Modes of inheritance in monogenic disorders

Question 1

In humans, as in many organisms, the expression of a particular genetic trait often
depends on many genes acting in concert. For some, however ?

Answer 1

A particular
genotype at a single locus (in other words, a single allele) is primarily responsible
for the genetic character: this character is then said to be Mendelian (if
chromosomal) or more generally monogenic (which would include
mitochondrial characters as well)

Question 2

What does the genotype describe ?

Answer 2

The genotype describes the combination of alleles for an organism, or its genetic constitution (as distinguished
from its physical appearance, the phenotype)

Question 3

In a single-gene or monogenic disorders, what causes the phenotype ?

Answer 3

• Genetic variation.
• Environmental factors.
• Epigenetic effects (independent of the base sequence of the DNA).
• Stochastic factors

Question 4

If a Mendelian trait (or disease) is manifested in the heterozygote (which carries both the mutant and normal, or wild-type, allele) then it is said to ?

Answer 4

It is said to be dominant

Question 5

If the character is instead only expressed in the homozygote, it is said to be?

Answer 5

Recessive

Question 6

If two phenotypes expressed by two different alleles are simultaneously displayed by the heterozygote, then they
are said to be ?

Answer 6

Co-dominant (example, the AB blood type)

Question 7

What is aneuploidy ?

Answer 7

Due to loss of one chromosome or to the presence of an extra one is lethal in most cases, due to gene dosage issues

Question 8

In the case of aneuploidy occurring to the X chromosomes, what happens ?

Answer 8

A potential imbalance in the two sexes is dealt with by the inactivation of one of the two sex chromosomes in females (X-inactivation)

Question 9

How is X-inactivation achieved ?

Answer 9

X-inactivation is achieved by silencing of essentially one entire X
chromosome which becomes condensed (Barr body)

Question 10

The choice of which

chromosome to inactivate, either the paternal or the maternal one, is made?

Answer 10

Early in the embryo, randomly in each cells. After the decision is made all the cells deriving from subsequent division will maintain that pattern, giving rise to mosaicism: the female will be a genetic mosaic with clones expressing a maternal allele and other expressing the paternal one, and this
affects X-linked disorders in females

Question 11

What is the proband ?

Answer 11

The proband is a person serving as the starting point for the genetic study of a family

Question 12

Explain the autosomal dominant inheritance?

Answer 12

In this type of disorders the disease locus is present on one of the autosomes and is manifested in heterozygotes

Question 13

In autosomal dominant inheritance, what would be the chance of each child developing the disease ?

Answer 13

Each child would have a 50% chance of
developing the disease (in the most common
case where only one parent carries the mutation,
and is heterozygous for it)

Question 14

Explain the autosomal recessive inheritance ?

Answer 14

In this type of disorders the disease locus is on one of the autosomes and is manifested in homozygotes

Question 15

In autosomal recessive inheritance, what would be the chance of each child developing the disease ?

Answer 15

Each child would have a 25% chance of
developing the disease (in the most common
case where both parents are carriers for the
mutation, and are heterozygous for it)

Question 16

What is compound heterozygotes ?

Answer 16

In the case of frequent disorders, there are generally several variant mutant alleles in the population, and the disease might
manifest with two allelic mutations in heterozygote form

Question 17

What is true homozygotes?

Answer 17

In the case of rare disorders, usually affected individuals carry the same mutant allele

Question 18

In the case of rare disorders, usually affected individuals carry the same mutant allele, which they have inherited by ?

Answer 18

Parents who are close relatives

Question 19

Explain X-linked recessive inheritance ?

Answer 19

In this type of disorders the disease locus is on the X chromosome and is manifested in all males and in homozygous females

Question 20

In the case where the father is affected and the mother is not a carrier, each child
would have? (X-linked recessive inheritance)

Answer 20

A 0% chance of developing the disease

Question 21

In the case where the father is not affected and the mother is a carrier, each child would have? (X-linked recessive inheritance)

Answer 21

A 0% chance of
developing the disease if female, and 50%
if male

Question 22

In the case where the father is affected and the mother is a carrier, each child would have? (X-linked recessive inheritance)

Answer 22

A 50% chance, irrespective of gender, of developing the disease

Question 23

Explain X-linked dominant inheritance?

