Download DDG2P

Deciphering Developmental Disorders (DDD)
DDG2P
David FitzPatrick
MRC Human Genetics Unit, University of Edinburgh
ClinVar/DECIPHER 2015
Deciphering Developmental Disorders
objectives
• research
• understand genetics of DD
• translation
• NHS diagnostics
• 13928 probands recruited
all variants
non-functional
common
allelism
not DD gene
diagnosis
consequence
ClinVar/DECIPHER 2015
DDG2P
aim:
• link genotype to developmental disorder with mutation
mechanism to enable rule-based reporting of variants
requirement:
• catalog of known developmental disorder loci
• record likely mutational consequence
• link to phenotypic ontology
• link to primary evidence (PMIDs)
ClinVar/DECIPHER May 2015
initial data sources
gene-disease pairs list
• Nature Genetics 2005-2012
• Am J Hum Genet 2005-2012
• XLID list (from Lucy Raymond)
• UKGTN etc
mutation mechanism
• OMIM
• Primary Literature
ClinVar/DECIPHER May 2015
DDG2P
• clinician-curated based on publications
• updated in pipeline every ~6 months
• allows iterative diagnostic reporting
GENE
EVIDENCE
MODE
CONSEQUENCE
[gene name]
Confirmed
Probable
Possible
Etc.
Monoallelic
Biallelic
Hemizygous
Etc.
LOF
Activating
Gene dosage
Etc.
ClinVar/DECIPHER 2015
allelic requirement
category
description
monoallelic
plausible disease-causing mutations identified on one allele in all or the vast majority of with specific developmental disorder
biallelic
plausible disease-causing homozygous or compound heterozygous mutations identified on both alleles in the majority of with
specific developmental disorder
both
plausible disease-causing mutations identified on either one or both alleles in a specific developmental disorder where the mono
allelic cases cannot be accounted for by false negative screens on the other allele
imprinted
plausible disease-causing mutations identified on one allele with the parent of origin determining the specific developmental
disorder
digenic
plausible disease-causing mutations identified on one or both alleles of two different genes causing a specific developmental
disorder where similar mutations of either gene would not
hemizygous
plausible disease-causing mutations identified on the x chromosome in a male as a cause of a specific developmental disorder, the
disorder being predominantly recessive in female carriers
x-linked dominant
plausible disease-causing mutations identified one copy of the x chromosome in females as a cause of a specific developmental
disorder, includes disorders where heterozygous females and hemizygous males are similarly affected e.g. smc1a mutations
mosaic
plausible disease-causing mutations identified on one allele in a proportion of cells with the others being wild-type as a cause of a
specific developmental disorder
mitochondrial
plausible disease-causing mutations identified on mitochondial dna where homoplasmy or heteroplasmy are associated with a
specific developmental disorder
uncertain
plausible disease-causing mutations in which the allele status is not recorded or is unclear with specific developmental disorder
ClinVar/DECIPHER May 2015
mutation consequence
category
description
loss of function
nonsense, frame-shifting indel, essential splice site mutation, whole gene deletion or any other mutation where
functional analysis demonstrates clear reduction or loss of function
all missense/in frame
where all the mutations described in the data source are either missense or in frame deletions and there is no
evidence favoring either loss-of-function, activating or dominant negative effect
dominant negative
mutation within one allele of a gene that creates a significantly greater deleterious effect on gene product function
than a monoallelic loss of function mutation
activating
mutation, usually missense that results in a constituative functional activation of the gene product
increased gene dosage
copy number variation that increases the functional dosage of the gene
cis-regulatory or promotor
mutation
mutation in cis-regulatory elements that lies outwith the known transcription unit and promotor of the controlled
gene
uncertain
where the exact nature of the mutation is unclear or not recorded
ClinVar/DECIPHER May 2015
gene-disease pair status
category
description
plausible disease-causing mutations* within, affecting or encompassing an interpretable functional region** of a single
gene identified in multiple (>3) unrelated cases/families with a developmental disorder***
plausible disease-causing mutations within, affecting or encompassing cis-regulatory elements convincingly affecting the
confirmed dd gene expression of a single gene identified in multiple (>3) unrelated cases/families with a developmental disorder
as definition 1 and 2 of probable dd gene (see below) with addition of convincing bioinformatic or functional evidence of
causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant
deficient enzymatic activity in other species; existence of animal mode which recapitulates the human phenotype
plausible disease-causing mutations within, affecting or encompassing an interpretable functional region of a single gene
identified in more than one (2 or 3) unrelated cases/families or segregation within multiple individuals within a single large
family with a developmental disorder
probable dd gene
plausible disease-causing mutations within, affecting or encompassing cis-regulatory elements convincingly affecting the
expression of a single gene identified in in more than one (2 or 3) unrelated cases/families with a developmental disorder
as definitions of possible dd gene (see below) with addition of convincing bioinformatic or functional evidence of causation e.g.
