Patterns of Single Gene Inheritance

Question 1

compound heterozygote

Answer 1

both alleles are variants, but at different locations in the gene

Question 2

hemizygous

Answer 2

variant gene is on X chromosome in male patient

Question 3

allelic heterogeneity

Answer 3

different mutations at the same gene locus causing the same phenotype

Question 4

phenotypic heterogeneity

Answer 4

different mutations in the same gene cause different phenotypes

Question 5

locus heterogeneity

Answer 5

mutations in multiple genomic loci (distinct genes) produce same phenotype

inheritance patterns can be different

Question 6

pleiotropy

Answer 6

single gene variants that affect multiple organ systems, produce diverse phenotypes, and show a variety of signs and symptoms

very common for these genes to be transcription factors

Question 7

you see a patient in clinic that has a rare disease in which the function of an important enzyme is severely limited. from this information alone, what inheritance pattern do you suspect?

Answer 7

autosomal recessive - limit/eliminate gene activity, often affect enzymes, are rare

AR diseases typically seen in one generation and typically seen among siblings

Question 8

you have a patient with a single gene disorder, yet their symptoms are widely dispersed through multiple organ systems, and they present with several phenotypes. What type of gene variant must this be?

Answer 8

pleiotropy - single gene producing a variety of effects in multiple organ systems

Question 9

two parents who are heterogenous for an autosomal recessive disorder have a child. What is the risk of an unaffected child being a carrier?

Answer 9

in other words, of the children that don’t have the disease (3/4), how many are carriers?

2/3

Question 10

Pt is a 4 yo F referred to pediatric clinic for evaluation of poor growth. PMH includes diarrhea, colic, cough, and upper respiratory infections. No pertinent FMx. Pt’s ht & wt is within 2nd percentile. PE reveals clubbing of digits. Sweat chloride level was 75 mmol/L (<40 mmol/L normal). What is your initial diagnosis?

Answer 10

cystic fibrosis

Question 11

A couples comes into clinic seeking genetic counseling. The father has cystic fibrosis (AR) and the mother is not sure whether she is a carrier, but her sister has CF (not her parents). They want to know the chance their child will have cystic fibrosis. What will you tell them?

Answer 11

the mother’s sister has CF but unaffected parents so they are both obligate carriers.
the mother’s chance of being a carrier is therefore 2/3
If she were a carrier, there would be a 1/2 chance of passing the mutated allele to the child

so the child’s risk is (2/3)(1/2) = 1/3

Question 12

name 2 factors that can affect the risk of inheritance for an AR disorder

Answer 12

1. carrier frequency of the disease in a given population
2. consanguinity increases the chance that both parents are carriers of the same mutant allele (as closer or closer than second cousins)

Question 13

what is the most common single-gene inherited disease in the US

Answer 13

hemochromatosis - affects iron storage, results in excess iron in the body which can be toxic

AR, but phenotype varies by sex because women have a physiologic mechanism to get rid of iron (menstruation, pregnancy) so their phenotype is less severe

Question 14

what about hemochromatosis makes it difficult to track in a pedigree?

Answer 14

hemochromatosis: affects iron storage, causing excess in the body (mutation in HFE)

AR disease, but difficult pedigree because phenotype varies by sex - women who can get pregnant or menstruate naturally lose iron, so their phenotype is less severe

Question 15

what is the associated gene mutation of cystic fibrosis? what is its inheritance pattern?

Answer 15

cAMP-regulated chloride channel

autosomal recessive

Question 16

what mutation is associated with sickle cell disease, and what is its inheritance pattern?

Answer 16

mutation in hemoglobin beta subunit

autosomal recessive

Question 17

what mutation is associated with thalassemia?

Answer 17

mutation in alpha or beta globin gene of hemoglobin

autosomal recessive

Question 18

Explain this:
A couple both have syndromic deafness, an AR disorder. They each have a sibling with the disease, but their parents do not. The couple has 5 children, none of which have syndromic deafness.

Answer 18

locus heterogeneity !

They each inherited 2 recessive genes that cause deafness, but there is a different gene mutation affecting each family. The different mutations cause the same phenotype

Question 19

In clinic you see a pair of monozygotic twins, a male and a female. Both have an AD mutation in the LH (luteinizing hormone) receptor gene such that it is constitutively active. However, only the male shows symptoms, exhibiting early-onset puberty. Explain this

Answer 19

male is affected by male-limited precocious puberty

sex-limited phenotype

disorder is transmitted via affected males or unaffected females (AD, but only carriers)

Question 20

why might disease-causing genotypes in AD disorders not be expressed as a phenotype?

Answer 20

incomplete penetrance: probability that a variant gene will have any phenotypic expression (all or none)

penetrance has to be factored into risk of phenotype (multiply penetrance by risk)

Question 21

If an AD disorder has a penetrance of 80%, what is the probability that a child with two affected heterozygous parents will have the phenotype?

Answer 21

penetrance = 0.8

probability of inheriting dominant allele from two heterozygous parents = 3/4 or 0.75

risk of phenotype = (0.8)(0.75)

Question 22

Explain this:
A male affected by an AD disorder has children with an unaffected woman. They have 4 children, 2 of whom are affected. One of the unaffected daughters has children of their own with an unaffected male. Two of their four children have the AD disorder.

