schema support for regulatory fusions

server/app/graphql/mutations/create_fusion_feature.rb

@@ -36,14 +36,22 @@ def ready?(organization_id: nil, five_prime_gene:, three_prime_gene:,**kwargs)
 
     #check that partner status matches gene_id presence
     [five_prime_gene, three_prime_gene].each do |gene_input|
-      if gene_input.gene_id.present? && gene_input.partner_status != 'known'
-        raise GraphQL::ExecutionError, "Partner status needs to be 'known' if a gene_id is set"
+      if gene_input.gene_id.present? && (gene_input.partner_status != 'known' || gene_input.partner_status != 'regulatory')
+        raise GraphQL::ExecutionError, "Partner status needs to be 'known' or 'regulatory' if a gene_id is set"
       end
-      if gene_input.gene_id.blank? && gene_input.partner_status == 'known'
-        raise GraphQL::ExecutionError, "Partner status can't be 'known' if a gene_id is not set"
+      if gene_input.gene_id.blank? && (gene_input.partner_status == 'known' && gene_input.partner_status != 'regulatory')
+        raise GraphQL::ExecutionError, "Partner status can't be 'known' or 'regulatory' if a gene_id is not set"
       end
     end
 
+    #check that maximuim one gene has regulatory_fusion_type set
+    if five_prime_gene.partner_status == 'regulatory' && three_prime_gene.partner_status == 'regulatory'
+      raise GraphQL::ExecutionError, "Only one Fusion partner can be marked 'regulatory'"
+    end
+    if five_prime_gene.regulatory_fusion_type.present? && three_prime_gene.regulatory_fusion_type.present?
+      raise GraphQL::ExecutionError, "Only one Fusion partner can have a regulatory fusion type set."
+    end
+
     return true
   end
 
@@ -54,12 +62,16 @@ def authorized?(organization_id: nil, **kwargs)
 
   def resolve(five_prime_gene:, three_prime_gene:, organization_id: nil)
 
+    #only one can be set
+    regulatory_fusion_type = five_prime_partner_status.regulatory_fusion_type || three_prime_partner_status.regulatory_fusion_type
+
     existing_feature_instance = Features::Fusion
       .find_by(
         five_prime_gene_id: five_prime_gene.gene_id,
         three_prime_gene_id: three_prime_gene.gene_id,
         five_prime_partner_status: five_prime_gene.partner_status,
         three_prime_partner_status: three_prime_gene.partner_status,
+        regulatory_fusion_type: regulatory_fusion_type
       )
 
     if existing_feature_instance.present?
@@ -74,6 +86,7 @@ def resolve(five_prime_gene:, three_prime_gene:, organization_id: nil)
         three_prime_gene_id: three_prime_gene.gene_id,
         five_prime_partner_status: five_prime_gene.partner_status,
         three_prime_partner_status: three_prime_gene.partner_status,
+        regulatory_fusion_type: regulatory_fusion_type,
         originating_user: context[:current_user],
         organization_id: organization_id,
       )

server/app/graphql/types/entities/fusion_type.rb

@@ -7,6 +7,8 @@ class FusionType < Types::Entities::FeatureType
     field :five_prime_partner_status, Types::Fusion::FusionPartnerStatus, null: false
     field :three_prime_partner_status, Types::Fusion::FusionPartnerStatus, null: false
 
+    field :regulatory_fusion_type, Types::Fusion::RegulatoryFusionTypeType, null: true
+
     def five_prime_gene
       Loaders::AssociationLoader.for(Features::Fusion, :five_prime_gene).load(object)
     end

server/app/graphql/types/fusion/fusion_partner_input_type.rb

@@ -6,5 +6,7 @@ class FusionPartnerInputType < Types::BaseInputObject
       description: 'The status of the fusion partner'
     argument :gene_id, Int, required: false,
       description: 'The CIViC gene ID of the partner, if known'
+    argument :regulatory_fusion_type, Types::Fusion::RegulatoryFusionTypeType, required: false,
+      description: "If the fusion partner status is set to regulatory, what type of regulatory fusion is it?"
   end
 end

