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Flashcards in Patterns of Single Gene Inheritance Deck (103):
1

What are the Mendelian patterns of inheritance?

1.) Autosomal Recessive
2.) Autosomal Dominant
3.) X-linked recessive
4.) X-linked dominant

2

What are the three exceptions of Mendelian patterns of inheritance?

1.) Reduced penetrance
2.) Variable Expressivity
3.) Sex-limited phenotypes

3

Determined primarily by an allele at a single chromosomal locus

-Caused by mutations that occur at a specific location on a locus

Single gene disorders

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Single gene disorders are the result of a mutation at a specific locus on the chromosome. These mutations occur on a specific gene and result in a different

Phenotype

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One of two or more alternative forms of a gene that arise by mutation and are found at the same place on a chromosome

Allele

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Set of alleles present at a single locus

-refers primarily to the autosomes

Genotype

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Observable expression of the genotype

Phenotype

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When the two alleles are the same (i.e. both WT or both mutant)

Homozygous

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When one allele is WT and the other allele is a mutation

Heterozygous

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When both alleles are mutant, but the mutation are at different locations in the gene

Compound heterozygotes

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When an abnormal gene is located on an X chromosome in a male patient

Hemizygous

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Distinct mutations in the same gene producing the same phenotype

Allelic Heterogeneity

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Distinct mutations in the same gene producing very different phenotypes

Phenotypic heterogeneity

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Descibes different mutations in the same gene that can sometimes give rise to strikingly different phenotypes

Phenotypic Heterogeneity

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When mutations in more than one gene can cause the same disease

-Ex: Long QT syndrome can be cause by mutations to sodium channels, potassium channels, or structural proteins

Locus Heterogeneity

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One gene that affects multiple traits

-Ex: Von Hippel-Lindau Syndrome

Pleiotropy

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A single gene defect that affects multiple organs, produces multiple diverse phenotypes, and results in a variety of signs and symptoms

Pleiotropy

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When multiple genes affect one trait

-Ex: Hair loss

Polygenic

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Mutations at different loci that produce the same phenotype

Locus Heterogeneity

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Affect 1:300 neonates and are responsible for 7% of pediatric hospitalizations

Single gene disorders

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Most single gene disorders follow a pattern of

Mendelian Inheritance

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Follow classic inheritance patterns and occurs in fixed and predictable proportions among offspring of specific types of matings

Mendelian Diseases

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For Mendelian diseases, you can predict the pattern of inheritance and the genotype from the

Pedigree

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Used to establish the pattern of transmission of single gene disorders

-Determined from the family history

Pedigrees

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Can establish a pattern of inheritance and can be used to determine the degree of risk of disease for family members

Pedigrees

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Early lethality of disorder, small family size, variable age of onset, and non-Mendelian inheritance can all

Confound pedigree interpretation

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If the disease occurs early after birth, or during pregnancy,

Early lethality

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The pattern of inheritance of single gene disorders is determined by what two factors?

1.) Whether phenotype is dominant or recessive
2.) Chromosomal location of gene locus

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Does not follow Mendelian inheritance

Mitochondrial Genome

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Most of the time when we are talking about mutations in the sex chromosomes, we are talking about mutations on the

X-chromosome

(Y mutations are very rare)

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An individual must have two mutant alleles and no wild type in order to have an

Autosomal Recessive (AR) Disease)

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In an AR disease, the type of mutation in each allele CAN be different, i.e. you could be a

Compound Heterozygote

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Reduce or eliminate function of the gene product

-Often affect the function of enzymes
-are RARE

AR Diseases

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Cystic fibrosis is a common representative of an

AR disease

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For an AR disease, the risk that a child will inherit the disorder is

25%

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For an AR disease, the risk that a child will be a carrier is

50%

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For an AR disease, the risk that a child will be an unaffected carrier is

2/3 (had to delete the affected)

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In an AR pedigree, the parents are

Unaffected asymptomatic carriers

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For an AR pedigree, what is the difference between number of affected males and females?

