Genetics Flashcards
What proportion of newborns do congenital defects affect
1 in 50
What are the 2 broad types of congenital defect
Single and multiple
What is malformation and give an example
Single congenital defect
Morphological defect of an organ due to abnormal development e.g. cleft lip, atrial septal defect
What is disruption and give an example
Single congenital defect
Morphological defect of an organ from intrinsic breakdown or interference with a normal process e.g. amniotic band
What is deformation and give an example
Single congenital defect
Abnormal form shape or position due to mechanical factors e.g. club foot
What is dysplasia and give an example
Single congenital defect
Abnormal organisation of cells into tissue and its morphologic results e.g. thanatophoric dysplasia
What is a sequence
Multiple congenital defects
Pattern of abnormalities derived form a single known or preserved prior anomaly e.g. Potters sequence
What is a syndrome
Multiple congenital defect
Multiple anomalies thought to be pathogenically related that is not a sequence e.g. Downs
What is an association
Multiple congenital defects
Non-random occurrence in 2 or more individuals of multiple abnormalities e.g. VATER association
Describe the packaging of DNA
DNA
Gene
Chromosome
Genome
What is the normal human karyotype
22 chromosomes and 1 sex chromosome (haploid) from 1 parents
What is nomenclature of chromosomes based on
bands
long arm= P
short arm = Q
What are the possible structural abnormalities of chromosomes
duplication inversion deletion ring - telomeres translocation - Transfer of genetic material from one chromosome to another
Describe Robertsonian translocation
The short arms (q) are lost while the long arms are combined
These become fused and therefore do not separate during division
If there is a balance, it is unlikely that there will be an abnormal phenotype
If unbalanced, disruption of a gene may occur or a fusion product
Give the possible consequences of robertsonian translocation on reproduction with a normal cell
normal
monosomy (lethal)
trisomy
Which monosomy abnormality is not lethal
Turner’s
Define aneuploidy
Loss or gain of 1 or more chromosome
Describe the different types of numerical abnormalities in chromosome
monosomy - loss of 1 chromosome
disomy - normal
trisomy - gain of 1 chromosome
tetrasomy - gain of 2 chromosome
Give 3 examples of trisomy
Downs - 21
Edwards - 18
Patau - 13
What is the most common form of trisomy
Chromosome 16
Lethal and leads to miscarriage
Describe the features of trisomy 21
hypotonia lethargy excess nuchal skin Cranofacial features Sandal gap Single palmar crease Septal and heart defects
What are the causes of trisomy 21
Non-disjunction in meiosis 1 where homologous chromosomes fail to separate
Translocation
Mosaicism
What is mosaicism caused by
mitotic non-disjunction
Children are less severely affected
Define dosage compensation
ensures equivalent gene expression in both sexes
Inactivation of an X chromosome in females (lyonisation)
What is Turner’s syndrome and its features
monosomy X
Loss of the X or Y in paternal meiosis
Webbed neck, low ears, normal intelligence
What is Klinefelter’s syndrome
47 XXY
X from either parent
Phenotypically male, learning disability, taller, learning disability, infertility
Identify the symbols used in pedigree charts for proposiatus, X-linked carrier, unspecified sex, abortion, unidentical twins and identical twins
arrow = proposiatus (first) solid with an outline = X-linked carrier diamond = unspecified sex little circle = abortion of still birth diagonal lines = unidentical twins diagonal twins + horizontal = identical twins
Describe the inheritance patterns for an autosomal dominant disease
Only 1 copy is needed to be presented in the phenotype At least one parent is affected M or F Vertical transmission Age of onset decreases further down
Describe Huntington’s disease
Autosomal dominant disease
Motor, cognitive and psychiatric disfunction
Caused by CAG repeats
The greater the no. of CAG, the more severe
Describe the inheritance patterns for an autosomal recessive disease
Both alleles must abnormal to be presented in the phenotype
No affected parents
M or F
Usually very little family history
Describe cystic fibrosis
Autosomal recessive disease
Thick mucous produced in the lungs
breathing problems, infectious, blocks the pancreas
CTFR gene incorrectly folded
Describe the inheritance patterns for a X-linked recessive disease
No affected parents
Only M affected
Transmitted by F carriers
Describe haemophilia
X-linked recessive disease
Blood clotting disorder
Easy bruising and bleeding
Types A and B
Give an example of how the same gene can have different mutations
The CFTR gene mutating can cause cystic fibrosis or CAVD
Give an example of how mutations in different genes can cause the same disease
Mutations in genes A and B can both cause haemophilia
Give an example of how different genes and inheritance can cause the same disease
AD and AR will cause epidermis bullosa
Define Mendelian inheritance
Individuals inherit and transmit to their offspring one out of the 2 alleles present in homologous chromosomes
Define polymorphism
Mutation present in >1% of the population which may contribute to complex disease
What are the types of point mutation
missense (1 amino acid for another)
nonsense (stop codon for an AA)
Define incomplete inheritance
Symptoms are not always present in an individual with a disease-causing mutation
Define variable expressivity
Disease severity may vary between individuals with the same disease-causing mutation
Define phenocopy
Having the same disease but with a different underlying cause
Define epistasis
Interaction between disease gene mutations and other modifier genes which can affect genotype
What are dominant conditions usually caused by and how may this be resolved
mutations that result in the presence of a toxic protein
Switch off the gene or neutralise the produced protein
What are recessive conditions usually caused by and how may they be resolved
Mutations that lead to the absence of a functional protein
Restore tha activity of the missing protein
What are co-dominat conditions usually caused by and how may they be resolved
Both the mutated and normal genes are apparent
Switch off the abnormal gene of neutralise the protein
What is the epigenome
Transcriptome
Surrounds the genome
Non-mendelian inheritance
What is imprinting
Involves DNA methylation. The genome carries an imprint of the parental origin.
