Short-rib thoracic dysplasia 11 with or without polydactyly

Summary

Short-rib thoracic dysplasia 11 with or without polydactyly (MONDO:0014287) is a disease caused by DYNC2I2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: DYNC2I2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 493

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	short-rib thoracic dysplasia 11 with or without polydactyly
Mondo ID	MONDO:0014287
OMIM	615633
DOID	DOID:0110095
UMLS	C3810200
MedGen	816530
GARD	0015996
Is cancer (heuristic)	no

Also known as: short-rib thoracic dysplasia 11 with or without polydactyly · SRTD11

Data availability: 493 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › ciliopathy › Jeune syndrome › short-rib thoracic dysplasia 11 with or without polydactyly

Related subtypes (23): asphyxiating thoracic dystrophy 1, Ellis-van Creveld syndrome, short-rib thoracic dysplasia 6 with or without polydactyly, short-rib thoracic dysplasia 9 with or without polydactyly, Beemer-Langer syndrome, asphyxiating thoracic dystrophy 2, asphyxiating thoracic dystrophy 3, asphyxiating thoracic dystrophy 4, short-rib thoracic dysplasia 7 with or without polydactyly, asphyxiating thoracic dystrophy 5, short-rib thoracic dysplasia 8 with or without polydactyly, short-rib thoracic dysplasia 10 with or without polydactyly, short-rib thoracic dysplasia 13 with or without polydactyly, short-rib thoracic dysplasia 14 with polydactyly, short-rib thoracic dysplasia 15 with polydactyly, short-rib thoracic dysplasia 16 with or without polydactyly, short-rib thoracic dysplasia 21 without polydactyly, short-rib thoracic dysplasia 19 with or without polydactyly, short-rib thoracic dysplasia 18 with polydactyly, short-rib thoracic dysplasia 20 with polydactyly, short-rib thoracic dysplasia 17 with or without polydactyly, Jeune syndrome - GRK2-related, short-rib thoracic dysplasia 22 without polydactyly

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

493 retrieved; paginated sample, class counts are floors:

212 likely benign, 200 uncertain significance, 33 pathogenic, 16 benign, 10 conflicting classifications of pathogenicity, 8 likely pathogenic, 7 pathogenic/likely pathogenic, 7 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1323763	NM_052844.4(DYNC2I2):c.1315_1318del (p.Phe439fs)	DYNC2I2	Pathogenic	criteria provided, multiple submitters, no conflicts
1325354	NM_052844.4(DYNC2I2):c.629del (p.Pro210fs)	DYNC2I2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1681194	NM_052844.4(DYNC2I2):c.1198_1201dup (p.Ser401fs)	DYNC2I2	Pathogenic	criteria provided, single submitter
1681251	NM_052844.4(DYNC2I2):c.347_348del (p.Glu116fs)	DYNC2I2	Pathogenic	criteria provided, single submitter
1911444	NM_052844.4(DYNC2I2):c.447_448del (p.Thr151fs)	DYNC2I2	Pathogenic	criteria provided, single submitter
2051598	NM_052844.4(DYNC2I2):c.361C>T (p.Arg121Ter)	DYNC2I2	Pathogenic	criteria provided, multiple submitters, no conflicts
2057434	NM_052844.4(DYNC2I2):c.1117_1118del (p.Arg373fs)	DYNC2I2	Pathogenic	criteria provided, single submitter
2109376	NM_052844.4(DYNC2I2):c.955del (p.Leu319fs)	DYNC2I2	Pathogenic	criteria provided, single submitter
2112236	NM_052844.4(DYNC2I2):c.1294C>T (p.Gln432Ter)	DYNC2I2	Pathogenic	criteria provided, single submitter
2135286	NM_052844.4(DYNC2I2):c.245_246del (p.His82fs)	DYNC2I2	Pathogenic	criteria provided, single submitter
2196170	NM_052844.4(DYNC2I2):c.1372+1G>A	DYNC2I2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2198627	NM_052844.4(DYNC2I2):c.1313dup (p.Phe439fs)	DYNC2I2	Pathogenic	criteria provided, single submitter
2703951	NM_052844.4(DYNC2I2):c.1461_1464dup (p.Glu489fs)	DYNC2I2	Pathogenic	criteria provided, single submitter
2718602	NM_052844.4(DYNC2I2):c.1315_1318dup (p.Ala440fs)	DYNC2I2	Pathogenic	criteria provided, single submitter
2806411	NM_052844.4(DYNC2I2):c.1531C>T (p.Gln511Ter)	DYNC2I2	Pathogenic	criteria provided, single submitter
2815325	NM_052844.4(DYNC2I2):c.51_64dup (p.Ala22fs)	DYNC2I2	Pathogenic	criteria provided, single submitter
2872998	NM_052844.4(DYNC2I2):c.1509_1515del (p.Gln504_Gly505insTer)	DYNC2I2	Pathogenic	criteria provided, single submitter
2885703	NM_052844.4(DYNC2I2):c.256del (p.Gln86fs)	DYNC2I2	Pathogenic	criteria provided, single submitter
2899243	NM_052844.4(DYNC2I2):c.1171dup (p.His391fs)	DYNC2I2	Pathogenic	criteria provided, single submitter
3622387	NM_052844.4(DYNC2I2):c.93_108del (p.Pro32fs)	DYNC2I2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3661883	NM_052844.4(DYNC2I2):c.33_36del (p.Ser11fs)	DYNC2I2	Pathogenic	criteria provided, single submitter
3684732	NM_052844.4(DYNC2I2):c.1284_1305dup (p.Lys436fs)	DYNC2I2	Pathogenic	criteria provided, single submitter
446625	NM_052844.4(DYNC2I2):c.544C>T (p.Arg182Trp)	DYNC2I2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4532118	NM_052844.4(DYNC2I2):c.1193_1194del (p.Val398fs)	DYNC2I2	Pathogenic	criteria provided, single submitter
4711218	NM_052844.4(DYNC2I2):c.1280_1283del (p.Pro427fs)	DYNC2I2	Pathogenic	criteria provided, single submitter
4724808	NM_052844.4(DYNC2I2):c.263_303dup (p.Gln102fs)	DYNC2I2	Pathogenic	criteria provided, single submitter
4729956	NM_052844.4(DYNC2I2):c.149C>A (p.Ser50Ter)	DYNC2I2	Pathogenic	criteria provided, single submitter
4731369	NM_052844.4(DYNC2I2):c.1428del (p.Lys477fs)	DYNC2I2	Pathogenic	criteria provided, single submitter
4763097	NM_052844.4(DYNC2I2):c.1206del (p.Phe403fs)	DYNC2I2	Pathogenic	criteria provided, single submitter
576613	NM_052844.4(DYNC2I2):c.26del (p.Pro9fs)	DYNC2I2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 3 · 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
DYNC2I2	Definitive	Autosomal recessive	short-rib thoracic dysplasia 11 with or without polydactyly	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DYNC2I2	Orphanet:474	Jeune syndrome
DYNC2I2	Orphanet:93271	Short rib-polydactyly syndrome, Verma-Naumoff type
SPTAN1	Orphanet:697160	Infantile epileptic spasms syndrome

