L11: Finding Mendelian Disease Genes

Question 1

Why is it important to identify the genetic causes of Mendelian disorders?

Answer 1

Apart from the obvious reason of treatment, diagnosis plays a huge part in:

• Closure
• Genetic counselling for families
• Screening other familiy members

Question 2

Mutation vs Polymorphism?

Answer 2

Mutation is an event that changes one allele to the other. However, the original allele is still the most common form.

Polymorphism is a variation in which BOTH alleles are common in the population. Neither is the ‘normal’ one.

Variant is classified as a polymorphism is it has a frequency of >1%.

Question 3

Describe the 4 sequencing methods in order of decreasing % of genome sequences / increasing sequencing depth.

Answer 3

1. Whole Genome Sequencing
2. Whole Exome Sequencing
3. Targeted Gene Panel
4. SNP array

Question 4

What is involved in targeted gene panel sequencing?

State two advantages and two limitations of this method.

Answer 4

Sequences a selected group of genes that are KNOWN to be associated with a specific disease.

Allows us to have high sequencing depth with limited costs.

Allows us to diagnose a single affected individual, when no other affected individuals are present (e,g, whole exome sequencing requires other family members)

BUT gaps in coverage can cause the disease causing gene to be missed.

Also, if the gene variant has not been discovered before it won’t be included in the panel.

Question 5

What is involved in whole exome sequencing?

Answer 5

All of the coding exons in the genome are sequenced - approx. 2% of the genome.

Useful when you have a whole family (e.g. affected child with parents) - uninformative with just one person.

WES can pick up mutations not already known to cause disease.

Question 6

What is involved in whole genome sequencing?

Answer 6

Determines the order of all nucleotides in the human genome

Not really used for diagnosis, as it is so expensive and slow.

However, it can pick up splice site variants unlike WES or targeted panel.

Question 7

What is involved in SNP array and linkage sequencing?

Answer 7

Large family pedigree is required. Checks molecular markets.

Rarely used on it own nowadays.

Helps narrow down the region of the genome that the disease causing variant lies through linkage mapping.

Question 8

What are some challenges in disease discovery?

Answer 8

• Incomplete penetrance
• Genetic heterogeneity (multiple genes cause the disease)
• Allelic heterogeneity (variety of mutations in each gene)
• Phenotypic heterogeneity
• Lack of knowledge about certain proteins/diseases

Question 9

List the 5 ACMG variant classes.

Answer 9

1. Class 1: Benign
2. Class2: Likely benign
3. Class 3: Variant of unknown significance
4. Class 4: Likely pathogenic
5. Class 5: Pathogenic

Variant must reach calss 4 before diagnosis.