Inherited Disease Flashcards
Pathological variants of which genes are associated with breast cancer
BRCA1
BRCA2
TP 53 (rare)
All tumour suppressor genes
oncogene
Mutated derivative of proto-oncogene
‘Gain of function mutation’-dominant manner at cell level
A female with a BRCA 1 or BRCA 2 mutation is a higher risk of which cancers?
Breast & Ovarian
Which BRCA mutation gives the highest risk of Breast Cancer for females?
BRCA1
Males with which BRCA mutation are at increased risk of prostate cancer?
BRCA2
BRCA 1 2 mutations are associated with increased risk of which cancers?
Breast, Ovarian, Pancreatic, Prostate
Clinical indication of Breast cancer; you should be referred for further assessment if you have: (6 criteria)
- one close relative who has had breast cancer before the age of 40
- two or more close relatives who have had breast cancer
- close relatives who have had breast cancer and others who have had ovarian cancer
- one close relative who has had breast cancer in both breasts (bilateral breast cancer)
- a male relative who has had breast cancer
- Ashkenazi Jewish ancestry”
Transcription
DNA copied to mRNA by RNA polymerase
Translation
process in which ribosomes in the cytoplasm or ER synthesize proteins
Codon
triplet nucleotides, 64 of these encode 20 amino acids (3 exceptions)
Polymorphism
Change in triplet code results in same amino acid production
UAU to UAC = Tyr
(conservative)
Mutation
Change in triplet code results in different amino acid production
UAU to UAG = STOP
(truncating)
UAU to UUC = Phe
(non-conservative substitution)
Expressivity
Degree to which a phenotype is expressed in individuals with the same geneotype
MEN2
Autosomal dominant Medullary Thyroid carcinoma Phaeochromocytoma RET gene mutation MEN2A represents 90%
MEN2
Autosomal dominant
MEN2 mutation
example of mutation in oncogene (gain of function)
Medullary Thyroid carcinoma, Phaeochromocytoma (benign)
Familial cancers involving tumour suppressor genes
Retinoblastoma- RB1
Li-Fraumeni syndrome (brain tumours, sarcomas, leukemia)-TP53
Familial adenomatous polyposis-APC
Breast and/or ovarian cancer-BRCA1/2
Colon Cancer Mutator pathway
Lynch Syndrome- MSH2, MLH1
<100 adenomas
High colorectal cancer risk
High endometrial cancer risk
Colon Cancer Suppressor pathway
FAP- APC gene
Classical-1000s of colonic adenomas
95% penetrant by 35
Malignancy risk ~100%
Gardeners Syndrome
FAP plus Osteomas Soft tissue tumours: Sebaceous cysts Fibromas Desmoid tumours
Germline Mutation
Affects all cells and can be passed on-responsible for hereditary cancers
Somatic mutation
acquired genetic changes- only affects cells where mutation occurs and their direct offspring Responsible for sporadic cancer development
Amsterdam Criteria
identifies families in which Lynch syndrome is likely
3 colorectal tumours
2 generations
1 diagnosed <50
Lynch syndrome management
Surveillance
Chemoprophylaxis-Aspirin
Surgical prophylaxis
Family cascade management
CHARGE Syndrome
Coloboma of the eye Heart defects Atresia of choanae Retardation of Growth and Development Genital and Urinary Tract abnormalities Ear abnormalities and hearing loss
Fetal Valporate Syndrome facial features
Tall forehead medial eyebrow deficiency flat nasal bridge broad nasal root Shallow philtrum Long upper lip thin vermillion border
Aneuploidy
An abnormal number of chromsomes
Viable autosomal trisomies (3)
21(Down Syndrome)
13 (Patau syndrome)
18 (Edward syndrome)
Only viable monosomy
45,X Turners syndrome
Balanced Rearrangement
No loss or gain of genetic material
Reciprocal translocation, Inversion, Insertion
Requires karyotype to detect
Unbalanced
Deletion
Duplication
Will be detected by microarray
Presentation of Turners Syndrome
45, X – 98% conceptions end in miscarriage
75% loss of X or Y in paternal meiosis
Presents at all ages
Prenatal ↑NT or generalised oedema, hypoplastic aortic arch
Neonates neck webbing puffy hands and feet
Children short stature
Adolescents pubertal arrest, amenorrhoea
Fluorescent In situ Hybridisation (FISH)
White cell culture as for G banded karyotype analysis
Metaphase spread
Uses DNA probes carrying a fluorescent label which hybridise specifically to a known chromosome region
Used to detects submicroscopic deletions
Used to detect chromosome rearrangements of relatively large DNA sequences
Requires prior knowledge of chromosome location of variant of interest
in this you glue down the chromosome and the probe is added which binds
How is X gene expression controlled
XIST functional RNA expression ‘turns off’ that X chromosome and results in variation in phenotype of carriers with X linked conditions- Skewed X inactivation
What if the XIST RNA region is methylated?
The XIST RNA is not expressed and that X is active
Lyonisation
The activation or inactivation of X via the XIST RNA
Paraganglioma
Imprinted inherited from paternal allele via dominant pattern SDHD
Unmethylated alleles (germline)
Are active and expressed when inherited-imprinting
Methylated alleles (germline)
Are hidden and not expressed even though person can be a carrier of a dominant condition because during oogenesis/spermatogenesis methylation and demethylation occur to match with maternally/paternally derived allele type-imprinting
Somatic imprinting
Random hypermethylation of the genes
Eg Colon Cancer;of the promoter of MLH1 (inactivates it)results in mutator pathway tumour phenotype, looks like Lynch syndrome but tumours acquire the BRAF V600E driver
mutation
Karyotype
Displays all of persons chromosomes and can identify the number, sex type, deletions, duplication, translocation, inversion and derivatives
Array Comparative Genomic Hybridisation (aCGH)
Microarray-looking at copy number variants- doesn’t require prior knowledge of chromosomal location of variants
Glue down the probe and add in DNA(labelled with dye)
Uses competitive hybridisation between control (red) and test DNA (Green)- Yellow indicates equal amounts of both, red means there is deletion in the test, and green means there are duplication’s
DNA sequencing
Single base changes to whole genome
Downs Syndrome
Flat facial profile epicanthal fold CHD duodenal atresia Brushfield spots on iris Single palmar crease Sandal Gap Cognitive impairment
Penetrance
in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (the genotype) that also express an associated trait (the phenotype)
