Genetics :( Flashcards
Define congenital
Any abnormality present at birth, whether due to a genetic disease or not.
Define Consanguinity
Reproductive union between two blood relatives
What proteins does DNA wind around?
Nucleosomes (made up of approx 8 histones)
What are Robertsonian chromosomes?
Chromosomes that lack a p arm (pairs 13,14,15,21,22)
Describe a chromosome
p arm (short) and a q arm (long) joined by a centromere
What are the 3 human genomes?
Somatic, germline, mitochondrial
When are changes to the genome heritable?
When the changes are in the germline or mitochondrial genome.
What is a mutagen?
Exposure to a substance damages the DNA base sequence and causes a mutation. Can be in the womb or post-natal. E.g. radiation
What is a teratogen?
Exposure to a substance damages embryo or fetal development, can also be a mutagen if DNA is damaged. E.g. alcohol, viruses
What is a mendelian mutation?
A monogenic mutation, where a single mutation on a gene is causing disease.
What is a somatic mutation?
The mutation causing disease is found only in the affected tissue.
What is a de novo mutation?
The variant occurs first in the germ line/ zygote so is present in offspring but not parents’ somatic genome, so wasn’t heritable.
What is dosage sensitivity?
Many genes are dosage sensitive so that deletion or duplication of genetic material causes an imbalance and results in disease.
Define benign variant
Gene variant known to have no impact on health.
What are the two types of chromosome translocations?
Balanced (no gain or loss of material)
Unbalanced (loss or gain of material, results in genetic conditions)
What causes down syndrome?
Trisomy 21 - an extra copy of all or some of chromosome 21.
What causes Edwards syndrome?
Congenital condition caused by trisomy 18.
What is autosomal dominant inheritance?
Disease occurs in the heterozygous state (variant on only one gene). Tends to cause a gain of (toxic) function.
It has a 50% recurrence risk.
What does an autosomal dominant pedigree look like?
M/F affected in equal proportions
Multiple generations affected
Both genders can pass on to either gender of offspring.
Define penetrance
% of individuals with the variant that develop the medical condition.
Can be age related (used in preventative medicine)
some variants have higher than others
some individuals never develop the condition
Define variable expressivity
Same variant causing different symptoms /signs in different people.
Anticipation
The condition manifests in successive generations earlier or with more severe symptoms.
What is autosomal recessive inheritance?
Occurs in homozygous state, tends to cause loss of function
What does an autosomal recessive pedigree look like?
M/F affected in equal proportions
Affected individuals only in one generation
Parents could be related
Carrier parents seeking advice
25% recurrence risk from 2 carrier parents, 2/3 chance being a carrier if affected sibling
Carrier frequency of recessive conditions varies in different populations due to culture, environment, location
Difference between X-linked recessive and X-linked dominant
recessive: unaffected female carriers, affected males
dominant: both M/F affected
Gonadal mosaicism
Mutation only found in ovary(germline?) and not in the blood DNA
Two different populations of cells in the gonads.
No clinical tests but prenatal tests
How to recognise multifactorial inheritance
Risk of condition (and incidence) much higher if relatives have it, greatest for 1st degree relative
Decreases rapidly in more distant relative
>1 affected relative increases risk for other relatives
Liability - genetic and environmental causation combined
Somatic mosaicism
Some tissues have the variant and some do not due to mutations occurring in the zygote, also cancer.
2 types of mitochondrial disease?
Homoplasmy - all mitochondria in the cell have the same genetic code
Heteroplasmy - certain proportion of mitochondria in a cell has a genetic variant
Always passed down from the mother
Imprinting disorders
Some genes are only active on the maternal or paternal copy (other is inactive).
Deletion if the active gene can cause disease
Synonymous mutation
Variant causes no change in the amino acid sequence
Non synonymous mutations
Missense - alters one amino acid (most common NS mutation)
Loss of function -(least common) IN FRAME shift multiples of 3 nucleotides are inserted/deleted - OUT OF FRAME shift non-multiple of 3, all codons change after variant, nonsense mediated decay occurs
Splice site - intron is translated into protein
Copy number variants
Deletion or duplication of a segment of chromosome
Trinucleotide repeat expansion
Repeats are duplicated or deleted X times
Form an elongated, toxic mRNA which resists degradation
occurs in non-coding DNA
e.g. huntingtons
Comparative genomic hybridisation
Probe binds to section on DNA
Different dye released if section isn’t there
Can detect CNVs
Genome test vs Exome test
Genome detects copy number variants, splice sites, trinucleotide repeats, promoter region
Exome detects mosaic variants, genome can miss them, exome is quicker
Why trio test?
picks up de novo variants, good for determining pathogenic(several ppl in family have variant and disease) vs benign variants(variant in unaffected patient and common in general population)
Predictive genetic testing
Adult can’t request test on child
For adult without symptoms for highly penetrant disease, seen as promoting autonomy
Prenatal diagnosis
Should only be done for a ‘serious genetic condition’ but what is in this category?
Could lead to genetic modifications, ending pregnancies
Preimplantation genetic testing
Pick embryos without genetic disease before putting into the womb
Direct to consumer testing
Quick online ordered tests, cheap, no counselling advice or other services
Costs the NHS as it misses out a lot of context
