CPPS403 - DevelopmentalGenetics - 6 - Copy Flashcards
(32 cards)
What does developmental genetics help to explain?
Human congenital diseases
Developmental genetics sheds insight on how genetic factors contribute to congenital malformations.
What is haploinsufficiency?
A condition where a single functional copy of a gene is insufficient to maintain normal function
Haploinsufficiency can lead to disease under certain genetic contexts.
What are the advantages of genetic screening?
Identifying genetic disorders, providing risk assessment, informing treatment options
Limitations include false positives/negatives, ethical concerns, and access to testing.
What disorder is caused by mutations in FGFR3?
Achondroplasia
Achondroplasia is the most common cause of human dwarfism and is an autosomal dominant disorder.
What is a modifier gene?
A gene that influences the penetrance of a disease without directly causing it
Modifier genes can result in significant phenotypic variability.
True or False: Modifier genes are an example of oligogenic disease.
False
Oligogenic disease involves mutations in two or more genes, whereas modifier genes do not directly cause the disease.
What is the significance of the LT gene in relation to the BFT phenotype?
It is a genetic modifier of the BFT phenotype
Different LT alleles can influence the phenotypic variance of individuals with the BFT mutation.
List the stages of embryonic development.
- 8-cell zygote
- 4 weeks post-conception embryo
- 10 weeks post-conception fetus
- 32 weeks post-conception fetus
These stages illustrate the progression from fertilization to later fetal development.
What role do developmental genes play in congenital malformations?
Loss of developmental genes often leads to congenital malformations
Mutations in these genes/pathways can disrupt normal development.
What is the most common birth defect?
Congenital Heart Defects (CHDs)
CHDs affect approximately 1% of live births and involve a spectrum of malformations.
How are developmental genes identified?
- Genotype
- Phenotype
- Reverse Genetics
- Forward Genetics
Techniques include CRISPR/Cas9, random mutagenesis screens, and natural variation.
Who is known for following segregation of spontaneous phenotypes in fruit flies?
Thomas Hunt Morgan
His work laid the foundation for modern genetics and earned him a Nobel Prize.
What is the purpose of a forward genetic screen?
To make random mutations, select a mutant phenotype, and identify the responsible gene
This process allows for unbiased discovery of new genes and alleles.
What mutagenesis methods are used in forward genetic screens?
- Chemical Mutagenesis
- Radiation Mutagenesis
- Insertional Mutagenesis
These methods introduce mutations that can be analyzed for phenotypic changes.
What percentage of offspring would be homozygous recessive in a forward genetic screen for recessive phenotypes?
25%
Alongside 50% heterozygous and 25% homozygous dominant.
What are some chromosomal abnormalities associated with congenital heart defects?
- Trisomy 13
- Trisomy 18
- Trisomy 21 (Down syndrome)
- Monosomy X (Turner syndrome)
- 22q11.2 deletion (DiGeorge syndrome)
These abnormalities account for 25% of sporadic CHD cases.
What technologies are used to identify genetic causes of congenital heart defects?
- Genome-wide linkage analyses
- SNP arrays
- Whole-exome sequencing
- Whole-genome sequencing
These techniques help identify structural variants and non-coding variants associated with CHDs.
What are the main characteristics of Holt-Oram Syndrome?
Cardiac septation defects, conduction defects, complex cardiac malformations, upper limb malformations
References: McDermott et al. (2005), Kumar et al. (2019)
What gene is associated with Holt-Oram Syndrome?
TBX5
TBX5 mutations are linked to limb and heart abnormalities.
What types of mutations in TBX5 are associated with Holt-Oram Syndrome?
- Null alleles
- Missense mutations
- Chromosomal rearrangements
- Splicing mutations
Basson et al. (1999) PNAS
What is haploinsufficiency in the context of Holt-Oram Syndrome?
A dominant phenotype in diploids that are heterozygous for a loss-of-function allele
Haploinsufficiency can lead to disease due to insufficient gene dosage.
What does TBX5 encode?
A transcription factor that activates genes associated with cardiac muscle maturation and septation
TBX5 is also important for forelimb bud outgrowth during development.
How does TBX5 mRNA expression relate to Holt-Oram Syndrome?
TBX5 mRNA is expressed in the developing mouse heart and forelimb
This expression is crucial for normal limb and heart development.
What is a dose-dependent reduction in the context of TBX5?
Expression of TBX5 target genes, ANF and cx40, shows a dose-dependent reduction in TBX5 +/+, +/-, and -/- mouse embryos
This indicates that gene dosage affects the expression of downstream targets.
