Genetics Semester 4 Flashcards
Philadelphia chromosome related disorder - type of inheritance?
No inheritance type, it occurs sporadically
Philadelphia chromosome related disorder - mechanism?
Translocation between chromosome 9 and 22 leading to fusion between ABL on ch.9 and BCR och ch.22.
Philadelphia chromosome related disorder - gain or loss of function?
Gain of function
Philadelphia chromosome related disorder - incidence?
1:100,000
Pathogenesis of Philadelphia chromosome related disorder?
Abnormal tyrosine kinase activity, which is cytoplasmic and nuclear protein needed for control of differentiation, division, adhesion and stress response.
Philadelphia chromosome related disorder, what does abnormal tyrosine kinase lead to?
Leads to uncontrolled growth and division of white blood cells.
Philadelphia chromosome related disorder, how many cases lead to chronic myelogenous leukemia?
90%
Philadelphia chromosome related disorder, how many cases lead to adult acute lymphoblastic leukemia?
25-30%
Philadelphia chromosome related disorder, how many cases lead to childhood acute lymphoblastic leukemia?
2-10%
Philadelphia chromosome related disorder, age of onset?
Later in adulthood, around age of 40-60.
Philadelphia chromosome related disorder, male to female ratio?
More common in males.
Symptoms of Philadelphia chromosome related disorder?
Development of fatigue
Malaise
Weight loss
Splenomegaly
Pancytopenia - anemia, thrombocytopenia and leukopenia
Philadelphia chromosome related disorder, treatment?
Inhibit BCR-ABL tyrosine kinase by binding to active binding site.
Examples: Imatinib/masitinib/nilotinib
Retinoblastoma - type of inheritance?
Autosomal dominant
Retinoblastoma - de novo mutations occurrence?
20-30%
Retinoblastoma - incidence?
1:15,000 - 1:20,000
Retinoblastoma - mechanism?
Mutation of tumor suppressor gene (RB1) on chromosome 13.
Retinoblastoma - what is RB1 gene responsible for?
Produces retinoblastoma protein pRB which controls cell cycle and prevents excessive cell growth.
Retinoblastoma - mutations can be caused due?
Point mutations, deletion, hypermethylation of promotor region.
Retinoblastoma - what does pRB do normally?
Binds to transcription factor complex E2F and surpasses transcription of genes needed for cell cycle progression to S phase.
Retinoblastoma - what is RB1 involved in?
Checkpoint in cell cycle, differentiation and apoptosis of genes. So mutation of RB1 can lead to increased proliferation of cells.
Retinoblastoma - locus or allelic heterogeneity?
Allelic
Retinoblastoma - what is two hit theory?
In hereditary retinoblastoma – one mutated copy if the RB1 gene in all cells including germ cells. They then get a second somatic mutation in the remaining normal copy in the retinal cell leading to tumor.
In sporadic retinoblastoma – both copies of the RB1 get the mutation independently.
Retinoblastoma - penetrance?
Incomplete penetrance
Retinoblastoma - pathogenesis in case of sporadic retinoblastoma?
Sporadic retinoblastoma usually occurs unilaterally (on eye) and late onset.
Retinoblastoma - pathogenesis in case of heriditary retinoblastoma?
Hereditary retinoblastoma usually occurs bilaterally (both eyes) and could be associated with other malignancies.
Retinoblastoma - when does intraocular malignancies usually manifest?
During childhood
Retinoblastoma - main symptoms?
Leukocoria - When light is shined on pupil it is rather white than red.
Strabismus: misalignment of eyes.
Loss of vision
Painful red eye
Retinal detachment
Lynch syndrome - type of inheritance?
Autosomal dominant
Lynch syndrome is also known as?
Heriditary non-polyposis colorectal cancer (HNPCC)
Lynch syndrome - mechanism?
Mutations of MSH2, MLH1, MSH6 gene.
MSH2 accounts for 60% of cases
MLH1 accounts for 30%
Lynch syndrome - what are the genes normally responsible for?
They are known as DNA mismatch repair genes (MMR), that correct errors during DNA replication (correct mismatched bases or insertions/deletions).
