DDG2P (Developmental Disorder Genotype-Phenotype Database) 

The DDG2P dataset integrates data on genes, variants and phenotypes relating to developmental disorders. It is produced and curated in good faith by UK consultant clinical geneticists, but we cannot guarantee its accuracy or comprehensiveness. It is primarily an inclusion list, although it contains a small number of genes that are not associated with developmental disorders. We are constantly working to update and improve the data, and caution should therefore be exercised in its application. Please do not distribute this file, but refer interested parties to ddg2p-help@sanger.ac.uk for further information.

Please acknowledge the DDD study (www.ddduk.org) if you use this list in your analyses or publications.

What follows is the definition of categories used in the list.
1. DDG2P status (confirmed, probable, not DD, IF, etc)
2. Inheritance (biallelic, monoallelic, hemizygous, etc)
3. Mutation consequence (LOF, activating, etc.)


1. DDG2P Status

Confirmed DD gene
(a) 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*** 
(b) 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 
(c) As definition (a) and (b) 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 (Recurrent de novo mutations convincingly affecting gene function; rare, fully-penetrant mutations - relevant genotype never seen in contols) 
** Interpretable functional region (ORF in protein coding genes; miRNA stem or loop)
*** DD: Developmental disorder in which the most prominent pathogenetic mechanism occurs during embryogenesis or early brain development. Early onset degenerative disorders that may mimic above definition are includes; for example Sanfillipo syndrome which can mimic global developmental delay

Probable DD gene
(a) 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
(b) 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 
(c) 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

Possible DD gene
(a) 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
(b) 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 
(c) 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
No plausible disease-causing mutations within, affecting or encompassing the coding region in a developmental disorder AND not an IF gene

Child IF
Plausible disease-causing mutations within, affecting or encompassing the coding region of a single gene identified in multiple (>3) unrelated cases/families with a incidental (non-developmental) disorder that has significant medical implications and presents during childhood

IF Gene: Adult Rx
Plausible disease-causing mutations within, affecting or encompassing the coding region of a single gene identified in multiple (>3) unrelated cases/families with a incidental (non-developmental) disorder that has recommended medical interventions and presents during adult life

IF Gene: Adult No Rx
Plausible disease-causing mutations within, affecting or encompassing the coding region of a single gene identified in multiple (>3) unrelated cases/families with a incidental (non-developmental) disorder that has no useful medical interventions and presents during adult life

Both DD and IF
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


2. Inheritance

Monoalellic : Plausible disease-causing mutations identified on one allele in all or the vast majority of with specific developmental disorder 

Bialellic : 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 


3. Mutation Consequence 

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 constitutive 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

