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Phase 3 > Genetics > Flashcards

Genetics Flashcards

1
Q

Give 4 examples of autosomal dominant conditions

A
  • Inherited breast or colon cancer
  • Adult polycystic kidney disease (APKD)
  • Neurofibromatosis type 1 (NF1)
  • Huntington disease (HD)
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2
Q

Explain autosomal dominant pattern of inheritance, including its characteristics

A
  • Only one copy of the faulty gene is needed to be affected by the condition (homozygotes + heterozygotes)
  • Multiple generations affected (vertical pattern of inheritance)

Characterised by
- Variable expression: range of symptoms in people with same condition
- Incomplete penetrance: some individuals who carry the pathogenic variant express the associated trait while others do not
- Modifier gene variants
- Offspring of affected individuals usually have a 50:50 risk

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3
Q

List features of neurofibromatosis type 1

A
  • Cafe au lait macules
  • Neurofibromas
  • Short stature
  • Macrocephaly
  • Learning difficulties in 30%
  • Variable expressivity
  • Lisch nodules in the eyes
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4
Q

Describe autosomal recessive pattern of inheritance including its characteristics

A
  • 2 copies of the faulty gene needed to express phenotype
  • Single generation affected - horizontal pattern of inheritance

Characteristics include
- Likely consanguinity in the family
- Disease expressed in homozygotes or compound heterozygotes
- Offspring of affected individuals have a low risk
- Expressivity more constant within family

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5
Q

List examples of autosomal recessive conditions

A

Cystic fibrosis (CF)
Phenylketonuria (PKU)
Spinal muscular atrophy (SMA)
Congenital adrenal hyperplasia
Wilson disease
Tay-Sachs disease

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6
Q

Describe the pathophysiology of cystic fibrosis

A

Mutation in CFTR gene in chromosome 7
> Leads to a defective chloride ion channel and increased thickness of secretions
> Mutation is usually p.F508del, in-frame deletion of 3bp (one codon)
> Deletion of phenylalanine prevents normal folding of protein & insertion into plasma membrane

Presents with
> Salty sweat
> Thick mucus blocking airway (High rates of sinus infection)
> Blockage of pancreatic duct
> Male infertility (congenital bilateral absence of vas deferens)
> Liver disease
> Meconium ileus

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7
Q

How is cystic fibrosis diagnosed?

A

Screening of newborns by immunoreactive trypsin (IRT) level

Confirmation by DNA testing for CF mutation (ARMS kit) or sweat testing for increased chloride concentration

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8
Q

Described X-linked recessive inheritance and its characteristics

A

X chromosome carries the faulty gene so

  • No male to male transmission
  • Mostly or only males affected
  • Occasional manifesting carriers due to skewed X inactivation
  • Knight’s move: two males who are related through an unaffected female are affected
    > Likely to be X-linked recessive as female has an additional unaffected X chromosome which protects her
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9
Q

Describe the pathophysiology of Duchenne Muscular Dystrophy (DMD)

A

Frameshift mutation (mostly out of frame deletions) results in shorter dystrophin protein, which damages the myocyte cell membrane
> allows creatine kinase exit and calcium entry, destroying myocytes

Muscle damage leads to progressive degenerative weakness
> onset 3y, wheelchair by 12y
> Mean life span of <30 years as heart and diaphragm are affected by muscle weakness

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10
Q

Describe the tests used to diagnose Duchenne Muscular Dystrophy

A
  • MLPA (multiplex ligation-dependent probe amplification) test to detect deletions
  • SCK test : measures serum creatine kinase released by damaged muscle
    > confirmed by muscle biopsy then tested for absence of presence of dystrophin gene and expression in muscle fibres via immunohistochemistry (IHC)
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11
Q

Describe the pathophysiology of Becker Muscular Dystrophy (BMD)

A
  • Mutations in dystrophin gene, but in-frame deletions, so there is reduced quantity of fully functional dystrophin OR full quantity of partially functional dsytrophin
  • Mild phenotype of DMD
  • onset age 11
  • may never need a wheelchair
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12
Q

Explain X-linked dominant inheritance and its characteristics

A
  • Pattern is like AD but no male-to-male transmission
  • Vertical pattern of inheritance
  • Male-female transmission: all daughters affected
  • Female-female transmission: 50% daughters affected
  • appears to be more females affected - due to male lethality
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13
Q

Give examples of X-linked dominant conditions

A

Vitamin D resistant rickets
- caused by pathogenic variants of PHEX gene

Incontinentia pigmenti
- Skin condition that causes rashes and patches of pigmentation
- Caused by partial deletions of IKBKG gene

Rett syndrome
- Causes child development to stop at 6-18 months with subsequent regression
- Due to pathogenic variants of MECP2
- Male lethality