Lynch syndrome - loss or gain of function?
Loss of function
Lynch syndrome - locus or allelic heterogeneity?
Both!
Lynch syndrome - penetrance?
Incomplete penetrance
Lynch syndrome - what theory does it follow?
Follows the two hit theory
Lynch syndrome - what percentage of colorectal cancer cases is related to microsatellite instability?
15% are related to microsatellite instability.
Out of which 90% are Lynch syndrome and 10% are sporadic.
Lynch syndrome - what is the age of onset?
Usually before the age of 50
Lynch syndrome - two types?
Lynch syndrome I – site specific colonic cancer.
Lynch syndrome II – extra colonic cancer (stomach, endometrium, biliary, pancreas, urinary tract)
Lynch syndrome - main symptoms?
Colorectal cancer or endometrial cancer.
Asymptomatic until progression of cancer.
Small polyps in right proximal colon.
Lynch syndrome - treatment?
- Surgery – resection or colectomy
- Prophylactic hysterectomy
- Bilateral salpingo-oophorectomy
- Cancer screening with Amsterdam II criteria
Familial adenomatous polyposis (FAP) - incidence?
1:20,000
Familial adenomatous polyposis (FAP) - inheritance type?
Autosomal dominant
Familial adenomatous polyposis (FAP) - mechanism?
Mutation of the APC gene located on chromosome 5q21.
Familial adenomatous polyposis (FAP) - what is APC responsible for?
It is a tumor suppressor gene that encodes for a protein needed in the beta-catenin pathway.
The protein is responsible for beta-catenin inhibition and degradation to prevent high expresser of genes and over activation of cell cycle.
Mutation will therefore lead to accumulation of beta-catenin in cell and increased proliferation and replication.
Familial adenomatous polyposis (FAP) - loss or gain of function?
Loss of function
Familial adenomatous polyposis (FAP) - what theory does it follow?
Two hit theory
Familial adenomatous polyposis (FAP) - pentrance?
Complete penetrance, by the age of 40 it is 100% penetrance.
Familial adenomatous polyposis (FAP) - locus or allelic heterogeneity?
Allelic
Familial adenomatous polyposis (FAP) - pathogenesis and main symptoms?
Variable age of onset
Mutation leads to large number of intestinal polyps (100-200) which could become malignancies
Initially asymptomatic until progression of colon cancer
Altered bowel habits
Heriditary breast/ovarian cancer - inheritance type?
Autosomal dominant, rarely de novo mutations.
Heriditary breast/ovarian cancer - mechanism?
Mutation in BRCA1 and BRCA2
Heriditary breast/ovarian cancer - what are the genes usually responsible for?
They are tumor suppressor genes. Involved in DNA repair.
BRCA1 is phosphorylated by ATM and CHEK2 in case of double stranded DNA breaks.
Then binds to BRCA2 and interacts with RAD51 to form a complex involved in DNA repair.
Supresses tumor formation through interactions with proteins p53, pRb and Myc.
Heriditary breast/ovarian cancer - follow what theory?
Two hit theory
Founder effect
Heriditary breast/ovarian cancer - penetrance?
Incomplete penetrance
Heriditary breast/ovarian cancer - locus or allelic heterogeneity?
Both
Li-Fraumeni syndrome - inheritance type?
Autosomal dominant
7-20% de novo mutations
Li-Fraumeni syndrome - incidence?
1:5000 - 1:20,000
Li-Fraumeni syndrome - mechanism?
Mutation of TP53 gene
Li-Fraumeni syndrome - what is TP53 usually responsible for?
It is a tumor suppressor gene.
Encodes for protein p53 that is needed for checkpoint control in case of damaged DNA sequences for downstream repair or apoptosis.
Li-Fraumeni syndrome - haploinsufficiency?
One affected copy of gene is enough to cause malignancies.
Li-Fraumeni syndrome - pathogenesis?
Manifest in young people.
50% of people with Li-Fraumeni syndrome develop at least one Li-Fraumeni syndrome associated cancer by the age of 30.
