Ciliary dyskinesia, primary, 40

Summary

Ciliary dyskinesia, primary, 40 (MONDO:0032664) is a disease caused by DNAH9 (GenCC Definitive), with 5 cohort genes.

At a glance

• Causal gene: DNAH9 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 136

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	ciliary dyskinesia, primary, 40
Mondo ID	MONDO:0032664
OMIM	618300
DOID	DOID:0111853
UMLS	C4749028
MedGen	1648365
GARD	0025717
Is cancer (heuristic)	no

Also known as: CILD40

Data availability: 136 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › primary ciliary dyskinesia › ciliary dyskinesia, primary, 40

Related subtypes (58): ciliary discoordination due to random ciliary orientation, ciliary dyskinesia with transposition of ciliary microtubules, ciliary dyskinesia with defective radial spokes, ciliary dyskinesia with excessively long cilia, Stromme syndrome, primary ciliary dyskinesia 1, ciliary dyskinesia, primary, 36, X-linked, primary ciliary dyskinesia 2, primary ciliary dyskinesia 3, primary ciliary dyskinesia 4, primary ciliary dyskinesia 5, primary ciliary dyskinesia 6, primary ciliary dyskinesia 7, primary ciliary dyskinesia 8, primary ciliary dyskinesia 9, primary ciliary dyskinesia 10, primary ciliary dyskinesia 11, primary ciliary dyskinesia 12, primary ciliary dyskinesia 13, primary ciliary dyskinesia 14, primary ciliary dyskinesia 15, primary ciliary dyskinesia 16, primary ciliary dyskinesia 17, primary ciliary dyskinesia 18, primary ciliary dyskinesia 19, primary ciliary dyskinesia 20, primary ciliary dyskinesia 21, primary ciliary dyskinesia 22, primary ciliary dyskinesia 23, primary ciliary dyskinesia 24, primary ciliary dyskinesia 25, primary ciliary dyskinesia 26, primary ciliary dyskinesia 27, primary ciliary dyskinesia 28, primary ciliary dyskinesia 29, primary ciliary dyskinesia 30, primary ciliary dyskinesia 32, primary ciliary dyskinesia 33, primary ciliary dyskinesia 34, primary ciliary dyskinesia 35, ciliary dyskinesia, primary, 46, ciliary dyskinesia, primary, 47, and lissencephaly, ciliary dyskinesia, primary, 48, without situs inversus, ciliary dyskinesia, primary, 39, ciliary dyskinesia, primary, 41, ciliary dyskinesia, primary, 42, ciliary dyskinesia, primary, 43, ciliary dyskinesia, primary, 44, ciliary dyskinesia, primary, 45, ciliary dyskinesia, primary, 37, ciliary dyskinesia, primary, 38, ciliary dyskinesia, primary, 54, ciliary dyskinesia, primary, 49, without situs inversus, ciliary dyskinesia, primary, 50, ciliary dyskinesia, primary, 51, ciliary dyskinesia, primary, 52, ciliary dyskinesia, primary, 53, CFAP46-related primary ciliary dyskinesia

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

136 retrieved; paginated sample, class counts are floors:

