summary of genetic diseases Flashcards
what is a single gene disorder
when a certain gene is known to cause a disease
where are single gene disorders catalogued
OMIM
what causes chromosomal diseases
changes in either the number or structure of chromosomes
what percentage of conceptions terminate due to chromosomal abnormalities
8%
what percentage of live births suffer anueuplodies, translocation etc
0.1%
what are mitochondrial disorders
genetic disorder that occurs when the mitochondria of the cell fail to produce enough energy for cell or organ function
any problems with mtDNA can lead to what
multisystem disorders
mtDNA is …. inherited
maternally
if the mother is heteroplasmic then the children can be
affected at different severities due to the varying level of mutation passed down
why do we need to identify variants for SGD (4 reasons)
- stop invasive testing
- allows introduction of appropriate treatment/stops any inappropriate treatment
- psychological benefits to affected and family
- scientific knowledge (telling us the role of different genes)
what was the very first gene that was mapped
huntingtin gene
what was the very first gene that was identified to be responsible for a disease
DMD gene
there has been a decrease in genes identified for SGD is recent years T/F
T
what is the difference between WGS and WES
whole genome sequencing (WGS) attempts to sequence the entirety of the genome whereas whole exome sequencing (WES) instead focuses on sequencing protein coding sequence
what are the advantages of WES over WGS
variants for SGDs so far are all in coding sequence
- cheaper
- fewer variants to analyse
what are the disadvantages to WES
may miss some causative alleles (WGS is becoming more feasible)
each individual will show over 20,000 variants after WES, how can we identify the causative variant
- predict effect on protein function
- use population databases (disease allele will be rare)
- pedigree info
- same allele in unrelated individuals with same disorder
- recapitulation in model system/organism
- databases of pathogenic variants
what are likely to cause loss of function
frame shift, protein terminating variants, splice sites and exon deletion
what is the exception of frame shift and PTV leading to LOF
if they are near the end of the protein sequence they dont affect protein structure - function maintained
what computer programs predict whether an amino acid substitution affects protein function
SIFT (sorts intolerant from tolerant)
Polyphen2 - polymorphism phenotypic version 2
what is ExAC
consortium which has generated the largest catalogue so far of variation in human protein-coding regions. it puts the information in a publicly accessible database
what does ExAC allow you to do
identify which alleles are very rare and which potentially harmful alleles occur frequently in apparently healthy individuals
what is key about the ExAC databas
size
some alleles arent very frequent in the population but can still occur in healthy individuals T/F
T
what may happen if the ExAC database is small
may muss alleles that although the are rare are not pathogenic
what has succeeded ExAC
GnomAD
frequencies can be different for different subpopulations. so an allele ay be rare worldwide but less rare in a subpopulation. if these individuals are healthy then it is not pathogenic T/F
T
we all carry 100s of potentially harmful mutations T/F
T
what is a compound heterozygote
The presence of two different mutant alleles at a particular gene locus (might not be exactly same bp change but will affect same gene)
how can you tell that a mutation is de novo dominant
new allele is not present in either parent
offspring of consanguineous relationships are on average more at risk of recessive disorders T/F
T
some diseases are very rare. to match affected individuals who are geographically isolated what is needed
controlled vocabulary to describe disease - human phenotype ontogeny
what is the major problem for datasharing about peoples diseasse phenotype/genetic data
ethics - fundamental right to privacy of genetic info
to ensure compatability between different countried with different medcal organisations and labs need standardisation. how is this achieved
American college of medical genetics and genomics guidelines. agree on set of guidelines to categorise variants
what is the simplest example of consanguinieous relationship
cousin marriage
what is dangerous about consanguineous parent
can have an allele that is rare becoming homozygous in the offspring
for each child there is a …… chance they will become homozygous for an allele that is heterozygous in their grandparent
1/64
the more distant the retationship among affecteds the fewer homozygous regions to analyse. how many rare variants do children of cousins have compared to children of third cousins
children of cousins have about 15-20 rare variants
children of third cousins have only 5-10 rare variants
what was the case study example given of a consanguineous autosomal recessive disorder
15yo saudi arabian girl with p.pro387leu mutation in SLC18A2 encoding the VMAT2 dopamine transporter
what was an example of a consanguineous autosomal recessive disorder given by the paper
3 siblings in pakistani family had postaxial polydactlyl type A with single homozygous ZNF141 variant
proline in the VMAT2 protein is highy conserved through evolution and in paralogous protein VMAT1 in c.elegans. what does this suggest
its substitution is likely to be deleterious
what is VMAT2
translocator of dopamine and serotonin into synaptic vesicles
how was the p.pro387leu mutation treated
direct dopamine agonist (pramipexole)
what does the SLC18A2/VMAT2 study show
homozygosity mapping
choosing candidate genes by hypothetical function
mutation affecting functional part of protein
-mutation in highly conserved residue
-recapitulation in in vitro mode (c.elegans)
diagnosis and treatment in a rare and novel disorder
how can you tell that a variant is autosomal dominant
heterozygous variant in affected family members not present in unaffected members
why is the identification of autosomal dominant harder
need mapping info
most dominant individuals are unlikely to have chioldren. why
most have severe health problems and dont want to pass on. they know they are affected
what is meant by de novo dominant
spontaneous mutations that occur when sperm/egg is being made that lead to dominant disorders
why are de novo dominant mutations easy to identify
each individual carries very few variants not found in either their parents
what can be sufficient for the identification of de novo mutations in the disease causing gene
analysis of 2 unrelated parent-child trios with a sporadic presentation of the same presumed autosomal dominant disorder
what are 2 examples of diseases caused by de novo mutations
floating harbour syndrome
weavers syndrome
what mutation causes floating harbour syndrome
mutations in SCRAP - SNf2 related chromatin remodelling ATPase; a cofactor for CREB binding proteins
what are the characteristics of floating harbour syndrome
dysmorphic features
short stature
intellectual disability
language defects
what is weaver syndrome
weaver syndrome is a condition that involves tall stature with or without a large head size (macrocephaly), a variable degree of intellectual disability
what was found as the causal gene of weaver syndrome
EZH2
how many unrelated parent child trios were needed to identify EZH2 as the causal gene for weaver syndrome
2
what mode of inheritance did diamond blackfan anemia be found to show
X linked
what did WES of diamond blackfan anaemia affected male siblings show
A single GATA1 variant on the X chromosome
disease causing mutations should be..
rare