Answer 23

In this type of disorders the disease locus is on the X chromosome and is manifested in all males and in heterozygotes
females

Question 24

In the case where the father is affected, who will be affected? (X-linked dominant inheritance)

Answer 24

In the case where the father is affected, no
sons will be affected, but all the daughters
will

Question 25

In the case where the mother is affected, who will be affected? (X-linked dominant inheritance)

Answer 25

In the case where the mother is affected,

50% of the children will be affected, regardless of gender

Question 26

What are pseudoautosomal regions? and what do they do ?

Answer 26

• The X and Y chromosomes bear largely different
  sequences but carry essentially identical sequences near
  the telomeres
• These pseudoautosomal regions recombine during meiosis (there is one obligate crossover in the major pseudoautsomal region) and behave like autosomes for inheritance

Question 27

Briefly explain Y-linked inheritance ?

Answer 27

Y-linked inheritance concerns only males. But given that
only 31 genes (mostly involved in male specific functions)
are present on the Y chromosome, it is very rare

Question 28

How would Y chromosomes be eliminated ?

Answer 28

Because harmful mutations cannot be eliminated on the Y chromosome by recombination, evolutionary pressure
has lead to a reduction in size of this chromosome to
delete accumulated deleterious changes

Question 29

Where is the Mitochondrial DNA is only inherited from?

Answer 29

The mother, not the father

Question 30

However, mothers can transmit the disease ?

Answer 30

Equally to sons and daughters

Question 31

MtDNAs within a cell can be?

Answer 31

Identical (homoplasmy) or mixed (heteroplasmy) when both normal and
mutant copies are present.

Question 32

Because rapid shifts in heteroplasmy are observed, a bottleneck hypothesis has been proposed which suggests?

Answer 32

That during early development germline cells pass through a
stage where they contain very few mtDNAs (bottleneck). The chance that normal or
mutant mtDNAs might be over-represented at the bottleneck stage will affect final ratio in the mature egg

Question 33

What’s an issues with determine inheritance?

Answer 33

• If a pedigree is small determining the mode of inheritance can be difficult
• One way to get around this is to look at the same disorder in different families and determine the
  segregation ratio in children overall. But this assumes that the same genetics (genes, alleles, etc) are at
  play in the different families
• Another issue is that by focussing only on affected families there will be an intrinsic bias in the
  genotypes examined, unless there is an independent way to identify healthy carriers (which is now being
  increasingly provided by exon sequencing)

Question 34

What are some issues with determining inheritance?

Answer 34

• If a pedigree is small determining the mode of inheritance can be difficult
• Locus heterogeneity
• Allelic and phenotypic heterogeneity

Question 35

What is Penetrance ?

Answer 35

Penetrance is defined as the proportion of individuals of a specified genotype that show the expected
phenotype (for example the proportion of individuals with a monogenic disorder allele that will express the
disease)

Question 36

What is non- penetrance ?

Answer 36

Dominant disorders sometimes have variable penetrance and can skip a generation

Question 37

What is Variable expression?

Answer 37

Variable expressivity refers to the degree in which a genotype is phenotypically expressed

Question 38

What is Imprinting ?

Answer 38

Imprinting describes the fact that mutant alleles can be transmitted by either sex but are expressed only when coming form either the mother or the father (there are examples of both kinds). This is due to epigenetic effects,
and the suppressed allele is referred to as the imprinted allele

Question 39

What is genetic anticipation?

Answer 39

The phenotype
varies in different generations in a directional manner,
becoming more severe and potentially with earlier onset

Question 40

Several human syndrome exist (collectively known at telomere

syndromes), where?

Answer 40

The replication of telomeric DNA is defective,
due to the mutation in various genes. As a consequence telomeres will shorten in successive generations, leading to earlier onset of diseases
and greater severity of symptoms