Week 1: Risk assessment & genetics principles

Question 1

Name DNA repair mechanisms and what types of errors they repair

Answer 1

-Homologous repair/recombination: DS breaks
-NHEJ: DS breaks
-Base excision repair: SS breaks, base damage
-Nucleotide excision repair: disruptive lesions
-MMR: misincorporation of nucleotides

Question 2

What genes associated with homologous recombination?

Answer 2

BRCA1/2, PALB2, BRIP1, BARD1, RAD51, ATM, CHEK2

Question 3

What conditions are associated with errors in nucleotide excision repair

Answer 3

Xeroderma pigmentosa
Cockayne syndrome

Question 4

What does deficient mismatch repair cause?

Answer 4

Microsatellite instability

Question 5

Describe dominant negative & give example of dominant negative disorder

Answer 5

Dominant negative mutation produces a protein that not only loses its normal function, but also interferes with the function of the normal protein from the other (healthy) allele.

This is especially common in proteins that work as part of a complex (e.g., transcription factors, collagen)

Further example of other AD mutations and difference in actual consequence:
-Haploinsufficiency: one working copy isn’t enough.
-Dominant negative: mutant protein interferes with the normal one.
-Gain of function: the mutant protein does something new and harmful.

Question 6

Allelic heterogeneity vs locus heterogeneity

Answer 6

Allelic: different variants on the same gene can cause the same disorder

Locus: variants in different gene cause the same disorder (ex: RP)

Question 7

Define pleiotropy

Answer 7

One gene variant influences many unrelated traits

Question 8

What are the acrocentric chromosomes

Answer 8

13, 14, 15, 21, 22

Question 9

What’s a marker chromosome

Answer 9

-Small piece of extra chromosome
-Can recognize on karyotype but often need CMA to tell what chromosome it is
-Symptoms or lack of depend on what genes implicated
-1/3 inherited
-If parent doesn’t have symptoms, wouldn’t expect child to either

Question 10

Pericentric vs paracentric inversions

Answer 10

-Pericentric involve the centromere
-Paracentric do not involve the centromere

Question 11

Define anticipation/differentiate it from repeat expansion

Answer 11

anticipation refers to a phenomenon where a genetic disorder appears earlier and with greater severity in subsequent generations, often due to repeat expansion

Question 12

The _____ applies to multifactorial conditions that are more common in one sex than the other

Answer 12

The liability threshold model

Individuals with liabilities exceeding the threshold are considered affected, while those below are unaffected. This model is often used to explain how multifactorial or polygenic traits, influenced by multiple genes and environmental factors, can manifest as binary (present or absent) traits.

Question 13

Most common feature of a ring chromosome

Answer 13

Growth delay

Question 14

___ a set of alleles at two or more neighboring loci on one of the two homologous chromosomes

Answer 14

Haplotype

Question 15

X-linked dominant inheritance can be distinguished from AD inheritance by lack of what?

Answer 15

Male to male transmission

Question 16

Define heteroplasmy

Answer 16

When daughter cells receive a mixture of mitochondria, some without and some with the mutation

Question 17

Define homoplasmy

Answer 17

When daughter cells receive a pure population of mitochondria with a mutation

Question 18

What’s a dicentric chromo

Answer 18

chromo containing two centromere as a result of a translocation

Question 19

Distinguish interstitial deletion from terminal deletion

Answer 19

Terminal: at end of chromo

Interstitial: deletion in middle of chromo

Question 20

Define an isochromosome

Answer 20

A chromo in which one arm is missing and the other arm is duplicated in mirror-image fashion

Question 21

Define sensitivity. Give formula.

Answer 21

-If a person has a disorder, how often will the test detect it
-High sensitivity=low false negative rate

sensitivity=true positive/(true positive+false negative)

Question 22

Define specificity. Give formula

Answer 22

-If a person does not have a disorder, how often will the test be negative
-High specificity=low false positive rate

specificity= true neg/(true neg+false positive)

Question 23

Define positive predictive value. Give formula.

Answer 23

-If the test is positive, how likely is it that the person has the disorder
-The proportion of positive results that are true positives

PPV=true positive/(true positive+false positive)

Question 24

Define NPV. Give formula.