server/app/graphql/types/fusion/fusion_partner_status.rb

@@ -3,5 +3,6 @@ class FusionPartnerStatus < Types::BaseEnum
     value 'KNOWN', value: 'known'
     value 'UNKNOWN', value: 'unknown'
     value 'MULTIPLE', value: 'multiple'
+    value 'REGULATORY', value: 'regulatory'
   end
 end

server/app/graphql/types/fusion/regulatory_fusion_type_type.rb

@@ -0,0 +1,7 @@
+module Types::Fusion
+  class RegulatoryFusionTypeType < Types::BaseEnum
+    Constants::REGULATORY_FUSION_ENUM_TYPES.each do |(name, _)|
+      value name.upcase, value: name
+    end
+  end
+end

server/app/models/actions/create_fusion_feature.rb

@@ -2,9 +2,9 @@ module Actions
   class CreateFusionFeature
     include Actions::Transactional
 
-    attr_reader :feature, :originating_user, :organization_id, :create_variant, :five_prime_partner_status, :three_prime_partner_status
+    attr_reader :feature, :originating_user, :organization_id, :create_variant, :five_prime_partner_status, :three_prime_partner_status, :regulatory_fusion_type
 
-    def initialize(originating_user:, five_prime_gene_id:, three_prime_gene_id:, five_prime_partner_status:, three_prime_partner_status:, organization_id: nil, create_variant: true)
+    def initialize(originating_user:, five_prime_gene_id:, three_prime_gene_id:, five_prime_partner_status:, three_prime_partner_status:, regulatory_fusion_type:, organization_id: nil, create_variant: true)
       feature_name = "#{construct_fusion_partner_name(five_prime_gene_id, five_prime_partner_status)}::#{construct_fusion_partner_name(three_prime_gene_id, three_prime_partner_status)}"
       @feature = Feature.new(
         name: feature_name,
@@ -14,10 +14,12 @@ def initialize(originating_user:, five_prime_gene_id:, three_prime_gene_id:, fiv
         three_prime_gene_id: three_prime_gene_id,
         five_prime_partner_status: five_prime_partner_status,
         three_prime_partner_status: three_prime_partner_status,
+        regulatory_fusion_type: regulatory_fusion_type,
         feature: feature,
       )
       @five_prime_partner_status = five_prime_partner_status
       @three_prime_partner_status = three_prime_partner_status
+      @regulatory_fusion_type = regulatory_fusion_type
       @originating_user = originating_user
       @organization_id = organization_id
       @create_variant = create_variant
@@ -26,6 +28,10 @@ def initialize(originating_user:, five_prime_gene_id:, three_prime_gene_id:, fiv
     def construct_fusion_partner_name(gene_id, partner_status)
       if partner_status == 'known'
         Features::Gene.find(gene_id).name
+      elseif partner_status == 'regulatory'
+        gene_name = Features::Gene.find(gene_id).name
+        rft = Features::Fusion.format_regulatory_fusion_type(regulatory_fusion_type)
+        "#{rft}@#{gene_name}"
       elsif partner_status == 'unknown'
         '?'
       elsif partner_status == 'multiple'

server/app/models/activities/create_fusion_feature.rb

@@ -1,13 +1,14 @@
 module Activities
   class CreateFusionFeature < Base
-    attr_reader :feature, :five_prime_gene_id, :three_prime_gene_id, :five_prime_partner_status, :three_prime_partner_status, :create_variant
+    attr_reader :feature, :five_prime_gene_id, :three_prime_gene_id, :five_prime_partner_status, :three_prime_partner_status, :create_variant, :regulatory_fusion_type
 
-    def initialize(originating_user:, organization_id:, five_prime_gene_id:, three_prime_gene_id:, five_prime_partner_status:, three_prime_partner_status:, create_variant: true)
+    def initialize(originating_user:, organization_id:, five_prime_gene_id:, three_prime_gene_id:, five_prime_partner_status:, three_prime_partner_status:, regulatory_fusion_type:, create_variant: true)
       super(organization_id: organization_id, user: originating_user)
       @five_prime_gene_id = five_prime_gene_id
       @three_prime_gene_id = three_prime_gene_id
       @five_prime_partner_status = five_prime_partner_status
       @three_prime_partner_status = three_prime_partner_status
+      @regulatory_fusion_type = regulatory_fusion_type
       @create_variant = create_variant
     end
 
