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Genetics > W5: Patterns of Inheritance > Flashcards

W5: Patterns of Inheritance Flashcards

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1
Q

What is the purpose of a pedigree?

A

Provides a visual representation of diseases that occur within a family. Can be included in a patient chart, that can be used by other healthcare providers. Can be used to asses

Risk for disease

Identify rare conditions

Identify conditions caused by inherited gene mutations

Can lead to prevention, early dx., and management

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2
Q

How to determine the degree of relationship between various family members (ie. second degree, first degree etc.)

A

Frist Degree relatives (share 50% of genes)= Children, parents, siblings

Second Degree relatives (share 25% of genes)= Aunts, uncles, grandparents, half siblings, nices and nephews

Third Degree relatives (share 12.5% of genes)=cousins and great grandparents

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3
Q

Geneder in a pedigree

A
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4
Q

Twins in a pedegree

A
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5
Q

Relationships (matings, offpsring, and consanguinious) in a pedigree

A
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6
Q

Number of generations in a pedigree

A
  • A basic pedigree consists of a minimum of three generations:
  • first-degree relatives (e.g., parents, children, siblings),
  • second-degree relatives (half siblings, grandparents, aunts and uncles, grandchildren), and
  • third-degree relatives (cousins, great-grandparents, great-grandchildren
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7
Q

What are risk factors or “red flags” in a pedigree?

A

Family history with multiple affected individuals in multiple generations

G: Group of congenital abnormalities

E: Extreme or exceptional presentation of common conditions ex. Early onset of melanoma in a young child, or colon cancer in a 20yo

N: Neurodevelopmental delay

E: Extreme or exceptional pathology: ex.multiple abnormal biopsies in different family members

S: Surprising lab values: high cholesterol in a otherwise healthy 20yo

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8
Q

What is consanguinity?

A

A genetic relationship between persons descended from a common ancestor

Increases likelihood of inheriting identical versions of a given gene

Autosomal recessive disease more likely

Increased probability of two copies of the same mutation

Common complex disease more likely

Greater proportion of shared genes

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9
Q

What is penetrance?

A

How often a gene is expressed in a population when it is present

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10
Q

Describe the X chromosome

A

Large chromosome

Contains 5% of nuclear genomes DNA

1100 genes have been isolated

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11
Q

Describe the Y chromosome

A

Much smaller than X chromosome

Only contains a few dozen genes

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12
Q

How many pairs of autosomes are there?

A

22 pairs =44 autosomes

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13
Q

Types of sex linked inheritance

A

X recessive

X dominant

Y-linked

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14
Q

Are X-linked disorders more common in men? Why?

A

Yes, X linked disorders are more common in men, because they only have one X chomosome

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15
Q

X-Linked Recessive Disorders: Key Concepts

A

Generally only males affected

Sons of heterozygous mothers have a 50% chance of being affected

Can pass on to her daughters, but are not affected

No male to male transmission in x-linked recessive, because the male never passes on an X chromosome

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16
Q

X-Linked Dominant

A
  • Male and female offspring of affected mother may be affected
  • All female offspring of the father will be affected
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17
Q

Y-Linked

A

Passed strictly from the father to the son

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18
Q

Mitochondrial Inheritance

A
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19
Q

Mitochondrial Inheritance Pedigree

A
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20
Q

Factors Complicating Inheritance Patterns

A

Mandellian inheritance does not always hold true

exceptions include:

  • new mutation
  • Germline Mosaicism
  • Delayed Age of onset
  • Reduced Penetrance
  • Variable expression
  • Pleiotropy and Heterogeneity
  • Genomic Imprinting
  • Anticipation
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21
Q

New Mutation

A

Gene transmitted by one of the parents undergoes a new mutation from normal to mutant allele

– The allele at the same locus in the parent’s cells would be normal

– However, the offspring of those affected would have substantially elevated risk

– 50% for autosomal dominant, 25% for autosomal recessive, as expected

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22
Q

Germline Mosaicism

A

– Mosaicism: Presence of more than one genetically distinct cell line in the body

– All or part of parent’s germline affected by a disease mutation, but parent’s somatic cells are not affected

– Mutation occurs during parent’s embryonic development in germline cells, but not somatic cells

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23
Q

Delayed Age of onset

A

Delayed age of penetrance

Several diseases do not present until after the patients reach reproductive age or adulthood

Not possible until later in life to determine is patient carries the mutation

ex. AD form of breast cancer, huntingtons disease, polycystic kidney, homochomotosis, familial alzheimers

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24
Q

What is penetrance?

A

the probability of expressing a phenotype given that the individual has inherited a predisposing genotype

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25
Q

What is reduced penetrance?

A

Those that have the appropriate genotype, fail to express the disease, though they may pass the gene on to the next generation

ex. retinoblastoma

26
Q

What is retinoblastoma?

A

Autosomal dominant, phenotype is malignant eye tumor,

incidence is 1 in 20,000.

Studies show that 10% of the obligate carriers (those with parents and children with the disease, and therefore must carry the gene) do not have the disease.

Therefore 10% exhibit reduced penetrance.

27
Q

What is variable Expression?