5-8% of women with breast cancer have a prevalence of TP53 mutations.
Li-Fraumeni syndrome - penetrance?
Complete penetrance
Li-Fraumeni syndrome - locus or allelic heterogeneity?
Allelic
Li-Fraumeni syndrome - accounts for what cancer types?
25-30% of Breast cancer
25-30% of Sarcomas
9-16% Brain tumors
10-14% Adrenocortical Carcinoma (ACC)
Li-Fraumeni syndrome - main symptoms and treatment?
Soft tissue sarcomas
Breast cancer
Brain tumors
Colon carcinoma
Leukemia
Adrenocortical carcinoma
Treatment: resection, mastectomy, chemotherapy, lupectomy etc.
Klinefelter syndrome - inheritance type?
Non disjunction of sex chromosomes during meiosis of parental germ cells
Klinefelter syndrome - karyotype?
47, XXY (most common)
48, XXXY (rare)
49, XXXXY (rare)
Klinefelter syndrome - mechanism?
Non-disjunction:
Male inherits one or more additional X chromosomes due to non-disjunction in either paternal or maternal meiosis.
Inactivation:
In women, 75-85% of genes on one of the X chromosomes are silenced. This does not happen in KS = both X chromosomes are active.
Copy number variations:
In pseudo autosomal genes
Duplications
Polymorphism of AR gene:
Might affect androgen receptor activity, and this could have implications for the development of certain physical and physiological characteristics.
Epigenetics:
Methylated autosomal CpGs
Klinefelter syndrome - main symptoms?
Small penis and testes
Low testosterone
Normal intelligence or retardation
Infertility - most likely due to over expression of TEX11 (= increased germ cell death)
Tall slender frame
Weak bones
Breast growth
48, XXYY syndrome - inheritance type?
Consecutive non-disjunction of sperm in both meiosis I and meiosis II.
48, XXYY syndrome - pathogenesis?
Sperm goes through two non-disjunction rounds.
X from mother and XYY from father.
48, XXYY syndrome - symptoms?
Tall and narrow stature
Broad hips
Sparse body hair
Congenital skeletal malformations
Low IQ
Infertility
Facial dysmorphism
Gynecomastia
49,XXXXY syndrome - inheritance type?
Non-disjunction of X chromosome in ovum.
49,XXXXY syndrome - main symptoms?
Males are severely affected
Microencephaly
Short stature
Ocular hypertelorism
Heart defect
Small gnitalia
Low IQ range
Friendly with occasional tantrums
47, XYY syndrome - inheritance type?
Also known as superman syndrome.
Due to:
Chromosomal aneuploidy
Non-disjunction in gametogenesis (meiosis)
47, XYY syndrome - main symptoms?
Often undetected
Tall
Reduced fertility
Impulsive, violent, psychiatric behaviour
47, XXX syndrome - inheritance type?
Also known as super female.
Due to:
Chromosomal aneuploidy
Non disjunction during gametogenesis (meiosis)
47, XXX syndrome - pathogenesis?
Symptoms relate to over expression of the genes in the PAR region and other genes that escape X activation that come from all 3 X chromosomes.
Woman quite often have normal phenotype so it is rarely diagnosed.
Turner syndrome - inheritance type?
X linked recessive
Turner syndrome - gene?
45, X = no Barr body. Caused by non-disjunction during meiosis.
Some cells have 45, X and some have 46 XX = Mosaicism and occurs after fertilisation.
Turner syndrome - pathogenesis?
Haploinsufficiency of X chromosome genes:
Loss of PAR1 and PAR2 regions
Loss of genes that may escape X inactivation
Loss of one SHOX gene copy
Gonadal steroid effects:
Ovaries degenerate after brith and lead to streak ovaries and reduced oestrogen levels.
X-linked recessive inheritance & functional disomy
Epigenetics:
Loss of an X chromosome has a much more profound consequence than gain of an additional X chromosome.
Turner syndrome - main symptoms?
Short stature
Shield chest
Widely spaced nipple
Small uterus
Cardiovascular issues
Renal issues
Sense organ issues
46, XY complete gonadal dysgenesis
