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MCP I > Unit II- Mendelian Patterns of Inheritance > Flashcards

Unit II- Mendelian Patterns of Inheritance Flashcards

1
Q

Single gene, multifactorial, and chromosomal

A
  • sometimes a particular genotype at one locus is both necessary and sufficient for the character to be expressed, given an otherwise normal genetic and environmental background- single gene
  • chromosomal disorders are due to problems at chromosomal levels (deletions and translocation)
  • on the other hand, many characters are dependent on a variety of genetic and environmental factors, and are said to be multifactorial
  • single-gene (1.25%)
  • chromosomal (0.4%)
  • multifactorial (65% lifetime, 6% congenital)
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2
Q

Proband, First, Second, Third Degree relatives

A
  • two individuals that are first degree relatives to each other share half their genes in common
  • a quarter of their genes with a second degree relative and so on
  • the sex chromosomes and mitochondria will be exceptions
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3
Q

Genotype

A

the genetic constitutionn (genome)

- the alleles present at one locus

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4
Q

Phenotype

A
  • the observed biochemical, physiological, and morphological characteristics of an individual, as determined by his or her genotype
  • modifier genes and the environment in which it is expressed
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5
Q

Genetic Heterogeneity

A
  • allelic (genotypic) heterogeneity
    • 2+ different mutant alleles at the same locus
    • e.g. CF has 1900+ CFTR mutations
  • locus (genotypic) heterogeneity
    • mutations at 2+ loci can produce the same or similar phenotypes e.g. Retinitis Pigmentosa RP2 on Xp, RP28 on 2p and RP5 on 3q; over 30 RP loci
    • e.g many genes result in mental retardation, in particular the X chromosome
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6
Q

Clinical or phenotypic heterogeneity

A
  • clinical (phenotypic) heterogeneity is the association of more than one phenotype with mutations at a single locus
    • examples are severity of disease (expressivity and penetrance)
  • different diseases can occur due to mutations in the same gene
  • several different clinical vision related diseases result of mutations in ABCR gene at 1p22.1
  • multiple endocrine neoplasa, type II or Hischspring disease result from different mutations at RET gene at 10q11.2
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7
Q

Hirschsprung disease (HSCR)- aganglionic megacolon

A

absence of some ganglionic cells
Severe constipation, intestinal obstruction, massive dilation of colon
-loss of function mutations of RET gene (chromosome 10), often in males, autosomal dominant

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8
Q

Multiple endocrine neoplasia type II (MENII)

A

thryoid cancer, pheochromocytoma (benign adrenal medulla tumor) and hyperplasia (overgrowth of the parathyroid) gland

  • autosomal dominant
  • mutations, primarily at the cysteines at codons 609, 618, 620 of the same RET gene. Alter substate specifically
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9
Q

Clinical phenotype

A
  • variable expression
  • phenotype depends on the severity of the CFTR mutations
  • male reproductive system lease tolerant to reduced CFTR product
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10
Q

Modes of inheritance

A
  • autosomal dominant
  • autosomal recessive
  • X-linked dominant
  • X-linked recessive
  • Codominant
  • Mitochondrial
  • Y-linked
  • Sex- limited
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11
Q

Mode of inheritance

A

used to describe a disease state and the mode of inheritance

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12
Q

Dominant

A
  • a trait is dominant if it is phenotypically expressed in heterozygotes i.e. carriers express disease
  • a disease will have a dominant mode of inheritance if heterozygotes are insufficient
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13
Q

Recessive

A
  • a trait or gene that is expressed only in homozygotes, and compound heterozygotes, not in carriers
  • a disease will have a recessive mode of inheritance if heterozygotes produce enough/sufficient product
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14
Q

Codominant

A

-if both alleles of a pair are expressed in the heterozygous state

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15
Q

Types of inheritance

A
  • autosomal inheritance- gene is located on one of the 22 pairs of autosomal chromosomes
  • X-linked inheritance- genes, or traits determined by genes located on the X chromosomes