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14
Q

Explains pseudo-autosomal and pseudo-dominant inheritance

A
  • Pseudo-autosomal: seems autosomal but is actually on the sex chromosomes
  • Pseudo-dominant (actually AR): if there’s a high carrier frequency or cosanguinity
    > e.g. Gilbert syndrome (TA insertion within promoter region of UGT1A1 gene) - causes intermittent jaundice due to episodes of mild unconjugated hyperbilirubinaemia
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15
Q

Describe mitochondrial inheritance giving an example

A
  • Smaller genome (37 genes, 17 kbp, no introns, circular)
  • Inherited only from mother
    > all children affected to variable extents
  • Syndromes often affect muscle, brain and eyes

E.g. Leigh’s disease
> In mitochondrial DNA, MT-ATP6 gene coding for ATP synthase

Heteroplasmy is when there is more than one type of mtDNA in an individual

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16
Q

Describe the causes of Down’s syndrome and its phenotypic features

A

Causes: trisomy 21 due to maternal nondisjunction or Robertsonian translocation (inheritance risk)

  • Phenotypic features
    > Upward slanting palpebral fissures and epicanthic folds
    > Sandal gap
    > Single transverse palmar crease
    > Small nose
    > Low set ears
    >macroglossia
    > High incidence of heart malformations, hypothyroidism, childhood leukaemias, early onset Alzheimer’s
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17
Q

Describe the cause of Edwards’ syndrome and list its clinical features

A

Caused by trisomy 18

Features
> Often stillborn or miscarried, survival usually <4 months due to infections/heart failure; profound intellectual disability if they survive

> Rockerbottom feet
Syndactyly
Malformations of ears, heart, kidneys…
Micrognathia: small lower jaw
Exomphalos: umbilical hernia at birth

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18
Q

Describe the cause of Patau syndrome and its clinical features

A
  • Caused by trisomy 13

Features
> Not compatible with life past a few week safter birth; many miscarriages
> Hypotelorism: eyes close together; cyclopia; microphthalmia
> Abnormal ears
> Clenched fists
> Cleft lip & palate
> Scalp defects, microcephaly
> Post-axial polydactyly
> Organ problems e.g. heart difficulties

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19
Q

Describe the cause and inheritance of myotonic dystrophy type 1 (DM1)

A

DM1 is caused by a CTG repeat expansion in the 3’ UTR of the DMPK gene (serine-threonine kinase)

> Inheritance is autosomal dominant with genetic anticipation
Repeat number of alleles increases with each generation; severity of disease is directly related to the number of repeats present

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20
Q

Describe the pathogenesis and clinical presentation of DM1

A

DM1 is characterised by abnormal DMPK mRNA which has an indirect toxic effect upon the splicing of other genes, e.g. chloride ion channel CLCN1 gene, causing myotonia
> Insulin receptor also affected, causing diaberes in some

Presents as adult-onset muscular dystrophy; myotonia (muscle relaxation is impaired) and cataracts

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21
Q

Describe the cause and inheritance of Huntington’s Disease (HD)

A

Caused by a CAG repeat sequence near the 5’ coding end of the huntingtin gene (HTT) on chromosome 4, which encodes a polyglutamine tract
> Expansion of the tract causes insoluble protein aggregates & neurotoxicity

Inheritance is autosomal dominant with genetic anticipation

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22
Q

Describe the pathogenesis and clinical features of HD, including diagnosis

A

Protein is cytoplasmic and ubiquitously expressed; may be involved in transport and trafficking within the brain as well as transcription and anti-apoptotic processes
> Selective neurodegeneration: neostriatum and cerebral cortex

Features include Huntington’s chorea (progressive) and dementia

Diagnosis via triplet primed PCR (TP-PCR)

23
Q

Describe the cause and clinical features of Fragile X

A

Caused by an expansion of the CGG repeat in the 5’ UTR of the FMR1 gene

Inheritance is X-linked recessive; most common inherited cause of learning difficulties

Can cause premature ovarian failure in female carriers and Fragile X-associated tremor ataxia in males

24
Q

Define 1) genetic heterogeneity 2) pleiotropy

A
  1. Genetic heterogeneity is a term used to describe a disorder having several different genetic causes
  2. Pleiotropy describes when one gene causes more than one condition e.g. RET gene causes MEN2 (AD) and Hirschprung’s disease
25
Q

List different types of gross lesions in genes

A
  • Large deletions
  • Inversion
  • Insertion
  • Duplication
26
Q

Explain the different types of microlesions in genes

A

Substitution
- Replacing one base for another
Can be missense if it changes a codon from coding from one amino acid to coding for another OR nonsense if the coding codon is exchanged for a stop codon