Answer 24

-If the test is negative, how likely is it that they do not have the disorder

NPV= true neg/(true neg+false neg)

Question 25

How does prevalence affect PPV?

Answer 25

PPV is higher when prevalence is higher

Question 26

What is analytic validity

Answer 26

How good a test is at detecting a known genetic variant

Question 27

What is clinical utility related to testing

Answer 27

How the test result is used in patient's care

Question 28

What 5 principles does Hardy Weinberg assume/rely on

Answer 28

1. Random mating 2. No gene flow 3. Infinite population size 4. No selection taking place 5. No new mutations

Question 29

Define what each letter/symbol in Hardy Weinberg represents

Answer 29

For p+q=1 p=dominant allele frequency q=recessive allele frequency For p^2+2pq+q^2=1 p^2= homozygous dominant frequency 2pq=heterozygous/carrier frequency q^2= homozygous/recessive/affected carrier frequency

Question 30

A PALB2 positive pt is pregnant and presents to clinic. No contact with the father. She says: “You said my future kids could have a blood cancer thing, right? What’s the chance that my child will have that?” (The prevalence of PALB2-associated Fanconi is 1/1,000,000)

Answer 30

1/2000

Question 31

What is the coefficient of inbreeding (F)? What's the equation for it

Answer 31

The probability that two alleles at a random location are identical and from the same ancestor F=(1/2)^n n=# of individuals in the inbreeding path

Question 32

What is the coefficient of inbreeding for: -1st degree relatives -2nd degree relatives -3rd degree relatives

Answer 32

1st: 1/4 2nd: 1/8 3rd: 1/16

Question 33

What is a pseudogene

Answer 33

-Resemble functional genes but are nonfunctional -May lack sequences needed for transcription or translation start -May be nonfunctional due to variants -Arise from: evolutionary remnants, RNA being reverse-transcribed back into DNA, DNA duplication

Question 34

Contrast euchromatin and heterochromatin

Answer 34

-Euchromatin: open for transcription -Heterochromatin: tightly wound, less gene expression

Question 35

T or F: chromosome size correlates with number of genes on chromosome

Answer 35

False! ex: chr13=800, chr17=1600

Question 36

T/F: genes are not typically clustered based on function

Answer 36

True! And not evenly distributed on chromosomes, may cluster spatially or if controlled by the same regulatory elements

Question 37

Which chromosomes have the fewest number of genes? How does this relate to pregnancy outcomes?

Answer 37

13, 18, 21 Trisomies are tolerated (somewhat) and don't result in earl demise

Question 38

What is the classic triad for cat eye syndrome?

Answer 38

C: coloboma A: anal atresia T: tag/pits (preauricular)

Question 39

Info about cat eye syndrome

Answer 39

Tetrasomy of 22p-22q11.21caused by small supernumerary bisatellited chromosome (sSMC) derived from chr22 Features: -Short stature -coloboma -congenital heart malformations -mild ID

Question 40

How to diagnose cat eye syndrome

Answer 40

CMA, karyotype or FISH

Question 41

What should the workup/follow up for cat eye syndrome be

Answer 41

Echocardiogram, renal US, eval by ophthalmology and audiology Surgery for anal atresia, cardiac malformations, and intestinal concerns. Consider GH for short stature. Dev therapies as indicated.

Question 42

Roughly, what is the parental transmission rate for cat eye syndrome

Answer 42

>20% Also relatively high rate of mosaicism (~40%)

Question 43

Deletion of which chromosome arm causes Cri-du-chat syndrome?

Answer 43

5p

Question 44

Tell about Cri-du-chat syndrome

Answer 44

5p deletion syndrome -Most cases de novo, ~10-15% due to unbalanced translocation Features -High pitched cat cry d/t abnormal epiglottis and/or larynx -Microcephaly -hypertelorism -Hypotonia -DD/ID with relative preservation of speech comprehension -May have cardiac or other organ defects

Question 45

How is cri-du-chat diagnosed?

Answer 45

CMA, karyotype or FISH

Question 46

What should workup/follow up include for cri-du-chat?

