Investigating a genetic disorder of childhood

Question 1

Clinical genetics

Answer 1

Provide a diagnostic service and genetic counselling for individuals or families with, or at risk of, conditions which may have a genetic basis

Question 2

Prenatal testing

Answer 2

Largest activity (>80%) is screening for the common aneuploidies

Question 3

Postnatal testing

Answer 3

Cytogenetics in malignancy
Molecular testing for a large number of rare single gene disorders
Genetic risk factors

Question 4

Prenatal cytogenetic

Answer 4

Karyotype

Aneuploidy

Question 5

Prenatal molecular

Answer 5

Sickle cell
Free foetal DNA- sex
CF
Long tail

Question 6

Postnatal cytogenetic

Answer 6

Solid tumours

Haematological malignancy

Question 7

Postnatal molecular

Answer 7

Fragile X
CF
Breast cancer
Haemochromatosis
Factor V Leiden

Question 8

Genetic markers

Answer 8

A marker tags a piece of DNA and can be used to track genes in families or populations
SNP- single nucleotide polymorphism
STR- short tandem repeat
Are polymorphic when frequency of the minor allele in the population is >1%

Question 9

Linkage analysis

Answer 9

Linked markers are physically close and together are called a haplotype
Mostly sat together through meiosis but will cross over in recombination events
Can be used to track location of a disease gene in families

Question 10

Positional candidates

Answer 10

Identified through genome wide genetic linkage analysis

Question 11

Functional candidates

Answer 11

Identified by a functional association with previously identified disease genes
Find one disease gene, investigate the pathway, find other disease genes
E.G. Genes causing Fanconi anaemia function in a DNA repair pathway

Question 12

Exome/genome sequencing

Answer 12

Identified as having rare variants in multiple unrelated affected individuals

Question 13

Exome sequencing

Answer 13

Exome- all protein coding regions
1.5% of genome
Most disease causing alleles are coding
e.g. identification of gene that causes Freeman-Sheldon syndrome

Question 14

Interpreting genetic variants

Answer 14

Want to classify them on scale of 1 to 5

1. benign
2. likely benign
3. variant of unknown significance (VUS)
4. likely pathogenic
5. pathogenic

Only 1 + 5 are v useful, 2+4 can be helpful
BUT often VUS

Question 15

Variant classification

Answer 15

Search medical literature
Search population database
Use in-silico tools –> predict severity of variant, but can’t rely solely on these tools