Week 1 Flashcards
What do TSGs require to exert their tumorigenic effect?
The inactivation of both alleles (two hit hypothesis; inheritance and deletion, recombination, epigenetic transcriptional repression)
How are most of the common cancer predisposition syndromes inherited?
Autosomal dominant, due to inheritance of an altered TSG
What is the normal function of proto-oncogenes?
They participate in the normal cellular response to growth factors (driving cell cycle forwards)
What are stability genes?
- A type of TSG
- Act to minimise genetic alterations
- Account for commonest hereditary predisposition syndromes (BRCA2 and colon cancer)
Differences between sporadic and familiar cancer:
Sporadic: - common - late onset - single primary tumour Familial: - uncommon - early onset - often multiple primary tumours (BRC and OVC)
What should you look for in a family history to establish risk of familial cancer?
More than one individual in same family (4 makes high risk) affected by similar cancers or cancers at related sites (breast & ovaries) with early age of onset
What genes cause familial breast cancer
- BRCA1
- BRCA2 (evident in male BRC)
less commonly - TP53
- PALB2
- PTEN
(at least 72 loci that confer an increased susceptibility to BRC)
What are the main features of HNPCC?
- Usually only a few polyps (less than 10)
- +/- uterus, stomach, ovary
- Due to inheritance of mutation in mismatch repair system genes
- 2 yearly colonoscopies from 25, plus 2 yearly upper GI endoscopies from 50
- MLH1 in ~50%, MSH2 ~40%
What are the main features of Familial Adenomatous Polyposis?
- Congenital hypertrophy of the retinal pigment epithelium in 80%
- Caused by APC (TSG) gene
- Annual bowel screening from age 11
- Many polyps (>100)
What are the main features of Li Fraumeni syndrome?
- Autosomal dominant
- BRC
- Brain tumours
- Sarcoma
- Leukaemia
- Adrenocortical carcinoma
- Chance of cancer 50% by 30, 90% by 50
- Mutations in master control gene, TP53
What does male-male transmission of genetic disease indicate?
The condition is not X linked
What is a vertical pattern of inheritance?
Condition inherited over generations
What is a horizontal pattern of inheritance?
Condition present in sibship (single generation)
What are the typical features of autosomal dominant?
- Vertical inheritance pattern
- Generally equal frequency and severity in M and F
- Variable expressivity
- Disease expressed in heterozygotes
What are the typical features of autosomal recessive?
- Carriers unaffected
- Equal frequency in males and females
- Disease expressed in homozygotes or cpd heterozygotes
- Expressivity more constant within a family
What is genetic anticipation?
- Increasing severity and earlier age of onset in successive generations
- Due to increasing repeats of trinucleotide as gene is passed from one generation to the next
What is pseudo-dominant inheritance?
Recessive inheritance with very high carrier frequency (or consanguinity) so appears like AD
What are the main features of X linked recessive?
- No male-male transmission
- Knight’s move inheritance pattern
- All daughters are carriers in male-female transmission
- 50% daughters carriers in female-female transmission
- M»F sex ratio
What are the main features of X linked dominant?
- No male-male transmission
- Vertical inheritance pattern
- All daughters affected in male-female transmission
- 50% daughters carriers in female-female transmission
- F:M = 2:1
What is the genetic basis for Huntington disease (HD)?
- AD with genetic anticipation
- Mutation in gene causes expansion of polyglutamine tract, which causes insoluble protein aggregates and neurotoxicity
- Genetic anticipation, prone to expansion during meiosis especially from father
What is the genetic basis for myotonic dystrophy?
- AD with genetic anticipation
- Unstable length mutation of a CTG repeat
- In the 3’ (transcribed but not translated) region of DMPK gene causing faulty DMPK mRNA
- Abnormal mRNA has toxic effect on other genes (CLCN1- chloride channel)
- Affected if 50 or more repeats
- Higher chance of expansion when transmitted by females
How does the genetic mutation cause myotonic dystrophy?
- Abnormal DMPK mRNA
- Indirect toxic effect upon splicing of other genes, e.g. CLCN1 gene causing myotonia
- Also affects insulin receptor
What is the pathogenic mechanism of cystic fibrosis?
- AR
- CFTR mutation, single codon deletion most common, causes defective chloride ion channel
- Increased thickness of secretions
What is the difference between in frame and out of frame deletion?