# Affected males = # affected females

40

The more rare or unusual a trait is in a population, the more likely that the parents are

Related

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Wilson's disease is an example of an

AR disease

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New mutations are VERY

Rare

(Not typically the right answer choice)

43

What factors can affect the risk of inheritance for an AR disorder?

1.) Carrier frequency
2.) Consanguinity
3.) Inbreeding
4.) Genetic Isolates

44

Increases the chance that both parents are carriers of the same mutant allele

-When second cousins or closer mate

Consanguinity

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When individuals from a small population choose mates from the same population

Inbreeding

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When certain races are more likely to develop a disease

-Ex: risk of Tay-sachs disease in Ashkenazi Jews (the carrier frequency is 10X higher than in other European populations)

Genetic Isolates

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Deposition of cholesterol in the tendons

Xanthoma

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Makes up more than 50% of known Mendelian disorders

-Only one mutant allele is required for disease
-Ex: Familial Hypercholesterolemia

Autosomal Dominant (AD) Disease

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The incidence of disorders can be high, especially in some populations, for

AD Diseases

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In general, BB homozygotes are exceedingly

Rare

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If an affected heterozygote (Bb) of an AD disease mates with an unaffected homozygote (bb), what is the chance that a child of either sex will be affected?

50%

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What is the risk that a phenotypically normal child has the mutant allele for an AD disease?

Zero (unless there is incomplete penetrance)

53

Do not skip generations (i.e. ever affected individual has an affected parent)

AD Pedigrees

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For an AD pedigree, what is the difference between number of affected males and females?

# Affected males = # affected females

55

For an AD pedigree, male-to-male transmission does occur, and a male can have an unaffected

Daughter

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For an AD pedigree, unaffected individuals will have

Unaffected Children

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Most AD disorders display

Incomplete dominance

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Implies that an individual that is HOMOZYGOUS for the AD mutation will be more severely affected than an individual who is HETEROZYGOUS

Incomplete dominance

59

What are two clinical examples of incomplete dominance?

Achondroplasia and Familial Hypercholesterolemia

60

Means that all genotypes, homozygous or heterozygous, display the same phenotype

Complete Dominance

61

What are two AD traits that create exceptions to the Mendelian Rules?

Reduced penetrance and Variable Expressivity

62

When discussing the probability that a mutant gene will have ANY phenotypic expression at all. If the probability is less than 100%, then the gene has

Reduced penetrance

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A phenotype can have age dependent

Penetrance

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When all individuals with the disease ARE affected, but the severity (phenotype) of the disease differs in people who have the same genotype

Variable expressivity

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Penetrance is considered to be "all or none" in the sense that if 100% of the people have the phenotypic expression, then the gene has complete penetrance, but anything less than 100% is

Reduced (Incomplete) Penetrance

66

An example of reduced penetrance is the AD form of split hand foot malformation, which has a reduced penetrance of

70%

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What is an example of a disease that has an age dependent penetrance and variable expressivity?

Neurofibromatosis

68

Can make a pedigree difficult to interpret because the disease may appear to skip a generation

Reduced Penetrance

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Genes occur on the autosomes and the mutations are present in BOTH sexes, but the phenotype is evident only in one sex

Sex-linked autosomal traits

70

The genes for the trait can be carried and transmitted by the opposite sex, although it is NOT displayed in that sex because of anatomical or physiological differences

Sex-linked autosomal traits

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What is the best characterized Sex-linked AD disorder?

Male-limited precocious puberty

72

Mutation in lutenizing hormone receptor gene (LHR), which results in LHR being "on" all the time

-Only expressed in males

Male-limited precocious puberty

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Males affected with Male-limited precocious puberty develop secondary sexual characteristics w/ a growth spurt by the age of

4

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In a pedigree, male-to-male transmission (i.e. dad passes disease to son) excludes

X-linked disorder

75

What is the most well documented sex-limited AR disorder?

