summary of genetic diseases

Question 1

what is a single gene disorder

Answer 1

when a certain gene is known to cause a disease

Question 2

where are single gene disorders catalogued

Answer 2

OMIM

Question 3

what causes chromosomal diseases

Answer 3

changes in either the number or structure of chromosomes

Question 4

what percentage of conceptions terminate due to chromosomal abnormalities

Answer 4

8%

Question 5

what percentage of live births suffer anueuplodies, translocation etc

Answer 5

0.1%

Question 6

what are mitochondrial disorders

Answer 6

genetic disorder that occurs when the mitochondria of the cell fail to produce enough energy for cell or organ function

Question 7

any problems with mtDNA can lead to what

Answer 7

multisystem disorders

Question 8

mtDNA is …. inherited

Answer 8

maternally

Question 9

if the mother is heteroplasmic then the children can be

Answer 9

affected at different severities due to the varying level of mutation passed down

Question 10

why do we need to identify variants for SGD (4 reasons)

Answer 10

• 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)

Question 11

what was the very first gene that was mapped

Answer 11

huntingtin gene

Question 12

what was the very first gene that was identified to be responsible for a disease

Answer 12

DMD gene

Question 13

there has been a decrease in genes identified for SGD is recent years T/F

Answer 13

T

Question 14

what is the difference between WGS and WES

Answer 14

whole genome sequencing (WGS) attempts to sequence the entirety of the genome whereas whole exome sequencing (WES) instead focuses on sequencing protein coding sequence

Question 15

what are the advantages of WES over WGS

Answer 15

variants for SGDs so far are all in coding sequence

• cheaper
• fewer variants to analyse

Question 16

what are the disadvantages to WES

Answer 16

may miss some causative alleles (WGS is becoming more feasible)

Question 17

each individual will show over 20,000 variants after WES, how can we identify the causative variant

Answer 17

• 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

Question 18

what are likely to cause loss of function

Answer 18

frame shift, protein terminating variants, splice sites and exon deletion

Question 19

what is the exception of frame shift and PTV leading to LOF

Answer 19

if they are near the end of the protein sequence they dont affect protein structure - function maintained

Question 20

what computer programs predict whether an amino acid substitution affects protein function

Answer 20

SIFT (sorts intolerant from tolerant)

Polyphen2 - polymorphism phenotypic version 2

Question 21

what is ExAC

Answer 21

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

Question 22

what does ExAC allow you to do

Answer 22

identify which alleles are very rare and which potentially harmful alleles occur frequently in apparently healthy individuals

Question 23

what is key about the ExAC databas

Answer 23

size

Question 24

some alleles arent very frequent in the population but can still occur in healthy individuals T/F

Answer 24

T

Question 25

what may happen if the ExAC database is small

Answer 25

may muss alleles that although the are rare are not pathogenic

Question 26

what has succeeded ExAC

Answer 26

GnomAD

Question 27

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

Answer 27

T

Question 28

we all carry 100s of potentially harmful mutations T/F

Answer 28

T

Question 29

what is a compound heterozygote

Answer 29

The presence of two different mutant alleles at a particular gene locus (might not be exactly same bp change but will affect same gene)

Question 30

how can you tell that a mutation is de novo dominant

Answer 30

new allele is not present in either parent

Question 31

offspring of consanguineous relationships are on average more at risk of recessive disorders T/F

Answer 31

T

Question 32

some diseases are very rare. to match affected individuals who are geographically isolated what is needed

Answer 32

controlled vocabulary to describe disease - human phenotype ontogeny

Question 33

what is the major problem for datasharing about peoples diseasse phenotype/genetic data

Answer 33

ethics - fundamental right to privacy of genetic info

Question 34

to ensure compatability between different countried with different medcal organisations and labs need standardisation. how is this achieved

Answer 34

American college of medical genetics and genomics guidelines. agree on set of guidelines to categorise variants

Question 35

what is the simplest example of consanguinieous relationship

Answer 35

cousin marriage

Question 36

what is dangerous about consanguineous parent

Answer 36

can have an allele that is rare becoming homozygous in the offspring

Question 37

for each child there is a ...... chance they will become homozygous for an allele that is heterozygous in their grandparent

Answer 37

1/64

Question 38

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

Answer 38

children of cousins have about 15-20 rare variants | children of third cousins have only 5-10 rare variants

Question 39

what was the case study example given of a consanguineous autosomal recessive disorder

Answer 39

15yo saudi arabian girl with p.pro387leu mutation in SLC18A2 encoding the VMAT2 dopamine transporter

Question 40

what was an example of a consanguineous autosomal recessive disorder given by the paper

Answer 40

3 siblings in pakistani family had postaxial polydactlyl type A with single homozygous ZNF141 variant

Question 41

proline in the VMAT2 protein is highy conserved through evolution and in paralogous protein VMAT1 in c.elegans. what does this suggest

Answer 41

its substitution is likely to be deleterious

Question 42

what is VMAT2

Answer 42

translocator of dopamine and serotonin into synaptic vesicles

Question 43

how was the p.pro387leu mutation treated

Answer 43

direct dopamine agonist (pramipexole)

Question 44

what does the SLC18A2/VMAT2 study show

Answer 44

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

Question 45

how can you tell that a variant is autosomal dominant

Answer 45

heterozygous variant in affected family members not present in unaffected members

Question 46

why is the identification of autosomal dominant harder

Answer 46

need mapping info

Question 47

most dominant individuals are unlikely to have chioldren. why

Answer 47

most have severe health problems and dont want to pass on. they know they are affected

Question 48

what is meant by de novo dominant

Answer 48

spontaneous mutations that occur when sperm/egg is being made that lead to dominant disorders

Question 49

why are de novo dominant mutations easy to identify

Answer 49

each individual carries very few variants not found in either their parents

Question 50

what can be sufficient for the identification of de novo mutations in the disease causing gene

Answer 50

analysis of 2 unrelated parent-child trios with a sporadic presentation of the same presumed autosomal dominant disorder

Question 51

what are 2 examples of diseases caused by de novo mutations

Answer 51

floating harbour syndrome | weavers syndrome

Question 52

what mutation causes floating harbour syndrome

Answer 52

mutations in SCRAP - SNf2 related chromatin remodelling ATPase; a cofactor for CREB binding proteins

Question 53

what are the characteristics of floating harbour syndrome

Answer 53

dysmorphic features short stature intellectual disability language defects

Question 54

what is weaver syndrome

Answer 54

weaver syndrome is a condition that involves tall stature with or without a large head size (macrocephaly), a variable degree of intellectual disability

Question 55

what was found as the causal gene of weaver syndrome

Answer 55

EZH2

Question 56

how many unrelated parent child trios were needed to identify EZH2 as the causal gene for weaver syndrome

Answer 56

2

Question 57

what mode of inheritance did diamond blackfan anemia be found to show

Answer 57

X linked

Question 58

what did WES of diamond blackfan anaemia affected male siblings show

Answer 58

A single GATA1 variant on the X chromosome

Question 59

disease causing mutations should be..

Answer 59

rare