Genetics: Test 1

Front 1

define allelic heterogeneity

Back 1

existence of different mutant alleles of the same gene

(e.g. different mutations on the same gene can cause the same disease)

Front 2

define locus heterogeneity

Back 2

occurrence of similar/identical phenotypes due to mutations at two or more different loci/genes

(e.g. different mutations on different genes can cause the same disease)

Front 3

define phenotypic/clinical heterogeneity

Back 3

different mutations in the same gene give rise to different phenotypes/clinical pictures

(e.g. different mutations on the same gene cause different diseases)

Front 4

define autosomal dominant

Back 4

gene is located on a chromosome other than the X or Y chromosome

need only one dose of a mutant allele to present with the disease/trait

affecteds are usually heterozygotes, but homozygotes may occur and may be more severely affected

Front 5

how does autosomal dominant appear in a pedigree?

Back 5

the trait typically appears in each generation (vertical transmission); isolated cases may be caused by new mutation

males and females are equally likely to inherit the mutant allele and either parental sex can transmit the mutant allele to either offspring sex

phenotypically "normal" family members don't transmit generally

Front 6

what are the chances that the offspring of a pt with an autosomal dominant disorder will be affected?

Back 6

50% if parent is A/a

100% if parent is A/A

Front 7

define penetrance

Back 7

the fraction of individuals with a genotype known to cause a disease who have any sign or symptoms of the disease

(# of affecteds)
-----------------------------------------
(# with "affected genotype")

Front 8

compare penetrance at an individual level to penetrance at a population level

Back 8

individual level: a disease gene (allele) is either penetrant or not

population level: fraction/percent of pts affected out of those who should be affected
(eg. fully penetrant AD disease means that everyone with a disease allele has the disease; fully penetrant AR disease means that everyone with homozygous mutant alleles has the disease)

Front 9

define pleiotropy

Back 9

presence of multiple phenotypic effects of a single allele or pair of alleles

**particularly used when the effects are not obviously related (e.g. impact different systems)**

Front 10

define expressivity

Back 10

extent or degree of expression (e.g. mild to severe)

Front 11

compare penetrance with expressivity

Back 11

penetrance is a measure of how many ppl are affected by the mutant allele, no matter the extent/severity of disease in the pts

expressivity is the range across which the extent/severity to which an individual can be affected by the disease can vary

Front 12

in a pedigree, there are six ppl with an autosomal dominant disorder, six ppl heterozygous for the mutant allele, and two people who are homozygous for the allele.

what is the chance that an unaffected heterozygous male, with a female who is homozygous for the normal allele, will have a child who is affected?

Back 12

risk = (chance that dad will pass on the mutant allele) x (penetrance)

risk = (1/2) x (6/8) = 3/8 = 0.375

Front 13

in a pedigree, there are 3 ppl with an autosomal recessive disorder, twelve ppl heterozygous for the mutant allele, and five people who are homozygous for the allele.

what is the chance that an unaffected heterozygous male, with a female who is homozygous for the mutant allele, will have a child who is affected?

Back 13

risk = (chance that dad will pass on the mutant allele) x (chance that mom will pass on the mutant allele) x (penetrance)

risk = (1/2) x (2/2) x (3/5) = 3/10 = 0.30

Front 14

what is the effect of late age of onset on a pedigree?

Back 14

if one/more generations/persons with the "affected genotype" is younger than the typical age of onset for the disorder, they may not be presenting yet; they may be mistakenly labeled non-penetrant individuals

Front 15

what is the inheritance pattern for achondroplasia?

Back 15

autosomal dominant

complete penetrance

Front 16

what is the inheritance pattern for osteogenesis imperfecta?

Back 16

autosomal dominant

Front 17

what is the inheritance pattern for marfan syndrome?

Back 17

autosomal dominant

variable expressivity
pleiotropy

Front 18

what is the inheritance pattern for neurofibromatosis?

Back 18

autosomal dominant

full penetrance
variable expressivity

often caused by new mutation

Front 19

what is the inheritance pattern for Huntington Disease?

Back 19

autosomal dominant

Front 20

what is the inheritance pattern for familial alzheimer disease?

Back 20

autosomal dominant

Front 21

what is the inheritance pattern for familial hypercholesterolemia?

Back 21

autosomal dominant

Front 22

what is the inheritance pattern for blood types?

Back 22

autosomal dominant

Front 23

define qualitative mutation

Back 23

mutation that causes a structural change in a protein (or RNA) that results in an abnormal gain of function that leads to disease

Front 24

define quantitative mutation

Back 24

mutation that causes a reduction in the amounts/levels of normal protein

**the body may need to have a certain minimal amount (threshold) of a particular protein (or gene expression); if both alleles of a specific gene need to be functional/normal to achieve the level, then mutation of one allele would result in a drop below the threshold level (haploinsufficiency)**

Front 25

what is the most common cause of dwarfism in man?

