AHDC1-related intellectual disability - obstructive sleep apnea - mild dysmorphism syndrome

Summary

AHDC1-related intellectual disability - obstructive sleep apnea - mild dysmorphism syndrome (MONDO:0014358) is a disease caused by AHDC1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: AHDC1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 242
• Phenotypes (HPO): 45

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

45 HPO clinical features (Orphanet curated; top 45 by frequency):

HPO ID	Term	Frequency
HP:0000750	Delayed speech and language development	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001270	Motor delay	Very frequent (80-99%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000925	Abnormality of the vertebral column	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001273	Abnormal corpus callosum morphology	Frequent (30-79%)
HP:0001382	Joint hypermobility	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001999	Abnormal facial shape	Frequent (30-79%)
HP:0002474	Expressive language delay	Frequent (30-79%)
HP:0002781	Upper airway obstruction	Frequent (30-79%)
HP:0002870	Obstructive sleep apnea	Frequent (30-79%)
HP:0011477	Upbeat nystagmus	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0012443	Abnormality of brain morphology	Frequent (30-79%)
HP:0031936	Delayed ability to walk	Frequent (30-79%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000369	Low-set ears	Occasional (5-29%)
HP:0000385	Small earlobe	Occasional (5-29%)
HP:0000411	Protruding ear	Occasional (5-29%)
HP:0000490	Deeply set eye	Occasional (5-29%)
HP:0000494	Downslanted palpebral fissures	Occasional (5-29%)
HP:0000565	Esotropia	Occasional (5-29%)
HP:0000582	Upslanted palpebral fissure	Occasional (5-29%)
HP:0000717	Autism	Occasional (5-29%)
HP:0001363	Craniosynostosis	Occasional (5-29%)
HP:0001601	Laryngomalacia	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0002353	EEG abnormality	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002779	Tracheomalacia	Occasional (5-29%)
HP:0004887	Respiratory failure requiring assisted ventilation	Occasional (5-29%)
HP:0005280	Depressed nasal bridge	Occasional (5-29%)
HP:0006951	Retrocerebellar cyst	Occasional (5-29%)
HP:0009909	Uplifted earlobe	Occasional (5-29%)
HP:0012448	Delayed myelination	Occasional (5-29%)
HP:0025267	Snoring	Occasional (5-29%)
HP:0025573	Mild myopia	Occasional (5-29%)
HP:0100704	Cerebral visual impairment	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	AHDC1-related intellectual disability - obstructive sleep apnea - mild dysmorphism syndrome
Mondo ID	MONDO:0014358
OMIM	615829
Orphanet	412069
DOID	DOID:0070055
UMLS	C4014419
MedGen	862856
GARD	0013409
Is cancer (heuristic)	no

Also known as: AHDC1-related intellectual disability - obstructive sleep apnea - mild dysmorphism syndrome · autosomal dominant intellectual disability 25 · mental retardation, autosomal dominant 25 · Xia-Gibbs syndrome

Data availability: 242 ClinVar variants · 7 GenCC gene-disease records · 4 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › syndromic intellectual disability › AHDC1-related intellectual disability - obstructive sleep apnea - mild dysmorphism syndrome

Related subtypes (16): Smith-Magenis syndrome, intellectual disability, Buenos-Aires type, intellectual disability, Wolff type, CK syndrome, 7p22.1 microduplication syndrome, 9p13 microdeletion syndrome, 3q27.3 microdeletion syndrome, 9q31.1q31.3 microdeletion syndrome, Rubinstein-Taybi syndrome, X-linked syndromic intellectual disability, 9q33.3q34.11 microdeletion syndrome, autosomal recessive syndromic intellectual disability, autosomal dominant syndromic intellectual disability, aplasia cutis-enamel dysplasia syndrome, 2p25.3 microduplication syndrome, dyneinopathy

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

242 retrieved; paginated sample, class counts are floors:

