Testing for Genetic Disease

Question 1

What is considered in genetic testing?

Answer 1

• Familial clustering= first an second degree relatives
• Rare mendelian forms= autosomal dominant/ recessive
• Endophenotypes= affects different individuals in different severity
• Gene-environment interactions= large-scale epidemiology

Question 2

Describe twin studies

Answer 2

-Monozygous twinning- embryo splits so genetically identical twins
-Dizygous- two fertilisation so individual embryos
=Discordant= one twin affected
=Concordant= both twins affected
*Rates between discordant and concordant for any disorder

twin studies which compare the concordance of disease between monozygous (identical) twins to the concordance of the same disease in dizygous (fraternal) twins

Question 3

Describe Genetic Association Studies

Answer 3

-Single gene would divide into dominant and recessive
-Cases genotype: allele frequency B>A
-Controls genotype: allele frequency A=B
How genetic a disease is

Question 4

What are the tests of asymptomatic individuals for mendelian disease?

Answer 4

• Population screening

- Predictive analysis

Question 5

How is new-born screening done in Scotland?

Answer 5

• Heel prick day 7

- Blood on blotting paper dried and sent to lab for analysis

Question 6

What does new-born screening test for?

Answer 6

• Phenylketonuria (PKU)
• Congenital hypothyroidism (CHT)
• Cystic fibrosis (CF)
• Medium chain acyl-CoA dehydrogenase deficiency (MCADD)
• Sickle cell disorder (SCD)
• Hearing loss (brainstem testing)

Question 7

Describe phenylketonuria

Answer 7

• Clinically silent in first months
• Eczema
• Hypopigmentation (pale)
• Severe developmental delay by toddlers
• “mousey” smell to urine
• Inborn error of metabolism
• Enzyme (phenylalanine hydroxylase) has coenzyme (TH4) converts phenylalanine (essential amino acid) to tyrosine
• Mutation takes out enzyme (PAH) build up, neurotoxin, converted to phenyl acetate (smell)

Question 8

Describe screening for PKU

Answer 8

• Initiated as practical solution by eliminating Phe from diet
• Prevents severe developmental delay
• Pedigree to find carriers- all babies tested at 7 days
• Positive result

Question 9

What is the treatment for PKU?

Answer 9

• Phenylalanine-restricted diet (Horst Bickel)
• Started <21days to avoid neurotoxicity
• Continue diet for life
• Normal outcome in most children

Question 10

What is the criteria for population based screening (Wilson and Jungner)?

Answer 10

• Well-defined disorder
• Known incidence
• Significant morbidity or mortality
• Effective treatment available
• Period before onset during which intervention improves outcome
• Ethical, safe, simple and robust screening test
• Cost-effect
• The informed participation of individuals (or their guardians)
• Information about the rationale and goals of the test must be available to all involved
• An effective system should be in place to do test and process results
• The testing method for that disorder should be sensitive (low false negative rate) and specific (low false positive rate)
• An ability to contact individuals with positive results and provide rapid access to medical management and/or counselling
• It must be possible to evaluate the outcome and impact of the testing program in medical social and economic terms

Question 11

What is the genetic diagnostic paradigm as an axiom?

Answer 11

-A constrained set of >0 regionally-defined genomic event(s) [locus and genotype]
-In >0 cells of common linage [constitutional/ mosaic]
DETERMINES [penetrance]
-A constrained set of >0 phenotypic anomaly(ies) of clinical significance [expressivity]
VIA
-A constrained set of perturbation(s) of the function of >0 gene(s) [consequence]

Question 12

How can you use phenotype testing to make genetic diagnosis?

Answer 12

-Does not always require DNA test
=clinical examination
=investigations
-If done for medical reasons
=should result in a preventative intervention
=family implications need to be considered
-Testing of children is appropriate if intervention starts in childhood

Question 13

Describe Marfan Syndrome

Answer 13

• Autosomal dominant
• Mutations in FBN1 gene (15q)
• Connective tissue disorder
• Skeletal complications
• Ophthalmological complications
• Cardiac complications

Question 14

Describe the skeletal complications of Marfan Syndrome

Answer 14

• Arachnodactyly= long fingers, thumb and wrist sign if overlap pinky and thumb
• Fist sign
• Scoliosis
• Pectus excavatum

Question 15

Describe the ophthalmological complications of Marfan Syndrome

Answer 15

-Large eyes
-Dislocation of lens= ectopia lentis
=Acute glaucoma
=Visual impairment

Question 16

Describe the cardiac complications of Marfan Syndrome

Answer 16

-Life-limiting
-Aortic dissection
-Change when dilatation of aortic root, measured using ultrasound
-Tears= blood tracks up smooth muscle layer
-Rapidly fatal and severe pain
=Prophylactic aortic root replacement using graft
=Losartan prevents progression

Question 17

What genetic conditions have interventions?

Answer 17

-Familial cancer syndromes
=BRCA1/2 
=von Hippel Lindau etc.
-Genodermatosis
=neurofibromatosis
=tuberous sclerosis 
-Cardiac genetics
=long QT syndrome
=HOCM
-Specific dysmorphic syndromes
=Beckwith Weidemann syndrome
=simpson-golabi-behmel etc.

Question 18

What pre-symptomatic testing is done for non-medical reasons?

Answer 18

Adult-Onset Neurodegenerative Disorders
-Untreatable
-No accurate prediction of age of onset
-Autosomal dominant
-DNA diagnosis available
-Children genetic testing
=Huntington's Disease

Question 19

Describe Huntington’s Disease neuropathology

Answer 19

• Caudate and Basal Ganglia
• Atrophy
• Cortical Atrophy

Question 20

Describe Huntington’s Disease clinical features

Answer 20

-Psychiatric
=depression
=dementia
=psychosis
=addiction
=impulse control
=suicide 
-Movement Disorder
=involuntary movements
=ataxia
=dystonia
=dysarthria

Question 21

What are the problems with pre-symptomatic testing?

Answer 21

• No medical benefit
• Side-effects unknown/ risk, survivor guilt
• Many people request test to confirm they do not have the condition
• Insurance/mortgage problems

Question 22

What are the benefits of pre-symptomatic testing?

Answer 22

• Removes uncertainty
• Clarifies reproductive risks
• Career/lifestyle choices

Question 23

What should pre-symptomatic testing for non-genetic reasons do?

Answer 23

• Performed only in specialist units
• Restricted to adults
• Obligate carriers are a problem
• May be done for reproductive reasons alone
• Should become rarer

Question 24

Ethical considerations in genetic testing

Answer 24

-Beneficence:
=the action should have a net benefit to the individual being tested.
-Autonomy:
=the action should depend on an informed decision by the individuals being tested
-Justice:
=the action should not be detrimental to society as a whole.

For simple diagnostic testing in treatable diseases there is usually no ethical concerns beyond obtaining adequately informed consent.

Question 25

What are cis-regulatory mutations?

Answer 25

mutations that are not in the coding regions but which have an effect on the expression on a developmentally critical gene

Question 26

What are developmental disorders?

Answer 26

condition that plausibly had its genesis during embryogenesis or early foetal brain development. Such disorders are common in paediatric practice e.g. global developmental delay, intellectual disability, epilepsy, cardiac malformations, autism etc.