Answer 22

the “unaffected” daughter must have incomplete penetrance to be able to pass it on

they have the genetic abnormality but for whatever reason did not develop the disease

Question 23

variable expressivity

Answer 23

varying severity of the phenotype among individuals with the same disease-expressing genotype

ex: neurofibromatosis

Question 24

contrast incomplete penetrance with variable expressivity

Answer 24

incomplete penetrance: same phenotype, but not all those with allele variant are affected. Use this number in genetic counseling

variable expressivity: variable phenotype, but all those with allele variant have SOME phenotype

Question 25

what is the associated gene mutation of familial hypercholesterolemia and what is its inheritance pattern?

Answer 25

autosomal dominant, mutation in low-density lipoprotein (LDL) receptor

shows incomplete dominance (as do most AD disorders)

Question 26

T/F: most AD disorders display incomplete dominance

Answer 26

TRUE: individuals that are homozygous will have more severe phenotype, but typically don’t see homozygotes because it is often lethal or not compatible with life

Question 27

incomplete dominance

Answer 27

for AD disorders, phenotype will be more severe for homozygotes than heterozygous

Question 28

what makes Huntington’s disease unique among AD disorders?

Answer 28

it is the only true autosomal dominant disorder - it does not show incomplete dominance

phenotype of heterozygous and homozygote is the same

Question 29

explain this:
female heterozygotes for an x-linked recessive disorder may have clinical phenotype

Answer 29

unbalanced x-inactivation: females are somatic mosaics of maternal and paternal X

(but typically have enough WT X not to show phenotype)

Question 30

what inheritance pattern does hemophilia A show? what is the mutation?

Answer 30

mutation in Factor VIII (8) - co-factor for clotting

X-linked recessive

amount of Factor VIII determines phenotype - most affected males have severe phenotype, some heterozygous females have mild disease (skewed X inactivation)

Question 31

for an X-linked recessive disorder, an unaffected male (XY) has a child with a carrier female (Xx). If the sex is unknown, what is the risk of the child being affected?

Answer 31

50% chance that females will be a carrier and 50% chance males will be affected (if inherit mutant x from mom)

50% chance of child being male or female

so risk is (1/2)(1/2) = 1/4 or 25% risk of affected child when sex is unknown

Question 32

given an XLR disorder, if an affected male mates with an unaffected female, how many males will be affected?

Answer 32

none - they will inherit mother’s X

with XLR, there is NO male to male transmission

all daughters will be carriers

Question 33

are males or females more affected by XLR disorders?

Answer 33

males, they only have 1 X

**however, disease is always inherited from mother (because if father has bad x, they will have the mother’s)

NO male to male transmission

Question 34

when are females obligate carriers of an x linked recessive disorder

Answer 34

when the mutation is inherited from the father (it’s the only X that can be given)

Question 35

for an x-linked recessive disorder, there is a 50% chance that a child of either sex will be affected.
what must be the genotypes of the parents?

Answer 35

affected male (xY)
carrier female (Xx)

Question 36

explain this:
a male with an x-linked recessive disorder mates with an unaffected female. they have an affected son

Answer 36

the mother must be a carrier

NO male to male transmission with XLR disorders

Question 37

what inheritance pattern does Duchene Muscular Dystrophy follow

Answer 37

XLR

(dystrophin gene mutation)

Question 38

what inheritance pattern does glucose 6 phosphate dehydrogenase deficiency follow?

Answer 38

XLR mutation in G6PD gene

Question 39

what inheritance pattern do Hemophilia A and B follow?

Answer 39

XLR

Hemophilia A: mutation in Factor VIII (more common)
Hemophilia B: mutation in Factor IX

Question 40

match with what sex is more affected:
male or female
X-linked recessive or X-linked dominant

Answer 40

XLR: more males affected
XLD: more females affected

NO male to male transmission either way

Question 41

what percentage of female children will be affected by a male parent with an XLD disorder

Answer 41

100%

no male progeny affected

Question 42

a male affected with an XLD disorder mates with an unaffected female. What is the probability that a child of unknown sex will inherit the disease?

Answer 42

50%, because it really just depends on whether it is a son (no male transmission) or daughter (all daughters affected of affected males)

Question 43

Rett syndrome is an X linked dominant disorder that is only observed in females. Why?

Answer 43

male lethality

Rett syndrome is neurological and developmental disorder

Question 44

X-linked epilepsy is an XLD disorder but only affects females. Why?

Answer 44

male sparing

Question 45

what are 2 reasons for an XLD disease only affecting females?

Answer 45

male lethality or male sparing

Question 46

when genetic lethal diseases appear in the population, such as severe forms of osteogenesis imperfecta (AD) or Duchenne muscular dystrophy (XLR), they are usually attributed to____

Answer 46

new mutations

these diseases are so severe that affected persons do not have children, so there is no inheritance pattern

Question 47

why might you suspect germ line mosaicism based off a pedigree?

Answer 47

parents are phenotypically normal and test negative for being a carrier

however, they have MORE THAN 1 child affected with a HIGHLY penetrant AD or XL disorder

could be new mutation if just one child, but more than one child with the same new mutation is virtually impossible

*the key is that the genetic test for being a carrier uses somatic cells, not germline cells, so mutation will not be apparent

Question 48

for the following situations, give a possible explanation:
a. AR disorder that appears unexpectedly
b. disease phenotype in F with XLR mutation
c. trisomy

Answer 48

a. maternal uniparental disomy for X chromosome
b. non-random X inactivation
c. non-disjunction in meiosis I