Answer 46

Echo, renal US, eval by ophthalmology and audiology

Question 47

What are important elements/concerns to address for cri-du-chat

Answer 47

intervention with developmental therapies as early as possible addressing feeding concerns is crucial and often requires managment by speech and ENT

Question 48

What oncologic condition do people with smith magenis need to be monitored for? When should screening start?

Answer 48

Birt hogg dube syndrome should start screening at 21 for renal tumors

Question 49

What do people with smith magenis love to do

Answer 49

lick fingers (lick and flip page turning) "self hug"

Question 50

What is the deletion that causes smith magenis syndrome

Answer 50

17p11.2 del

Question 51

Tell about smith magenis syndrome

Answer 51

-ID -infantile hypotonia -decreased pain sensation -peripheral neuropathy -difficulty sleeping -self destructive behavior may see: -short stature -bachycephaly -midface hypoplasia -brachydactyly -scoliosis -obesity -hearing loss -cardiac defects

Question 52

what's critical gene for smith magenis

Answer 52

RAI1

Question 53

What should the diagnostic workup (1st and 2nd tier) be for smith magenis

Answer 53

1st: CMA 2nd: RAI1 single gene testing or broader molecular testing

Question 54

What workup/specialists should smith magenis see

Answer 54

Echo, spine radiograph, sleep study, qualatative immunoglobulins, thyroid function testing eval by neuropsych, ophthal, audiology May benefit from psychotropic medication to increase attention/decrease hyperactivity

Question 55

Wolf hirsschhorn caused by what deletion

Answer 55

4p16.3 del

Question 56

What is the most common prenatal rearrangement in Wolf-hirschhorn syndrome

Answer 56

4 and 8, t(4p;8p)

Question 57

Tell me about wolf hirschhorn

Answer 57

4p16.3 del de novo in >85-90% Features: -microcephaly -hypertelorism -protruding eyes -prominent glabella -wide nasal bridge -cleft lip/palate -polydactyly -hypotonia May have: -cardiac defects -fused ribs/vertebrae -absent uterus -seizures -Dev differences

Question 58

What is the critical region in wolf hirschhorn called and what genes are in it

Answer 58

Region is called WHSCR Key genes include: LEMT1 WHSCR1 WHSCR2

Question 59

How is wolf hirschhorn dx

Answer 59

CMA

Question 60

What should workup for wolf hirschhorn include

Answer 60

cardiac, urinary tract, skeletal imaging. Consider EEG and ECG as clinically indicated

Question 61

What medications might people with wolf hirschhorn benefit from

Answer 61

-Valproic acid: for atypical absence seizures -Avoid sodium channel blockers

Question 62

Seizures occur in what percent of patients with wolf hirschhorn

Answer 62

>90% Peak incidence 6-12 months of age

Question 63

Tell me about Williams syndrom

Answer 63

7q11.23 del Gene of interest: ELN Features: -DD -Friendly personality -Cardiac: SUPRAvalvar aortic stenosis -Renal artery stenosis -Hypercalcemia -Connective tissue issues (~90%) have joint hypermobility -Wide mouth Diagnosis: -CMA or FISH Workup should include echo, EEG, ophthal and hearing eval, renal US, serum calcium level, thyroid screening, dental exam, neuropsych testing

Question 64

Tell me about 22q11.2 del

Answer 64

22q11.2 del Critical gene: TBX1 Features: -Short stature -hypertelorism -low set ears -palatal defects -micrognathia -cardiac defects -learning differences -hypocalcemia -hearing/vision concerns -renal anomalies -seizures -psych illness (ASD--15-50%, schizophrenia--25-30%) Diagnosis: CMA, karyotype, or FISH Workup: echo, EKG, spine radiograph, renal US, serum tests (CBC w diff, calcium, parathyroid hormone, thyroid function tests), eval by ophthal and audiology, immunology, ENT

Question 65

What's CATCH22 stand for related to 22q del

Answer 65

C: cardiac anomalies A: abnormal facies T: thymic hypoplasia C: cleft palate H: hypocalcemia 22q11.2 del

Question 66

Tell me about WAGR syndrome

Answer 66

W: willms tumor A: aniridia G: genitourinary anomalies (seen more often in males, but females can have streak ovaries and bicornate uterus) R: ID/DD Some have obesity Deletion of 11p Critical genes: WT1 (willms tumor) and PAX6 (aniridia)