Genetics Flashcards
What is the genetic defect in Turner’s syndrome?
What are the clinical features?
Females missing X-chromosome i.e. XO sex chromosome type
- Neck webbing
- Short stature
- Ovarian failure
Which syndrome does Noonan’s syndrome resemble?
Noonan’s resembles Turner’s syndrome and has similar features.
Underlying genetic defect is different and Noonan’s is due to mutations in PTPN11, SOS1, RAF1, KRAS, NRAS and BRAF.
The carrier frequency of an AR disorder is 1 in 20. Assuming a homogenous population, what is the risk of a child being born homogenous-affected?
Risk = 1/20 x 1/20 x 1/4 = 1/1600
i.e. carrier risk of mother x carrier risk of father x mendelian probability of homogenous-affected
As a general rule of genetic abnormalities, what is the inheritance pattern for:
- Structural proteins abnormalities (most cardiomypathies and primary arrhythmogenic diseases)
- Metabolic disorder (phenylketouria in newborns)
- Structural proteins abnormalities (most cardiomypathies and primary arrhythmogenic diseases)
Autosomal DOMINANT
- Metabolic disorder (phenylketouria in newborns)
Autosomal RECESSIVE
What are the 2 types of single nucleotide polymorphisms (SNPs), how are they difference in terms of affecting the amino acid sequence of proteins?
Synonymous SNP = do NOT change amino acid sequence and therefore not likely to change gene function
Non-synonymous SNP = DO change amino acid sequence and may change gene function, two type missense and nonsense.
What percentage of offspring are likely to be affected from a single parent (either male or female) with an autosomal dominant trait?
Approximately 50% - males and females affected equally
When two parents that are carriers of an autosomal recessive trait mate, then what % of the offspring are:
- Homozygous affected
- Homozygous unaffected
- Heterozygous unaffected
- Homozygous affected = 25%
- Homozygous unaffected = 25%
- Heterozygous unaffected = 50%
What is the pattern of inheritance of X-linked recessive?
- Only manifests in sons of carrier or affected mothers (i.e. X’X or X’X’)
- Affected fathers only render daughters compulsory carriers
What is the pattern of inheritance for X-linked dominant?
- No transmission from father to son
- Affected father will transmit to all daughters
- Carrier/Affected mother has 50% of transmitting normal and 50% of transmitting affected gene.
Genetic imprinting is an epigenetic phenomenon that causes an inheritance pattern independent of Mendelian inheritance.
What methylation of which parts of the gene does it involved?
Does is affect the genetic sequence?
Methylation of DNA and histones WITHOUT altering the genetic sequence.
T/F: genetic imprinting occurs within the germline cells (sperm and eggs cells) of the parents
True
In maternal imprinting, which inherited allele is silenced and which is expressed:
- Mother’s allele
- Father’s allele
Maternal imprinting: mother’s allele is SILENCED and fathers allele is expressed
Paternal imprinting: father’s allele is SILENCED and mother’s allele is expressed
Which 2 condition involve genetic imprinting?
Angelman syndrome (maternal imprinting) Prader-Willi syndrome (paternal imprinting)
T/F: linked genes sit close together on a chromosome and are more likely to be inherited.
True
What is somatic mosaicism?
Given an example.
Some tissues carry the mutation and others do not.
Example: Mosaic Turner syndrome (46XX/45XO)
T/F: Phenylketouria is autosomal dominant
False - autosomal recessive
Given the incidence of an autosomal recessive disease. How does one calculate the carrier frequency?
carrier frequency = a
a (mother) x a (father) x 1/4 = incidence
a^2 = 4 x incidence
a = sqrt [4 x incidence)
Name 4 genetic conditions with triplet expansion that have genetic ‘anticipation’ (earlier phenotypic manifestation with subsequent generations).
- Friedreiche’s ataxia (female)
- Myotonic dystrophy (female) - type 1
- Fragile X (female)
- Huntington’s disease (male)
T/F: triple expansion is often associated anticipation.
True
What is the genetic mutation in Lynch syndrome (HNPCC)?
Mutations in mismatch repair genes (MMR)
Name 4 most common type of cancers related to HNPCC (Lynch syndrome) that have mutations in mismatch repair genes (MMR).
ECOG:
Endometrial cancer (50%) Colorectal cancer (50%) Ovarian cancer (10%) Gastric cancer (10%)
T/F: HNPCC is NOT associated with multiple polyps.
True.
What does maternal imprinting mean?
- Gene or allele is inherited but is methylated which leads to gene silencing (switched off)
- Therefore maternal copy is switched off and therefore child does not get the disease despite inheriting the mutation.
T/F: SDHD is subject to paternal imprinting.
False - maternal imprinting, gene/allele inherited from mother is silenced in the child.
Mitochondrial DNA has a few unique features, comment on the following:
- Which parent are they inherited from?
- Mutation rate?
- Number of copies per mitochondria?
- Which parent are they inherited from?
Maternal inheritance - Mutation rate?
HIGH mutation rate - Number of copies per mitochondria?
Multiple (2-10) copies per mitochondria
What does the ‘heteroplamy’ of mitochondria DNA (mtDNA) mean?
Co-existence of mutant and wild type mtDNA
What is the mtDNA bottleneck?
In early oogenesis, a small number of mtDNA genomes are ‘selected’ to repopulate the oocyte, allowing rapid shifts in heterplasmy.
What is the mtDNA threshold effect?
A minimum critical number of mtDNA is needed for each tissue to become dysfunctional.
Chromosomal translocations are common (1:500).
What are the 4 types of chromosomal translocations?
RRUB:
- Reciprocal
- Robertsonian
- Unbalanced
- Balanced
What is a Reciprocal chromosomal translocations?
Exchange of material between non-homologous chromosomes
What is a Robertsonian chromosomal translocations?