Back 25

achondroplasia

**causes short-limbed dwarfism in 1/15,000-40,000 live births**

Front 26

what are the clinical features of achondroplasia?

Back 26

short stature
macrocephaly (lg head)
frontal bossing (prominent forehead)
reduced fertility
limbs that are short proximally
curvature of the spine (lumbar lordosis)
depressed nasal bridge

AFFECTED PERSONS ARE OF NORMAL INTELLIGENCE

Front 27

what gene/protein is affected in achondroplasia?

Back 27

FGFR3 (Fibroblast Growth Factor Receptor 3)

**typically a G380R substitution**
(G->C or G->A in first position of codon 380)

Front 28

what is the most common single base mutation in humans?

Back 28

C to T transition

Front 29

what does it mean for the genetic code to be degenerate?

Back 29

different sequences of nucleotide bases can code for the same amino acid

e.g. AGG=Arg and CGG=Arg

Front 30

define transition

Back 30

substitution of a purine for another purine or of a pyrimidine for another pyrimidine

Front 31

define transversion

Back 31

substitution of a purine for a pyrimidine or vice versa

Front 32

describe the heterogeneity of achondroplasia

Back 32

no locus heterogeneity (ONLY a mutation in the FGFR3 gene can cause achondroplasia

very little allelic heterogeneity (90% of the mutations of FGFR3 are G380R substitutions)

Front 33

what is the normal function of FGFR3? how is it altered in achondroplasia?

Back 33

fibroblast growth factor receptor 3 (FGFR3) is a transmembrane tyrosine kinase receptor that, on activation by FGF, inhibits the proliferation of chondrocytes and thereby arrests growth

in achondroplasia, a G380R substitution causes FGFR3 to be constitutively active and to always inhibit growth rather than only in response to signal

Front 34

how do most pts with achondroplasia inherit the disorder?

Back 34

in most cases, the parents of the pt with achondroplasia are not affected b/c about 80% of cases are caused by new mutations

Front 35

when does the risk of new achondroplasia-causing mutations increase?

Back 35

advanced paternal age (>35 yrs)

Front 36

in what types of disorders are new mutations likely to be the cause of the majority of cases?

Back 36

more likely in severe disorders (e.g. those that are lethal in childhood or that prevent reproduction for some reason)

Front 37

what is the most severe type of osteogenesis imperfecta?

Back 37

type II

Front 38

where do most cases of type II osteogenesis imperfecta arise?

Back 38

new mutations

type II OI is perinatal lethal

Front 39

what are the clinical features of type II osteogenesis imperfecta?

Back 39

generally lethal perinatally

- large, unmineralized skull
- small thoracic cavity
- short & deformed long bones of arms and legs
- flattened vertebral bodies
- undermineralization of all bones
- many congenital or prenatal fractures

Front 40

define true/pure dominant

Back 40

individuals present with the same phenotype whether they are heterozygous or homozygous for the mutant allele(s)

ex. Huntington's Disease

Front 41

define incomplete dominant

Back 41

trait that is inherited in a dominant manner, but that is more severe/extreme in a homozygote than in a heterozygote

ex. achondroplasia

Front 42

define codominant

Back 42

a trait where if both alleles of a pair are expressed in the heterozygous state, then the alleles (or traits determined by them) are both presented to some degree

ex. A and B blood types

Front 43

achondroplasia homozygotes

Back 43

more severe disease than heterozygotes

lethal in utero or in early infancy

incomplete dominant

Front 44

familial hypercholesterolemia homozygotes

Back 44

more severe disease than in heterozygotes

heterozygotes have elevated cholesterol levels, but homozygotes have astronomical levels

incomplete dominant

Front 45

Huntington disease homozygotes

Back 45

homozygotes and heterozygotes have similar phenotype

true dominant

Front 46

what disorders involve mutations of FGFR3?

Back 46

1. achondroplasia
2. thanatophoric dysplasia
3. hypochondroplasia
4. severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN)
5. muenke coronal craniosynostosis
6. crouzon syndrome with acanthosis nigricans

significant phenotypic/clinical heterogeneity

Front 47

thanatophoric dysplasia

Back 47

caused by mutation of FGFR3

severe perinatal lethal

similar disease to achondroplasia homozygotes

Front 48

hypochondroplasia

Back 48

caused by mutation of FGFR3

milder disease than achondroplasia

Front 49

what is the most common type of osteogenesis imperfecta?

