Genetic Influenes On Disease Flashcards
Genotype
genetic constitution of an individual
Phenotype
appearance of an individual (physical, biochemical, physiological) which results from the interaction of the environment and the genotype
Allele
• One of several alternative forms of a gene
at a specific locus
• normal allele, wild type
• Disease allele carrying a pathogenic variant
Polymorphism
Frequent hereditary variations at a locus
Genetics
Single gene disorders
Genomics
Study of the entirety of DNA, the genome, together with the technologies which allow sequencing, interpretation and analysis
Genomic medicine
Application of genomics to clinical care
Gene
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
Pathogenic variant
An alteration in genetic sequence that increases an individual’s susceptibility on predisposition to a certain disorder
Benign variant
An alteration in genetic sequence which is not disease causing
Variant of unknown significance
An alteration in a genetic sequence whose association with disease risk is unknown
Additional looked-for finding
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
Penetrance
The proportion of individuals with a particular genotype who expresses the associated phenotype/ develop features of a condition
Diagnostic testing
Genomic/ genetic testing in someone affected with features of a condition to aid diagnosis
Predictive testing
Genomic/genetic testing in an unaffected individual, specially for a pathogenic variant known to be present in a family member
Homozygous
both alleles the same at a locus
Heterozygous
alleles at a locus are different
Hemizygous
only one allele (genes that are carried on an unpaired chromosome) refers to a locus on an X chromosome in a male
ACMG criteria
formal scoring system to decide if a gene variant is “pathogenic”
Pathogenic
Causes disease
Recognising rare disease in primary care
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
Primary care action
3 generation family tree
use symptoms to search diagnostic tools (e.g. Phenomizer)
Recognising rare disease in primary care using GENES acronym
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)
Red flags
Young age of onset
Multiple generations
Unusual symptoms
Unusually severe
Developmental delay
Epilepsy
No environmental risk factors
Bilateral disease in paired organs
Red flags (cardiac)
Young age onset
Sudden unexplained deaths
Multiple affected relatives
Classification of genetic disease
Chromosomal
Mendelian: autosomal dominant, autosomal recessive,
X-Linked
Non traditional: Mitochondrial, imprinting, mosaicism
Autosomal Dominant Inheritance
Disease which is manifest in the heterozygous state
Autosomal recessive inheritance
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
X-Linked Recessive Inheritance
Caused by pathogenic variants in genes on the X chromosome
Rare Genetic subset of a multifactorial disease – Familial Hypercholesterolaemia and Coronary Heart Disease
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
Examples of genetic disease
• Hereditary breast and ovarian cancer due to BRCA genes
• Inherited alzheimers due to pre-senilin 1 variants
• Inherited Parkinsons due to LRRK2 variants
Cystic fibrosis
- 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