-Most common single-gene inherited disease in the US

Hemochromatosis

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More common in males (5-10x) who have no physiologic process to reduce excess iron

-In women, pregnancy and menstruation reduce iron levels (10-20% incidence of males)

Hemochromatosis

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How many genes are there on the x-chromosome associated with disease phenotype?

300

78

The dominant and recessive patterns of X-linked inheritance depends on the phenotype in

Heterozygous women

79

You can have a female who is heterozygous for an X-linked disorder still display the phenotype because of

X-inactivation

80

When discussing X-linked recessive (XLR) disorders, males are referred to as being

Hemizygous (XY)

81

When a woman heterozygous for an XLR disorder mates with an unaffected male, what are the odds for the male and female children of being affected?

1.) 1:2 Risk that males will be affected
2.) 1:2 risk that females will be carriers

82

For an XLR, what are the odds if the male is affected but the female is unaffected?

1.) All females will be carriers
2.) All males are normal

83

What are the characteristics of an XLR pedigree?

1.) Males are affected more than females
2.) Heterozygous females are unaffected (depending on X-inactivation)
3.) Gene is transmitted from affected male to ALL daughters

84

In an X-linked dominant (XLD) disorder, the trait is NEVER passe from the father to the

Son

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In an X-linked dominant (XLD) disorder, if an affected male and a normal female have kids, all the daughters are

Affected

86

What is a characteristic of XLD disorders?

More females are affected than males

87

Presence in an individual of at least two cell lines that differ genetically (due to a mutation) but are derived from a single zygote

-An exception to Mendelian inheritance

Mosaicism

88

What are the two types of mosaicism?

1.) Pure somatic (occurs in somatic cells)
2.) Pure germline (mutation occurs in germ cells)

89

When parents who are phenotypically normal and who test negative for being a carrier have more than one child affected with a highly penetrant AD or XLR disorder, we suspect

Germline Mosaicism

90

What are three examples of germline mosaicism?

Osteogenesis imperfecta, Hemophilia A and B, and Duschenne muscular distrophy

91

Very rare in AR, but are a common cause of some diseases

-probability is 10^-6 to 10^-7 per gamete
-another cause for divergence from Mendelian inheritance

New Mutations

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Diseases that are produced by dominant alleles with effects so severe that persons with them do not have children (genetic lethal), are typically only observed when there are

New Mutations

93

When looking at pedigree, if thing seem to REALLY not make sense, it is possible that there has been

Mis-attributed paternity

94

Says that genes originating from maternal and paternal genomes are equally expressed in the offspring

Mendel's Law

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What is a clear violation of Mendel's law?

-Affects about 100 human genes located on select chromosomes

Genomic imprinting

96

When the maternal allele is methylated and the methylated gene is NOT expressed

Maternal imprinting

97

Nearly all mutations that create enzyme deficiency and matabolic disease are

-Because a single defective allele will only reduce function by 50%

Recessive

98

What are the three major routes to dominance?

1.) Gain-of-function
2.) Haploinsufficiency
3.) Dominant-negative effect

99

Mutation allows protein to function in ways not possible for the normal gene product.

Example: constitutive activity of ras, can be produced by amino acid substitutions that reduce GTPase activity, so that ras is always active, not just when growth factors bind receptors.

Gain-of-function

100

When one functional allele cannot provide sufficient product for normal function.

Ex: 50% of normal protein C activity is not sufficient to prevent risk of thrombosis

Haploinsufficiency

101

Created by nonsense, frameshift, or splicesite mutations that block production of any protein by the mutant allele

Haploinsufficiency

102

If the active form of the protein is an oligomer, a single defective subunit can block function of the entire protein. This is an example of the

Dominant-negative effect

103

The transcription factor p53 is a tetramer. Mutations that block DNA-binding by one of the four subunits can prevent function of the tetramer, leading to the

Dominant-negative effect

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