Investigating a Genetic disorder in childhood

Question 1

What is the role of a clinical geneticist?

Answer 1

• Diagnosis of genetic disorders
• Investigation and genetic risk assessment
• Genetic counselling
• Appropriate follow-up support to patient and extended family
• Liaison with genetic laboratories
• Education and training
• Research

Question 2

Name some genetic conditions that you can get

Answer 2

• chromosomal abnormalities
• cancer
• thrombophilia
• single gene disorders

Question 3

Name an disease example of chromosomal abnormalities

Answer 3

down syndrome

Question 4

what can increase you risk of thrombophilia

Answer 4

• factor V linden can increase the risk of thrombophillia by 5 times

Question 5

Downs syndrome is a ..

Answer 5

aneuploid disease

Question 6

describe what is screened in prenatal testing for genetics

Answer 6

The largest activity (>80%) is screening for the common aneuploidies (Downs syndrome)
Specific testing for a large number of rare single gene disorders

Question 7

What does aneuploid mean?

Answer 7

Aneuploidies –anything that is not 2 (diploid) e.g. trisomies

Question 8

What does postnatal genetic testing involve

Answer 8

• Cytogenetics (take cells from the idnivdiual and look at the shape and size of the chromosomes) in malignancy
• Gene panels, screening for suspected single gene disorders – set genes based around a phenotype – rule
• Genetic risk factors – get an idea about what the genetic makeup is, in terms of common genetic risk factors that predispose you to some condition

Question 9

What is a genetic marker

Answer 9

• a marker tags a piece of DNA and can be used to track genes in families or populations

Question 10

name two examples of genetic marker

Answer 10

SNP = single nucleotide polymorphism 
STR = short tandem repeat (these are variable in length)

Question 11

What does polymorphism mean

Answer 11

• they are polymorphic when the frequency of the minor allele in the population is >1%.

Question 12

What is the minor allele frequency

Answer 12

this is the percentage of the gene in the population

Question 13

Describe what a single nucleotide polymphorms is

Answer 13

• these are changes in one gene that happen in a population, for example someone could have either a C or a T, therefore they can have 3 types of allele either CC, CT, or TT.

Question 14

what are short term tandem repeats

Answer 14

Short tandem repeats (STRs) are regions of the human genome that vary in length between people based on a repeated DNA sequence that repeats itself in the DNA

Question 15

what is an allele

Answer 15

This is a different version of the same gene

Question 16

what does linkage mean

Answer 16

• Linkage = means physical proximity, genetic markers can be close to each other

Question 17

What is genetic markers in linkage analysis about

Answer 17

• idea that linked markers are physically close and are called a haplotype
• these markers stay together during meiotic recombination and can cross over in recombination
• they can be used to tract a location of a disease in gene in families

Question 18

name the three ways how you can identify disease genes

Answer 18

• positional candidates
• functional candidates
• exome/genome sequencing

Question 19

How is positional candidates identified

Answer 19

• Identified through genome wide genetic linkage analysis.

Question 20

How are functional candidates identified

Answer 20

Identified by a functional association with previously identified disease genes

Question 21

How are genome/exome sequencing identified

Answer 21

Identified as having rare variants in multiple unrelated affected individuals – an allelic series

• for example you remove all the common variants and this leaves the candidates genes
• you then get multiple people with the same condition and compare the cases to see which genes are shared between the individuals
• eventually you end up with on candidate gene that causes the condition

Question 22

What is an exome

Answer 22

the protein coding regions of the genome

Question 23

What percentage does the exome make up of the genome

Answer 23

• Makes up 1.5% of the genome

Question 24

How do you know if a genetic variant is causing a disease

Answer 24

1. Benign
2. Likely benign
3. Variant of unknown significance (VUS)
   a. Don’t know what to do.
4. Likely pathogenic
5. Pathogenic.

Question 25

Name three ways in which you can approach hairnet classification

Answer 25

Searching medical literature - Can be decisive, clear known precedent Searching population databases - Can be decisive, clear incompatible population frequency - Genome Aggregation Database (gnomAD) Using in-silico tools - Acceptable to predict the severity of a variant - Unacceptable to rely solely on these predictions to assign pathogenicity to a previously unclassified variant.

Question 26

describe examples of - benign - supporting evidence - moderate evidence - definitive disease cause

Answer 26

= Minor allele frequency is too high for disorder OR observation in controls inconsistent with disease penetrance = benign = Multiple lines of computational evidence support a deleterious effect on the gene /gene product = supporting evidence = De novo (without paternity & maternity confirmed) – in the child but no in the parents so this is moderate evidence of support = Prevalence in affected statistically increased over controls = comes up in variant but never in controls so definite disease cause

Question 27

What is the impact of a genetic disease on the family

Answer 27

• diagnosis: - confirmation, clarification - pre-symptomatic, monitoring, search for donor - pattern of inheritance, carrier testing - prenatal, preimplantation, genetic counselling

Question 28

What is the treatment of a genetic disease

Answer 28

- tailor treatment: appropriate drugs - storing cells - rational drug design - gene therapy