69 pathogenic, 57 uncertain significance, 42 benign/likely benign, 30 likely pathogenic, 19 conflicting classifications of pathogenicity, 17 benign, 5 pathogenic/likely pathogenic, 3 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1048789	NM_001371928.1(AHDC1):c.1125dup (p.Pro376fs)	AHDC1	Pathogenic	criteria provided, single submitter
1064444	NM_001371928.1(AHDC1):c.2424_2425dup (p.Gly809fs)	AHDC1	Pathogenic	no assertion criteria provided
1164008	NM_001371928.1(AHDC1):c.1814_1819delinsT (p.Ala605fs)	AHDC1	Pathogenic	no assertion criteria provided
1320043	NM_001371928.1(AHDC1):c.1481_1482del (p.Lys494fs)	AHDC1	Pathogenic	criteria provided, multiple submitters, no conflicts
133326	NM_001371928.1(AHDC1):c.2373_2374del (p.Cys791fs)	AHDC1	Pathogenic	criteria provided, multiple submitters, no conflicts
133327	NM_001371928.1(AHDC1):c.2898del (p.Tyr967fs)	AHDC1	Pathogenic	criteria provided, single submitter
133328	NM_001371928.1(AHDC1):c.2547del (p.Ser850fs)	AHDC1	Pathogenic	criteria provided, multiple submitters, no conflicts
1341366	NM_001371928.1(AHDC1):c.2036del (p.Gly679fs)	AHDC1	Pathogenic	no assertion criteria provided
1675324	NM_001371928.1(AHDC1):c.3656G>A (p.Trp1219Ter)	AHDC1	Pathogenic	criteria provided, single submitter
1685514	NM_001371928.1(AHDC1):c.2719del (p.Ala907fs)	AHDC1	Pathogenic	criteria provided, single submitter
1700688	NM_001371928.1(AHDC1):c.1181_1182del (p.Cys394fs)	AHDC1	Pathogenic	criteria provided, single submitter
1804100	NM_001371928.1(AHDC1):c.3182del (p.Ser1061fs)	AHDC1	Pathogenic	criteria provided, single submitter
208157	NM_001371928.1(AHDC1):c.3809del (p.Gln1270fs)	AHDC1	Pathogenic	criteria provided, single submitter
208158	NM_001371928.1(AHDC1):c.1945del (p.Ala649fs)	AHDC1	Pathogenic	criteria provided, single submitter
224806	NM_001371928.1(AHDC1):c.1402dup (p.Cys468fs)	AHDC1	Pathogenic	criteria provided, single submitter
2430037	NM_001371928.1(AHDC1):c.1122del (p.Pro376fs)	AHDC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2583159	NM_001371928.1(AHDC1):c.1653del (p.Lys552fs)	AHDC1	Pathogenic	criteria provided, single submitter
2584546	NM_001371928.1(AHDC1):c.3060_3073del (p.Ala1021fs)	AHDC1	Pathogenic	criteria provided, single submitter
2584775	NM_001371928.1(AHDC1):c.3543dup (p.Phe1182fs)	AHDC1	Pathogenic	criteria provided, multiple submitters, no conflicts
2626754	NM_001371928.1(AHDC1):c.3376C>T (p.Gln1126Ter)	AHDC1	Pathogenic	criteria provided, single submitter
2626756	NM_001371928.1(AHDC1):c.809del (p.Glu270fs)	AHDC1	Pathogenic	criteria provided, single submitter
2626757	NM_001371928.1(AHDC1):c.2651del (p.Gly884fs)	AHDC1	Pathogenic	criteria provided, single submitter
2626758	NM_001371928.1(AHDC1):c.1125del (p.Pro376fs)	AHDC1	Pathogenic	criteria provided, single submitter
266028	NM_001371928.1(AHDC1):c.2229del (p.Ser744fs)	AHDC1	Pathogenic	criteria provided, single submitter
280407	NM_001371928.1(AHDC1):c.1759C>T (p.Arg587Ter)	AHDC1	Pathogenic	criteria provided, multiple submitters, no conflicts
280482	NM_001371928.1(AHDC1):c.2691del (p.Val898fs)	AHDC1	Pathogenic	criteria provided, single submitter
280607	NM_001371928.1(AHDC1):c.2908C>T (p.Gln970Ter)	AHDC1	Pathogenic	criteria provided, single submitter
3024258	NM_001371928.1(AHDC1):c.2268del (p.Ser757fs)	AHDC1	Pathogenic	criteria provided, single submitter
3024280	NM_001371928.1(AHDC1):c.2968C>T (p.Gln990Ter)	AHDC1	Pathogenic	criteria provided, multiple submitters, no conflicts
3237162	NM_001371928.1(AHDC1):c.4540del (p.Ala1514fs)	AHDC1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
AHDC1	Definitive	Autosomal dominant	AHDC1-related intellectual disability - obstructive sleep apnea - mild dysmorphism syndrome	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AHDC1	Orphanet:412069	AHDC1-related intellectual disability-obstructive sleep apnea-mild dysmorphism syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
AHDC1	HGNC:25230	ENSG00000126705	Q5TGY3	Transcription factor Gibbin	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AHDC1	Transcription factor Gibbin	Transcription factor required for the proper patterning of the epidermis, which plays a key role in early epithelial morphogenesis.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AHDC1	Other/Unknown	no		DUF4683, AHDC1

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

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

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 10	1
frontal pole	1
paraflocculus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AHDC1	232	ubiquitous	marker	paraflocculus, Brodmann (1909) area 10, frontal pole

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AHDC1	787

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AHDC1	Q5TGY3	38.82

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
skin morphogenesis	1	1404.3×	0.002	AHDC1
mesoderm formation	1	495.6×	0.003	AHDC1
cell differentiation	1	29.1×	0.034	AHDC1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AHDC1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	1	AHDC1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
AHDC1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.