Genetics of Complex Disorders and Inheritance Patterns

Question 1

complex disorders

Answer 1

-also called multifactorial conditions
+combination of environment and genetics
-includes most isolated birth defects (clefts, ONTDs, CHDs)
-many common diseases (diabetes, psychiatric disorders, heart disease, dementia, arthritis)
-aggregate, but don’t segregate-diagnosis comes from ruling out other etiologies

Question 2

family studies

Answer 2

comparing frequency among close biological family members in that of an affected and non-affected individual to establish possible increased genetic risk, but can’t parse out the significance

Question 3

multifactorial condition research pipeline

Answer 3

1. establish condition runs in family
2. use twin studies to find out genetic involvement
3. use traditional studies to define which genetic factors play a role
4. establish why these factors play a role

Question 4

twin studies

Answer 4

• based on assumption MZ twins share nearly 100%, DZ share 50%, but share same in-utero environment
• allow us to generate estimates of heritability

Question 5

concordance

Answer 5

chance that another twin is affected, when one is

-expect it to be higher in MZ than DZ, but not 100%

Question 6

heritability

Answer 6

statistical measure of variance in a phenotype across a population
-like census data-average across a population

Question 7

linkage studies

Answer 7

useful for identifying genetic differences that play a large role in phenotype
-tend to generate more equivocal results between different studies

Question 8

association studies

Answer 8

more useful for identifying underlying genetic associations that have smaller effects

• often study SNPs and comparing frequency of these in population of people with and without phenotype
• difficulties in replication again

Question 9

GWAS

Answer 9

thought to be even more advanced-like doing thousands or millions of association studies at once
-requires very large sample sizes and a stringent threshold for statistical significance (p<5x10^-8)

Question 10

jar model

Answer 10

-in order to experience effects of a complex condition jar has to be filled to the top
+combo of purely genetic factors and environmental ones
-we all start out with a certain varying baseline vulnerability (DNA sequence based)
-environmental vulnerability factors can accumulate on top of the genetic factors (ex: even obstetric complications, childhood head injury)
-additional environmental factors from stressful life events, then leads to active episodes of illness
*can also explain variability in phenotype

Question 11

estimating chance for recurrence

Answer 11

does not equal risk, it is a probability

Question 12

chance of recurrence in absence of family history

Answer 12

• approximately square root of frequency of condition in the general population for first degree relative
• by third degree relative it is approximately general population level

Question 13

limits of empiric data

Answer 13

average probability that’s influenced by many factors including characteristics of an affected individual, characteristics of the individual for whom probability is being calculated, characteristics of family history

Question 14

affected individual risk factors

Answer 14

• earlier age of onset increases probability
• if they are of the less typically affected sex
• experienced more severe illness onset (this can be challenging to quantify though)

Question 15

characteristics affecting person whose probability is being calculated

Answer 15

• age
• sex
• medical history

Question 16

characteristics of family history that effect probability

Answer 16

• greater number of affected family members increases chance of recurrence
• consanguinity-greater sharing of vulnerability alleles

Question 17

heritability calculation

Answer 17

h^2=Ve/(Ve+Vg) or h^2=(Vdz-Vmz)/Vdz

• Ve=Vmz
• Vdz=Ve+Vg=Vmz+Vg
• Vg=Vdz-Vmz

Question 18

reduced penetrance

Answer 18

• individual with a disease-genotype may not show the phenotype
• offspring are still at risk
• ex: heritable PAH
• all or nothing

Question 19

age-dependent penetrance

Answer 19

• symptom onset delay
• individual could have children before knowing they are affected
• individuals could also die prior to symptom onset
• ex: HBOC and HD

Question 20

variable expressivity

Answer 20

phenotype severity varies significantly

• some individuals may be unaware they are affected and pass on a condition to their children
• can be influenced by environmental effects and/or modifier genes
• ex: NF1
• level of affectedness

Question 21

anticipation

Answer 21

more severe expression or earlier age of onset in younger generations

• sometimes caused by DNA repeat expansions; may be more likely when inherited in mom v. dad, depending on condition
• ex: HD or myotonic dystrophy

Question 22

de novo/new mutation

Answer 22

• affected proband with no history of disease in family (especially if AD)
• if genes in other germ cells (gonadal mosaicism) do not have the mutation risk to siblings is not increased over gen pop and risk to offspring depends on condition

Question 23

germline or gonadal mosaicism

Answer 23

-rare phenomenon of two or more offspring being affected in the absence of family history
+due to the presence of more than one distinct reproductive cell line
-poses increased risk to siblings of an affected proband
-ex: DMD, Hem A, achondroplasia, NF1, OI2

Question 24

sex-influenced transmission

Answer 24

-phenotype can be limited to or severity influenced by mutation presence in a male or female
+due to tissues or hormonal differences

Question 25

male lethality

Answer 25

• type of sex-influenced/limited transmission
• often with XLD conditions
• ex: incontinentia pigmenti

Question 26

incontinentia pigmenti

Answer 26

• XLD IKBKG mutation leads to only affected females (male lethality); often mosaic
• skin abnormalities include a blistering rash in childhood, followed by wart-like skin growths and eventual swirls and lines of hyper and hypo pigmentation
• alopecia, pitted or lined nails, dental and vision abnormalities and sometimes neurological effects may be seen

Question 27

skewed X-inactivation

Answer 27

• seen in XLR conditions
• the majority of active X chromosomes carry the mutation, causing heterozygote females to manifest condition symptoms
• ex: FRAX, DMD

Question 28

phenocopies

Answer 28

individual in family displays a similar phenotype, but does not have a disease-causing allele
-ex: HBOC

Question 29

small families

Answer 29

pattern of inheritance is less evident in a family

-ex: Lynch syndrome