@@ -25,6 +26,7 @@ def call_actions
         three_prime_gene_id: three_prime_gene_id,
         five_prime_partner_status: five_prime_partner_status,
         three_prime_partner_status: three_prime_partner_status,
+        regulatory_fusion_type: regulatory_fusion_type,
         originating_user: user,
         organization_id: organization&.id,
         create_variant: create_variant

server/app/models/constants.rb

@@ -138,4 +138,38 @@ module Constants
   ENSEMBL_TRANSCRIPT_ID_FORMAT = /\AENST\d{11}\.\d{1,2}\z/
 
   REPRESENTATIVE_FUSION_VARIANT_NAME = 'Fusion'
+
+  # INSDC regulatory class vocabulary as required here: https://fusions.cancervariants.org/en/latest/nomenclature.html#regulatory-nomenclature
+  REGULATORY_FUSION_TYPES = [
+      ["attenuator", "SO:0000140"],
+      ["CAAT_signal", "SO:0000172"],
+      ["DNase_I_hypersensitive_site", "SO:0000685"],
+      ["enhancer", "SO:0000165"],
+      ["enhancer_blocking_element", nil],
+      ["GC_signal", "SO:0000173"],
+      ["imprinting_control_region", nil],
+      ["insulator", "SO:0000627"],
+      ["locus_control_region", "SO:0000037"],
+      ["matrix_attachment_region", "SO:0000036"],
+      ["minus_35_signal", "SO:0000176"],
+      ["minus_10_signal", "SO:0000175"],
+      ["polyA_signal_sequence", "SO:0000551"],
+      ["promoter", "SO:0000167"],
+      ["recoding_stimulatory_region", "SO:1001268"],
+      ["recombination_enhancer", "SO:0002059"],
+      ["replication_regulatory_region", "SO:0001682"],
+      ["response_element", nil],
+      ["ribosome_binding_site", "SO:0000552"],
+      ["riboswitch", "SO:0000035"],
+      ["silencer", "SO:0000625"],
+      ["TATA_box", "SO:0000174"],
+      ["terminator", "SO:0000141"],
+      ["transcriptional_cis_regulatory_region", "SO:0001055"],
+      ["uORF", "SO:0002027"],
+      ["other", nil]
+    ].map { |(type, soid)|  ["reg_#{type}", soid] }
+
+    REGULATORY_FUSION_ENUM_TYPES = REGULATORY_FUSION_TYPES.map { |(type, _)| [type, type] }.to_h
+
+    FUSION_PARTNER_STATUSES = [ 'known', 'unknown', 'multiple', 'regulatory' ].map { [_1, _1] }.to_h
 end

server/app/models/features/fusion.rb

@@ -6,49 +6,33 @@ class Fusion < ActiveRecord::Base
     belongs_to :five_prime_gene, class_name: 'Features::Gene', optional: true
     belongs_to :three_prime_gene, class_name: 'Features::Gene', optional: true
 
-    enum five_prime_partner_status: {
-      known: 'known',
-      unknown: 'unknown',
-      multiple: 'multiple',
-    }, _prefix: true
+    enum five_prime_partner_status: Constants::FUSION_PARTNER_STATUSES, _prefix: true
+    enum three_prime_partner_status: Constants::FUSION_PARTNER_STATUSES, _prefix: true
 
-    enum three_prime_partner_status: {
-      known: 'known',
-      unknown: 'unknown',
-      multiple: 'multiple',
-    }, _prefix: true
+    enum regulatory_fusion_type: Constants::REGULATORY_FUSION_ENUM_TYPES
 
     has_many :variant_groups
     has_many :source_suggestions
 
     #TODO - move to feature?
     has_many :comment_mentions, foreign_key: :comment_id, class_name: 'EntityMention'
 
