Developmental Genetics + Clinical Genetics + Genetic variations

Question 1

Structural variation vs substitution variation

Answer 1

Structural: In/dels

Substitution: SNPs

Question 2

Common vs Rare variant

Answer 2

Common: both alleles @ +1% frequency

Rare: allele present @ less than 1% frequency

Question 3

SNP definition

Answer 3

Less common allele of a single nucleotide substituition is present @ +1%

Usually bi-allelic

If muation is in coding region, usually silent or conservative missense

Question 4

Sickle cell anemia mutation

Answer 4

Glu6 >> Val6 (missense)

Question 5

Beta thalassemia mutation

Answer 5

Glu6>>STOP (nonsense)

Question 6

Non coding region mutations can occur in __, __ and ___.

Give 2 examples of this

Answer 6

Promoter, enhancer/silencer, 5’ and 3’ UTR

Beta thalassemia mutation in promoter region

Repeats in CFTR gene (Intron 8)

Question 7

Structural variants: What are the 2 ways you could get CF?

Answer 7

Phenylalanine deletion at position 508

(TG)n(T)n repeats in Intron 8 >> exon exclusion of Exon 9

Question 8

How do repeats that cause Huntington’s disease and Fragile X syndrome vary in terms of phenotype + which repeat? (HD)

Answer 8

HD: CAG repeat

Fragile X: CGG

HD: CAG repeats in ORF; more repeats = earlier age of onset

Fragile X: repeats in 5’ UTR = loss of function

Question 9

Fragile X repeat phenotype

Answer 9

Question 10

Copy number variants: what’s the effect of a mutation in the AMY (amylase) gene?

Answer 10

More copies = faster carbohydrate breakdown + improved glycemic homeostasis/decreased diabetes risk

Question 11

Use alpha thalassemia to explain copy number variations

Answer 11

Repeats can become misaligned, results vary based on mutation (nonsense >> 1/2 normal, missense >> 1/4 normal)

Question 12

How does an inversion cause hemophilia?

Answer 12

Mispairing of similar factor 8 sequences

Question 13

Genotype and phenotype correlation:Osteogenesis imperfecta (what’s the effect of a missense vs a nonsense mutation?)

Answer 13

Missense: 1/4 normal

Nonsense: 1/2 normal

Question 14

What is a frameshift mutation?

Answer 14

Frameshift is an inserted or deleted fragment that is not divisible by 3

Question 15

Explain why a deletion of Exon 45 in the DMD gene would lead to classical DMD but a deletion in a larger fragment will lead to Becker’s Muscular Dystrophy (a much milder disease)

Answer 15

The DMD gene is such that each segment contributes to a protein that on the whole will act as a shock absorber (a lot of individual components lined together). A del in Exon 45 (total number of genes NOT divisible by 3) will disrupt the remainder of the gene, thereby destabilizing all the other pieces of the protein/shock absorber. A del in a larger chunk of genetic material, however, would cause less damage b/c the remaining exons would still be translated to functional pieces of the shock absorber thus some function would be retained.

Question 16

Disease associated (susceptibility) variants:

The MATP gene codes for ___. A mutation in this gene could lead to ___, resulting in___.

Answer 16

Melanin production.

Lighter skin.

Vitamin D deficiency/Malignant malinoma

Question 17

A lower copy number of an AMY mutation could lead to___

Answer 17

Increased predisposition to obesity

Question 18

Malformation definition

Answer 18

Damage that results from intrinsic GENETIC abnormalities

Question 19

Major malformation

Answer 19

If uncorrected/incorrectable, defect impairs normal function/reduces life expectancy

Question 20

Minor malformation

Answer 20

Defect that is of mostly cosmetic significance

Question 21

Major malfomation examples

Answer 21

NTDs

cleft lip +/- palate

Brachydactyly

Fetal alcohol syndrome

Trisomy 13

Question 22

Fetal alcohol syndrome cause + symptoms

Answer 22

Cause - Teratogen

Symptoms -

Thin upper lip

Growth retardation

Learning disabilities

Smooth philtrum

Question 23

Cleft lip +/+ palate characteristics

Answer 23

More common in males than females

Usually isolated

One of the most common multifactorial birth defects

Question 24

Cleft palate

Answer 24

More common in females more than males

Usually syndrome-associated

Not as common

Question 25

Isolated malformation

Answer 25

Restricted to one part of the body

Question 26

What are the risks of having 3+ minor malformations?

Answer 26

Increased chance of dysmorphic syndrome Increased risk of major malformation

Question 27

Syndrome definition

Answer 27

Condition in which one causative agent affects multiple organ systems simultaneously OR Pattern of malformations that either are or have to be etiologically related

Question 28

Waadernburg syndrome characteristics + symptoms

Answer 28

Cause: Type I and 3 = Pax3 mutation (NC cells); Type 2 = MitF mutation (melanocytes) Phenotype: Skin pigmentation issues Pale eyes White patch of hair + Upper limb abnormalities if Type 3 + Hearing loss if Type 2

Question 29

Sequence definition

Answer 29

Chain of developmental malformations (one leads to the other) resulting from single causative agent

Question 30

Pierre-Robin sequence

Answer 30

"The small chin baby" Small mandible Tongue pushed back U shaped cleft palate

Question 31

Association definition

Answer 31

Non-random occurence of multiple congenital abnormalities not known to be a sequence or syndrome

