Trigger 9: DDs examples Flashcards
schizophrenia has a lifetime prevalence of
1%
schizophrenia is …..% heritable
80%
thought to be caused by high burden of
de novo mutations
autism spectrum disorder prevalence
1.5%
autism is ….% heritable
50-90%
autism spectrum disorder have a comple
genetic architecture
ASD can be
monogenic and syndromic forms
- complex multifactorial causes
ASD caused by
high burden of de novo mutations and large CNVs
ASD is caused by an interplay between
familial background and high risk events (e.g. de novo mutation), explaining varying clinical manifestations
prevalence of intellectual disability
1-2%
heritability of intellectual disability
50-90%
intellectual disability is defined as having and IQ below
70
intellectual disability is
very heterogenous
intellectual disability like ASD has
monogenic and syndromic forms
intellectual disability can be caused by
environmental factors (e.g. mother drinking whilst pregnant)
intellectual disability caused by a
ugh burden of de novo mutations and large CNVs
many disorders are overlapping
conditions
e. g. ASD overlapping with SCZ
e. g. ASD overlapping with ID
de novo heterozygous mutations are a common
cause of dominant DD
inherited variants are a
common cause of recessive DD
homozygous
two copies of the same variant, one from each parent
compound heterozygous
The presence of two different mutant alleles at a particular gene locus, one on each chromosome of a pair.
halpoinsufficnecy
only having a single functioning copy of a gene is not enough for normal function mutations caused by a dominant phenotype
severe HI means that
genes are intolerant to loss of one functioning copy
better explanation of HI
when the normal phenotype requires the protein product of both alleles and reduction of 50% (e.g. loss of function of one allele) of gene function results in an abnormal phontype
a situation in which the total level of gene product (protein) produced by a cell is
about half of the normal level and not sufficient enough to permit normal cell functioning
causes of HI
- inherited loss of function mutations in one allele
- de novo loss of function mutations in one allele
although the wild-type allele still produces the standard amount products..
the total product is insufficient to produce standard phenotype
NGLY1 is an
autosomal recessive disease which leads to N-glycanase 1 deficiency
N-glycanase 1 deficiency
o Impaired ability to deglycosylate protein cells accumulate misfolded glycoproteins
physical and neurological symptoms of NGLY1
o Lack of tears, developmental delay, movement disorder, elevated enzymes
coffin-siris syndrome occurs due a mutation in
ARID1B
what sort of mutation occurs in ARID1B to cause Coffin-Siris
de novo loss of function
ARID1B is a
o Chromatin remodeller (changes DNA accessibility for gene expression)
ARID1b is the
top diagnostic gene in DD-0.7%
phenotype of Cofin-Siris (ARID1B)
♣ Developmental delay, speech delay, abnormalities in pinky finger or toes, short sighted, feeding difficulties
♣ Overlaps with other disorders
treatment for coffin-siris
no treatment- genetic counselling
16p11.2 microdeletion/ duplication
- Copy number variants (deletion or duplication)
- Usually new ‘de novo’ dominant mutation
16p11.2 microdeletion/ duplication phenotypes
- intellectual disability, autism, developmental delay
o duplication- risk of being underweight
o deletion- risk of obesity
16p11.2 microdeletion/ duplication within
7-8 MB of DNA (over 60 genes)
Bardet-biedl syndrome (BBS)
and autosomal recessive disease, caused by SNVs and indells in one of 20 genes
phenotypes of BBS (primary)
Rod cone dystrophy, polydactyly obesity genital anomalies renal anomalies learning difficulties
phenotypes of BBS (Secondary)
speech delay
developmental delay
DM
