Deciphering Developmental Disorders (DDD) DDG2P

Transcription

1 Deciphering Developmental Disorders (DDD) DDG2P David FitzPatrick MRC Human Genetics Unit, University of Edinburgh

2 Deciphering Developmental Disorders objectives research understand genetics of DD translation NHS diagnostics probands recruited all variants non-functional common not DD gene allelism diagnosis consequence

3 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

4 initial data sources gene-disease pairs list Nature Genetics Am J Hum Genet XLID list (from Lucy Raymond) UKGTN etc mutation mechanism OMIM Primary Literature ClinVar/DECIPHER May 2015

5 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.

6 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 both imprinted digenic hemizygous x-linked dominant mosaic mitochondrial uncertain plausible disease-causing homozygous or compound heterozygous mutations identified on both alleles in the majority of with specific developmental disorder 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 plausible disease-causing mutations identified on one allele with the parent of origin determining the specific developmental disorder 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 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 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 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 plausible disease-causing mutations identified on mitochondial dna where homoplasmy or heteroplasmy are associated with a specific developmental disorder plausible disease-causing mutations in which the allele status is not recorded or is unclear with specific developmental disorder ClinVar/DECIPHER May 2015

7 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

8 gene-disease pair status category confirmed dd gene probable dd gene possible dd gene not dd gene both dd and if 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 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 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 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 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

9 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

10 how to validate DDD data DDG2P autocoding from OMIM are developmental disease genes special? where now live version (next talk) reconcile with other similar lists unbiased phenotype data

11 validation of DDG2P using DNMs bialellic DD genes monoalellic DD genes Number of mutations P>0.05 P> Observed 100 Expected P>0.05 P=10-47 P>0.05 P> Missense LoF Silent In-frame Frameshift 40 Observed Expected P=10-31 P=10-44 P>0.05 P>0.05 Missense LoF Silent In-frame Frameshift Number of mutations P=10-7 P>0.05 P=10-4 non-dd genes Observed Expected P=10-2 P=10-5 Missense LoF Silent In-frame Frameshift

12 dominant alleles s = 0.9 s = 0.5 s = 0.2 recessive alleles s = 0.9 s = 0.5 s = 0.2 number of generations

13 mutation tolerance within species (evs) disease genes non-disease genes across species (gerp++)

14 DDG2P genes

15 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

16 DDG2P vs non-ddg2p genes

17 unbiased phenotype data facial photographs HPO terms quantitative data

18 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

19 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