Genetics Flashcards by Manoshy Sooriyakumaran

QUESTION 23
Parents of a child diagnosed with tuberous sclerosis want to know the risk of a 2nd child being born with the same condition. DNA analysis from the affected child of the gene TSC2 shows a pathogenic mutation. There is no family history of tuberous sclerosis. On physical examination and imaging, the father has multiple kidney angiomyolipomas. There is nothing else identified on examination or imaging of either parent. The child is identified to have a specific gene mutation for tuberous sclerosis on gene testing. The parents are tested and both have wild type genes.
What is the most likely explanation for this?
A. Non paternity
B. Gonadal mosaicsm
C. Laboratory error
D. Uniparental disomy
E. Somatic mosaicism
F. Incomplete penetrance

E (Somatic mosaicism)

The mosaicism explains why the father’s genetic testing could be negative and yet still have features of the condition.
We only test the chromosomes of one/a few cells, and assume that that chromosomal pattern is universal throughout the body – in this case we assume that the entire body is free of the TSC gene but the father probably has some cells throughout the body with TSC mutation
The father appears to display somatic mosaicism, not gonadal, as there is kidney involvement (somatic cells).

Gonadal mosaicism could explain the inheritance pattern of the son having a condition that wasn’t detected in the parents’ genotype (because the mutation is confined only to the germline cells, and even then to only some). However, it would not explain why the father has features of TSC in his kidneys, which are made up of somatic cells

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Which cells undergo meiosis?

Gonadal cells

They end with 23 chromosomes

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Name the gene and syndrome that matches with this phenotype:

Breast cancer and sarcoma in a 25F

TP53

Li Fraumeni

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Name the gene and syndrome that matches with this phenotype:

Optic glioma with multiple cafe au lait spots

Neurofibromin 1

Neurofibromatosis 1

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Name the gene and syndrome that matches with this phenotype:

Breast and follicular thyroid cancer

PTEN

Cowden Syndrome

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Name the gene and syndrome that matches with this phenotype:

1000s of bowel polyps in a 20M

APC

FAP

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Name the gene and syndrome that matches with this phenotype:

Parathyroid, pituitary and pancreatic adenomas

MENIN

MEN-1

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Name the gene that matches with this phenotype:

Hereditary male breast cancer

BRCA 2

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Name the gene and syndrome that matches with this phenotype:

Triple negative breast cancer

BRCA 1

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Name the gene and syndrome that matches with this phenotype:

100s of bowel polyps in a 40yo who is APC gene negative

MUTYH

MUTYH polyposis

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What is the probability of a being a carrier for a autosomal recessive condition if your sibling has the condition?

2/3

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Freidrich ataxia has a carrier frequency of 1/100

What is the incidence?

Square, then multiply by 4

= 1/40,000

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Cystic fibrosis has an incidence of 1/2,500

What is the carrier frequency?

1/25

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Question 43
Small interfering RNAs (also called “micro-RNAs”) influence gene expression. The mechanism of action is best explained by their effect on:

A. gene promoter activation.
B. gene promoter repression.
C. RNA synthesis rate.
D. RNA degradation rate.
E. chromatin compaction.

D. RNA degradation rate – act by inducing degradation of mRNA prior to translation.

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Question 23
Tumour suppressor genes are involved in the development of malignancy. What is the most likely
mechanism?

A. Missense mutation
B. Telomerase inactivation
C. Chromosome rearrangement
D. Increased gene amplification
E. Loss of heterozygosity

Loss of heterozygosity – this is one of the hallmarks of tumour suppressor gene activity

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QUESTION 1
A 19-year-old female presents with short stature, neck webbing, wide spaced nipples and primary amenorrhea.
Which of the following is her most likely karyotype result?

A. 48,XXXX
B. 46,XY
C. 47,XXX
D. 45,X
E. 47,XXY

D. 45,X

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QUESTION 68
Which one of the following mutation categories is most likely to result in a gene product with new or enhanced function?

