Mendelian Patterns of Inheritence

Question 1

single gene

Answer 1

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
-1.25%

Question 2

chromosomal disorder

Answer 2

• due to problems at the chromosomal level-deletions, translocations
• 0.4%

Question 3

multifactorial disorders

Answer 3

• many characters are dependent on a variety of genetic and environmental factors
• 65%, 6% congenital

Question 4

relatedness

Answer 4

• two individuals that are first degree relatives share half their genes
• second degree= 1/4 genes
• travel down and across pedigrees as long as not a marriage line

Question 5

mendels first law of segregation

Answer 5

-we are equally related to our siblings as we are to our parents

Question 6

phenotype

Answer 6

-genotype and environment

Question 7

allelic (genotypic) heterogeneity

Answer 7

• 2 different mutant alleles at same locus
• same gene, different mutation, same disease
• CFTR-1900+ mutations-all result in CF

Question 8

locus heterogeneity

Answer 8

• mutations at 2+ loci that produce the same or similar phenotype
• different gene, same phenotype (different mutations)
• retinitis pigmentosa- RP2 on Xp, RP28 on 2p and RP5 on 3q; over 30 RP loci

Question 9

clinical (phenotypic) heterogeneity

Answer 9

• association of more than one phenotype with mutations at a single locus
• severity of a disease
• different disease from mutations in same gene
• same gene, different mutation, different disease
• multiple endocrine neoplasia II result from different mutations at RET gene 10q11.2

Question 10

Hirschsprung disease

Answer 10

• absence of ganglionic cells
• severe constipation, intestinal obstruction, massive dilation of colon
• loss of function mutation on RET gene, more often in males
• autosomal dominant

Question 11

Multiple endocrine neoplasia II (MENII)

Answer 11

• thyroid cancer, pgeochromocytoma (benign adrenal medulla tumor), hyperplasia of parathyroid gland
• autosomal dominant
• mutations are at cysteins at codons 609,618,620 of RET gene
• alter membrane specificity

Question 12

Variable expression

Answer 12

• different mutations of same gene (genotypic phenotypic heterogeneity)
• can be as mild as normal female or male with no vas deferens to classic CF

Question 13

modes of inheritence

Answer 13

• autosomal dominant
• autosomal recessive
• X-linked dominant/recessive
• codominant
• mitochondrial
• Y-linked
• sex limited

Question 14

autosomal dominant

Answer 14

• phenotypically expressed in heterozygotes

- carriers express gene

Question 15

autosomsal recessive

Answer 15

-trait or gene that is expressed only in homozygotes and compound heterozygotes

Question 16

codominant

Answer 16

-both alleles are expressed in heterozygous state

Question 17

dominance and recessive

Answer 17

• properties of characters, not genes
• if product from heterozygote isn’t enough to cross threshold, mutation is dominant
• if product from heterozygote is enough to cross threshold, disease is recessive

Question 18

deaf and blind

Answer 18

• homozygotes and compound heterozygotes are blind and deaf but heterozygotes are only deaf
• blindness is revessive and deaf is dominant

Question 19

autosomal dominant inheritance criteria

Answer 19

• most affected individuals will be heterozygotes
• expressed in every generation, but more likely to have reduced penetrence compared to a recessive
• half of the offspring of an affected individual are affected (recurrence risk of 50%)
• affected individuals usually have affected parents
• male to male transmission indicated not likely X-linked

Question 20

autosomal recessive inheritance criteria

Answer 20

• 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 disease, parents more likely to be consanguinous
• recurrence risk is 25%
• affecteds have two mutations-homozygotes or compound heterozygotes

Question 21

compound heterozygote

Answer 21

• 2 recessive mutations on same gene but arent the same and cause disease
• mom and dad are each carriers for a different CFTR mutation and child results in CF

Question 22

chance sib is carrier?

Answer 22

• 1st child affected

- 2nd child born and unaffected- 2/3 chance of being a carrier (no chance of having it)

Question 23

X-linked recessive inheritance

Answer 23

• usually males affected (hemizygous)
• unless an affected male marries a carrier female, or extreme X-inactivation
• all daughters of affected males are carriers
• half the sons of female carriers are affected
• no male to male transmission (pass on y)
• many more affected males than females, mostly males more sever than females (occasionally in extreme x-inactivation results in mildly affected females)
• in genetic lethal diseases, a significant portion of cases are de novo mutations (Haldane’s Rule)

Question 24

X-linked dominant inheritance

Answer 24

• affected males have normal sons and affected daughters
• twice as many affected females as males in pop
• most affected females will be heterozygous so half their offspring will be affected
• usually more severe or lethal in males
• hypophosphatemic rickets

Question 25

Y-linked

Answer 25

• apart from male infertility, no/few known y linked diseases
• only males affected, all sons affected
• affected males would have an affected father, all sons affected and no affected daughters
• only about 78 protein coding genes on y

Question 26

mitochondrial inheritance

Answer 26

• trait appears to be exclusively inherited through females
• all offspring of affected females will probably be affected
• highly mutable compared to nuclear DNA, heteroplasmy (mixed pop of mito) common
• variable expression and can show lack of penetrance
• not inherited from affected males

Question 27

new mutation

Answer 27

• disease will appear sporadic but will be familial in descendants of affected individuals, but not in earlier generations of other branches of family
• mito have high mutation rate
• estimated that every y chromosome differs by 600 bp from fathers y
• estimated that there are as many as 100-200 new bp changes in each person, and perhaps 1000s of gene conversion events

Question 28

mosaic

Answer 28

• germline and somatic
• tissue has two or more cell lines of different genotype derived from a single zygote
• mosaicism more common than chimerism
• patchy diseases
• examples in lymphoma and leukemia (PKS)

Question 29

gonadal mosaicism

Answer 29

-in DMD still significant recurrence rate even if mutation seen in boy is not in mothers blood-mutation is in her germline

Question 30

chimeric

Answer 30

• derived from cells from 2 different zygotes
• recipient of a bone marrow transplant from donor\
• complete chimerism if all HSCs are from donar
• mixed if donar and recipient HSCs coexist after allotransplantation
• can find a donors XX cell line in the blood of a recipient male

Question 31

Locus

Answer 31

• position of a gene on a chromosome

- different forms of a gene (alleles) may occupy the locus

Question 32

Expressivity

Answer 32

The extent to which a genetic defect is expressed, mild to severe but never completely unexpressed

Question 33

Penetrance

Answer 33

All of none expression of a genetic disease genotype

Question 34

Polymorphism

Answer 34

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

Question 35

Examples of polymorphisms

Answer 35

• single nucleotide polymorphisms SNPs

- microsattelite, variable number of tandem repeats

Question 36

Pleiotropy

Answer 36

• multiple phenotypic effects of 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
• nearsightedness and malformation of sternum seen in Marfan due to fibrillin gene mutation

Question 37

Haldane’s Rule

Answer 37

• three rules: x-linked, genetic lethal, neg relevant family history
• boy is 1/3 chance of de novo mutation, 2/3 chance mom is carrier
• gonadal mosaicicm can affect carrier status–can be in germline.

Question 38

Haldane exceptions

Answer 38

• mutation only in males- no de novo, all moms carriers

- mutation only in females- 1/2 boys will be new mutations and 1/2 mom carriers