Hereditary attention deficit-hyperactivity disorder

Summary

Hereditary attention deficit-hyperactivity disorder (MONDO:0100518) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 20

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary attention deficit-hyperactivity disorder
Mondo ID	MONDO:0100518
OMIM	143465
Is cancer (heuristic)	no

Data availability: 20 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › psychiatric disorder › mental disorder › developmental disorder of mental health › specific developmental disorder › attention deficit-hyperactivity disorder › hereditary attention deficit-hyperactivity disorder

Related subtypes (2): attention deficit hyperactivity disorder, inattentive type, attention deficit-hyperactivity disorder 8

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

20 retrieved; paginated sample, class counts are floors:

14 uncertain significance, 5 conflicting classifications of pathogenicity, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3065214	NM_000797.4(DRD4):c.155dup (p.Asn52fs)	DRD4	Likely pathogenic	criteria provided, single submitter
1206183	NM_000797.4(DRD4):c.860A>C (p.Gln287Pro)	DRD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2507405	NM_000797.4(DRD4):c.933T>G (p.Ala311=)	DRD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2507412	NM_000797.4(DRD4):c.807T>C (p.Leu269=)	DRD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2507415	NM_000797.4(DRD4):c.816T>C (p.Gly272=)	DRD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1287057	NM_000798.5(DRD5):c.*47T>C	DRD5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1678227	NM_000797.4(DRD4):c.763del (p.Gln255fs)	DRD4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2346771	NM_000797.4(DRD4):c.922T>C (p.Ser308Pro)	DRD4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2346772	NM_000797.4(DRD4):c.925A>G (p.Asn309Asp)	DRD4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2507404	NM_000797.4(DRD4):c.-11C>T	DRD4	Uncertain significance	criteria provided, single submitter
2507406	NM_000797.4(DRD4):c.1058-32G>C	DRD4	Uncertain significance	criteria provided, single submitter
2507413	NM_000797.4(DRD4):c.812G>A (p.Arg271Gln)	DRD4	Uncertain significance	criteria provided, single submitter
2507414	NM_000797.4(DRD4):c.815G>A (p.Gly272Asp)	DRD4	Uncertain significance	criteria provided, single submitter
2507416	NM_000797.4(DRD4):c.850A>G (p.Ser284Gly)	DRD4	Uncertain significance	criteria provided, single submitter
2585270	NM_000797.4(DRD4):c.52_62del (p.Pro18fs)	DRD4	Uncertain significance	criteria provided, single submitter
2585465	NM_000797.4(DRD4):c.869_870insTGG (p.Gly291_Pro292insGly)	DRD4	Uncertain significance	criteria provided, single submitter
3065404	NM_000797.4(DRD4):c.759_806dup (p.Pro270_Arg271insGlnAspProCysGlyProAspCysAlaProProAlaProGlyLeuPro)	DRD4	Uncertain significance	criteria provided, single submitter
3236631	NM_000797.4(DRD4):c.485T>G (p.Leu162Arg)	DRD4	Uncertain significance	criteria provided, single submitter
4292888	NM_000797.4(DRD4):c.285+2T>G	DRD4	Uncertain significance	criteria provided, single submitter
2507407	NM_000798.5(DRD5):c.978C>T (p.Pro326=)	DRD5	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 0 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DRD4	HGNC:3025	ENSG00000069696	P21917	D(4) dopamine receptor	clinvar
DRD5	HGNC:3026	ENSG00000169676	P21918	D(1B) dopamine receptor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DRD4	D(4) dopamine receptor	Dopamine receptor responsible for neuronal signaling in the mesolimbic system of the brain, an area of the brain that regulates emotion and complex behavior.
DRD5	D(1B) dopamine receptor	Dopamine receptor whose activity is mediated by G proteins which activate adenylyl cyclase.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
GPCR	2	23.9×	0.002

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DRD4	GPCR	yes		GPCR_Rhodpsn, Dopamine_rcpt, Dopamine_D4_rcpt
DRD5	GPCR	yes		GPCR_Rhodpsn, Dopamine_D5_rcpt, Dopamine_rcpt

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lower esophagus mucosa	1
male germ line stem cell (sensu Vertebrata) in testis	1
right uterine tube	1
ileal mucosa	1
pancreatic ductal cell	1
tibialis anterior	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DRD4	130	broad	yes	male germ line stem cell (sensu Vertebrata) in testis, lower esophagus mucosa, right uterine tube
DRD5	64	tissue_specific	yes	pancreatic ductal cell, tibialis anterior, ileal mucosa

