DD genomics Flashcards
DD are individually rare but collectively common
A. True
B. False
A. True
why is molecular/genetic diagnosis is important DD?*
- management - informs management (sometimes)
- treatment - helps to access special needs services
- prognosis - informs prognosis (sometimes)
- reproductive counselling - informs future reproductive decisions
why majority of DD remain undiagnosed after the standard NHS testing?
- diverse clinical features
- diverse molecular causes and inheritance
- majority is genetic
what are the range of phenotype associated with DD?*
- intellucrtual disability (87%)
- seizures (24%)
- autism spectrum disorder (10%)
- congenital heart defects (11%)
- hearing impairment (7%)
- oral cleft (6%)
- scoliosis (5%)
- polydactyl (1%)
what are the range of genes and genetic variants that can cause DD*
- > 1500 genes linked to DD
- genetic variants includes
1. single nucleotide variant (SNV)
2. insertion/deletion (indels)
3. copy number variations (CNVs)
4. chromosomal aneuploidies
what are three main types of DNA variants based on location?
- intronic/intergenic (non-coding)
- between genes or axons
- do not affect protein directly
- could affect regulation of transcription or splicing - gene/coding/exonic variants
- silent variant (synonymous)
- missense variant (non-synomous) changes AA
- nonsense variant resulting in premature STOP
- frameshift variants altering reading frame (deletions and insertions) - multi-expo/multigene
- structural variant can affect multiple genes e.g. copy number
what is two standard diagnostic testing for DD?*
- molecular genetics - sequencing of genes for genotyping specific small mutations
- uses sequencing and PCR
- detects SNVs and indels
- requires a priori hypothesis - cytogenetics - evaluating the genome for large structural changes that could reflect/explain the phenotype
- uses karyotyping, FISH, microarrays
- detects CNVs, chromosomal anueploidies, translocations, inversions
- do not require a priori hypothesis of cause
name two DD
- 16p11.2 mcirodeletion/duplication (de novo dominant mutation)
- Barnet-biedl syndrome (BBS) (autosomal recessive inheritance)
- Prader willi syndrome
- down syndrome
- SZ
what are the features of 16p11.2 micro deletion/duplication?
- CNVs (deletion/duplication-indels)
- de novo dominant mutations
- 7-8MB of DNA, >60 genes
- ID, autism, developmental delay
what does duplication and deletion in 16p11.2 micro deletion/duplication result in?
duplication -> risk of being underweight
deletion - risk of obesity
what are the features of BBS?
- SNVs and indels in one of ~20 genes
2. autosomal recessive inheritance
what are the modern diagnostic testing in DD?
- standard diagnostic testing
- targeted next generation sequencing
- genome wide sequencing using NGS
what is trio sequencing approach? and why is it powerful?*
genetic data from child and both parents are collected which hugely reduces number of candidate casual variants
how is exome sequencing used to diagnose rare diseases?*
- rare mutations in ~4000 genes are known to cause disease and there are many genes with unknown function
- therefore, exome sequencing enables the discovery of novel disease causing variation in previously unclassified genes
what are the challenges in working with GWS data?*
- enormous amount of genetic variation
- every genome contains a novel variation
- most genetic variation is benign
- phenotypic and genotypic heterogeneity
- disease inheritance and mechanism is unknown
- phenotypes may have more than one genetic cause
what is DDD?
deciphering developmental disorder is UK-collaborative studies of families, NHS and Sanger institute
what is Coffin-Siris (ARID1B) syndrome
a. caused by
b. prevalence
c. phenotypic spectrum
d. treatments
- cause by de novo loss of function of ARID1B - chromatin remodeller; changes DNA accessibility for gene expression
- top gene in DDD - diagnosis in 0.7% cases
- broad phenotypic spectrum - developmental delay, speech delay, abnormalities of fifth (pinky) fingers or toes, short sighted, feeding difficulties; overlapping with other disorders
- no current treatments - can counsel parents about low recurrence risk
what is Coffin-Siris (ARID1B) syndrome
- caused by
- its prevalence and rate of diagnosis
- phenotypic spectrum
- treatments
- cause by de novo loss of function of ARID1B - chromatin remodeller
- top gene in DDD - diagnosis in 0.7% cases
- broad phenotypic spectrum - developmental delay, speech delay, abnormalities of fifth (pinky) fingers or toes, short sighted, feeding difficulties; overlapping with other disorders
- no current treatments - can counsel parents low recurrence risk
how to find out more DD genes?
- recruit more patients
- persuade other researchers to give us their data (i.e. collaborate with other similar cohorts)
- share our data with other researchers
what is the cause and diagnosis for KMT2B mutations?
- de novo mutations cause dystonia and ID
- diagnosis involve es DNA packing and gene expression
- patients successfully treated with deep brain stimulation
what is the advantage of NGS and how is it beneficial for us?*
- has enabled simultaneous sequencing of all genes
- many new disease caused by genes are discovered
- large burden of casual de novo mutations through trio sequencing
- helps target treatments
what are the ethical issues in sequencing and what is it caused by?
- caused by data size and broad applicability
- since variation interpretation is challenging so need to share data
- concerns for handling incidental and secondary findings