A. Splicing mutation 
B. Nonsense mutation 
C. Missense mutation 
D. Silent mutation 
E. Promoter mutation

C. Missense mutation – best answer. Refers to substitution that changes a single base pair resulting in the codon producing a single different amino acid (which may be conservative or non-conservative). The size of the mRNA and protein are not changed, but the composition and sometimes the function (non-conservative) of the protein does change and this may be increased function or decreased function or altered function.

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QUESTION 2010 B3
Parents of a child with a rare autosomal dominant genetic disorder asking for advice re: the risk for
future pregnancy. The mutated gene is identified in the child, and he expresses the phenotype.
However, both the mother and father do not have this mutation nor are they symptomatic. The most
likely cause for this is
A. Lab error
B. Non-paternity
C. Incomplete penetrance
D. Mosacism
E. Expressivity

D - Mosaicism

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Which of the following observations regarding a rare disorder would provide the best evidence of autosomal dominant inheritance? 
A. Father and son affected 
B. Father and daughter affected 
C. Mother and son affected 
D. Mother and daughter affected 
E. Male and female cousins affected

A. Father and son affected

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Achondroplasia is an autosomal dominant condition. Heterozygotes have achondroplasia, while
homozygotes usually die at birth. If two people with achondroplasia meet and marry, what is the
probable outcome for their children?

a. 25% achondroplasia, 50% normal, 25% perinatal death
b. 25% normal, 50% achondroplasia, 25% perinatal death
c. 25% normal, 50% perinatal death, 25% achondroplasia
d. 25% achondroplasia, 50% perinatal death, 25% normal
e. 50% achondroplasia, 50% normal

B - 25% normal, 50% achondroplasia, 25% perinatal death

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QUESTION 2012 A40
Trisomy 21 is associated with multi-system functional impairment. However trisomy of the X chromosome often results in a normal phenotype or mild problems with behavior, coordination and tall stature. What is the primary explanation for the milder phenotype in trisomy X?
A. X chromosome imprinting
B. X chromosome inactivation
C. Less genes on the X chromosome
D. Different mechanism of action in embryogenesis
E. X chromosome pathology is not dosage dependent

B - X chromosome inactivation

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Some autosomal recessive diseases have high prevalence in particular populations, even though they are often fatal (e.g. Alpha thalassaemia in South East Asia; G6PD deficiency in the Mediterranean). Which of the following is the most likely explanation?

A. Consanguinity.
B. High mutation rates in specific populations.
C. Survival advantage in heterozygous carriers.
D. Survival advantage in wild type homozygotes.
E. Founder effect

C – correct; thalassaemia and G6PD protective against malaria

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Genetic 2010A Q30
An autosomal recessive disease has an incidence of 1 in 6400. What is the carrier frequency?

A. 1/20
B. 1/40
C. 1/60
D. 1/80
E. 1/120

B - 1/40

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Question 94 
Angela and Robert are a married couple who come to see you with regards to a planned pregnancy. They met at a cystic fibrosis support group and each has a sibling with cystic fibrosis. Both Angela and Robert are healthy. What is the probability that they will have a child with cystic fibrosis? 
A. 1/2 
B. 1/4 
C. 1/9 
D. 1/16 
E. 1/25

2/3 x 2/3 = probability that they are both carriers

Then we need to work out the probability that they will have a child with the disease if they are both carriers • there is a ¼ chance of aa (child being affected)

So 2/3 x 2/3 x 1/4 = 1/9

C - 1/9

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``` Question A 23 year old man presents with café au lait spots and cutaneous neurofibromas in his leftarm only. What is the genetic predisposition for this presentation? A. Chimerism B. Gonadal mosaicism C. Heteroplasmy D. Skewed X- inactivation E. Somatic mosaicism ```

E - somatic mosaicism

Genetics 2006A Question 50 Which one of the following statements is the best description of the molecular basis of a chimeric (fusion) protein (eg Bcr-Abl)? A. Formation of disulphide bonds between cytosine residues on different peptides. B. Post-transcription ligation of non-homologous messenger RNA (mRNA) molecules. C. Hybrid messenger RNA (mRNA) synthesis from a bi-directional promoter. D. Deletion of an exon from one gene. E. In-frame ligation of the 5`-end of one gene to the 3`-end of another.

