Genetic Influenes On Disease

Question 1

Genotype

Answer 1

genetic constitution of an individual

Question 2

Phenotype

Answer 2

appearance of an individual (physical, biochemical, physiological) which results from the interaction of the environment and the genotype

Question 3

Allele

Answer 3

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

• normal allele, wild type

• Disease allele carrying a pathogenic variant

Question 4

Polymorphism

Answer 4

Frequent hereditary variations at a locus

Question 5

Genetics

Answer 5

Single gene disorders

Question 6

Genomics

Answer 6

Study of the entirety of DNA, the genome, together with the technologies which allow sequencing, interpretation and analysis

Question 7

Genomic medicine

Answer 7

Application of genomics to clinical care

Question 8

Gene

Answer 8

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

A recipe/instruction/computer programme for something about us. Eg, eye colour, hair

Question 9

Pathogenic variant

Answer 9

An alteration in genetic sequence that increases an individual’s susceptibility on predisposition to a certain disorder

Question 10

Benign variant

Answer 10

An alteration in genetic sequence which is not disease causing

Question 11

Variant of unknown significance

Answer 11

An alteration in a genetic sequence whose association with disease risk is unknown

Question 12

Additional looked-for finding

Answer 12

Results which provide info about variants which are unrelated to the clinical indication for testing: patient opts in and consents to testing for these.

These tend to be conditions with significant health implications, whose clinical course can be altered by screening and/or risk-reducing measures

Question 13

Penetrance

Answer 13

The proportion of individuals with a particular genotype who expresses the associated phenotype/ develop features of a condition

Question 14

Diagnostic testing

Answer 14

Genomic/ genetic testing in someone affected with features of a condition to aid diagnosis

Question 15

Predictive testing

Answer 15

Genomic/genetic testing in an unaffected individual, specially for a pathogenic variant known to be present in a family member

Question 16

Homozygous

Answer 16

both alleles the same at a locus

Question 17

Heterozygous

Answer 17

alleles at a locus are different

Question 18

Hemizygous

Answer 18

only one allele (genes that are carried on an unpaired chromosome) refers to a locus on an X chromosome in a male

Question 19

ACMG criteria

Answer 19

formal scoring system to decide if a gene variant is “pathogenic”

Question 20

Pathogenic

Answer 20

Causes disease

Question 21

Recognising rare disease in primary care

Answer 21

A rare disease affects fewer than 1: 2000 people

Collectively 1:17 people in the UK have a rare disease

Around 10 000 rare diseases

100 diseases account for 80% of rare disease patients

Question 22

Primary care action

Answer 22

3 generation family tree

use symptoms to search diagnostic tools (e.g. Phenomizer)

Question 23

Recognising rare disease in primary care using GENES acronym

Answer 23

G: Group of congenital anomalies.

E: extreme presentation of common conditions (e.g. very early onset IHD, recurrent miscarriages)

N: Neurodevelopmental delay or early onset
neurodegeneration

E: extreme pathology

S: surprising laboratory values (e.g. very high cholesterol)

Question 24

Red flags

Answer 24

Young age of onset
Multiple generations
Unusual symptoms
Unusually severe
Developmental delay
Epilepsy
No environmental risk factors
Bilateral disease in paired organs

Question 25

Red flags (cardiac)

Answer 25

Young age onset

Sudden unexplained deaths

Multiple affected relatives

Question 26

Classification of genetic disease

Answer 26

Chromosomal

Mendelian: autosomal dominant, autosomal recessive,
X-Linked

Non traditional: Mitochondrial, imprinting, mosaicism

Question 27

Autosomal Dominant Inheritance

Answer 27

Disease which is manifest in the heterozygous state

Question 28

Autosomal recessive inheritance

Answer 28

Disease which is manifest in the homozygous recessive state

Two defective genes required.

CARRIER PARENTS: 25% chance of offspring (from 2 carrier parents) have condition. 50% chance of offspring being a carrier. Calculations at conception. Healthy siblings have a 2/3 chance of being carriers.

Male and females affected in equal proportions.

Affected individuals only in a single generation.

Parents can be related e.g consanguineous (recessive disorders most common in these types of family) Example. CYSTIC FIBROSIS

Question 29

X-Linked Recessive Inheritance

Answer 29

Caused by pathogenic variants in genes on the X chromosome

Question 30

Rare Genetic subset of a multifactorial disease – Familial Hypercholesterolaemia and Coronary Heart Disease

Answer 30

Lipids absorbed in intestinal cell packaged with proteins. In the liver associated with cholesterol to form lipoproteins

• High levels of low density lipoproteins associated with increased risk of heart disease

• Some people have a pathogenic variant in the gene for LDL receptor and have increased genetic predisposition for CHD

Question 31

Examples of genetic disease

Answer 31

• Hereditary breast and ovarian cancer due to BRCA genes
• Inherited alzheimers due to pre-senilin 1 variants
• Inherited Parkinsons due to LRRK2 variants

Question 32

Cystic fibrosis

Answer 32

• Most common autosomal recessive condition affecting whites in UK
• Chronic condition affecting mainly the lungs and gut, variable presentation
• Incidence of 1 in 25,000
• Population carrier frequency for cystic fibrosis is 1/25 (i.e 25% of the population is a carrier)
• NOTE, YOU ARE A 50% CHANCE OF CARRIER IF BOTH PARENTS ARE CARRIERS
• NOTE: when looking at probabilities to see risk of being carriers etc. the already
  AFFECTED CHILD is disregarded, so if you get one unaffected, 2 carriers and one affected, the probability of being a carrier is NOT 1/2 since affected child is disregarded, instead it is a 2/3