Y-linked- very few known disease genes on the Y chromosome

Mitochondrial

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16
Q

Autosomal Dominant Inheritance Criteria

A
  • most affected individuals will be heterozygous
  • expressed in every generation; but more likely to have reduced penetrance compared to a recessive
  • half offspring of an affected individual are affected (recurrence risk of 50%)
  • affected individuals usually have infected parents
  • normal individuals usually don’t have affected offspring (except for reduced penetrance)
  • male to male transmission indicates trait probably not X- linked
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17
Q

penetrence

A

the proportion of individuals in a population that carry a particular variant of a gene that also express an associated trait

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18
Q

Autosomal recessive inheritance criteria

A
  • expect both parents of affected individuals to be carriers
  • affected individuals usually have asymptomatic parents
  • may appear as sporadic
  • often more severe than dominant disorders
  • if rare, parents more likely to be consanguinous
  • recurrence risk 1 in 4
  • affecteds have two mutations, are homozygous, or compound heterozygotes
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19
Q

Compound heterozygote

A
  • the two mutations are in the same gene but do not need to be identical
  • CF has more than a 1,900 disease-associated alleles
20
Q

Recessive- chance that sibling is a carrier

A

-once it is clear after birth that a child is not affected, the risk that an unaffected offspring is a carrier is 2/3

21
Q

X-linked recessive inheritance

A
  • usually males affected (hemizygous)
  • unless an affected male marries are carrier female, or extreme X-inactivatioin
  • all daughters of affected males are carriers
  • half the sons of carrier females are affected
  • no male to male transmission (since pass on their y)
  • many more affected males than females, mostly males more severe than females
  • in “genetic lethal” disorders a significant proportion of cases will be due to new mutations
22
Q

X-linked dominant inheritance

A
  • rare
  • affected males have normal sons and affected daughters
  • twice as many affected females as males in the population
  • most affected females will be heterozygous so half the offspring of affected females will be affected
  • usually more severe or even lethal in males
  • e.g. hypophosphatemic rickets
23
Q

Y linked

A
  • apart from male infertility, no/few known Y linked diseases
  • only males would be affected, all sons affected
  • affected males would have an affected father and all their sons would be affected and no affected daughters
  • only about 78 protein-coding genes on the Y
24
Q

Mitochondrial inheritance

A
  • trait appears to be inherited exclusively through females
  • all offspring of affected females will probably be affected
  • highly mutable 2x compared to nuclear DNA
  • variable expression and can show lack of penetrance
  • not inheritied from affected males
25
Q

New mutation

A
  • disease will appear sporadic but will be familial in descendants of affected individuals but not in earlier generations or in other branches of family
  • mitochondria have high mutation rate
  • estimated that every Y chromosome differs by 600 base pairs from father’s Y chromosomes
  • estimated that there are as many as 100-299 new base pairs changes in each person, and perhaps thousands of gene-conversion events
26
Q

Mosaic

A
  • germline and somatic mosaicism
  • tissue has two or more cell lines of different genotype derived from a single zygote
  • mosacism much commoner than chimerism
  • patchy disease
  • examples of a somatic mosaicism is lymphoma or leukemia
27
Q

Germline Mosaic

A
  • the new mutation may have arisen in the germ line and so not seen in the soma
  • can account for multiple affected offspring with a dominant disease not seen in the parent
  • recurrent affected offspring to unaffected parent
28
Q

Blaschko’s Lines

A
  • the lines of Blaschko visualize the clonal proliferation of two functionally different populations of cells during embryogenesis of the skin
  • they represent a marker of normal development of human skin not usually visible
  • originates from one zygote
29
Q

Ramification of Gonadal Mosaicism

A
  • there is still significant recurrence rate even if mutation in affected boy is not seen in mother’s blood
    -mutation could be in her germline, even if not in her blood,
    important in genetic counseling
30
Q

Chimeric

A
  • chimeric individual derived from cells from two different zygotes
  • an example would be the recipient of a bone marrow transplant from a donor
  • complete chimerism if all hematopoietic cells are from donor
  • mixed chimerism if donor and recipient hematopoiesis coexist after allotransplantation
  • can find a donors XX cell line in the blood of a recipient male, post transplant
31
Q

