Genetic influences of disease 03.10.22

Question 1

What is the NHS clinical genetics?

Answer 1

It is a diagnostic speciality which sees patients of all ages and is run by Consultant Geneticists and Genetic counsellors and then analysed by laboratory and bioinformatics staff.

Question 2

How is NHS clinical genetics done?

Answer 2

• Moving towards all testing being done on Whole Genome Sequencing, which can look at a whole range of genes based on the symptoms your patient has.
• Now a Genomic Test Directory which lists all the different types of tests the NHS can provide.
• Genomic Medicine services are a large supra- regional network, testing millions of patients all over the country.

Question 3

What is genetic counselling?

Answer 3

Gives you the information about how genetic conditions might affect you or your family. The genetic counsellor or other healthcare professional will collect your personal and family health history. They can then use this information to determine how likely it is that you or your family member has a genetic condition.
You can use this to test for cancer screenings or planning for pregnancy or even making changes to your lifestyle and health.

Question 4

What are the three causes of disease?

Answer 4

• Completely environmental e.g. poor diet, infection, drugs
• Completely genetic e.g. Down’s syndrome, Huntington, haemophilia
• Multifactorial (most common): genetic predisposition with interacts with environmental risk factor which causes a disease

Question 5

What is a genotype?

Answer 5

Genetic constitution of an individual

Question 6

What is a phenotype?

Answer 6

Appearance of an individual which results from the interaction of the environment and the genotype

Question 7

What is an allele?

Answer 7

One of the several alternative forms of a gene at a specific locus

Question 8

What is a polymorphism?

Answer 8

Frequent hereditary variations at a locus

Question 9

What is genetics?

Answer 9

Single gene disorders

Question 10

What is genomics and genomic medicine?

Answer 10

Study of the entirety of DNA, the genome, together with the technologies which allow sequencing, interpretation and analysis. Application of genomics to clinical care

Question 11

What is a gene?

Answer 11

A segment of DNA that contains the biological instructions for a particular polypeptide, usually specific protein

Question 12

What is a pathogenic and benign variant?

Answer 12

Pathogenic: alteration in genetic sequence that increases individual’s chance to getting a certain disorder
Benign: alteration in genetic sequencing which is not disease-causing

Question 13

What is a variant of unknown significance?

Answer 13

an alteration in a genetic sequence whose association with disease risk is unknown. Don’t know if pathogenic or benign

Question 14

What is secondary and additional findings?

Answer 14

Secondary: results which provide info about variants which are unrelated to primary reason, may not want to know
Additional: results which provide info about variants which are unrelated but the patient opts in and consents for testing for these.

Question 14

What is secondary and additional findings?

Answer 14

Secondary: results which provide info about variants which are unrelated to primary reason, may not want to know
Additional: results which provide info about variants which are unrelated but the patient opts in and consents for testing for these.

Question 15

What is penetrance?

Answer 15

Proportion of individuals with a particular genotype who express the associated phenotype

Question 16

What is diagnostic and predictive testing?

Answer 16

Diagnostic: genomic/genetic testing in someone affected with features of a condition to aid diagnosis
Predictive: genomic/genetic testing in someone unaffected, specifically for a pathogenic variant known to be present in a family member

Question 17

What is homozygous?

Answer 17

both alleles the same at a locus

Question 18

What is heterozygous?

Answer 18

alleles at a locus are different

Question 19

What is hemizygous?

Answer 19

only one allele refers to a locus on an X chromosome in a male

Question 20

What is a rare disease?

Answer 20

• affects fewer than 1: 2000 people
• 1:17 people in the UK have a rare disease
• Around 10,000 rare disease
• difficult to diagnose, not a lot of expertise, no medications

Question 21

How do we recognise rare diseases in primary care?

Answer 21

GENES
G: group of congenital anomalies (born with)
E: extreme presentation of common conditions (very early onset)
N: neurodevelopment delay or early onset neurodegeneration (walking and talking)
E: extreme pathology
S: surprising laboratory values (very high cholesterol)

Question 22

How do we classify genetic diseases?

Answer 22

• Chromosomal
• Mendelian: autosomal dominant, autosomal recessive, X-Linked
• Non-traditional: mitochondrial, imprinting, mosaicism

Question 23

What is autosomal dominant inheritance?

Answer 23

Disease which is manifest in the heterozygous state.
If one parent has disease then child has a 50% chance of developing the disease.

Question 24

What is autosomal recessive inheritance?

Answer 24

Disease which is manifest in the homozygous state
If both parents are unaffected carriers, child has a 25% chance of getting the disease e.g. cystic fibrosis

Question 25

What is X-linked recessive inheritance?

Answer 25

Caused by pathogenic variants in genes on the X-chromosomes
Women are unaffected, men are vulnerable
No male to male transmission
e.g. haemophilia

Question 26

What is mitochondrial inheritance?

Answer 26

• found in eggs
• can’t pass from an affected male to children because sperm are so small as number of mitochondria are so small
• uncommon but can be very severe
• babies with severe epilepsy
• others are later in life (deafness)

Question 27

What is gonadal mosaicism?

Answer 27

• an affected child with two unaffected parents
• occurs because mutation has occurred in the testes as developing and as a man ages

Question 28

What is familial hypercholesterolaemia and coronary heart disease?

Answer 28

• lipids absorbed in intestine packed with proteins
• in the liver associated with cholesterol to form lipoproteins
• some people have pathogenic variant in the gene for LDL (low density lipoproteins) receptor and have increased genetic predisposition for CHD
• if they have a high cholesterol not really due to diet, more genetic
• other examples: hereditary breast and ovarian cancer due to BRCA genes, inherited alzheimers due to pre-senilin 1 variants, inherited parkinsons due to LRRK2 variants