T2: Single Gene Pathology II

Question 1

What is gnomAD used for?

Answer 1

Variant frequency - For rare diseases, we usually discount anything found in more than 1%. Anything found in more than 1%, it is considered too frequent to be rare. Clinical data base: gnomAD. We can look up the variant and see how many people in the population have the condition.

Question 2

What is ClinVar used for?

Answer 2

Variant pathogenicity

• Conserved in evolution and therefore seen across species. If it is an important variant, and present in multiple species, this suggests it is a critical position and so intolerable to change. If a variant is found in a critical position, it is likely to cause harm.

If poorly conserved region, it is likely to just cause variation and not cause disease.

ClinVar We can look up individual variants or genes and see if they have ever been reported before in patients and get an interpretation of pathogenicity.

Question 3

What is the ACMG pathogenicity classification used for?

Answer 3

Classify variants into 5 categories:

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

We cannot act on class 3 clinically: we cannot offer testing to there family members, treatment or screening. Given limitations in generating evidence, about 20% of variants are class 3.

We can act on both 4 and 5 variants in the clinic.

Question 4

What would you use to predict the variant effect?

Answer 4

Ensembl Has a variable effect predictor. You can input a variant, the reference variant and the altered variant. The VEP will produce all the evidence it has found on the variant. This helps as you do not need to consult each data base individually.

Question 5

What would you use to check the gene against the phenotype?

Answer 5

OMIM

Question 6

What is DNA instability?

Answer 6

The acquisition of new DNA variants between one generation and the next
• In the germline: source of individual variation and new disease variants
• In somatic cells: driving force for cancer
• Includes:
• Point mutations
• Chromosomal rearrangements
Aneuploidy

Question 7

What is the cause of DNA instability?

Answer 7

• Fragile sites including repetitive DNA sequences

- DNA replication defects

Question 8

What are transposable genes?

Answer 8

A transposable element (TE, transposon, or jumping gene) is a DNA sequence that can change its position within a genome, sometimes creating or reversing mutations and altering the cell’s genetic identity and genome size. These interspersed repeats can function as jumping genes. TE’s are mutagenic. They can cause new variation in the next generation. They can do this by:

• Insertion into a functional gene can disable it
• When it jumps out of the gene, an unrepaired gap in a gene can damage it
• Repetitive sequence can hinder precisechromosomalpairing duringmitosisandmeiosis → unequalcrossing over → generation of deletions and duplications.

Question 9

What is the genetic cause of DMD?

Answer 9

Duchenne Muscular Dystrophy is a progressive muscular degeneration in boys. The majority is due to large deletions, some large duplications and some other changes such as small changes.

When testing for DMD:
- Array CGH to test for large deletions and duplications
- Sequence analysis to look for point mutations is the above did not find anything
Specialist deletion/duplication analysis

Question 10

What is the cause of William’s syndrome?

Answer 10

Williams syndrome, due to a contiguous gene deletion at 7q11. 23, is associated with a distinctive facial appearance, cardiac abnormalities, infantile hypercalcemia, and growth and developmental retardation. The deletion is approximately 1.5Mb and includes approximately 17 genes.

Question 11

What the cause of DiGeorge’s syndrome?

Answer 11

22q11 deletion - is a disorder caused when a small part of chromosome 22 is missing on the long arm. It leads to an overly friendly personality, developmental delay, organ system defects etc.

Question 12

Using Huntington’s disease as an example, what are triplet repeat disorders?

Answer 12

Triplet repeat disorders are caused when the number of triplet repeats goes above the threshold and causes disease - there are more than 50 disorders described.

In Huntington’s Disease, the gene HTT has the repeat sequence CAG. The normal range is 6-35, the disease range is 26-250. HD is a dominant progressive neurodegenerative disorder. It leads to involuntary movement, dementia and psychiatric disturbances. When mutant allele inherited paternally, shows anticipation - The number of repeats can get bigger expansions through generations.