In frame is deletion of whole codon(s), out of frame deletion of base pairs
What explains the difference in severity of DMD and BMD?
DMD - 65% deletions - most out of frame BMD - 85% deletions - in-frame Genotype-phenotype correlation
Describe neurofibromatosis:
Commonly
- Cafe au lait macules and neurofibromas (from teens), short stature and macrocephaly
- LDs in 30% (severe in 3% or less)
- Very variable expressivity due to modifier genes
What are the possible complications of NF1?
- Hypertension
- Scoliosis (requiring surgery)
- Pathological tibial fractures
- Significant tumours
- Phaeochromocytomas
- Sarcomas
- Optic pathway gliomas
What is fragile X syndrome?
- X linked
- Genetic anticipation (due to repeats in the 5’ UTR region of FMR1 gene)
- Most common inherited cause of significant LD
- Phenotype can be severe in males, some carrier females also affected but more mildly
Describe Edwards syndrome:
- Trisomy 18
- Small chin
- Clenched hands with overlapping fingers
- Malformations of heart, kidney and other organs
- If strive first year, generally have profound LD
Describe Patau syndrome:
- Trisomy 13
- Congenital HD is usual
- About 50% die within 1 month
- Approx only 10% survive first year, generally profound LD
What are the clinical features of Patau syndrome ?
- Cleft lip and palate
- Micropthalmia
- Abnormal ears
- Clenched fists
- Post-axial polydactyly
How do trisomies normally arise?
- Maternal non-disjunction in meiosis
- Trisomies more frequent with increased maternal age
- Potential mutation of enzyme or protein factors that help in separation
Which aspects of clinical history are helpful for clinical genetic purposes?
- Patient’s clinical history
- with age of onset of symptoms, progression?
- Family history
- consanguinity, miscarriages or stillbirths
- Examination
- any dysmorphic features
- normal growth (height; occipital-frontal circumference)
Which aspects of clinical exam are helpful for clinical genetic purposes?
Dysmorphic features:
- head shape and size (micro or macrocephaly)
- eyes
- palpebral fissures (slant?)
- spacing (hypertelorism- pupils too far apart)
- ears
- size, shape, position (low-set?)
- rotated anteriorly or posteriorly (top of ear)
- nose: size, nares
- mouth (size, lips, teeth)
- limbs: disproportion
- skin (lumps, abnormal pigmentation)
- hands and feet
- palmar creases
- fingers and toes (correct number? poly and syndactly)
- normal palmar creases
What is pre-implantation genetic diagnosis (PGD)?
One or two cells removed from embryo when it contains 6-10 cells, then tested by FISH or (QF-) PCR
What are the pros and cons of PGD?
Pros
- permits implantation of unaffected embryos
- termination of pregnancy then unnecessary
Cons
- possible long wait
- not available to all women
- difficulty with multiple visits and procedures
- “take home baby rate” usually <50% per cycle
Which genetic conditions is screening currently carried out for during pregnancy and which tests are used?
- DS: CUBS screening in 1st trimester with maternal blood biochemical markers
- Ultrasound: nuchal translucency increased in DS
- Prenatal if family history of serious disorder, or a high risk from a prenatal screening test
- amniocentesis
- CVS
Which genetic conditions is screening currently carried out for neonatally and which tests are used?
Blood spot from a heel
- Mass spectrometry
1. phenylketonuria
2. MCADD - Immuno-assay
1. congenital hypothyroidism
2. cystic fibrosis - HPLC
1. sickle cell disorder
Which genetic conditions is screening currently carried out for postnatally and which tests are used?
- Tay Sachs disease screening for Jewish people
- Thalassaemia, population carrier screening for thalassameia
What are the basic principles of PCR-related sequencing?
PCR requires template DNA, two oligonucleotide primers that are complementary to sequences flanking the target DNA sequence, deoxyribose and a thermostable DNA polymerase. The PCR product can then be analysed by DNA sequencing, or other methods to detect small scale deletions
What are the applications and limitations of fluorescent Sanger DNA sequencing?
Applications:
- Single gene
Limitations:
- Single gene
What is aCGH and what is it used for?
Array comparative genomic hybridisation, used for whole chromosome analysis
What is non-invasive prenatal testing?
- Maternal plasma and free fetal DNA
- Tests for fetal sex determination (for X linked conditions)
- Tests soon to be introduced for paternal mutations (eg FGFR3)
- Also test aneuploidy
