Clinical genetics

Question 1

Describe Gene mapping in the past

Answer 1

• In the past researchers had to laboriously “walk” from the RFLP (restriction fragment length polymorphism) associated with a disease to the mutated gene.
• In the case of Huntington’s disease, the RFLP analysis indicated a target area of several million bases which proved to contain over 50 genes.
• It took 10 years from the identification of the RFLP to the identification of the Huntingtin gene, even though the mutation itself is dramatic—a triplet repeat expansion.

Question 2

How do SNPs Allow Better Mapping?

Answer 2

• Now, markers (both RFLP and SNP) are more closely spaced, so the target regions are smaller.
• With MAPVIEW (or other genome annotation systems) it is now easy to identify candidate genes in a region.
• Candidates can be prioritised according to structure, function, and expression patterns.
• Reference Sequences and polymorphisms are available for each gene for comparison to the subjects.
• From the hard work of identifying the best families to study, identifying the target region and the right gene could now take as little as a year.

Question 3

What are the two common approaches to identifying genes associated with a disease?

Answer 3

• Family-Based Linkage Studies: Following alleles through pedigrees.
• Association Studies: Following alleles through populations

Question 4

Approaches to Identifying Susceptibility Genes for Common Diseases

Answer 4

Question 5

Case Control Design

Answer 5

Question 6

In Linkage Analysis and Association
Studies the Identified SNP May Not Be The Disease Risk SNP/Mutation

Answer 6

Question 7

Genome-Wide Association Studies work best when

Answer 7

• Work best when the number of genes involved is small or the effect is large (for example, AP0E4 as a risk factor for Alzheimers).
• If each patient has a different mutation, the variation gets lost in the noise.

Question 8

What is the Undiagnosed Diseases Network?

Answer 8

• To provide answers to patients with mysterious conditions that have long eluded diagnosis To advance medical knowledge about rare and common diseases
• Organised by the National Human Genome Research Institute.
• Funded by the National Institutes of Health

Question 9

Describe NGS (Next Generation Sequencing)

Answer 9

Figure 1. Clinical Next-Generation Sequencing (NGS) Test Types.

• Exome, genome, and panel NGS tests have different genomic coverage characteristics.
• NGS gene panel tests cover a set of genes defined by the clinical diagnostic laboratory.
• The panel will typically cover genes associated with a set of related medical conditions (e.g., heritable epilepsy disorders).
• Exome sequencing covers the majority of known genes, including genes that have not yet been associated with human disease.
• Genome sequencing covers a majority of both genes and intergenic regions.
• Each test type has an associated pattern of false negative results.
• For instance, a gene panel may not include a mutated gene and an exome may miss deep intronic splice mutation.
• In addition, some regions of the genome are difficult to sequence with any existing method.

Question 10

Our Genomes Have Lots of Variants

Answer 10

Question 11

Red/Green Color Blindness Is a Model for the Importance of Genomic Context

Answer 11

Figure 1. Structure and Expression of the Red–Green Color Blindness Loci.

• Genes encoding the red (OPN1LW) and green (OPN1MW1 and OPN1MW2) opsins are organized in a head-to-tail configuration on the X chromosome (Panel A).
• The locus control region (LCR) couples to the promoter of the red opsin or the first green opsin gene to drive transcription and leads to the formation of either red or green cones in the retina.
• 5 Below the canonical organization (Panel B), five different human mutations are shown, including deletion of the green opsins, leading to green color blindness (Panel C); a stop codon mutation in the red opsin gene, resulting in red color blindness (Panel D); a gene conversion event creating a red–green hybrid gene, resulting in protanomalous color vision (Panel E); a stop codon in the most proximal gene, resulting in green color blindness (Panel F); and a duplication and stop mutation in distal green opsin genes, which have no effect on color vision because distal copy genes are rarely expressed in the retina (Panel G).
• The sequence structure, regulation, and copy-number variation are key to understanding the genotype–phenotype correlation of this human trait.

Question 12

Different Forms of Variation
Require Different Sequencing
Approaches

Answer 12

• Next Generation Sequncing is good for SNPs
• Copy number variations need Long Reads (10kb)
• Chromosomal Rearrangements need Karyotyping

Question 13

Clinical Genetic Landscape of HSCR

Answer 13

It is not all SNPs in the Coding Regions!

Question 14

Describe Precision Personalised Medicine
for Common Complex Diseases

Answer 14

• Sounds nice but does it make sense?
• If n=1, we will have lots of uncertainty in predicting
• treatment outcomes
• If we group or stratify patients to reduce uncertainty

it will no longer be fully personalised