-    validate :partner_status_valid_for_gene_ids
-    validate :at_least_one_gene_id
+    validates_with FusionFeatureValidator
 
-    def partner_status_valid_for_gene_ids
-      if !self.in_revision_validation_context
-        [self.five_prime_gene, self.three_prime_gene].zip([self.five_prime_partner_status, self.three_prime_partner_status], [:five_prime_gene, :three_prime_gene]).each do |gene, status, fk|
-          if gene.nil? && status == 'known'
-            errors.add(fk, "Partner status cannot be 'known' if the gene isn't set")
-          elsif !gene.nil? && status != 'known'
-            errors.add(fk, "Partner status has to be 'known' if gene is set")
-          end
-        end
-      end
+    def display_name
+      name
     end
 
-    def at_least_one_gene_id
-      if !self.in_revision_validation_context && self.five_prime_gene_id.nil? && self.three_prime_gene_id.nil?
-        errors.add(:base, "One or both of the genes need to be set")
+    def self.format_regulatory_fusion_type(rft)
+      if rft == 'reg_enhancer'
+        'reg_e'
+      elsif rft == 'reg_promoter'
+        'reg_p'
+      else
+        rft
       end
     end
 
-    def display_name
-      name
-    end
-
     def editable_fields
       [
         :description,

server/app/models/variant_type.rb

@@ -3,6 +3,7 @@ class VariantType < ActiveRecord::Base
 
   has_and_belongs_to_many :variants
   has_and_belongs_to_many :pipeline_types
+  enum regulatory_fusion_type: Constants::REGULATORY_FUSION_ENUM_TYPES
 
   def url
     if self.soid != "N/A"

server/db/migrate/20250102170055_add_regulatory_fusion_types_enum.rb

@@ -0,0 +1,26 @@
+class AddRegulatoryFusionTypesEnum < ActiveRecord::Migration[7.1]
+  def up
+    create_enum :regulatory_fusion_types, Constants::REGULATORY_FUSION_TYPES.map(&:first)
+    add_enum_value :fusion_partner_status, "regulatory"
+
+    add_column :variant_types, :regulatory_fusion_type, :enum, enum_type: :regulatory_fusion_types, null: true
+    add_column :fusions, :regulatory_fusion_type, :enum, enum_type: :regulatory_fusion_types, null: true
+    add_index :variant_types, :regulatory_fusion_type
+
+    Constants::REGULATORY_FUSION_TYPES.each do |(type, soid)|
+      if soid.present?
+        vt = VariantType.find_by!(soid: soid)
+        vt.regulatory_fusion_type = type
+        vt.save!
+      end
+    end
+  end
+
+  def down
+    remove_column :variant_types, :regulatory_fusion_type
+    remove_column :fusions, :regulatory_fusion_type
+    execute <<-SQL
+      DROP TYPE regulatory_fusion_types;
+    SQL
+  end
+end

server/db/schema.rb

@@ -10,15 +10,17 @@
 #
 # It's strongly recommended that you check this file into your version control system.
 
-ActiveRecord::Schema[7.1].define(version: 2024_09_14_154057) do
+ActiveRecord::Schema[7.1].define(version: 2025_01_02_170055) do
   # These are extensions that must be enabled in order to support this database
   enable_extension "plpgsql"
 
