Mapping Mendelian Disease Flashcards
What is the Lymphatics system known as?
The Cinderella of the circulatory system
What are the functions of the Lymphatic system?
- Fluid homeostasis
- Immune function
- Fatty acid transport
What is the lymphatics system in regards to the capillary bed?
An integral part of the interweaving network in the capillary bed
What is primary lymphoedema?
- It is a chronic Oedema
- Often progressive
What are the two causes of primary Lymphoedema?
- A developmental abnormality
- A dysfunction of the lymphatics system
How does the phenotypes of primary lymphoedema vary?
- Age of onset
- Site
- Inheritance patterns
- Associated features
- Genetic causes
What are the physical implications of primary lymphoedema?
Lymphoedema can be
- Debilitating
- Embarrassing
- Stressful
- Causes recurrent infections
Why is this research important?
Has no medical cure
How do we study genetic diseases? (PART 1)
Clinically first Through:
- Patients
- Families
How do we study genetic diseases? (PART 2)
It then gets sent to the laboratory for:
- Genetic identification
- Functional studies
How do we study genetic diseases? (PART 3)
It then gets sent back to the clinic for:
- Diagnostic tests
- Counselling
- Treatments
How do we study genetic diseases?
How is gene identification carried out?
Gene identification by gene mapping
- Homozygosity mapping
- Linkage analysis
- GWAS
How do we study genetic diseases?
How do we find disease causing mutations?
Through Sequencing
How do we study genetic diseases?
How do we prove they cause disease?
Using in silico, in vitro and in vivo tools
What is genetic linkage?
Genetic linkage is the tendency for alleles at neighbouring loci to segregate together at meiosis. Therefore to be linked, two loci must lie very close together
What is a haplotype?
- Defines multiple alleles at linked loci
- Mark chromosomal segments which can be tracked through pedigrees and populations
When is crossing over likely to happen?
Most likely to happen During meiosis between loci separated by some distance than those close together
How can we use information about linked alleles to identify disease causing genes?
1). If an allele is linked to a disease locus, the same allele will be inherited by 2 affected relatives than expected by chance
2). If the alleles and the disease locus are linked, all the affected individuals in a family are more likely to inherit this haplotype block
How can we use information about linked alleles to identify disease causing genes?
3). If the alleles and the disease locus are unlinked to the disease locus, the affected individuals in a family are less likely to inherit the same marker alleles.
How is linkage analysis used?
- Gene mapping tools
- Using observed loci (alleles) to draw interferences about an unobserved locus (disease gene)
- Family based design
- The goal is to find genomic regions linked to the disease
What two processes that identifies the cause of primary lymphoedema?
Traditional linkage analysis and Sanger sequencing identifies the cause of autosomal recessive form of primary lymphoedema
What is generalised lymphatic dysplasia? Hennekam syndrome (HS)
- Antenatal hydrops with ascites and pleural effusions
- Oedematous at birth
- Intestinal lymphangiectasia
- Peripheral lymphoedema; arms, legs, face
- Mild developmental delay
Steps for something idk
1). First take a pedigree and get as many DNA samples as possible
2). Use some kind of tool to observe alleles (generating genotyping data for your pedigree)
Steps for something idk (PART 2)
3). Generate a file with your pedigree information plus the genotyping data from the SNP array
4). Run your file in a linkage programme
What does NPL stand for?
- Nonparametric linkage
- Gives you a plot for each chromosome
What is the problem with NPL?
- No rules are imposed
- Inheritance pattern is not taken into consideration
What is the advantage of using parametric analysis?
Imposes rules about inheritance and disease frequency
- If you have a pedigree showing autosomal recessive inheritance, you apply a rule for affected family members to be homozygous for the mutant allele
- If you have a pedigree showing autosomal dominant inheritance you apply a rule for affected family members to be heterozygous
After carrying out an autosomal recessive model, what do you do next?
The parametric test results are displayed for each of the 23 chromosomes
What happens to LOD scores above 3.0 (>3.0)?
- LOD scores >3.0 are taken as significant evidence for linkage
What does an LOD score (>3.0) mean?
- These results are taken as significant evidence for linkage
- A LOD score > 3 translates to a p-value of approximately 0.05
- This means the genetic locus is significantly linked to disease
What happens to LOD scores below -2.0?
- LOD scores below -2.0 show significant non linkage
- LOD scores between -2 and 3 are inconclusive
What are some features of 4 limb lymphoedema?
- Autosomal dominant
- Pubertal/adult onset
- Associated with venous incompetence
- No other abnormalities
How do we find disease causing mutations?
- Traditional Sanger sequencing: Candidate gene screen
- Next generation sequencing (NGS) (WGS (WES)
Summary (Open answers)
- Rare disease is often caused by mutations in a single gene
- Genetic analysis can identify the causative mutations
- Linkage analysis is an examples of such technique
- Things are not always straight forward and a good understanding of genetics and the tools applied is necessary