75 genes are affected
The DNA sequence remains normal while function changes
Reflects that parental origin of chromosomes is important
What is methylation
Methyl groups are attached to the 5 position of the pyrimidine ring cytosine on DNA
Decreases gene expression as it blocks transcription factors
Describe Prader-Willis syndrome
Loss of function of the paternal chromosome
Critical region is deleted OR 2 maternal copies are inherited (uniparental isodomy)
What are the symptoms of Prader-Willis syndrome
Hyperphagia (overeating with loss of regulatory process) Obesity Mental retardation Hypotonia (reduced muscle tension) short Infertile
Describe Angelman syndrome
Loss of function of the maternal chromosome
Imprinting defects OR UB3A mutations
How is Prader-Willis syndrome treated
Diet restriction
Exercise for muscle
Growth hormones
Hormone replacement
What is the karyotype of the mitochondria
36 genes
2-10 copies are circular genomes
Describe mitochondrial inheritance
Only inherited through females
The sperm lose their mitochondria as they meet the egg
What is heteroplasmy
Mixture of mitochondria with some containing mutant DNA while others are maternal
Give some examples of mitochondrial diseases
MELAS LHON MERRF DEAF NARP
Describe MELAS
Mitochondrial myopathy Encephalopathy Lactic Acidosis and Stroke
Progressive neurodegenerative disorder
The muscle and brain have lots of mitochondria so they are heavily affected
What are the symptoms of MELAS
muscle weakness
episodic seizures
stroke-like episodes
vomiting
Describe LHON
Leber’s hereditary Optic Neuropathy
More common in males
What are the symptoms of LHON
Bilateral vision (loss of central vision)
Optic atrophy
Blindness
What are the emerging therapies for LHON
3 parent babies
donor gives an empty egg cell
What is the newborn screening programme in the UK
Physical exam
Hearing test
Blood spot (Guthric acid) - sickle cell, cystic fibrosis, PKU(9 in total)
Describe PKU and its symptoms and treatment
Phenylketonuria Deficiency of phenyladenine hydroxylase Severe retardation Eczema Blonde hair and blue eyes Reduced melanin Remove phenylalanine from the diet
Describe MCAD deficiency and its treatment
Medium chain Acyl coA dehydrogenase deficiency
Common disorder of fatty acid oxidation
Sudden death
Beta oxidation cannot occur so fasting an hypoglycaemia is dangerous
adjust caloric intake and avoid fasting
Compare somatic to germline mutations
somatic - occurs in a single body cell and cannot be inherited
gremlin - occurs in the gametes and can be inherited
Give examples of types of mutations
Aneuploidy Translocation chromosome: Macro-deletions Macro-insertions gene: Large insertion Large or deletions
Point mutation
What are the hallmarks of cancer
Dysregulated growth Evasion of apoptosis Limitless replication Sustained angiogenesis Invasion/ metastasis Genome instability and mutation (disordered growth, disordered death, disordered behaviour)
Explain what a polyclonal disease is
Cancer is polyclonal
Many clones of varied genetically distinct cells
Compare driver to passenger mutation
driver - The 1st key mutation
Can cause a normal cell to become a cancer cell
passenger - mutations that don’t contribute to the development of cancer but have occurred during cancer growth
What are the 2 main classes of cancer causing genes
proto-oncogenes
tumour suppressors
What is Knudson’s 2 hit hypothesis
Most TS genes require damage to both alleles to make the cell cancerous
Hit 1 reduces transcript/protein levels but there is no phenotypic affect
hit 2 causes a total loss of transcription (usually a deletion) and causes malignant potential
Give an example of Knudson’s two hit hypothesis in practice
Retinoblastoma
When TF E2F is bound it is not functional
Mutated RB does not bind
RB phosphorylated by cyclin CDK, releasing E2F
Genes transcribed to cause pro-growth signals
Familial - child born with 1 mutation, second is somatic
Sporadic - one somatic mutation acquired, second somatic mutation in the same cell
What is an SNP
Single nucleotide polymorphism where the base on the genes of different chromosomes are different
DNA cannot be sequenced without an SNP
How can SNPs be used to guess the cause of disease
1st hit = SNP
2nd hit = Large deletion
If there is not SNP then it is likely there was a large deletion
What percentage of breast cancers are caused by germline mutation and of what genes
2.4%
BRCA1 or BRCA2
BRCA2 predisposes to breast cancer in men
Describe breast cancer as mutations
Hit 1 is inherited
hit 2 may not always occur
BRCA genes are TS genes that repair DNA by homologous recombination which cannot happen with mutation
Which defects in cell division or DNA repair influence the risk of familial colorectal cancer
Familial adenomatous polyposis
Lynch syndrome
Describe familial adenomatous polyposis
Thousands of intestinal polyps which contribute risk to colorectal cancer
Caused by the APC gene on chromosome 6
Autosomal dominant
Describe HNPCC
hereditary non polyposis colorectal cancer
Most common inherited form
mutation of MLH1 or MSH2 (DNA repair genes)
Describe oncogenes and tumour suppressors
Proto-oncogenes promote growth and proliferation in cells and those that are in overdrive are oncogenes.