Break at or near centromeres of 2 acrocentric chromosomes (p-arm so short that it is hard to observe)
What is a balanced chromosomal translocations?
No genetic material is lost
What is an unbalanced chromosomal translocations?
What complications might it lead to?
Genetic material lost.
- Azoo/oligospermia
- Difficulty conceiving
- Miscarriages
- Liveborn
Chromosome microarrays often report in terms of copy number variants (CNVs).
What are the 5 dispositions in a microarray report of CNVs?
Which of these will be reported?
- Benign
- Likely benign
- VUS (variants of uncertain significance)
- Likely pathogenic (disease causing)
- Pathogenic
3-5 is reported.
T/F: Chromosome microarrays do NOT detect on ‘balanced’ chromosomal translocations and only detect abnormal copy number variants (CNV).
True
What is the Hardy-Weinberg equilibrium?
Allele and genotype frequencies in a population will remain constant from generation to generation in the absence of the other evolutionary influences.
p + q = 1
(p + q)^2 = 1
p^2 + 2pq + q^2 = 1
p + q = 1 (proportion of alleles)
p = wild type allele q = disease allele p^2 = frequency of homozygous for p q^2 = frequency of homozygous for q 2pq = frequency of heterozygous for p + q
What are the microdeletions in the following 2 syndromes:
- Prader-Willi syndrome
- Di George syndrome
- Prader-Willi syndrome - 15q11
2. Di George syndrome - 22q11
What type of genetic test is used to diagnose Angelman or Prader-Willi syndromes?
Which chromosome is implicated in both of these disorders?
DNA methylation analysis for parental imprinting:
Angelman = maternal imprinting Prader-Willi = paternal imprinting
Chromosome 15.
What is Uniparental Disomy (UPD)?
UPD occurs when a person receives 2 copies of a chromosome, or part of a chromosome, from one parent and no copies from the other parent.
2 possibilities:
- Isodisomy = 2 identical alleles from same parent
- Heterodisomy = 2 different alleles from the same parent
What genetic phenomena disrupts genetic imprinting?
Uniparental disomy
Compare the following types of mutation by their effects on protein synthesis:
- Missense
- Nonsense
- Silent
- Missense - changes type of protein made
- Nonsense - causes premature stop in translation, therefore disrupts protein production
- Silent - changes bases, but no effect on protein made
What is a point mutation?
Change of 1 base along the DNA sequence.
Describe the following 3 types of point mutations:
- Substitution
- Insertion
- Deletion
Which of these cause a ‘Frameshift’ mutation?
- Substitution - replace 1 base with a different one
- Insertion - add an extra base into the sequence
- Deletion - removal of 1 base from the sequence
Insertion and Deletion mutations cause ‘Frameshift’ mutations.
Do frameshift mutations alter the type of protein produced?
Yes.
Mutations in a number of different genes cause the same disease or phenotype.
What genetic phenomena is this?
Give an example of this.
Locus heterogeneity = mutation in genes at different loci that cause the same disease
Example: HOCM is causes by
MHY7
MYBPC3
TNNI
Regarding Huntington’s Disease (HD), comment on the following:
- Which gene and what type of genetic abnormality?
- Age of presentation and number of years to eventual neuronal loss?
- Correlation of number of CAG repeats to age of onset and severity of disease?
- What is the cause of anticipation over subsequent generations?
- Anticipation is higher with maternal or paternal transmission?
- Which thresholds of triplet repeats yield variable vs. full penetrance?
- Which gene and what type of genetic abnormality?
- CAG trinucletide repeats in HTT gene - Age of presentation and number of years to eventual neuronal loss?
- middle age onset with neuronal loss at 10-20 years - Correlation of number of CAG repeats to age of onset?
Higher CAG repeats = earlier onset and more severe disease - What is the cause of anticipation over subsequent generations?
Germline and somatic instability cause expansion of the CAG repeat number - Anticipation is higher with maternal or paternal transmission?
Anticipation is more common in PATERNAL transmission - Which thresholds of triplet repeats yield variable vs. full penetrance?
- HD develops with 36 and above triplet repeats (36-39 variable penetrance)
- 40 and above yields full penetrance
T/F: Duchenne muscular dystrophy is X-linked recessive.
True - only manifests in males
What are the following mutations associated with:
- Prolactin receptor inactivating mutation
- Aryl hydrocarbon receptor-interacting protein (AIP) mutation
- SDHB (Succinate dehydrogenase subunit B) mutation
- SDHD (Succinate dehydrogenase subunit D) mutation
- Menin mutation
- Prolactin receptor inactivating mutation
- Hyperprolactinaemia and galactorrhoea - Aryl hydrocarbon receptor-interacting protein (AIP) mutation
- Familial Pituitary Adenoma - SDHB (Succinate dehydrogenase subunit B) mutation
- Phaeochromocytomas and paragangliomas (functional)
- SDHB - despite B is not benign - SDHD (Succinate dehydrogenase subunit D) mutation
- Phaeochromocytomas and paragangliomas (benign) - Menin mutation
- MEN 1 (not MEN 2)
Spinal Muscular Atrophy is autosomal recessive and has a disease incidence of 1/6400.
Calculate the carrier frequency.
Assume carrier frequency = a
chance of mother as carrier x chance of father as carrier x chance of progeny being homozygous = 1/6400
a x a x 1/4 = 1/6400
a^2 = 4/6400
a = 2/80 = 1/40
What is the Hardy-Weinberg equation?
p^2 + 2pq + q^2 = 1
For rare autosomal recessive disorders.
Given
p = carrier frequency of A
q = carrier frequency of B
2pq = heterozygous carrier frequency p^2 = homozygous carrier frequency of allele A q^2 = homozygous carrier frequency of allele B
