Genetics Ethics

Onset of huntington disease

between 30 and 50

Symptoms of Huntington disease

progressive chorea (invol movements), dementia and

psychiatric symptoms

What causes Huntington disease?

• CAG is a repeat unit within the coding sequence

• encodes a polyglutamine tract

• expansion of tract (to 40 or more repeats of CAG) causes insoluble protein aggregates and neurotoxicity

How can Huntington disease be found?

• Possible DNA testing

• Testing unaffected relatives

• Presymptomatic test (only after full discussion of pros and cons and with full written consent)

Is there a cure for huntington disease?

no

Inheritanjce of Myotonic dystrophy

Autosomal dominant with genetic anticipation

Symptoms of myotonic dystrophy

• progressive muscle weakness in early adulthood

• myotonia

• cataracts

Genetic cause of myotonic dystrophy

• unstable length mutation of a CTG repeat

• in the 3’ (i.e. the downstream end of the gene) transcribed but untranslated region of DMPK gene

• affected if 50 or more repeats

• higher chance of expansion when transmitted by females

Pathogenic cause of Myotonic dystrophy

Abnormal DMPK mRNA

• Indirect toxic effect upon splicing of several other genes e.g. the chloride ion channel CLCN1 gene (causing myotonia)

Inheritance of cystic fibrosis

Autosomal recessive

How common is cystic fibrosis?

• 1 in 2500 UK newborns

• Carrier frequency is 1 in 20 - 25

What is the most common life limiting AR disease in Caucasians?

Cystic Fibrosis

Symptoms of cystic fibrosis

recurrent lung infections

exocrine pancreatic insufficiency (85-90% of cases

Diagnosis of Cystic Fibrosis

• screening of newborns by immunoreactive trypsin (IRT) level

• confirmation by DNA testing (for CF mutations) and/or sweat testing (for increased chloride conc)

Pathogenic mechanism of cystic fibrosis

• CFTR mutations

• defective chloride ion channel

• increased thickness of secretions

Genetic basis of Cystic Fibrosis

over 1000 different mutations in CFTR gene

most common is “F508del”:

• an in-frame deletion of 3bp (one codon)

• Deletion (loss) of a phenylalanine (“F”) at position 508

• prevents normal folding of protein and insertion into the plasma membrane

What is the purpose of the “cascade screening for Cystic Fibrosis?

identification of mutations permits prenatal diagnosis if desired and the subsequent testing of relatives (“cascade screening”) to identify carriers

What is the first step when interpreting a pedigree for a genetic condition?

Identify the inheritance pattern (autosomal dominant, autosomal recessive, or X-linked).

Why are risk calculations important in genetic counselling?

To estimate the chance that relatives may be carriers or affected.

What is the risk that two carriers will have an affected child (AR condition)?

25%

If someone has a sibling with an autosomal recessive condition but is unaffected, what is their chance of being a carrier?

2/3 67%

What is “cascade screening”?

Testing relatives of an affected individual to identify carriers.

Which website gives basic patient-friendly information on genetic conditions?

MedlinePlus.

Which database gives detailed rare disease information used by clinicians?

orphanet

Which resource gives the most detailed clinical and genetic information on rare conditions?

GeneReviews.

What is NORD?

National Organization for Rare Disorders (provides rare disease information).

Where should patients be referred for specialist genetic advice?

A Clinical Genetics unit.

What department is involved in genetic testing?

Laboratory medicine

What is genetic heterogeneity?

When different mutations or different genes can cause the same condition.

Give one example of genetic heterogeneity

Cystic fibrosis (many different CFTR mutations).

What is presymptomatic (predictive) testing?

Testing a healthy person to see if they will develop a genetic disease later.

Why must presymptomatic testing be done carefully?

Because it can have major psychological and ethical consequences.

Why is genetic testing of children ethically controversial?

Because the child cannot consent and the condition may only affect them in adulthood.

Why is confidentiality especially important in genetics?

Because genetic results affect not only the patient but also family members.