Question 32

VACTERL association

Answer 32

Vertebral Anal Cardiac Tracheo-Esophageal Renal Limb

Question 33

CHARGE association/syndrome

Answer 33

Coloboma (of eye) Heart defect Atresia Retardation of growth Genital anomalies Ear anomalies

Question 34

Deformation

Answer 34

Damage to a part of the body that would've otherwise formed normally; Due to external force e.g. Breech deformation Can be combined with NTD (e.g. omphalocele w/ club foot)

Question 35

Disruption

Answer 35

**Destruction** of part of the body that would've developed normally e.g. Amniotic bands

Question 36

Pleiotropy

Answer 36

Single causative agent affects more than one organ system Syndrome or sequence

Question 37

Teratogen

Answer 37

Transient effect, no change in dna therefore damage is not heritable, direct impact of fetus

Question 38

Mutagens

Answer 38

Change in DNA therefore heritable

Question 39

Less restricted cell fate

Answer 39

Pluripotent stage (cell can become whatever)

Question 40

More restricted cell fate

Answer 40

Approaching or at terminal differentiation (basically cell can't become much else)

Question 41

Specification/Differentiation

Answer 41

Characteristics of cell still changeable in response to environmental cues (basically, less-restricted cell type kinda thing)

Question 42

Determination

Answer 42

Basically cell = terminally differentiated

Question 43

Factors controlling cell fate

Answer 43

Too Much Information Transcription factors Morphogens Induction

Question 44

Transcription factors and functions (3)

Answer 44

MyoD (myoblasts\>\>myocytes) Pax3 - "Pax of NiCotine" - differentiation of neural crest cells Hox - axis specification and limb development

Question 45

How do Hox genes work? (say it out) Which end of a Hox gene cluster (3' vs 5') codes gives rise to proximal/anterior and distal/posterior?

Answer 45

Question 46

What results from a mutation in HoxD13? What kind of mutation is this?

Answer 46

Synpolydactyly Gain of function

Question 47

What is a morphogen and how does it affect development? What is an example of a morphogen and its source?

Answer 47

Diffusible signal that acts a distance; concentration varies by distance from the source Sonic Hedge Hog (SHH) and the Zone of Polarizing Activity

Question 48

What is the effect of a high SHH concentration vs low SHH concentration (as measured by distance from the ZPA)?

Answer 48

High SHH = posterior Low SHH = anterior

Question 49

Explain how the absence of SHH affects the GLI transcription factors, and the transcription of SHH responsive genes

Answer 49

No SHH = PTCH1 receptor inhibits SMO SMO cannot inhibit PKA, which will add (P) GLI1-3 complex Phosphorylated GLIs acts as repressors of SHH responsive genes

Question 50

Explain how the presence of SHH affects the GLI transcription factors and transcription of SHH responsive genes

Answer 50

SHH binds to PTCH1 receptor\>\> SMO no longer inhibited SMO inhibits PKA \>\> GLI proteins NOT phosphorylated Unphosphorylated GLI proteins now active and act as activators for SHH responsive genes

Question 51

What ultimately determines cell fate through the action of SHH?

Answer 51

The ratio of the concentration of GLI activator/GLI repressor

Question 52

Holoprosencephaly (causes + symptoms)

Answer 52

Mutation in SHH Cleft lip + palate Midline single central incisor (if mild) Hypotelorism Microcephaly

Question 53

What disease results from a mutation in GLI3?

Answer 53

GCPS (Greig's cephalopolysyndactyly)/Pallister Hall syndrome Defects in: Limbs Craniofacial Nervous system Airway Genitourinary

Question 54

A disease characterized by GCPS combined with dental cysts and basal carcinoma is likely due to a mutation in the ___ receptor of the SHH signaling pathway

Answer 54

PTCH1

Question 55

A mutation in a coactivator of GLI3 results in \_\_\_, which is characterized by a broad thumb as well as \_\_\_. What is the name of the coactivator?

Answer 55

Facial abnormalities Hand abnormalities (broad thumb) Mental retardation Congenital HD CREB-binding protein

Question 56

Describe the process of induction using the role of FGF8 and Pax6 in lens development as an example

Answer 56

A signal from one region of embryonic development influences the cells in another region, therefore the fate of those cells is "induced" by that signal

Question 57

A ___ mutation in the core promoter of the Beta-globin gene results in \_\_\_

Answer 57

Beta thalassemia

Question 58

Preaxial polydactyly arises from a mutation in the ___ element, an \_\_\_, of the SHH gene

Answer 58

"Enhancing SHH's ZRS (pronounced scissors) gives you too many fingers" ZRS element

Question 59

A ___ mutation, specifically that of ___ repeats in the DUX4 gene leads to \_\_-\_\_-\_\_ dystrophy

Answer 59

"**D4Z4** is **silent** b/s his **FACE, SCAPULA and HUMERUS** are **weak**

Question 60

Treacher Collins syndrome results from a mutation in the ___ site of the ___ gene

Answer 60

YY1 binding site (activator) TCOF1

Question 61

Achondroplasia results from a mutation in the ___ gene. What is the effect of this mutation such that it leads to disease?

Answer 61

FGFR3 (G380R) Mutation results in constitutively active Tyrosine Kinase (constant negative regulation of long bone growth)