Variability in Mendelian Genetics

Question 1

variability

Answer 1

often refers to the expression range in phenotypes

Question 2

variation

Answer 2

refers to the different genotypes associated with same or different phenotypes

Question 3

etiologic heterogeneity

Answer 3

similar phenotype caused by different underlying causes (one environmental and one genetic)

Question 4

example of etiologic heterogeneity (phenocopies)

Answer 4

thalidomide embryopathy (environmental) and Roberts syndrome (AD); causes odd limb formation

Question 5

genetic heterogeneity

Answer 5

same or similar phenotype having different genetic cause; disease can be multifactorial, mitochondrial, chromosomal, or epigenetic but produce similar phenotypes

Question 6

example of genetic heterogeneity (genocopies)

Answer 6

isolated human growth hormone deficiency (AR) and familial short stature (multifactorial)

Question 7

locus heterogeneity

Answer 7

for the same kind of inheritance (i.e. mendelian), different genes cause the same basic phenotype; variations in the same basic phenotype from different genes on one locus

Question 8

example of locus heterogeneity

Answer 8

retinitis pigmentosa - RP9 gene and RP1 gene

Question 9

allelic heterogeneity

Answer 9

mutations at different sites in same gene may cause different disease severity in different people (variable expression)

Question 10

example of allelic heterogeneity

Answer 10

cystic fibrosis (AR)

Question 11

clinical heterogeneity

Answer 11

mutations at different sites in same genes cause different diseases

Question 12

example of clinical heterogeneity

Answer 12

mutations in the FGFR3 can cause achondroplasia, hypochondroplasia, muenke, crouzon, and others

Question 13

What occurs the variable expression in CF, an AR disease?

Answer 13

first, the number of mutations possible (each one with different effect) and second, how the two diseased alleles come together (can be compound heterozygotes with two different mutations at each allele or homozygous) and third, environmental effects and modifier genes

Question 14

examples of modifying genes in CF

Answer 14

TGFB1 for tissue fibrosis and MBL2 for microbe elimination

Question 15

How does variable expression occur in autosomal dominant disorders?

Answer 15

largely unknown, suspected modifier genes (definitely not allelic heterogeneity)

Question 16

example of variable expressed AD disease

Answer 16

neurofibromatosis type 1

Question 17

incontinentia pigmenti

Answer 17

caused by mutation in IKBKG gene on X chromosome; fatal to males before birth but females will have inflammation, blistering, and hyperpigmentation

Question 18

achrondroplasia mating

Answer 18

can cause lethality because 1/4 of children will get the AA phenotype (lethal)

Question 19

autosomal dominant adult polycystic kidney disease

Answer 19

two hit mechanism; ADPKD1 occurs earlier and is more severe while ADPKD2 occurs late in life and not severe

Question 20

digenic inheritance

Answer 20

mutations at 2 separate loci cause one disease

Question 21

linked genes in digenic inheritance

Answer 21

will display an AD characteristic inheritance

Question 22

unlinked genes in digenic inheritance

Answer 22

will display an AR characteristic inheritance

Question 23

sex-limited traits

Answer 23

disease will only occur in one sex, with no effect in the other

Question 24

example of sex-limited traits

Answer 24

male limited precocious puberty (AD) that constitutively activates LH

Question 25

sex-influenced traits

Answer 25

traits that will preferentially be expressed in one sex

Question 26

example of sex-influenced trait

Answer 26

pattern baldness (androgenic alopecia)

Question 27

skewed X-inactivation

Answer 27

if maternal copies are more active than they should be, a female child can develop symptoms of an XLR disorder (Duchenne muscular dystrophy)

Question 28

What explains having two children with a new mutation AD disease?

Answer 28

gonadal mosaicism

Question 29

gonadal mosaicism

Answer 29

normal germ cell lines and mutation germ cell lines both exist in the gonad and are passed on to child

Question 30

How do CNVs occur?

Answer 30

non-allelic homologous recombination

Question 31

dynamic mutations

Answer 31

mostly tri-nucleotide repeats that expand into regulatory/structural region of gene and affect transcription

Question 32

pedigree of dynamic mutations

Answer 32

can look like AD or XLD but with reduced penetrance

Question 33

Huntington disease repeat expansions occur primarily with _

Answer 33

paternal transmission

Question 34

Fragile X expansion is primarily through _

Answer 34

maternal transmission

Question 35

myotonic dystrophy type 1

Answer 35

CTG repeat in DMPK gene causes mutated mRNA that will associate with splicing proteins, preventing them from carrying out proper function

Question 36

DM1 phenotype

Answer 36

the more repeats, the more severe the phenotype

Question 37

How does mitochondrial inheritance differ from Mendelian>

Answer 37

males can not transmit DNA to offspring and replicative segregation in mitosis (random assortment)

Question 38

expression of mtDNA mutations depends on _

Answer 38

1. abundance of mutant mtDNAs 2. threshold effect --> more mutant than normal 3. tissue distribution --> which tissues have the abundant mutant mtDNA (each organ varies in threshold requirement)