known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic
activity in other species; existence of animal mode which recapitulates the human phenotype
plausible disease-causing mutations within, affecting or encompassingan interpretable functional region of a single gene
identified in one case or segregation within multiple individuals within a small family with a developmental disorder
possible dd gene
plausible disease-causing mutations within, affecting or encompassing cis-regulatory elements convincingly affecting the
expression of a single gene identified in one case/family with a developmental disorder
possible disease-causing mutations within, affecting or encompassing an interpretable functional region of a single gene
identified in more than one unrelated cases/families or segregation within multiple individuals within a single large family with a
developmental disorder
not dd gene
both dd and if
no plausible disease-causing mutations within, affecting or encompassing the coding region in a developmental disorder
and not an if gene
plausible disease-causing mutations within, affecting or encompassing the coding region of a single gene identified in multiple
(>3) unrelated cases/families with both a developmental disorder and an incidental (non-developmental) disorder
ClinVar/DECIPHER May 2015
DDG2P
• 1442 reportable genes
• 1968 gene-disease relationships: evidence
– 73% confirmed
– 12% probable
– 10% possible
• gene-disease relationships: allelic requirements
– 34% monoallelic: autosomal
– 9.3% monoallelic: X
– 55% biallelic
• gene-disease relationships: mutation consequence
– 69% loss-of-function
– 4.5% activating
– 14% all missense/in-frame
ClinVar/DECIPHER 2015
DDG2P
• how to validate
– DDD data
– autocoding from OMIM
• are developmental disease genes
special?
• where now
– live version (next talk)
– reconcile with other similar lists
– unbiased phenotype data
ClinVar/DECIPHER 2015
“validation” of DDG2P using DNMs
bialellic DD genes
40
120
P>0.05
Observed
100
Expected
P>0.05
10
P>0.05
Observed
Expected
P=10-31
60
P>0.05
20
P=10-47
80
30
P=10-44
40
P>0.05
P>0.05
20
0
Missense
LoF
Silent
0
In-frame Frameshift
Number of mutations
Number of mutations
50
monoalellic DD genes
800
700
600
500
400
300
200
100
0
Missense
P=10-7
LoF
Silent
P>0.05
In-frame Frameshift
Observed
Expected
P>0.05
P=10-4
Missense
LoF
P=10-2 P=10-5
Silent
In-frame Frameshift
non-DD genes
ClinVar/DECIPHER 2015
dominant alleles
recessive alleles
s = 0.9
s = 0.5
s = 0.2
s = 0.9
s = 0.5
s = 0.2
number of generations
ClinVar/DECIPHER 2015
within species (evs)
mutation tolerance
non-disease
genes
disease
genes
across species (gerp++)
ClinVar/DECIPHER 2015
DDG2P genes
ClinVar/DECIPHER 2015
comparison with “G2P” autocoding via OMIM API
• autocoding
– OMIM morbid
– gene-disease pair associated PMID -> confidence
– associate variants -> consequence
– clinical synopsis: inheritance -> allelic requirements
– correlation very high (allowing 6 mo time lag) with DDG2P
– … now have coding for non-DDG2P genes
ClinVar/DECIPHER 2015
DDG2P vs non-DDG2P genes
ClinVar/DECIPHER 2015
unbiased phenotype data
facial photographs
HPO terms
quantitative data
ClinVar/DECIPHER 2015
DDG2P challenges
• upgrading and downgrading gene-disease pairs
• we need a genotype-based phenotypic database for
developmental disorders
• implementing this diagnostic approach in UK health
service
• (others to) expand to different disease areas
ClinVar/DECIPHER 2015
DDD team at Sanger
Lab: Kirsty Ambridge, Daniel Barrett, Tanya Bayzetinova, Sebastian Gerety, Susan Gribble, Netra
Krishnappa, Laura Mason, Elena Prigmore, Di Rajan
Informatics & Analysis: Stephen Clayton, Tom Fitzgerald, Phil Jones, Wendy Jones, Dan King,
Margriet van Kogelenberg, Jeremy McRae, Ray Miller, Kate Morley, Vijaya Parthiban, Adrian Tivey
DECIPHER: Paul Bevan, Eugene Bragin, Eleni Chatzimichali, Jawahar Swaminathan
Ethics: Anna Middleton
Management: Jeff Barrett, [Nigel Carter], Helen Firth, David FitzPatrick, Matt Hurles, Mike Parker,
Caroline Wright
Sanger pipelines
24 Regional Genetics Services
Patients and families
ClinVar/DECIPHER 2015