatments for Angelman Syndrome?

A

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

58
Q

What is the karyotype of the mitochondrial genome?

A

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

59
Q

What is MELAS?

A

Mitochondrial Encephalomyopathy with Lactic Acidosis and Strobe-like episodes.

60
Q

What are the symptoms of MELAS?

A

The symptoms are progressive and fatal.

Muscle weakness; vomiting; episodic seizures; headache; hemiparesis; dementia.

61
Q

What gene mutations cause MELAS?

A

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

62
Q

What is LHON?

A

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

63
Q

What are the symptoms of LHON?

A

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

64
Q

How is LHON diagnosed and treated?

A

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

65
Q

How is MELAS diagnosed and treated?

A

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

66
Q

What mutations cause LHON?

A

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

67
Q

What is heteroplasmy?

A

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

68
Q

What is PKU?

A

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

69
Q

What are the symptoms of PKU?

A

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.

70
Q

How is PKU treated?

A

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

71
Q

What is MCAD Deficiency?

A

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

72
Q

What are symptoms of MCAD Deficiency?

A

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

73
Q

What are the treatments for MCAD deficiency?

A

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

74
Q

What are the characteristics of malignant tumours?

A

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.

75
Q

What are driver mutations in cancer?

A

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

76
Q

What are Tumour Suppressor (TS) genes?

A

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.

77
Q

What are Proto-oncogenes?

A

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.

78
Q

What is Knudson’s two-hit hypothesis?

A

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.

79
Q

What is familial and sporadic cancer?

A

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

80
Q

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

A

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.

81
Q

What are BRCA genes?

A

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

82
Q

What is homologous recombination?

A

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

83
Q

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

A

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

84
Q

How does genetic mutation cause FAP?

A

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.

85
Q

What are the effects of FAP?

A

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.

86
Q

How does genetic mutation causes Lynch Syndrome?

A

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.

87
Q

What are the prenatal testing steps in a normal pregnancy?

A

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.

88
Q

What are the aims of the 12 week scan?

A

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

89
Q

What is Nuchal Translucency?

A

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.

90
Q

What does Nuchal Translucency (NT) indicate?

A

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.

91
Q

What is the purpose of the mid-trimester scan?

A

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.

92
Q

What is the purpose of the combined test?

A

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.

93
Q

When is extra prenatal testing offered?

A

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.

94
Q

What are the aims of the prenatal testing?

A

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

95
Q

What are two minimally invasive methods of prenatal testing?

A

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

96
Q

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

A

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

97
Q

What is maternal serum screening?

A

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

98
Q

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

A

1st trimester screening at 11-14 weeks: hCG, PAPP-A.

2nd trimester screening at 16-20 weeks: AFP, uE3, hCG.

99
Q

What is Non-invasive Prenatal Diagnosis (NIPT)?

A

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.

100
Q

What are the uses of NIPD?

A

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.

101
Q

What are the limitations of NIPD vs invasive methods?

A

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.

102
Q

What are the benefits of NIPD vs invasive methods?

A

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

103
Q

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

A

Chorionic villus sampling (CVS) and amniocentesis.

104
Q

What is chorionic villus sampling (CVS)?

A

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.

105
Q

What is amniocentesis?

A

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.

106
Q

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

A

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

107
Q

What is Preimplantation genetic diagnosis (PGD)?

A

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

108
Q

What is intracytoplasmic sperm injection (ICSI)?

A

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

109
Q

What are the main eligibility criteria for PGD?

A

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

110
Q

What are the downsides of PGD?

A

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

111
Q

What is role of genetic counselling in prenatal testing?

A

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

MCD Year 1 (8 decks)

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