59 uncertain significance, 23 likely pathogenic, 14 benign, 11 conflicting classifications of pathogenicity, 10 pathogenic, 10 benign/likely benign, 9 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
617522	NM_001372.4(DNAH9):c.[5641A>G;8894G>A]		Pathogenic	no assertion criteria provided
1065458	NM_001372.4(DNAH9):c.4234C>T (p.Gln1412Ter)	DNAH9	Pathogenic	criteria provided, single submitter
1322757	NM_001372.4(DNAH9):c.760_761del (p.Phe254fs)	DNAH9	Pathogenic	criteria provided, single submitter
1324274	NM_001372.4(DNAH9):c.8839C>T (p.Arg2947Ter)	DNAH9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455970	NM_001372.4(DNAH9):c.308del (p.Phe103fs)	DNAH9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1710144	NM_001372.4(DNAH9):c.5266C>T (p.Gln1756Ter)	DNAH9	Pathogenic	criteria provided, single submitter
1911635	NM_001372.4(DNAH9):c.4030C>T (p.Arg1344Ter)	DNAH9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2186539	NM_001372.4(DNAH9):c.8293del (p.Glu2765fs)	DNAH9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2715538	NM_001372.4(DNAH9):c.12320_12323del (p.Tyr4107fs)	DNAH9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2782150	NM_001372.4(DNAH9):c.70C>T (p.Arg24Ter)	DNAH9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2980546	NM_001372.4(DNAH9):c.6602G>A (p.Trp2201Ter)	DNAH9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3013954	NM_001372.4(DNAH9):c.1733del (p.Leu578fs)	DNAH9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
523437	NM_001372.4(DNAH9):c.308dup (p.Leu104fs)	DNAH9	Pathogenic	criteria provided, multiple submitters, no conflicts
617518	NM_001372.4(DNAH9):c.12367G>A (p.Asp4123Asn)	DNAH9	Pathogenic	no assertion criteria provided
617519	NM_001372.4(DNAH9):c.10193G>T (p.Arg3398Leu)	DNAH9	Pathogenic	no assertion criteria provided
617521	NM_001372.4(DNAH9):c.8251C>T (p.Gln2751Ter)	DNAH9	Pathogenic	no assertion criteria provided
617524	NM_001372.4(DNAH9):c.3354-1G>T	DNAH9	Pathogenic	no assertion criteria provided
617525	NM_001372.4(DNAH9):c.10127dup (p.Leu3376fs)	DNAH9	Pathogenic	no assertion criteria provided
430852	NM_003136.4(SRP54):c.343ACA[2] (p.Thr117del)	SRP54	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1029327	NM_001372.4(DNAH9):c.12925C>T (p.Arg4309Ter)	DNAH9	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324278	NM_001372.4(DNAH9):c.11599C>T (p.Arg3867Ter)	DNAH9	Likely pathogenic	criteria provided, single submitter
1324282	NM_001372.4(DNAH9):c.12106-1G>A	DNAH9	Likely pathogenic	criteria provided, single submitter
1333258	NM_001372.4(DNAH9):c.6669G>A (p.Trp2223Ter)	DNAH9	Likely pathogenic	criteria provided, single submitter
1499334	NM_001372.4(DNAH9):c.615-2A>G	DNAH9	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1514281	NM_001372.4(DNAH9):c.1901+1G>A	DNAH9	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1722374	NM_001372.4(DNAH9):c.4918C>T (p.Arg1640Ter)	DNAH9	Likely pathogenic	criteria provided, single submitter
1927508	NM_001372.4(DNAH9):c.11406+1G>T	DNAH9	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2635324	NM_001372.4(DNAH9):c.1944T>G (p.Tyr648Ter)	DNAH9	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2664692	NM_001372.4(DNAH9):c.2021del (p.Ser674fs)	DNAH9	Likely pathogenic	criteria provided, single submitter
2724515	NM_001372.4(DNAH9):c.6847+1G>A	DNAH9	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 9 · 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
DNAH9	Definitive	Autosomal recessive	ciliary dyskinesia, primary, 40	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DNAH9	Orphanet:101063	Situs inversus totalis
DNAH9	Orphanet:157769	Situs ambiguus
DNAH9	Orphanet:244	Primary ciliary dyskinesia
SRP54	Orphanet:675767	Severe congenital neutropenia-developmental delay syndrome due to SRP54 deficiency
DSG2	Orphanet:154	Familial isolated dilated cardiomyopathy
DSG2	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
DSG2	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
DSG2	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
DVL1	Orphanet:3107	Autosomal dominant Robinow syndrome

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DNAH9	HGNC:2953	ENSG00000007174	Q9NYC9	Dynein axonemal heavy chain 9	gencc,clinvar
SRP54	HGNC:11301	ENSG00000100883	P61011	Signal recognition particle subunit SRP54	clinvar
DSG2	HGNC:3049	ENSG00000046604	Q14126	Desmoglein-2	clinvar
DVL1	HGNC:3084	ENSG00000107404	O14640	Segment polarity protein dishevelled homolog DVL-1	clinvar
E2F6	HGNC:3120	ENSG00000169016	O75461	Transcription factor E2F6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DNAH9	Dynein axonemal heavy chain 9	Force generating protein required for cilia beating in respiratory epithelia.
SRP54	Signal recognition particle subunit SRP54	Component of the signal recognition particle (SRP) complex, a ribonucleoprotein complex that mediates the cotranslational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER).
DSG2	Desmoglein-2	A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion.
DVL1	Segment polarity protein dishevelled homolog DVL-1	Participates in Wnt signaling by binding to the cytoplasmic C-terminus of frizzled family members and transducing the Wnt signal to down-stream effectors.
E2F6	Transcription factor E2F6	Inhibitor of E2F-dependent transcription.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 4 · 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
Scaffold/PPI	1	3.5×	0.269
Other/Unknown	4	1.4×	0.269

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DNAH9	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail
SRP54	Other/Unknown	no		SRP54_GTPase_dom, AAA+_ATPase, Signal_recog_particle_SRP54_M
DSG2	Other/Unknown	no		Cadherin-like_dom, Desmosomal_cadherin, Cadherin-like_sf
DVL1	Scaffold/PPI	no		DEP_dom, DIX, PDZ
E2F6	Other/Unknown	no		E2F_WHTH_DNA-bd_dom, E2F, E2F_CC-MB

Expression context

Cohort genes with no expression data: 0.