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
DYNC2I2	HGNC:28296	ENSG00000119333	Q96EX3	Cytoplasmic dynein 2 intermediate chain 2	gencc,clinvar
SPTAN1	HGNC:11273	ENSG00000197694	Q13813	Spectrin alpha chain, non-erythrocytic 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DYNC2I2	Cytoplasmic dynein 2 intermediate chain 2	Acts as one of several non-catalytic accessory components of the cytoplasmic dynein 2 complex (dynein-2 complex), a motor protein complex that drives the movement of cargos along microtubules within cilia and flagella in concert with the i…
SPTAN1	Spectrin alpha chain, non-erythrocytic 1	Fodrin, which seems to be involved in secretion, interacts with calmodulin in a calcium-dependent manner and is thus candidate for the calcium-dependent movement of the cytoskeleton at the membrane.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 0 · 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	2	17.3×	0.003

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DYNC2I2	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_dom_sf
SPTAN1	Scaffold/PPI	no		SH3_domain, Spectrin_repeat, EF_hand_dom

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
pancreatic ductal cell	1
right uterine tube	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DYNC2I2	238	ubiquitous	marker	right uterine tube, pancreatic ductal cell, apex of heart
SPTAN1	293	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SPTAN1	3,083
DYNC2I2	1,099

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SPTAN1	Q13813	7
DYNC2I2	Q96EX3	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 38. 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
Caspase-mediated cleavage of cytoskeletal proteins	1	475.8×	0.031	SPTAN1
Apoptotic cleavage of cellular proteins	1	237.9×	0.031	SPTAN1
Nephrin family interactions	1	237.9×	0.031	SPTAN1
Apoptotic execution phase	1	237.9×	0.031	SPTAN1
Interaction between L1 and Ankyrins	1	184.2×	0.031	SPTAN1
Sensory processing of sound	1	154.3×	0.031	SPTAN1
RHOV GTPase cycle	1	142.8×	0.031	SPTAN1
RHOU GTPase cycle	1	139.3×	0.031	SPTAN1
NCAM signaling for neurite out-growth	1	135.9×	0.031	SPTAN1
Sensory processing of sound by outer hair cells of the cochlea	1	102.0×	0.034	SPTAN1
Intraflagellar transport	1	100.2×	0.034	DYNC2I2
Apoptosis	1	84.0×	0.034	SPTAN1
Sensory processing of sound by inner hair cells of the cochlea	1	81.6×	0.034	SPTAN1
Programmed Cell Death	1	73.2×	0.034	SPTAN1
Cell-Cell communication	1	68.8×	0.034	SPTAN1
ER to Golgi Anterograde Transport	1	66.4×	0.034	SPTAN1
MAPK1/MAPK3 signaling	1	65.6×	0.034	SPTAN1
L1CAM interactions	1	60.1×	0.035	SPTAN1
COPI-mediated anterograde transport	1	54.9×	0.035	SPTAN1
MAPK family signaling cascades	1	51.4×	0.035	SPTAN1
Transport to the Golgi and subsequent modification	1	51.4×	0.035	SPTAN1
Sensory Perception	1	47.6×	0.036	SPTAN1
RAF/MAP kinase cascade	1	30.5×	0.050	SPTAN1
Asparagine N-linked glycosylation	1	30.1×	0.050	SPTAN1
RHO GTPase cycle	1	30.1×	0.050	SPTAN1
Axon guidance	1	22.6×	0.064	SPTAN1
Nervous system development	1	21.5×	0.065	SPTAN1
Membrane Trafficking	1	18.5×	0.072	SPTAN1
Vesicle-mediated transport	1	17.4×	0.072	SPTAN1
Signaling by Rho GTPases	1	17.1×	0.072	SPTAN1

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
actin filament capping	1	766.0×	0.004	SPTAN1
intraciliary retrograde transport	1	561.7×	0.004	DYNC2I2
intraciliary transport	1	280.9×	0.006	DYNC2I2
actin cytoskeleton organization	1	39.6×	0.027	SPTAN1
cilium assembly	1	36.8×	0.027	DYNC2I2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SPTAN1	1	2
DYNC2I2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	SPTAN1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SPTAN1	7	Binding:7

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

1 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)
MOLIBRESIB	2	SPTAN1

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	1	SPTAN1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	DYNC2I2

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)
DYNC2I2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.