Developmental Genetics + Clinical Genetics + Genetic variations Flashcards
Structural variation vs substitution variation
Structural: In/dels
Substitution: SNPs
Common vs Rare variant
Common: both alleles @ +1% frequency
Rare: allele present @ less than 1% frequency
SNP definition
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
Sickle cell anemia mutation
Glu6 >> Val6 (missense)
Beta thalassemia mutation
Glu6>>STOP (nonsense)
Non coding region mutations can occur in __, __ and ___.
Give 2 examples of this
Promoter, enhancer/silencer, 5’ and 3’ UTR
Beta thalassemia mutation in promoter region
Repeats in CFTR gene (Intron 8)
Structural variants: What are the 2 ways you could get CF?
Phenylalanine deletion at position 508
(TG)n(T)n repeats in Intron 8 >> exon exclusion of Exon 9
How do repeats that cause Huntington’s disease and Fragile X syndrome vary in terms of phenotype + which repeat? (HD)
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
Fragile X repeat phenotype
Copy number variants: what’s the effect of a mutation in the AMY (amylase) gene?
More copies = faster carbohydrate breakdown + improved glycemic homeostasis/decreased diabetes risk
Use alpha thalassemia to explain copy number variations
Repeats can become misaligned, results vary based on mutation (nonsense >> 1/2 normal, missense >> 1/4 normal)
How does an inversion cause hemophilia?
Mispairing of similar factor 8 sequences
Genotype and phenotype correlation:Osteogenesis imperfecta (what’s the effect of a missense vs a nonsense mutation?)
Missense: 1/4 normal
Nonsense: 1/2 normal
What is a frameshift mutation?
Frameshift is an inserted or deleted fragment that is not divisible by 3
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)
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.
Disease associated (susceptibility) variants:
The MATP gene codes for ___. A mutation in this gene could lead to ___, resulting in___.
Melanin production.
Lighter skin.
Vitamin D deficiency/Malignant malinoma
A lower copy number of an AMY mutation could lead to___
Increased predisposition to obesity
Malformation definition
Damage that results from intrinsic GENETIC abnormalities
Major malformation
If uncorrected/incorrectable, defect impairs normal function/reduces life expectancy
Minor malformation
Defect that is of mostly cosmetic significance
Major malfomation examples
NTDs
cleft lip +/- palate
Brachydactyly
Fetal alcohol syndrome
Trisomy 13
Fetal alcohol syndrome cause + symptoms
Cause - Teratogen
Symptoms -
Thin upper lip
Growth retardation
Learning disabilities
Smooth philtrum
Cleft lip +/+ palate characteristics
More common in males than females
Usually isolated
One of the most common multifactorial birth defects
Cleft palate
More common in females more than males
Usually syndrome-associated
Not as common
Isolated malformation
Restricted to one part of the body
What are the risks of having 3+ minor malformations?
Increased chance of dysmorphic syndrome
Increased risk of major malformation
Syndrome definition
Condition in which one causative agent affects multiple organ systems simultaneously
OR
Pattern of malformations that either are or have to be etiologically related
Waadernburg syndrome characteristics + symptoms
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
Sequence definition
Chain of developmental malformations (one leads to the other) resulting from single causative agent
Pierre-Robin sequence
“The small chin baby”
Small mandible
Tongue pushed back
U shaped cleft palate
Association definition
Non-random occurence of multiple congenital abnormalities not known to be a sequence or syndrome
VACTERL association
Vertebral
Anal
Cardiac
Tracheo-Esophageal
Renal
Limb
CHARGE association/syndrome
Coloboma (of eye)
Heart defect
Atresia
Retardation of growth
Genital anomalies
Ear anomalies
Deformation
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)
Disruption
Destruction of part of the body that would’ve developed normally
e.g. Amniotic bands
Pleiotropy
Single causative agent affects more than one organ system
Syndrome or sequence
Teratogen
Transient effect, no change in dna therefore damage is not heritable, direct impact of fetus
Mutagens
Change in DNA therefore heritable
Less restricted cell fate
Pluripotent stage (cell can become whatever)
More restricted cell fate
Approaching or at terminal differentiation (basically cell can’t become much else)
Specification/Differentiation
Characteristics of cell still changeable in response to environmental cues (basically, less-restricted cell type kinda thing)
Determination
Basically cell = terminally differentiated
Factors controlling cell fate
Too Much Information
Transcription factors
Morphogens
Induction
Transcription factors and functions (3)
MyoD (myoblasts>>myocytes)
Pax3 - “Pax of NiCotine” - differentiation of neural crest cells
Hox - axis specification and limb development
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?
What results from a mutation in HoxD13?
What kind of mutation is this?
Synpolydactyly
Gain of function
What is a morphogen and how does it affect development?
What is an example of a morphogen and its source?
Diffusible signal that acts a distance; concentration varies by distance from the source
Sonic Hedge Hog (SHH) and the Zone of Polarizing Activity
What is the effect of a high SHH concentration vs low SHH concentration (as measured by distance from the ZPA)?
High SHH = posterior
Low SHH = anterior
Explain how the absence of SHH affects the GLI transcription factors, and the transcription of SHH responsive genes
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
Explain how the presence of SHH affects the GLI transcription factors and transcription of SHH responsive genes
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
What ultimately determines cell fate through the action of SHH?
The ratio of the concentration of GLI activator/GLI repressor
Holoprosencephaly (causes + symptoms)
Mutation in SHH
Cleft lip + palate
Midline single central incisor (if mild)
Hypotelorism
Microcephaly
What disease results from a mutation in GLI3?
GCPS (Greig’s cephalopolysyndactyly)/Pallister Hall syndrome
Defects in:
Limbs
Craniofacial
Nervous system
Airway
Genitourinary
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
PTCH1
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?
Facial abnormalities
Hand abnormalities (broad thumb)
Mental retardation
Congenital HD
CREB-binding protein
Describe the process of induction using the role of FGF8 and Pax6 in lens development as an example
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
A ___ mutation in the core promoter of the Beta-globin gene results in ___
Beta thalassemia
Preaxial polydactyly arises from a mutation in the ___ element, an ___, of the SHH gene
“Enhancing SHH’s ZRS (pronounced scissors) gives you too many fingers”
ZRS element
A ___ mutation, specifically that of ___ repeats in the DUX4 gene leads to __-__-__ dystrophy
“D4Z4 is silent b/s his FACE, SCAPULA and HUMERUS are weak
Treacher Collins syndrome results from a mutation in the ___ site of the ___ gene
YY1 binding site (activator)
TCOF1
Achondroplasia results from a mutation in the ___ gene. What is the effect of this mutation such that it leads to disease?
FGFR3 (G380R)
Mutation results in constitutively active Tyrosine Kinase (constant negative regulation of long bone growth)