Splicing
- If splice site is abolished, some exons may be spliced to different locations so the resulting mRNA has a missing exon

Regulatory
- Altering transcription start site can change the affinity for transcription factors

Small insertions/deletions
- Can result in a frameshift mutation if not a mutliple a 3; changes codons downstream (out of frame)
- In-frame mutations result in a loss or altered amino acid at a specific point but does not change others

27
Q

Give an example of 1) gain of function mutation 2) loss of function mutation

A
  1. Mutant FGFR1 can dimerize without a growth factor leading to osteoglophonic dysplasia, which presents with craniosynostosis and dwarfism
  2. Kallman syndrome (haploinsufficiency) presents with anosmia and hypogonadotrophic hypogonadism
28
Q

List the 9 characteristics of cancer cells

A
  • Self-sufficiency (proliferation in absence of growth factors)
  • Insensitivity to growth-inhibitory signals (inactivation of TSGs)
  • Evasion of apoptosis (overexpression of BCL2)
  • Limitless replication potential (upregulation of telomerase)
  • Sustained angiogenesis
  • Tissue invasion & metastasis
  • Avoiding immune destruction
  • Genome instability and mutation
  • Deregulating cellular energetics
29
Q

Define oncogenes and give examples

A

Oncogenes are mutated forms of normal genes (proto-oncogenes) involved in signalling pathways that regulate cell proliferation, inducing tumour formation

E.g. in the nucleus; Myc & cyclin D

30
Q

Define proto-oncogenes and give examples

A

Proto-oncogenes are normal cellular genes that encode proteins involved in regulating cell growth/division
- Only need one mutated gene copy (dominant effect) for tumorigenic effect (oncogene)

E.g.
> Growth factors such as PDGF & growth factor receptors e.g. EGFR, HER2
> Cytoplasmic signalling intermediates e.g. Ras, MEK, BRAF
> Nuclear proteins e.g. Myc, Fos, Jun
> Cell cycle regulators e.g. BCL1, cyclin D
> Proteins influencing cell survival e.g. BCL2

31
Q

Define tumour suppressor genes and give examples

A

TSGs are genes whose encoded proteins inhibit cell cycle progression

Loss of function mutation is oncogenic; usually recessive (both copies must be mutated) but the EXCEPTION is p53 (acts as a tetramer, dominant negative)

Examples: RB, BRCA1, MEN1

Mutation in p53 (TP53) results in Li Fraumeni syndrome - inherited predisposition for cancer (AD inheritance)

32
Q

Describe the causes and management of familial adenomatous polyposis (FAP)

A

Caused by APC gene mutations, AD inheritance

Results in a carpet of small adenomatous polyps: high risk of adenocarcinoma so total colectomy done at young age

33
Q

Describe the causes and management of familial breast cancer

A

BRCA1/2 mutations as these proteins are involved in DNA repair by homologous recombination of double-stranded breaks
> Increased risk of ovarian and breast cancer

Other mutations include TP53, PALB2, PTEN

Prevention; testing via next generation sequencing, examinations, screening by mammography or MRI, prophylactic bilateral mastectomy/oopherectomy

34
Q

List mutations that increase the risk of ovarian cancer and the treatment for this cancer

A

Mutations in BRCA1/2, MLH1, MSH2

Treatment is surgical or via a PARP (poly ADP ribose polymerase) inhibitor - olaparib

35
Q

Why would you suspect an inherited cancer syndrome in an individual?

A
  • Young age of onset for cancer
  • Multiple primary tumours in one individual
  • Several genetically related individuals with same/related cancer
36
Q

List the tests used to detect point mutations

A
  • DNA sequencing
    > Sanger sequencing
    > Next generation sequencing (NGS)
    > Allele specific (ARMS) PCR
37
Q

Explain the mechanism behind Sanger sequencing

A

Sequences 1 gene at a time using fluorescent dideoxynucleotide sequencing to detect point mutations

38
Q

Explain the mechanism behind next generation sequencing (NGS)

A
  • Aka massively parallel or high throughput sequencing
  • Illumina method
    > Hundreds of millions of DNA fragments sequenced at once on a flow cell
    > Use computer to identify variants compared to the reference sequence
    > Produces a variant call format (VCF) file - a list of all the variants
    > User filters variants to just those that are not common (Not polymorphisms) and are predicted to be damaging to the protein

Can sequence a single gene, several genes (gene panel); exome (all protein coding regions of all genes) or the genome

39
Q

Explain the mechanism behind an ARMS PCR

A

Special PCR that analyses only specific known mutations

40
Q

List the tests used to detect sub-microscopic duplications and deletions

A
  • MLPA
  • Chromosomal microarray (CMA)
  • FISH
41
Q

Explain the mechanism behind MLPA

A

Multiplex ligation dependent probe amplification is a PCR-based method that targets a group of specific known positions - chromosomal loci - where there might be a deletion

