Lecture 6 - neurogenetics (research)

Question 1

Major limitations of genetic studies in tinnitus

Answer 1

• Self-reported
• Lack of replication
• Selection bias of candidate genes

Question 2

Extreme phenotype (EP)

Answer 2

Individuals with EP characterized by extreme clinically relevant attributes, toxic effects, or extreme responses to a treatment

Question 3

Allelic frequency and phenotype penetrance of Tinnitus SYMPTOM

Answer 3

HIGH allelic frequency and LOW phenotype penetrance

Question 4

Allelic frequency and phenotype penetrance of Tinnitus SYNDROME

Answer 4

LOW allelic frequency but HIGH phenotype penetrance

Question 5

How DNA sequencing techniques look at coding and non-coding regions

Answer 5

1. GWAS (Coding + Non)
2. Exome (Coding)
3. Genome sequencing (Coding and Non)

Question 6

Advantages of genome sequencing

Answer 6

• Very cheap
• Easy to do - sample from saliva and blood
• Dna extraction > dna fragmentation > sequencing > analysis

Question 7

When is gene burden analysis is needed?

Answer 7

When investigating Tinnitus syndrome as opposed to symptom

Question 8

Symptoms of Meniere’s Disease (MD)

Answer 8

• Vertigo
• Hearing loss
• Tinnitus AND
• Migraine, autoimmunity, allergy: more variation

Question 9

Epidemiology of MD

Answer 9

Prevalence: 0.5-1/1000
Onset: 30-50 years
Bilateral MD: 25-45%

Question 10

Molecular subtypes of MD

Answer 10

• Non-immune GENETICS (42%)
• Type 2 inflammation IgE (24%)
• Autoimmune (19%)
• Monocyte-driven auto-inflammation (14%)

Question 11

Sporadic vs. Familial MD

Answer 11

• Sporadic: 90%
• Familial: 10%

Question 12

Most common genes associated with MD

Answer 12

OTOG 16%
MYO7A 9%
TECTA 6%
But more than 61% unknown

Question 13

What is OTOG

Answer 13

Protein that is associated with the tip of the stereocilia that interacts with the tectorial membrane (TM)
* secreted 2975 AA glycoprotein

Question 14

Compound Recessive familial MD

Answer 14

Multiple families shared variants in OTOG (missense)

Question 15

What is MYO7A

Answer 15

Encodes for specific myosin protein in stereocilia
* Autosomal dominant
* Digenic variance

Question 16

TECTA gene deletions

Answer 16

Stop codons in TECTA lead to the loss GPI-anchor signal peptide that prevent diffusion of alpha tectorin
* TM will detach from stereocilia
* ** Auto**somal dominant

Question 17

GJD3 (CX31.9)

Answer 17

In familial and sporadic MD
* CX31.9 protein is an inner ear novel connexin

Question 18

Missense variants in Familial and Sporadic MD

Answer 18

71 enriched genes shared in SMD and FMD (28.1% in SMD).
9 enriched genes with inner ear phenotype (29% (9/31)).

Question 19

LoF variants Familial and Sporadic MD

Answer 19

3 enriched genes shared between SMD and FMD