A

– Variable Expression: A trait in which the same genotype can produce phenotypes of varying severity or expression

– Penetrance is complete, but severity is variable

– Parent with mild expression may unknowingly transmit the gene

– Provides a mechanism for disease genes to survive at higher frequencies in populations

28
Q

Causes of Variable Expression?

A

Many possible causes, including:

-Environmental factors

– Diet, exposure to toxic agents

– Modifier genes

– Additional gene interactions

– Allelic heterogeneity – Different types of mutations at the same disease locus cause the same disorder

29
Q

Neurofibromatosis

A

– Genotype: AD

– Incidence: 1 in 3,000 (one of the most common AD disorders) – Phenotype:

  • Expression can vary significantly, even in the same family
  • Some patients have only a few neurofibromas or hyperpigmented skin patches
  • Others have hundreds to thousands of neurofibromas, optic pathway gliomas, learning disabilities, hypertension and scoliosis
30
Q

What is pleiotrophy?

A

Pleiotropy: Describes genes that have effects on multiple aspects of physiology or anatomy

– Common feature of many genes to have more than one discernable effect on the human body

ex. cystic fibrosis, marfan syndrome

31
Q
A

– Genotype: AD, mutation on 15q

– Gene for fibrillin, component of connective tissue in most organs

– Phenotype:

– Pleotropic: Several ocular, skeletal and cardiovascular deformities

– Incidence: 1/10,000

32
Q

What is locus heterogeneity?

A

– Locus Heterogeneity: Single disease phenotype caused by mutations at different loci in different families

– Disease states are often phenotypically indistinguishable – Risk of testing for the wrong mutation!

– Case: APKD is caused by mutations on either chromosome 16 (PKD 1) or 4 (PKD 2)

33
Q

Example of locus heterogeneity

A

– Additional example: Osteogenesis Imperfecta

– Subunits of procollagen triple helix coded by two genes on chromosomes 17 and 7

– A mutation on either of these genes can alter collagen structure, ultimately resulting in osteogenesis imperfecta

34
Q

What is genomic imprinting?

A

Genomic Imprinting: The process in which genetic material is expressed differently when inherited from the mother than when inherited from the father

– For some human genes, one of the alleles is transcriptionally inactive (no mRNA is produced) depending on the parent from whom the allele was received

Transcriptionally silenced genes are said to be “imprinted”

– It is possible that several hundred genes are imprinted in humans, thus normal individuals would have only one transcriptionally active copy of the gene

– Example: – Prader-Willi and Angelman Syndromes

35
Q

What is anticipation?

A

– Anticipation: The progressively earlier onset and increased severity of certain diseases in successive generations of a family

– Caused by expansion of the number of unstable repeats within the gene responsible for the disease

ex. fragile x, myotonic dystrophy

36
Q

What is myotonic dystrophy?

A

– Genotype: AD, mutation of protein kinase gene on chromosome 19, Expanded CTG trinucleotide repeat

– Phenotype: – Progressive muscle deterioration and myotonia – Cardiac arrhythmias – Testicular atrophy, insulin resistance, cataracts

– Incidence: 1/8000

37
Q

What is the wild-type allele?

A

For many genes, the single prevailing allele present in the majority of individuals (Also “common allele”)

38
Q

What is the variant, or mutant allele?

A

Alleles that vary from the wild type due to the presence of a mutation

39
Q

What is a haplotype?

A

Haplotype: An individual’s set of alleles at a locus or cluster of loci on a chromosome

40
Q

What is homozygous?

A

Individual with two identical alleles at a DNA locus

41
Q

What is heterozygous?

A

Individual with two different alleles at a DNA locus

42
Q

Dominant Allele

A

Allele expressed in the same way as a single copy (Heterozygote) and double copy (Homozygote)

43
Q

Recessive

A

Allele phenotypically expressed only in the homozygous state

44
Q

Single Gene Disorders:

Determined by

Characterized by

A

Primarily determined by alleles at a sigle locus

Characterized by their patterns of transmission in families

Recurrence risk describes the likelihood of passing gene to an individual

45
Q

Mandelian Genetics

A

Concerned with Mendelian, monogenetetic or single-gene traits (Who is Mendel?)

– Variation of traits is caused by presence of different alleles at individual loci

– Genotype vs. Phenotype –Homozygous dominant allele and heterzygote have different genotype, same phenotype

–Same genotype can result in different phenotype in a different environment

46
Q

Principle of Segregation

A

Sexually reproducing organisms produce genes that occur in pairs

– Only one member of this pair is transmitted to offspring (i.e. segregates during meosis)

– Genes remain intact and distinct (i.e. do not blend) – Key to modern genetics!

