9 - genomics about developmental disorders

Question 1

SWAN

Answer 1

syndromes without a name

Question 2

prevalence of developmental disorders

Answer 2

individually very rare

collectively common

Question 3

problems with diagnosis

Answer 3

many remain undiagnosed after standard NHS testing

can describe problem but dont know the cause

often very lengthy –> 5-15 years before confirmed clinical diagnosis
–> expensive

Question 4

phenotypes of developmental disorders

Answer 4

broad

united by children not developing normally

Question 5

common symptoms of developmental disorders

Answer 5

80-90% have intellectual disability
10% have congenital heart defects
abnormal growth of specific parts of the body
deformities

Question 6

how many genetic variants per individual

Answer 6

4-5 million

Question 7

most common type of genetic variant

Answer 7

SNV

Question 8

how many new de novo mutations in individuals

Answer 8

70-120

Question 9

types of genetic variant

Answer 9

SNV
indel
CNV

Question 10

location of variants

Answer 10

anywhere in genome

majority intronic/intergenic

Question 11

intronic/intergenic variants

Answer 11

variants between genes or exons
do not affect protein directly
mostly benign –> however could affect transcription

Question 12

how do variants cause disease

Answer 12

reduced/loss of function of proteins

increased/gain of function of proteins

Question 13

problem with increased/gain of function of proteins

Answer 13

produced elongated with extra repeats
starts to aggregate
toxic

Question 14

major classes of inheritance

Answer 14

autosomal dominance

autosomal recessive

X-linked

Question 15

autosomal dominant inheritance

Answer 15

inherited from diseased parent
one gene enough to cause disease

could also be de novo

Question 16

autosomal recessive

Answer 16

offspring require both copies of the gene to be affected

often loss of function

Question 17

X-linked disease

Answer 17

gene causing disease is on X-chromosome

if gene is recessive, males will get disease as they only have one X chromosome

Question 18

cytogenetics

Answer 18

diagnostic technique

looks for large structural changes across the genome to explain the phenotype

Question 19

karyotyping

Answer 19

looking for an unusual number of chromosomes, incorrectly arranged chromosomes, or malformed chromosomes
–> could be signs of a genetic condition

Question 20

symptoms/features associated with bardet biedel syndrome

Answer 20

polydactyly
obesity
rod-cone dystrophy

Question 21

syndromic

Answer 21

multiple phenotypes

Question 22

3 sub categories of DD phenotypes

Answer 22

abormal growth (whole body of specific parts)

birth deformities (cleft lip, extra fingers)

intellectual disability (learning/behaviour problems)

Question 23

16p11.2 syndrome

Answer 23

causes developmental delay and intellectual disability
associated with autism and ADHD

duplication –> underweight risk

deletion –> obese risk

Question 24

brachydactyly

Answer 24

shortened finger/toe bones

common in bardet biedl syndrome

Question 25

gene

Answer 25

made of DNA
basic physical and functional unit of hereditary
some code for proteins

Question 26

exons

Answer 26

protein coding regions of genome

1-2%

Question 27

introns

Answer 27

non-coding region of genome

30-40%

Question 28

number of genes in genome linked to DD

Answer 28

1500 genes out of 20,000

Question 29

why are genetic variants important

Answer 29

make us all individual from the reference genome

Question 30

where do majority of disease coding variants occur

Answer 30

in exons

Question 31

types of exonic variant

Answer 31

silent variant
nonsense
missense
frameshift

Question 32

missense

Answer 32

variant in exons

codon substituted for different codon –> changes amino acid

Question 33

nonsense variant

Answer 33

occurs in exons

introduces premature stop codon
results in no protein

Question 34

frameshift variant

Answer 34

alters how sequence is read

results in no protein

Question 35

multiexon variant

Answer 35

large variant

duplication or deletion of an entire exon, multipple exons or multiple genes

Question 36

de novo mutation

Answer 36

• arise spontaneously
• genetic alteration present for the first time in a family member
• due to a variant in a germ cell of a parent, or in the fertilized egg during embryogenesis

Question 37

genetic mutation

Answer 37

rare
permanent alteration of the nucleotide sequence of the genome
results from an error in DNA replication

Question 38

truncated protein

Answer 38

protein not very active

shortened protein

Question 39

disease caused by variants in ARID1B gene

Answer 39

Coffin-Siris syndrome

also associated with ASD

Question 40

function of ARID1B gene

Answer 40

component of chromatin remodelling complex

alters how tightly the DNA is packaged

Question 41

Dystonia 28 disease

Answer 41

caused by mutations in KMT2B gene

characterised by sustained involuntary muscle contractions (spasms) –> lead to abnormal postures

progressive, begins in lower limbs

Question 42

transition base substitution

Answer 42

purine to purine
or
pyramidine to pyramidine

Question 43

transversion base substitution

Answer 43

purine to pyramidine