Back 49

type I (1/15,000 live births)

Front 50

clinical features of type I osteogenesis imperfecta

Back 50

mild disease

- brittle bones with tendency to fractures
- fractures generally heal w/o deformity
- blue sclerae
- deafness

Front 51

where do most cases of type II osteogenesis imperfecta come from?

Back 51

new mutations

Front 52

clinical features of type III osteogenesis imperfecta

Back 52

some fractures at birth
progressive deformity
growth retardation
some blue sclerae

Front 53

clinical features of type IV osteogenesis imperfecta

Back 53

tendency for fractures
normal sclerae

Front 54

how does the mutation in type I OI differ from the mutation in type II OI?

Back 54

in type I OI, the mutation is a null mutation (a mutation in the early coding or promoter region) in the alpha1 allele of collagen; this mutation doesn't allow production of proalpha1 collagen from this allele, but since normal proalpha1 collagen can be made from the other copy some normal collagen can still be made (though it is less)

in type II OI, the mutation is later in the coding sequence, so abnormal proalpha1 collagen is made and then pairs with other procollagen molecules; this results in destruction of the abnormal proteins

rather than just producing insufficient protein, the abnormal protein actually causes the destruction of normal/good proteins

Front 55

define dominant-negative mutation

Back 55

disease-causing allele, or the effect of such an allele, that results in disruption of the function of the wild-type allele or protein

aka protein suicide

Front 56

what are the clinical features of Marfan syndrome?

Back 56

skeletal: long, thin extremities and fingers (arachnodactyly); arm span:height ratio>1.05; lax joints; bony deformities of the spine and sternum

eye: nearsightedness and lens dislocation (ectopia lentis) (usually upward)

cardiovascular: widening/dilation of aortic root (dissecting aneurysms); valvular incompetence (mitral valve prolapse)

Front 57

define genetic compound

Back 57

aka compound heterozygote

individual that is heterozygous for two different mutant alleles at a single gene

Front 58

sex-limited vs. sex-influenced traits

Back 58

sex-limited: trait expressed in only one sex

sex-influenced: trait expressed differently (in degree/frequency) in males vs. females

Front 59

male pattern baldness

Back 59

hair recedes in an "m" shape

the crown bald patch eventually meets the top points to form a horseshoe shape

Front 60

define mosaicism

Back 60

presence in an individual (or a tissue) of two or more cell lines that differ genetically but that came from one zygote

can be somatic or germline mosaicism

Front 61

what is the result of somatic mosaicism?

Back 61

segmental/modified disease expression

e.g. neurofibromatosis 1 (NF1)

Front 62

what is the result of germline mosaicism?

Back 62

multiple affected offspring from two unaffected parents

e.g. osteogenesis imperfecta

Front 63

what are the clinical features of neurofibromatosis 1 (NF1)?

Back 63

multiple neurofibromas (benign, fleshy skin tumors)

multiple cafe-au-lait spots (flat irregular pigmented skin lesions)

Lisch nodules (small benign iris nodules)
- not found in NF2

inc. risk for certain neoplasms (optic nerve gliomas, brain tumors, malignant myeloid disorders)

axillary freckling

Front 64

why is germline mosaicism a more plausible explanation than random mutations in a family where an unaffected couple has two children afflicted with an autosomal dominant disease (assuming complete penetrance)?

Back 64

mutations are RARE
- 1/10,000 to 1/1,000,000 gametes

since mutations are so rare, it is HIGHLY unlikely that two mutations will occur in the same family

Front 65

how can somatic and germline mosaicism coexist in the same individual?

Back 65

the mutation must occur during embryogenesis

Front 66

how does an autosomal recessive disease present in a pedigree?

Back 66

parents are usually not affected, but are probably carriers

the offspring of an affected individual can only be a carrier or an affected

see multiple affected individuals only in sibship, with males and females affected equally

see affecteds in one generation, therefore called horizontal transmission

Front 67

what is the inheritance pattern of alkaptonuria?

Back 67

autosomal recessive

Front 68

what is the inheritance pattern of Tay-Sachs Disease?

Back 68

autosomal recessive

Front 69

what is the inheritance pattern of cystic fibrosis?

Back 69

autosomal recessive

Front 70

what is the inheritance pattern of sickle cell anemia?

Back 70

autosomal recessive

Front 71

what is the inheritance pattern of phenylketonuria?

Back 71

autosomal recessive

Front 72

what is a generalization about autosomal recessive conditions?

Back 72

most are caused by mutations that result in loss of function, esp. of an enzyme