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DRD4	1,480
DRD5	1,086

Intra-cohort edges

A	B	Sources
DRD4	DRD5	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DRD4	P21917	2
DRD5	P21918	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Dopamine receptors	2	2284.0×	5e-07	DRD4, DRD5
G alpha (s) signalling events	1	36.6×	0.041	DRD5
G alpha (i) signalling events	1	19.5×	0.051	DRD4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
phospholipase C-activating dopamine receptor signaling pathway	2	2106.5×	8e-06	DRD4, DRD5
response to amphetamine	2	495.6×	8e-05	DRD4, DRD5
intracellular calcium ion homeostasis	2	145.3×	7e-04	DRD4, DRD5
obsolete negative regulation of NAD(P)H oxidase activity	1	8426.0×	1e-03	DRD5
regulation of female receptivity	1	8426.0×	1e-03	DRD5
positive regulation of MAPK cascade	2	80.6×	1e-03	DRD4, DRD5
chemical synaptic transmission	2	77.3×	1e-03	DRD4, DRD5
norepinephrine-epinephrine vasoconstriction involved in regulation of systemic arterial blood pressure	1	4213.0×	0.001	DRD5
sensitization	1	2808.7×	0.001	DRD5
positive regulation of dopamine uptake involved in synaptic transmission	1	2808.7×	0.001	DRD4
response to histamine	1	2106.5×	0.002	DRD4
regulation of systemic arterial blood pressure by vasopressin	1	1685.2×	0.002	DRD5
adenylate cyclase-inhibiting dopamine receptor signaling pathway	1	1685.2×	0.002	DRD4
positive regulation of adenylate cyclase activity	1	1685.2×	0.002	DRD5
fear response	1	1404.3×	0.002	DRD4
cellular response to catecholamine stimulus	1	1203.7×	0.002	DRD5
synaptic transmission, dopaminergic	1	1053.2×	0.002	DRD5
G protein-coupled dopamine receptor signaling pathway	1	936.2×	0.002	DRD5
regulation of dopamine metabolic process	1	842.6×	0.002	DRD4
inhibitory postsynaptic potential	1	842.6×	0.002	DRD4
adenylate cyclase-activating dopamine receptor signaling pathway	1	766.0×	0.003	DRD5
behavioral response to ethanol	1	601.9×	0.003	DRD4
adenylate cyclase-activating adrenergic receptor signaling pathway	1	601.9×	0.003	DRD5
negative regulation of protein secretion	1	443.5×	0.004	DRD4
long-term synaptic depression	1	443.5×	0.004	DRD5
behavioral response to cocaine	1	421.3×	0.004	DRD4
arachidonate secretion	1	351.1×	0.004	DRD4
transmission of nerve impulse	1	324.1×	0.004	DRD5
negative regulation of blood pressure	1	324.1×	0.004	DRD5
regulation of postsynaptic neurotransmitter receptor internalization	1	312.1×	0.004	DRD4

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
DRD4	CABERGOLINE
DRD5	IMIPRAMINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DRD4	119	4
DRD5	36	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CABERGOLINE	4	DRD4, DRD5
APOMORPHINE	4	DRD4, DRD5
HALOPERIDOL	4	DRD4, DRD5
ROPINIROLE	4	DRD4, DRD5
DOPAMINE	4	DRD4, DRD5
CLOTRIMAZOLE	4	DRD4
IMIPRAMINE	4	DRD4, DRD5
ARIPIPRAZOLE	4	DRD4, DRD5
AMOXAPINE	4	DRD4, DRD5
DESLORATADINE	4	DRD4
NEFAZODONE HYDROCHLORIDE	4	DRD4
DIHYDROERGOTAMINE MESYLATE	4	DRD4, DRD5
HALOPERIDOL DECANOATE	4	DRD4
THIOTHIXENE	4	DRD4
DYCLONINE	4	DRD4
IPRINDOLE	4	DRD4
SALMETEROL	4	DRD4
SERTINDOLE	4	DRD4
ROTIGOTINE	4	DRD4
AURANOFIN	4	DRD4
PIMOZIDE	4	DRD4
ILOPERIDONE	4	DRD4
TEGASEROD MALEATE	4	DRD4, DRD5
DOPAMINE HYDROCHLORIDE	4	DRD4, DRD5
VILAZODONE HYDROCHLORIDE	4	DRD4
PALIPERIDONE	4	DRD4, DRD5
MECLIZINE	4	DRD4
DOXEPIN	4	DRD4, DRD5
LOPERAMIDE HYDROCHLORIDE	4	DRD4
PRAZOSIN	4	DRD4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
DRD4	951	Binding:787, Functional:154, ADMET:9, Unclassified:1
DRD5	313	Binding:280, Functional:28, ADMET:5

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
DRD4	951
DRD5	313

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
CABERGOLINE	4	DRD4, DRD5
APOMORPHINE	4	DRD4, DRD5
HALOPERIDOL	4	DRD4, DRD5
ROPINIROLE	4	DRD4, DRD5
DOPAMINE	4	DRD4, DRD5
CLOTRIMAZOLE	4	DRD4
IMIPRAMINE	4	DRD4, DRD5
ARIPIPRAZOLE	4	DRD4, DRD5
AMOXAPINE	4	DRD4, DRD5
DESLORATADINE	4	DRD4
NEFAZODONE HYDROCHLORIDE	4	DRD4
DIHYDROERGOTAMINE MESYLATE	4	DRD4, DRD5
HALOPERIDOL DECANOATE	4	DRD4
THIOTHIXENE	4	DRD4
DYCLONINE	4	DRD4
IPRINDOLE	4	DRD4
SALMETEROL	4	DRD4
SERTINDOLE	4	DRD4
ROTIGOTINE	4	DRD4
AURANOFIN	4	DRD4
PIMOZIDE	4	DRD4
ILOPERIDONE	4	DRD4
TEGASEROD MALEATE	4	DRD4, DRD5
DOPAMINE HYDROCHLORIDE	4	DRD4, DRD5
VILAZODONE HYDROCHLORIDE	4	DRD4
PALIPERIDONE	4	DRD4, DRD5
MECLIZINE	4	DRD4
DOXEPIN	4	DRD4, DRD5
LOPERAMIDE HYDROCHLORIDE	4	DRD4
PRAZOSIN	4	DRD4

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	DRD4, DRD5
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.