E. In-frame ligation of the 5`-end of one gene to the 3`-end of another.

What is the most distinguishing feature of loss of imprinting of a growth-promoting imprinted gene? A. Restoration of normal methylation patterns. B. Inhibition of cell growth. C. Reduced expression of the imprinted gene product. D. Activation of the normally silent allele. E. Ablation of biallelic gene expression

D – correct; loss of imprinting causes allele to be express

``` 2008 QUESTION 37 The concept that genetic counselling should be nondirective arises mostly from respect for which of the following principles of medical ethics? A. Justice. B. Beneficence. C. Autonomy. D. Non-maleficence. E. Dignity. ```

C - autonomy

2010 Question 50 A genetic trait/ protein is coded by a paternal gene with maternal imprinting of the corresponding maternal gene. Which of the following would result in increased production/expression of the gene/protein product ``` A. Deletion of the paternal gene B. Duplication of the maternal gene C. Loss of imprinting of the maternal gene D. Deletion of the maternal gene E. Uniparental maternal disomy ```

C. Loss of imprinting of the maternal gene – would result in expression of both paternal and maternal gene. May result in different genetic expression with both genes being expressed resulting in ?increased or decreased protein

QUESTION 2014 A27 A new gene therapy aims to insert a copy of the normal gene into the cells. Conditions with which of the following modes of inheritance are most likely to show improvement with this therapy? a. Autosomal dominant with complete penetrance b. Autosomal dominant with incomplete penetrance c. Autosomal recessive d. Polygenic e. X linked dominant

C. Autosomal Recessive - Gene therapy aims to provide a normally functioning gene to an individual who has inherited a pathogenic gene variant. Insertion of a normal gene leads to low level expression that may be sufficient to greatly improve a disease.

A disease phenotype can be caused by a mutation in more than 1 gene. What is the most likely cause for this? ``` A. Heterozygosity B. Allelic heterogeneity C. Locus heterogeneity D. Digenic inheritance E. Hemizygosity ```

C. Locus heterogeneity

QUESTION 2007A3 X-linked dominant inheritance is distinguished by: A. Females often being more invariably and mildly affected than males B. Affected males having affected daughters and healthy sons C. Affected females having affected daughters and healthy sons D. Males often being more variably and mildly affected than females E. Healthy females having affected sons and healthy daughters

B. Affected males having affected daughters and healthy sons

Genetics 2009A Q59 What inheritance pattern is most likely to be encountered in a family with an X‐linked genetic disease such as Haemophilia A? ``` A. Male to male transmission B. Female to female transmission C. Male to female transmission D. Female to male transmission E. Consanguinity ```

D. Female to male transmission

QUESTION 2007 A34 What is the most likely consequence of inheriting a mutated, maternally imprinted gene? A. 100% of the children of a carrier mother will be affected. B. 50% of the children of a carrier mother will be affected. C, None of the children of a carrier mother will be affected. D. 100% of the children of a carrier father will be affected. E. None of the children of a carrier father will be affected

C, None of the children of a carrier mother will be affected.

Question 2010 B39 19 year old man with marfanoid features, he presented with musculoskeletal marfanoid features, wide armspan, high arched palate, pectus excavatum but he does not have kyphoscoliosis, joint or skin changes. He is adopted. What is the most appropriate next investigation to perform? A. Bone mineral density B. Echocardiography C. Genetic testing for fibrillin-1 mutation D. Karyotypes E. Serum testicular and gonadotrophin hormones

B. Echocardiography - The cardiac abnormalities need to be screened for as they can have dangerous sequelae

Where in the codon can a mutation be that has the least effect on the amino acid?

Last letter of codon has least effect on amino acid. If there is a point mutation here -> lowest chance of change

Order these types of mutations in terms of likely severity = nonsense mutation missense mutation splicing mutation

LEAST missense mutation splicing mutation nonsense mutation MOST

In Prader-Willi Syndrome, what is the genetic defect?

Loss of paternally active allele at 15q11-13 Maternal imprinting

In Angelman Syndrome, what is the genetic defect?

Loss of maternally active allele at 15q11-13 Paternal imprinting

What types of abnormalities can SNP array detect?

Can detect copy number-neutral changes that result in genotype abnormalities

Name some key differences between Duchenne's and Becker's muscular dystrophy (4)