5 cohort genes 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	2
bronchial epithelial cell	1
epithelium of bronchus	1
right uterine tube	1
body of pancreas	1
islet of Langerhans	1
pancreas	1
colonic mucosa	1
jejunal mucosa	1
mucosa of sigmoid colon	1
hindlimb stylopod muscle	1
lower esophagus mucosa	1
muscle of leg	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DNAH9	184	broad	marker	right uterine tube, bronchial epithelial cell, epithelium of bronchus
SRP54	296	ubiquitous	marker	body of pancreas, pancreas, islet of Langerhans
DSG2	238	ubiquitous	marker	mucosa of sigmoid colon, colonic mucosa, jejunal mucosa
DVL1	290	ubiquitous	marker	hindlimb stylopod muscle, gastrocnemius, lower esophagus mucosa
E2F6	140	ubiquitous	marker	primordial germ cell in gonad, gastrocnemius, muscle of leg

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DVL1	2,949
E2F6	2,108
DSG2	2,033
DNAH9	1,841
SRP54	299

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DSG2	Q14126	12
SRP54	P61011	9
DVL1	O14640	3
DNAH9	Q9NYC9	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
E2F6	O75461	71.37

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. Enrichment computed across 5 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Negative regulation of TCF-dependent signaling by DVL-interacting proteins	1	571.0×	0.020	DVL1
WNT mediated activation of DVL	1	356.9×	0.020	DVL1
Apoptotic cleavage of cell adhesion proteins	1	259.6×	0.020	DSG2
WNT5:FZD7-mediated leishmania damping	1	237.9×	0.020	DVL1
Disassembly of the destruction complex and recruitment of AXIN to the membrane	1	89.2×	0.032	DVL1
G1/S-Specific Transcription	1	89.2×	0.032	E2F6
PCP/CE pathway	1	75.1×	0.032	DVL1
Transcriptional Regulation by E2F6	1	73.2×	0.032	E2F6
Degradation of DVL	1	59.5×	0.035	DVL1
RHOG GTPase cycle	1	37.1×	0.049	DSG2
RAC2 GTPase cycle	1	31.7×	0.049	DSG2
RAC3 GTPase cycle	1	29.7×	0.049	DSG2
TCF dependent signaling in response to WNT	1	29.4×	0.049	DVL1
SRP-dependent cotranslational protein targeting to membrane	1	25.0×	0.053	SRP54
Formation of the cornified envelope	1	22.0×	0.057	DSG2
RHO GTPases Activate Formins	1	19.4×	0.060	DVL1
Translation	1	15.5×	0.070	SRP54
Keratinization	1	13.9×	0.074	DSG2
Metabolism of proteins	1	3.1×	0.286	SRP54

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
Purkinje myocyte development	1	1685.2×	0.014	DSG2
positive regulation of protein localization to presynapse	1	1685.2×	0.014	DVL1
convergent extension involved in neural plate elongation	1	1123.5×	0.014	DVL1
positive regulation of protein localization to cell-cell junction	1	1123.5×	0.014	DSG2
SRP-dependent cotranslational protein targeting to membrane, signal sequence recognition	1	842.6×	0.014	SRP54
negative regulation of endothelial cell differentiation	1	674.1×	0.014	DSG2
bundle of His cell-Purkinje myocyte adhesion involved in cell communication	1	481.5×	0.014	DSG2
desmosome organization	1	421.3×	0.014	DSG2
SRP-dependent cotranslational protein targeting to membrane	1	421.3×	0.014	SRP54
SRP-dependent cotranslational protein targeting to membrane, translocation	1	421.3×	0.014	SRP54
positive regulation of neuron projection arborization	1	421.3×	0.014	DVL1
skeletal muscle acetylcholine-gated channel clustering	1	374.5×	0.014	DVL1
exocrine pancreas development	1	337.0×	0.014	SRP54
negative regulation of inflammatory response to wounding	1	337.0×	0.014	DSG2
mesenchymal to epithelial transition	1	306.4×	0.014	DSG2
regulation of ventricular cardiac muscle cell action potential	1	280.9×	0.014	DSG2
protein localization to microtubule	1	259.3×	0.014	DVL1
mucociliary clearance	1	259.3×	0.014	DNAH9
granulocyte differentiation	1	240.7×	0.014	SRP54
collateral sprouting	1	240.7×	0.014	DVL1
presynapse assembly	1	240.7×	0.014	DVL1
protein targeting to ER	1	224.7×	0.014	SRP54
prepulse inhibition	1	224.7×	0.014	DVL1
maternal process involved in female pregnancy	1	187.2×	0.016	DSG2
dendritic spine morphogenesis	1	177.4×	0.016	DVL1
cerebrospinal fluid circulation	1	177.4×	0.016	DNAH9
synaptic vesicle exocytosis	1	153.2×	0.018	DVL1
neurotransmitter secretion	1	140.4×	0.018	DVL1
cilium movement involved in cell motility	1	134.8×	0.018	DNAH9
positive regulation of sprouting angiogenesis	1	134.8×	0.018	DSG2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 3 of 5 evidence-associated genes (60%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DNAH9	0	0
SRP54	0	0
DSG2	0	0
DVL1	0	0
E2F6	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
DVL1	11	Binding:10, Functional:1
SRP54	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	5	DNAH9, SRP54, DSG2, DVL1, E2F6

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DNAH9	0	—
SRP54	2	—
DSG2	0	—
DVL1	11	—
E2F6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.