Genetics

Question 1

What karyotype is most commonly found in patients with symptoms and signs consistent with Turner syndrome?

Answer 1

45X makes up 60% of Turner syndrome. Rarely, some of it’s clinical features can be seen in 46XX if a small or defective X chromosome is present. In 45X patients, they may have a male appearance due to presence of a Y chromosome for part of embryology that was lost in utero.

Question 2

In patient’s with 45X karyotype, what is thought to give rise to their pathological phenotype?

Answer 2

Haploinsufficiency (not enough gene to generate the right quantitiy of functional protein) of the genes located on the X and Y chromosomes, particularly the PAR1 (pseudoautosomal region 1 - at the Xp terminus) region, common to the X and Y chromosomes.

Question 3

Mosaic Turner’s syndrome can occur. What does this mean?

Answer 3

It means that during early embryogenesis, a cell loses one copy of the X or the Y chromosome during division, leading to a 45X cell that goes on to form a population of cells (mosaic) with the characteristic, whist the remainder have 46XX or 46 XY.

Question 4

What would a fragmented X chromosome (delXp, iXq, or ring X or Y chromosomes with substantial deletions) lead to phenotypically?

Answer 4

Turner Syndrome

Question 5

What are the pathgnomonic features on clinical exam of Turner Syndrome?

Answer 5

Proportionate short stature 99%
High arched palate 70%
Widely spaced nipples 40%
Low posterior hairline 40%
Widy carrying angle 40%
Short fourth metacarpal 35%
Low-set or malrotated ears 30%
Webbing of the neck 25%
Peripheral lymphoedema 15%
Madelung deformity 5% - deformity at distal radial physis.

Question 6

What is a circle on a pedigree?

Answer 6

Female

Question 7

What is the square on a pedigree?

Answer 7

Male

Question 8

How is cystic fibrosis inherited?

Answer 8

Autosomal recessive

Question 9

How is Tay-Sach’s disease inherited?

Answer 9

Autosomal recessive

Question 10

How is Huntington’s disease inherited?

Answer 10

Autosomal dominant. It also demonstrates anticipation - that is, each generation with the dominant gene will get the disease earlier in life.

Question 11

What are the cardiovascular abnormalities associated with Turner’s syndrome? What makes them more likely?

Answer 11

Coarctation of the aorta, bicuspid aortic valve (up to 50%) and renal anomalies. The former 2 are more likley in the presence of neck webbing and childhood lympoedema.

Question 12

What are the comorbidities associated with Turner’s syndrome?

Answer 12

Congential heart defects (44%), renal anomalies (18% - horseshoe kidney, renal agenesis, duplicated collecting ducts), thyroid disease (55%), Liver disorders (36%), hypertension (34%), Hearing loss (36%)

Question 13

Define penetrance?

Answer 13

The percentage of people with an autosomal dominant pathological variant who will express any of the clinically relevant pathological traits associated with that variant.

Question 14

Define expression of a pathological variant?

Answer 14

With relation to autosomal dominant conditions, expression refers to the degree to which the pathological traits are expressed in affected individuals who have the pathological gene variant. Contrast with penetrance which is the percentage of patients who have the pathological gene variant who demonstrate any pathological and clinically significant trait.

Question 15

Name four trinucleotide repeat diseases that have autosomal dominant inheritence patterns with anticipation?

Answer 15

Huntington disease, myotonic dystrophy, spinocerebellar ataxia and fragile X syndrome.

Question 16

What do half shaded circles and squares indicate on a pedigree?

Answer 16

These are heterozygous family members. They have one normal gene, and one pathological variant. In autosomal recessive conditions, they have no pathological traits associated with their gene variant.

Question 17

What does heteroplasmy and homoplasmy refer to with regards to mitochondrial genetics?

Answer 17

Whether or not a person presents with a disease phenotype due to their mitochondrial DNA depends on the percentage of their mtDNA that has a pathological varient. If all mtDNA copies have pathological varients in them, they are said to have homoplamsy. For patients with a mixture of normal and abnormal mtDNA, they are said to have heteroplasmy.

Question 18

What does a diamond mean on a pedigree?

Answer 18

Sex unknown

Question 19

What does a triangle mean on a pedigree?

Answer 19

Still birth/miscarriage

Question 20

What does a single strike through a square or a circle on a pedigree mean?

Answer 20

The individual is dead.

Question 21

2 lines between 2 individuals indicates what on a pedigree?

Answer 21

Consanguinous marriage

Question 22

How are monozygotic and non-identical twins represented on a pegidree?

Answer 22

See pic

Question 23

What is a balanced anomalie in a chromosomal variation?

Answer 23

No overall loss or gain of material, however the genes are in the wrong order. Can lead to wrong number of chromosomes of missing material in the resultant egg or sperm.

Question 24

What disease is associated with karyotype 47XXY?

Answer 24

Klinefelter’s disease

Question 25

What are the classic clinical features of Klinefelter’s disease?

Answer 25

Micropenis, small testes, late puberty, tall (legs longer than arms), learning difficulties, osteoporosis, gynaecomastia, infertility.

Question 25

What is a Robertsonian translocation?

Answer 25

It’s when two acrocentric chromosomes (the ones that have their centromere near the end) join their q arms on either side of the centromere, and losing their short p arms.