``` Beckers = In-frame deletion (vs frame-shift) Less weakness, later onset More prominent cardiac involvement than Duchenne's Less severe cognitive effects ```

What is the mechanism of transmission of Duchenne's and Becker's muscular dystrophy?

X-linked | Carriers may have a phenotype

Which is more severe: Neurofibromatosis type 1 or type 2?

NF Type 2 More severe than NF-1, earlier age of death (~36)

What new medical treatment is being used for NF-2?

Bevacizumab -> for shrinking tumours

What is the genetic defect in tuberous sclerosis?

Mutation in TSC-1 or TSC-2 (locus heterogeneity) -> tumour suppressor genes

What are some main clinical features of tuberous sclerosis?

Multiple benign hamartomas of multiple organs Can have cardiac rhabdomyomas Epilepsy Intellectual disability

What medical treatment option may be beneficial in tuberous sclerosis?

mTOR inhibitors -> can reduce size of tumours

What is Fabry Disease in brief?

Lysosomal storage disorder X-linked inborn error of glycosphingolipid pathway

The risk of Steven-Johnson Syndrome is increased in those with HLA B1502 who are exposed to which medication?

Carbamazepine

At what stage of the cell cycle does DNA replication occur?

S phase

What do female carriers of X-linked adrenoleukodystrophy usually present with?

Peripheral neuropathy or myelopathy

Gene in X-linked adrenoleukodystrophy?

ABCD1

What is allelic heterogeneity?

Same gene location Different allele mutation Same disease e.g. CF

What is locus heterogeneity?

Different gene location Same disease e.g. HOCM

What is locus homogeneity?

Same gene location Different mutation Different disease phenotype e.g. DMD, BMD. Thalassaemia

What occurs in G2 of the cell cycle?

Cell produces microtubules required for mitosis

What occurs in G1 of the cell cycle?

Cell grows and synthesizes mRNA and proteins, organelles

IN what direction is DNA synthesised?

5' to 3'

What is the role of transcription factors?

Regulate binding of RNA polymerase

What type of genetic alteration occurs in DMD?

Exon deletion

In familial CJD, which type of mutation usually occurs?

Missense

What is deletion at C4 (complement factor 4) locus a/w?

SLE

What is deletion at FCGR3B locus a/w?

GPA

What is FISH testing useful for?

Structural chromosomal changes, aneuploidy Deletions and duplications **small mutations cannot be identified

IN the 2 hit hypothesis of cancer development in genetically susceptible individuals, what is the 2nd hit?

Loss of heterozygosity

What is linkage disequilibrium?

When a particular allele at one locus is found together on the same chromosome with a specific allele at a second locus, with more frequency than expected

What is histone modification?

Proteins which wind around DNA and make parts of DNA inactive

What is a Barr body?

The inactivated X chromosome in female somatic cells (result of Lyonisation)

In Prada-Willi, what is the genetic defect?

Loss of active paternal copy on chromosome 15 Area is usually maternally imprinted

In Angelmen, what is the genetic defect?

Loss of maternally active copy Area is usually paternally imprinted