Chimera

A

-two independent origins in two zygotes

Karen from Bosten, two of her children did not shre alleles with her. She had absorbed her DZ sister in the womb

32
Q

Gene

A

a hereditary unit; in molecular terms, a sequence of chromosomal DNA that is required for production of a functional product

33
Q

Locus

A
  • the position of a gene on a chromosome

- different forms of the genes (alleles) may occupy the locus (an address)

34
Q

Allele

A

-one of the alternative versions of a gene that may occupy a given locus

35
Q

mutation

A

a permanent inherited change in the DNA

36
Q

Expressivity

A

-the extent to which a genetic defect is expressed- mild to severe but never completely unexpressed

37
Q

penetrance

A

-all or none expression of a genetic disease genotype

38
Q

Polymorphism

A

-the occurance together in a population of two or more alleles, each at a frequency greater than 1%, so that the heterozygote frequency is at least 2%. Alleles with a frequency of less than 1% are called rare genetic variants
-particularly useful in linkage studies when cannot find disease causing mutations
-over 60% of all loci exhibit polymorphisms uses:
+mapping genes to chromosomes
+presymptomatic and prenatal diagnosis
+carrier detection of heterozygotes

39
Q

Polymorphism types

A
  • single nucleotide polymorphisms

- microsatellites (variable number of tandem repeats, VNTRs)

40
Q

Retinitis Pigmentosa

A
  • progressive degeneration of photoreceptor cells in the retina
  • most forms cause the degeneration of rod cells which provide peripheral vision and also help in dimly lit environment- usually starts with night blindness
  • sometimes central vision is affected first. With the loss of cone cells also results in disturbances in color perception
41
Q

Phenocopy

A
  • a mimic of a phenotype that is usually determined by a specific genotype, produced instead by the interaction of some environmental factor with a different genotype
  • example pregnant women taking Thalidomide
42
Q

Pleiotrophy

A
  • multiple phenotypic effects of an allele or gene on tissues/systems not ordinarily thought to be related
  • reflects the diversity of cell types that use a common molecular pathway for transcriptional regulation

-e.g. The seemingly unrelatedness of nearsightedness and malformation of the sternum seen in Marfan syndrome becuase of mutations of fibrillin-1 gene

43
Q

Haldane’s rule requirements

A
  • X-linked recessive
  • Reduced fitness e.g genetic lethal
  • negative relevant family history (Fragile X syndrome and other X-linked diseasses caused by dynamic mutations are excluded
44
Q

Haldane’s rules explains…

A
  • why not all mothers of affected boys with X-linked recessive disorders are carriers, as one would otherwise expect
  • is applied to X-linked recessives when there is one affected boy and no other relevant family history of the disease and when there is reduced genetic fitness (f<1)
  • classic example is DMD (f=0)
  • does not apply to fragile X (triplet repeats)
45
Q

Duchenne Muscular Dystrophy (DMD)

A
  • Haldane’s rule
  • X-linked recessive and if only one affected boy
  • genetic lethal therefore 1/3 patients are de novo mutations and 2/3 mothers are carriers
  • gonadal mosaicism- still significant recurrence rate even if mutation seen in affected boy is not seen in mother’s blood. Mutation could be in her germline, even if not in her blood
46
Q

Haldane’s rule mutation

A
  • if mutation only occurs in males (u=0) no boys will be new mutations, all mothers of affected boys are carriers (Hemophilia A inversion)
  • if mutations only occur in females (v=0) then 1/2 boys will be new mutations and 1/2 of mothers will be carriers
  • in Hemophilia A and Lesch-Nyhan v>u, so more mothers are carriers than when u=V
  • in DMD v=u
47
Q

Modes of inheritance for selected genes

A 
Hemophilia A - XLR
CF- AR
Alpha1 antitrypsin def - AR
DMD - AR
Tay Sachs- AR
Sickle cell disease - AR
alpha and beta thalassemia - AR
fragile x= X?
HD= AD
DM - AD

MCP I (24 decks)

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