Question 26

Which is the arm and which is the short arm of the chromosome?

Answer 26

P is the short arm. Q is the long arm.

Question 27

What is a missense variant?

Answer 27

Single base pair substitution. Note: does not change the reading frame. Given the redundancy of the genetic code, may not even alter the residue encoded.

Question 28

What is a nonsense variant?

Answer 28

Alteration to a single base pair that creates a stop codon, prematurely terminating gene transcription.

Question 29

What is a frameshift variant?

Answer 29

Insertion or deletion of 1-2 base pairs leading to a complete shift in the reading frame. Usually leads to the formation of a premature stop codon that terminates transcription early.

Question 30

What is a splicing variant?

Answer 30

An alteration to the intron/exon interface. That tyically leads to either the loss of an exon and the gain of intron during mRNA processing as the interfaces signal were introns should be spliced out.

Question 31

Sometimes mitochondrial diseases can be inherited in a mendelian manner. Why is this?

Answer 31

It used to be thought that diseases of mitochondrial dysfunction could only be inherited from the mother because sperm mitochondria are rapidly degraded at fertilisation. It is now known however that mitchondrial activity is coordinated in part by the nucleaus of the cell, so mutations in nuclear DNA can lead to mitochondrial dysfunction.

Question 32

What is imprinting? How is it clinically relevant?

Answer 32

It really just means gene silencing through methylation. The language is a little confusing - but if I say “this gene is maternally imprinted” - what I mean is that the allele passed down to the subject from the mother has been silenced through methylation. Imprinting of genes is dependent on the sex of the person who has passed the gene down. So a pathogenic gene variant that is normally maternally imprinted and is passed from the mother to their child will typically have no impact on the child. However, a pathogenic gene variant with paternal gene imprinting passed from the mother to child will lead to a disease phenotype.

Question 33

Why is imprinting relevant to Prader-Willi, Angelman and Beckwith-Wiedemann syndrome? Hint: uniparental disomy is key.

Answer 33

These conditions are all the result of inheriting two copies of a gene or genes that imprinted from the one parent rather than an imprinted gene from one, and the active gene from the other. This phenomenon is called uniparental disomy. It only results in an problem if the gene in question is subject to imprinting, becuase otherwise you just end up with 2 active genes from one parent which usually works out fine.

Question 34

How is haemochromatosis inherited? What gene is usually a pathological variant?

Answer 34

Autosomal recessive. HFE.

Question 35

How is familial mediteranean fever inherited? What gene is normally a patholigical variant?

Answer 35

Autosomal recessive. MEFV.

Question 36

What is the Hardy-Weinberg equation?

Answer 36

It’s a calculation that shows the relationship between the population prevelance of all the possible outcomes of a punnet square for a given condition. Given 2 alleles A and a, with respective prevalence p and q, p+q = 1. Therefore, to find at the prevelance of combinations of AA, Aa and aa are, you need a quadratic.

(p+q)^2 = p^2 (AA) + 2pq (Aa) + q^2 (aa) = 1.

You can use this formular to work out the population prevelance of each combination based on the others.

Question 37

What is the CF population carrier risk in caucasion people?

Answer 37

1/25

Question 38

Phenylketouria is inherited how?

Answer 38

Autosomal recessive

Question 39

What protein accumulates in the livers and spleens of patients with Niemann-Pick disease types A and B?

Answer 39

Niemann-Pick disease types A and B are caused by defects in the sphingomyelin phosphodiesterase-1 gene (SMPD1). This leads to the deposition of sphingomyelin (the primary component of myelin sheaths) in inappropriate places all over the body.

Question 40

How are the Niemann-Pick types A, B and C all inherited?

Answer 40

Autosomal recessive

Question 41

What accumulates in tissue causing ataxia, opthalmoplegia and hepatosplenomegaly in patietns with Niemann-Pick type C?

Answer 41

Mutations in the NPC1 (95%) or NPC2 genes leads to accumulation of unesterfied cholesterol in tissues. Both genes are involved in the trafficing of cholesterol. Note that type C is the Niemann-Pick variant that occurs in adults.

Question 42

Hermansky-Pudlak syndrome is a rare autosomal recessive disorder characterised by what?

Answer 42

Oculocutaneous albinism, bleeding diathesis and other organ involvement depending o the subtype. There are 11 subtypes each associated with a different mutation.

Question 43

How is Hermansky-Pudlak syndrome inherited?

Answer 43

Autosomal recessive

Question 44

What is the primary organelle impacted in Hermansky-Pudlak syndrome?

Answer 44

Lysosomes. There is defective inftracellular protein trafficking in this disease.

Question 45

What gene is mutated in Marfan syndrome? What protein dose it encode?

Answer 45

FBN1. The protein is called fibrillin-01. This protein is a structural macromolecule that is present in all connective tissues.

Question 46

What are the syndromic features of FBN-1 pathogenic variants?

Answer 46

Marfan syndrome is the most common phenotype for this gene’s pathogenic variants. The syndrome includes tall stature, arachnodactyly, ectopia lentis, and thoracic aorta aneurysms and dissection.

Question 47

What is the inheritence pattern for Marfan syndrome?

Answer 47

in 3/4 of cases its autosomal dominant