42
Q

Explain the mechanism behind FISH

A

Fluorescence in-situ hybridisation (FISH) uses a specific DNA probe that binds to a location on a chromosome

E.g. FISH using a Williams syndrome probe can find a deletion of the elastin gene at 7q

43
Q

List methods for the detection of aneuploidies

A
  • Karyotyping; examining chromosomes using light microscopy
  • Quantitative fluorescence PCR (QF-PCR): whole chromosome analysis
44
Q

Explain the mechanism behind non-invasive prenatal testing (NIPT)

A

Aka cell free foetal DNA (cffDNA) screening
> Uses complex new DNA analysis techniques to identify tiny amounts of foetal DNA in maternal blood
> cffDNA migrates into the maternal bloodstream via apoptotic trophoblast cells shed from placental tissue

Testing involves taking a blood sample from the mother and performing massively parallel sequencing - no risk to foetus

45
Q

List the appliactions of NIPT

A
  • Sex determination; detecting Y chromosome sequences to test for X-linked conditions
  • Single gene disorders: detects paternally inherited alleles e.g. FGFR3 causing achondroplasia; also where parents are carriers of different mutations in the same gene for AR conditions such as CF
  • Non-invasively determined foetal Rh type
    > detection of RHD gene in an RhD negative pregnant woman indicates RHD positive foetus
  • Aneupolidy: screening for trisomies, may need confirmation via CVS or amniocentesis
  • Microdeletion syndromes/other chromosomes
46
Q

Explain the function of the CF drug ivacaftor (and tezacaftor, elexacaftor…)

A

Targets G551D - 3rd most common CF mutation - which blocks the opening of the CFTR chloride ion channel; ivacaftor reopens the channel, improving CFTR function

47
Q

Explain the system used for gene editing

A

CRISPR/CAS9 system can be used to correct mutations in the DNA sequence

> CRISPR is a guide RNA that finds a target sequence

> in trials for beta-thalassaemia and sickle cell disease

> important to avoid off-target effects (other genes)

> gene replacement: Zolgensma for spinal muscular atrophy (SMA); introduces normal SMN1 gene copy to motor neurons via an adenovirus vector

48
Q

Describe new therapies used for DMD

A

Oral drug (ataluren or translarna)
> small molecule that may cause read-through of premature stop codons, allowing the ribosome to finish synthesising dystrophin

49
Q

Describe the cause hereditary non-polyposis colon cancer (Lynch syndrome)

A

AD inherited cancer predisposition (colorectal + uterus + stomach + ovary)
- usually only a few polyps

Mutations inherited in one of they key DNA mismatch repair genes: MLH1, MSH2, MSH6, PMS2

> Screening if at high risk, 2 yearly colonoscopies from 25 & 2 yearly upper GI endoscopy from 50

> aspirin reduces risk of colorectal cancer

50
Q

Describe the cause of MYH/MUTYH polyposis

A

AR inheritance
15-200 polyps, like mild FAP

> Normal function: base excision repair gene (BER gene) - encoding DNA glycosylase

Mutation leads to high risk of carcinoma; 2 yearly colonoscopy for screening

51
Q

Explain the DNA mismatch repair complex

A

Heterotetramer of proteins that track along DNA following DNA polymerase

> MSH2/MSH6 (MSH2/MSH3) heterodimer recognises and binds mismatch
then recruits MLH1/PMS2 (MLH1/PMS1, MLH1/MLH3) heterodimer

DNA exonuclease digests nucleic acids and DNA polymerase adds on new bases

52
Q

Explain nucleotide excision repair

A

Used for single base repair; NER multi enzyme complex tracks along DNA molecule and identifies lesion

Endonuclease cuts within the molecule; DNA polymerase fills gap and DNA ligase seals it

53
Q

Describe the repair of double strand breaks

A

2 types

  • Homology-dependent repair: germline cells
    > single stranded overhang is used to search entire genome to find homologous chromosome as a template
  • Non-homologous end-joining: somatic cells
    > 2 broken ends of DNA are tested against each other and through coincidence some bases match and are attached together
54
Q

Describe the cause of MutYH-associated polyposis

A

AR inherited loss of function mutation of MYH gene - encodes a component of the base excision repair pathway

  • MutYH recognises oxoguanine paired with A, another chance is given for OGG1 to pick up damage and repair it, returning to G-C base pair
  • If this is not repaired, O (Oxo-G) pairs with A, resulting in T-A base pair during replication (oncogenes, TSGs)

Phase 3 (14 decks)

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