Week 6

Question 1

Bainbridge paper—subjects

Answer 1

two siblings with dopa-responsive dystonia

treated with l-dopa, high dose side effects, lower dose some symptoms

Family history complicated

Question 2

Bainbridge paper—genes

Answer 2

no identified deleterious variants in TOr GCH1 genes (known recessives)

sequencing of the spr gene was not available

SOLID platform used for whole genome sequencing
-find 3 candidate genes

Question 3

spr mutation in bainbridge twins

Answer 3

recommends treatment change in bainbridge study

Serotonin precursor 5-HTP added
-potentially also SSRI

Sanger confirmation before treatment changes

Improvements with treatment change—sleep and concentration, taper l-dopa

Question 4

Critiques of bainbridge paper

Answer 4

data filtered by coding mutations—might as well have done exome sequencing

Spr was known candidate gene, mutations found were known

But family presentation was muddled

Question 5

Considerations for future—bainbridge

Answer 5

CLIS—standard in us for any lab studies with potential risk clinic consequences

Here, variants have been previously reported

Question 6

VOUS or VUS

Answer 6

variant of unknown significance, uncertainty of variants

Question 7

exome sequencing for unknown patients with severe diseases

Answer 7

…

Question 8

copy number variations

Answer 8

de novo mutations—genetic but not inherited
-compare monozygotic vs dizygotic twin rates: of higher in mz, genetic but not inherited (other story)

can have large effects on risk of autism, schizophrenia, …

Question 9

autism and schizophrenia twin data

Answer 9

6-7 percent of autism…

Question 10

cnvs in health and disease

Answer 10

Recently recognized form of mutation with major impact on human variation, evolution, diseases

Over 20,000 normal cnvs have been found

New mutations responsible for up to 10-15% of severe intellectual deficiency

Normal cnv mutation rate around 1-3 x 10^-2 per haploid genome per generation

Question 11

mechanism for deletion/duplication in microdeletions/duplications

Answer 11

mediated by unequal recombination between segmental duplications or low copy repeats flanking the regions

Sds are usually large and almost identical

Question 12

Recurrent cnvs

Answer 12

Associated with distinct but variable phenotypes—formed by NAHR during meiosis mediated by flanking repeat sequences

Question 13

Non recurrent cnvs

Answer 13

…

Question 14

Parental origin of cnvs

Answer 14

Studied rare de novo cnvs (pathological)

-significant paternal bias observed

Question 15

Paternal age and autism

Answer 15

Paternal age increase over time, and increased paternal age increases autism

But advancing paternal age at birth not associated with a decrease in school grades

Question 16

How to measure cnvs

Answer 16

Chromosomal microarrays by competitive genomic hybridization

-patient and control dna, if same cancel out, if not colors when hybridize

Chromosomal deletion detection: NGS

Question 17

what is genetic testing used for?

Answer 17

explanation for the disease comforts individuals and relatives (upbringing guilt)

Recurrence risk within family—can test relatives

Consider abortion, sometimes marriage

Medically monitor some cnvs associated with conditions (eg heart)