47
Q

Principle of Independent Assortment

A

– Genes at different loci are transmitted independently

– Thus, transmission of a specific allele at one locus has no effect on transmission of another allele at a different locus

48
Q

Autosomal Dominant

A

More than 3,700 AD traits (mostly diseases) known, often structural

– Each is rare in population (.001 gene frequency), though collectively 1 in 200 individuals has an AD disease

– Affected offspring are generally produced by a union between a heterozygote and homozygous normal

49
Q

Autosomal Domiant Pedigree and Punet Square

A
50
Q

key things to remember with autosomal dominant

(gender expression, skipping of generations, probability of inheritance)

A

Key things to remember:

– Females and males exhibit the trait in approximately equal proportions

– There is no skipping of generations (if an individual has polydactyly, a parent must also)

– Probability of inheriting the disease from Aa and aa parents is 0.5 (recurrence risk of 50%)

– Thus, on average, half of the children will express the disease and half will not

– Father to son transmission may be observed

51
Q

Common AD Disorders

A

Common AD disorders include: – Breast cancer genes – BRCA 1 and BRCA 2

– Neurofibromatosis

– Marfan Syndrome

– Familial Hypercholesterolemia

– Autosomal Dominant Polycystic Kidney Disease – Achondroplasia –

Huntington’s Disease

52
Q

Cautions with AD disorders

A

– Dominant diseases are usually more severe in affected homozygotes than heterozygotes,

– Both Aa and AA will present the disease

– Example: Achondroplasia

– Heterozygotes: Reduced stature, nearly normal life span – Homozygotes: Much more severe, usually die in infancy from respiratory failure

53
Q

Autosomal Recessive Disorders

A

– Fairly rare in populations

– Heterozygous carriers for recessive genes much more common than affected homozygotes

– Parents of affected homozygotes are generally both heterozygous carriers (Aa)

– Higher prevalence of consanguinity, the mating of related individuals

54
Q

Some cautions with recessive conditions

A

– Heterozygous recessive carriers may be diagnosed due to reduced enzyme activity

55
Q

Things to remember with autsomal recessive

A

Key things to remember:

–Females and males exhibit the trait in approximately equal proportions

–Usually seen in one or more siblings but not in earlier generations

–Probability of inheriting the disease from Aa and Aa parents is 0.25 (recurrence risk of 25%)

–Consanguinity is present more often in pedigrees involving AR inheritance than with other inheritance patterns

56
Q

Cautions with AR and AD

A

Remember that the terms “dominant and “recessive” refer to traits and not genes

– Disease may be inherited in both AD and AR fashion

–Example: A small number of β thalassemia cases are inherited in a AD fashion, though most are AR. This is due to a mutation in exon 3 of the β globin gene, versus exons 1 or 2 that cause AR, which produces unstable β globin in both homo- and heterozygotes.

57
Q

Tips for probability and dominant disorders

A

– It only takes a single dominant mutant allele in the heterozygote to produce the phenotype ( Note: A person with the disease phenotype may possibly be homozygous with two copies of the mutant allele)

– Affected person generally has affected parent

– Affected heterozygous person has a 50% chance of passing the abnormal gene to offspring

– Affected individuals are present in every generation

– Family members that are phenotypically normal do not transmit the condition to their offspring (They are homozygous for two normal alleles)

– Females and males are equally affected in the pedigree

– Male to male transmission distinguishes this mode of inheritance from X-linked inheritance

58
Q

Probability and Autosomal Recessive

A

– Two copies of mutant gene present in homozygote for the disease to occur

– Both parents of the affected person must be heterozygous carriers of the gene

– Offspring of two carriers have a 25% chance of being homozygous

– 50% chance of getting the mutant gene from each carrier parent

– 1/2x1/2=1/4

– Clinically normal offspring have a 50% chance of being a carrier

– Affected individuals present in only one generation of the family (appears to skip generations)

– Females and males equally affected

– Can see male to male transmission

– Consanguinity increases odds that both parents will be carriers

– (Also to note: Genetic or locus heterogeneity can affect whether a phenotype is present in a child who is the offspring of two parents who have a recessive disease. In Locus Heterogeneity the same phenotype is caused by mutations in genes at different chromosomal loci. Recall the week 6 quiz question # 7, in which two parents with autosomal recessive albinism have a child who does not have albinism. The child was unaffected because the parent’s gene mutations were in different locations on the chromosome).

59
Q

Probability and X-Linked Recessive

A

– Most X-linked disorders demonstrate a recessive pattern

– Males more affected than females

– Female must be homozygous to be affected

– No male-to-male transmission

– Any male affected will have carrier daughters

– Female carriers have 50% chance that sons will be affected

– Female carriers have 50% chance that daughters will be carriers

60
Q

Probability and X-Linked Dominant

A

X-linked Dominant

– Present if heterozygous female carriers demonstrate signs and symptoms of the disorder

– All daughters and none of the sons of an affected male have the condition

– Male and female offspring of an affected woman have a 50% chance of inheriting the condition

– About twice as many females as males are affected in the pedigree

– X-linked dominant disorders are rare

61
Q

Probability and Mitochondrial Inheritance

A

Mitochondrial Inheritance

Passed down maternally (although some mitochondria can be passed on in sperm too see the Jorde text for further information)

In the pedigree you would see Mother’s passing the disease on to their offspring

Since mitochondria are involved in cellular respiration, diseases with mitochondrial inheritance patterns usually have muscular or neurologic symptoms (ie. Muscle weakness etc.)

62
Q

What is an allele?

A

An alternate or variable form of a gene at a specific chromosome location

Genetics (7 decks)

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