Patterns of Single Gene Inheritance Flashcards
compound heterozygote
both alleles are variants, but at different locations in the gene
hemizygous
variant gene is on X chromosome in male patient
allelic heterogeneity
different mutations at the same gene locus causing the same phenotype
phenotypic heterogeneity
different mutations in the same gene cause different phenotypes
locus heterogeneity
mutations in multiple genomic loci (distinct genes) produce same phenotype
inheritance patterns can be different
pleiotropy
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
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?
autosomal recessive - limit/eliminate gene activity, often affect enzymes, are rare
AR diseases typically seen in one generation and typically seen among siblings
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?
pleiotropy - single gene producing a variety of effects in multiple organ systems
two parents who are heterogenous for an autosomal recessive disorder have a child. What is the risk of an unaffected child being a carrier?
in other words, of the children that don’t have the disease (3/4), how many are carriers?
2/3
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?
cystic fibrosis
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?
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
name 2 factors that can affect the risk of inheritance for an AR disorder
- carrier frequency of the disease in a given population
- consanguinity increases the chance that both parents are carriers of the same mutant allele (as closer or closer than second cousins)
what is the most common single-gene inherited disease in the US
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
what about hemochromatosis makes it difficult to track in a pedigree?
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
what is the associated gene mutation of cystic fibrosis? what is its inheritance pattern?
cAMP-regulated chloride channel
autosomal recessive
what mutation is associated with sickle cell disease, and what is its inheritance pattern?
mutation in hemoglobin beta subunit
autosomal recessive
what mutation is associated with thalassemia?
mutation in alpha or beta globin gene of hemoglobin
autosomal recessive
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.
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
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
male is affected by male-limited precocious puberty
sex-limited phenotype
disorder is transmitted via affected males or unaffected females (AD, but only carriers)
why might disease-causing genotypes in AD disorders not be expressed as a phenotype?
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)
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?
penetrance = 0.8
probability of inheriting dominant allele from two heterozygous parents = 3/4 or 0.75
risk of phenotype = (0.8)(0.75)
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.
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
variable expressivity
varying severity of the phenotype among individuals with the same disease-expressing genotype
ex: neurofibromatosis
contrast incomplete penetrance with variable expressivity
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
what is the associated gene mutation of familial hypercholesterolemia and what is its inheritance pattern?
autosomal dominant, mutation in low-density lipoprotein (LDL) receptor
shows incomplete dominance (as do most AD disorders)
T/F: most AD disorders display incomplete dominance
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
incomplete dominance
for AD disorders, phenotype will be more severe for homozygotes than heterozygous
what makes Huntington’s disease unique among AD disorders?
it is the only true autosomal dominant disorder - it does not show incomplete dominance
phenotype of heterozygous and homozygote is the same
explain this:
female heterozygotes for an x-linked recessive disorder may have clinical phenotype
unbalanced x-inactivation: females are somatic mosaics of maternal and paternal X
(but typically have enough WT X not to show phenotype)
what inheritance pattern does hemophilia A show? what is the mutation?
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)
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?
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
given an XLR disorder, if an affected male mates with an unaffected female, how many males will be affected?
none - they will inherit mother’s X
with XLR, there is NO male to male transmission
all daughters will be carriers
are males or females more affected by XLR disorders?
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
when are females obligate carriers of an x linked recessive disorder
when the mutation is inherited from the father (it’s the only X that can be given)
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?
affected male (xY)
carrier female (Xx)
explain this:
a male with an x-linked recessive disorder mates with an unaffected female. they have an affected son
the mother must be a carrier
NO male to male transmission with XLR disorders
what inheritance pattern does Duchene Muscular Dystrophy follow
XLR
(dystrophin gene mutation)
what inheritance pattern does glucose 6 phosphate dehydrogenase deficiency follow?
XLR mutation in G6PD gene
what inheritance pattern do Hemophilia A and B follow?
XLR
Hemophilia A: mutation in Factor VIII (more common)
Hemophilia B: mutation in Factor IX
match with what sex is more affected:
male or female
X-linked recessive or X-linked dominant
XLR: more males affected
XLD: more females affected
NO male to male transmission either way
what percentage of female children will be affected by a male parent with an XLD disorder
100%
no male progeny affected
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?
50%, because it really just depends on whether it is a son (no male transmission) or daughter (all daughters affected of affected males)
Rett syndrome is an X linked dominant disorder that is only observed in females. Why?
male lethality
Rett syndrome is neurological and developmental disorder
X-linked epilepsy is an XLD disorder but only affects females. Why?
male sparing
what are 2 reasons for an XLD disease only affecting females?
male lethality or male sparing
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____
new mutations
these diseases are so severe that affected persons do not have children, so there is no inheritance pattern
why might you suspect germ line mosaicism based off a pedigree?
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
for the following situations, give a possible explanation:
a. AR disorder that appears unexpectedly
b. disease phenotype in F with XLR mutation
c. trisomy
a. maternal uniparental disomy for X chromosome
b. non-random X inactivation
c. non-disjunction in meiosis I
