4. Genetic Counselling

Question 1

Inheritance pattern of cystic fibrosis?

Answer 1

Autosomal recessive inheritance

Most common fatal inherited disease in Caucasians

Question 2

What is CF?

Answer 2

Mutated chloride channel leading the thick mucus in the lungs

Question 3

What is the newborn screening programme for CF?

Answer 3

Identification of babies with CF to allow early treatment interventions
Based on heel-prick immuno-reaction trypsinogen (IRT) level. To look at pancreas stress
CF is suspected if..
-IRT raising
-1 pathogenic mutation found

CF confirmed if… 2 pathogenic mutations found

Question 4

R117H as a mutation for CF?

Answer 4

Mild mutation
Makes up 9% of CF mutations identified on postnatal screen
Does not normally present in CF in childhood
Effect of R117H varies according to Intron 8 splice site efficiency

Question 5

What does CFTR stand for?

Answer 5

CF transmembrane conductor receptor

Question 6

Effects of CFTR Intron 8 variants

Answer 6

Intron sequences removed. DNA in intron determines efficency of splcing
Some intron between exon 8 and 9 that determines in exon 9 is skipped. If skipped then abnormal protein coded for.
Dependent on 5T poor splicing resulting in exon 9 skipping.
R117H alone is not enough to cause CF, but effect compounded is also 5T i.e. not producing full length protein.

Question 7

What about poly T status?

Answer 7

5T with R117H is a combination that favours CF

Question 8

Presentation of spinal muscular atrophy (SMA)?

Answer 8

Respiratory difficulties
Difficult sucking and swallowing
Flopping
Unable to sit

Question 9

Other name for SMA?

Answer 9

Werdnig-Hoffmann Disease

Question 10

Pathophysiology of SMA?

Answer 10

Progressive muscle weakness from degeneration of anterior horn cells.
Autosomal recessive
95% cases due to deletion of SMN1 (Survival motor neurone 1)

Question 11

Haplotyping

Answer 11

For of genetic analysis
Genetic markers amplified around mutation
Help draw map of chromosomes
Some chromosome pairs have same sequence so indistinguishable, not helpful as you cannot pinpoint which chromosome is passed on

Question 12

Why can’t you look directly for SMA?

Answer 12

Single cell= Too low a number of DNA copies

Problems with contamination = False positive result from mum and dad

Allele drop out= False negative result from failure to amplify mutation

Question 13

What is an encephalocoele?

Answer 13

Encephalocoele, also known as meningoencephalocele, is a form of neural tube defect and a type of cephalocoele where brain tissue and overlying meninges herniate out through a defect in the cranium

Question 14

What is meckel gruber syndrome?

Answer 14

Autosomal recessive disorder with variable phenotype. At least 6 genes are mutated.
The most common features are:
- enlarged kidneys with numerous fluid-filled cysts
-an occipital encephalocele
-the presence of extra fingers and toes (polydactyly)

Question 15

Trisomy 13, aka…

Answer 15

Patau syndrome

Question 16

Features of trisomy 13?

Answer 16

Microcephaly
Mental retardation
Renal defect
Cleft lip and palate
Rocker-bottom feet
Umbilical hernia
Cardiac defect

Question 17

What is the mutation for alzhiemers?

Answer 17

Replacement of histidine with tyrosine in the PSEN-1 protein.
Missense mutation

Question 18

Main CF mutations

Answer 18

G551D ** (4-5% of CF patients)
R117H (2%)

Allows CFTR protein to be present in right place but is insufficient as a Cl channel

Question 19

Role of Ivacaftor (Kalydeco) therapy in CF treatment?

Answer 19

Help open Cl channel to aid conductance artificially

Specific for G551D

Question 20

Features of cleavage stage biopsy?

Answer 20

Need lots of embryos. Remove 1 cell day 5. Whole genome amplification.
From of Preimplantation genetic diagnosis for Spinal Muscular Atrophy

Question 21

Process of pre-symptomatic testing?

Answer 21

• No preventative treatment available

• Pre-symptomatic testing protocol
– Full information on test and limitations: Non-directive
– Opportunity for facilitated decision making
– Issues to consider: Insurance, Employment, Relationships