Signalling cascades and mitogenic pathway activation
TS genes regulate cell division, DNA damage, apoptosis and DNA repair
mutations cause loss of function and faulty cell division
Describe chronic myeloid leukaemia
Clonal myeloproliferative disorder => overproduction of mature granulocytes
Middle ages/elderly
3 phases: chronic (benign), accelerated (omnious), blast crisis (acute leukaemic, invariably fatal)
Philadelphia chromosome is found in >90% produces a new tyrosine kinase
What are the indications of testing
Nuchal scan Mid-trimester Previous pregnancies with DS or CF Parents are carriers of chromosome rearrangement or genetic condition FH of genetic condition
Describe the nuchal scan
Looks at the thickness of the fluid at the back of the fetal neck
> 3mm indicates a chromosomal abnormality
Not a diagnostic test
Could be Down’s, Edwards, Patau or cardiac
What is the combined test for Down’s
Combined test =levels of the hormone free beta-hCG +protein PAPP-A
High hCG and Low levels of PAPP-A.
Describe the mid-trimester scan
20 weeks
dates the pregnancy
Diagnose miscarriage or fatal anomalies
What are the reproductive options available
Planning prenatal testing
Facilitating decision making
Seeing patients in clinic following diagnosis in utero
Arrange termination if necessary
Discuss recurrence risks and plans for future pregnancies
Taking into account: previous experiences, family situation, personal beliefs, psychosocial situation, miscarriage risk with genetic risk
What types of scanning are done in pre-natal testing
ultrasound - early scan, nuchal, anomalies in hands, feet, face, lip
MRI at 20 weeks
Describe non-invasive pre-natal testing
Maternal serum screening = testing serum markers in the blood for trisomy 21 or 18 + nuchal measurement
cell-free fetal DNA = analysing DNA fragments in the maternal plasma during pregnancy. baby at 9 weeks. Only 10-20% from the placenta
ultrasound
What are the disadvantages of non-invasive testing
Both not as useful for multiple pregnancies
non-invasive is harder with a greater BMI
Describe Amniocentesis
Invasive
16 weeks onwards
Sample the amniotic fluid which contains fetal cells
1% miscarriage risk, infection, Rh sensitisation
Define heritability
The study of genetic contribution to increased risk of disease
Studies usually use mono and dizygotic twins
Why may estimates on heritability vary
different populations
different ages
baseline risk of disease in population
sampling variance
What is GWAS
genome wide association studies that studies SNPs
What is the copy number variant
Repeated code
Deletions, duplications, insertions that increase polygenic disease risk
Found in obeisty
What are the types of obesity
Monogenic - dominant or recessive single gene disorder
Common - general population
Syndromic - e.g. Prader Willis
What is leptin
Hormone made by adipocytes inwards white adipose tissue which circulates in proportion to the amount of adipose tissue
Inhibits appetite via the hypothalamus
High with high fat
What are the symptoms of monogenic leptin deficiency
hunger obesity no puberty poor growth Low thyroid
Give examples of genes that cause single gene obesity
MC4R = dominant PCSK1 = recessive POMC = recessive MRAP2 = recessive
How is obesity clinically management
Lifelong prevention
Lifestyle measures
Medication
bariatric (weight loss) surgery
How is obesity diagnosed
PCR for diagnosis
Pre-implantation diagnosis for IVF embryos
Mitochondrial transfer (3 parent babies)
What is Sanger sequencing
Amplifying the region of interest with nucleoside terminators
Genetic sequence of the region of interest
What is Next generation sequence
Fragmentation, sequencing and mapping of reads
sequence of the genome/transcriptome
What are the advantages and disadvantages of Sanger sequencing
quick
gives sequence
cannot multiplex
Limited to 2000bp
What are the advantages and disadvantages of next generations sequencing
Massively multiplex
Multiple different libraries
Cost Time Read-depth Data overload Library bias
Describe chorionic villus sampling
Invasive 11-14 weeks 1-2% miscarriage risk Sample of chorionic villi part of developing placenta (same DNA as the foetus) Ealier result than amniocentesis