   # Custom types defined in this database.
   # Note that some types may not work with other database engines. Be careful if changing database.
   create_enum "exon_coordinate_record_state", ["stub", "exons_provided", "fully_curated"]
   create_enum "exon_offset_direction", ["positive", "negative"]
-  create_enum "fusion_partner_status", ["known", "unknown", "multiple"]
+  create_enum "fusion_partner_status", ["known", "unknown", "multiple", "regulatory"]
+  create_enum "regulatory_fusion_partner", ["five_prime", "three_prime"]
+  create_enum "regulatory_fusion_types", ["reg_attenuator", "reg_CAAT_signal", "reg_DNase_I_hypersensitive_site", "reg_enhancer", "reg_enhancer_blocking_element", "reg_GC_signal", "reg_imprinting_control_region", "reg_insulator", "reg_locus_control_region", "reg_matrix_attachment_region", "reg_minus_35_signal", "reg_minus_10_signal", "reg_polyA_signal_sequence", "reg_promoter", "reg_recoding_stimulatory_region", "reg_recombination_enhancer", "reg_replication_regulatory_region", "reg_response_element", "reg_ribosome_binding_site", "reg_riboswitch", "reg_silencer", "reg_TATA_box", "reg_terminator", "reg_transcriptional_cis_regulatory_region", "reg_uORF", "reg_other"]
   create_enum "variant_coordinate_record_state", ["stub", "fully_curated"]
 
   create_table "acmg_codes", id: :serial, force: :cascade do |t|
@@ -106,6 +108,20 @@
     t.index ["user_id"], name: "index_affiliations_on_user_id"
   end
 
+  create_table "api_keys", force: :cascade do |t|
+    t.string "bearer_type"
+    t.bigint "bearer_id"
+    t.text "token_prefix", null: false
+    t.text "token_suffix", null: false
+    t.text "token_digest", null: false
+    t.boolean "revoked", default: false, null: false
+    t.datetime "created_at", null: false
+    t.datetime "updated_at", null: false
+    t.index ["bearer_type", "bearer_id"], name: "index_api_keys_on_bearer"
+    t.index ["revoked"], name: "index_api_keys_on_revoked"
+    t.index ["token_digest"], name: "index_api_keys_on_token_digest", unique: true
+  end
+
   create_table "assertions", id: :serial, force: :cascade do |t|
     t.text "description"
     t.datetime "created_at", precision: nil
@@ -536,6 +552,7 @@
     t.enum "three_prime_partner_status", default: "unknown", null: false, enum_type: "fusion_partner_status"
     t.datetime "created_at", null: false
     t.datetime "updated_at", null: false
+    t.enum "regulatory_fusion_type", enum_type: "regulatory_fusion_types"
     t.index ["five_prime_gene_id"], name: "index_fusions_on_five_prime_gene_id"
     t.index ["three_prime_gene_id"], name: "index_fusions_on_three_prime_gene_id"
   end
@@ -963,8 +980,10 @@
     t.integer "parent_id"
     t.integer "lft"
     t.integer "rgt"
+    t.enum "regulatory_fusion_type", enum_type: "regulatory_fusion_types"
     t.index ["display_name"], name: "index_variant_types_on_display_name"
     t.index ["name"], name: "index_variant_types_on_name"
+    t.index ["regulatory_fusion_type"], name: "index_variant_types_on_regulatory_fusion_type"
     t.index ["soid"], name: "index_variant_types_on_soid"
   end
 

server/test/fixtures/feature_fusions.yml

@@ -0,0 +1,27 @@
+braf_vhl_fusion:
+  five_prime_gene: braf
+  three_prime_gene: vhl
+  five_prime_partner_status: known
+  three_prime_partner_status: known
+  regulatory_fusion_type: reg_enhancer
+
+braf_fusion:
+  five_prime_gene: braf
+  three_prime_gene: null
+  five_prime_partner_status: known
+  three_prime_partner_status: unknown
+  regulatory_fusion_type: null
+
+vhl_fusion:
+  five_prime_gene: null
+  three_prime_gene: vhl
+  five_prime_partner_status: unknown
+  three_prime_partner_status: known
+  regulatory_fusion_type: null
+
+regulatory_fusion:
+  five_prime_gene: braf
+  three_prime_gene: vhl
+  five_prime_partner_status: regulatory
+  three_prime_partner_status: known
+  regulatory_fusion_type: reg_enhancer

server/test/fixtures/features.yml

@@ -13,3 +13,8 @@ msi:
   full_name: Microsatellite Instability
   description: The description for the MSI factor
   feature_instance: msi (Features::Factor)
+
+braf_fusion:
+  name: BRAF::?
+  description: BRAF and unknown partner
+  feature_instance: braf_fusion (Features::Fusion)