Short-rib thoracic dysplasia 8 with or without polydactyly

Summary

Short-rib thoracic dysplasia 8 with or without polydactyly (MONDO:0014214) is a disease caused by DYNC2I1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: DYNC2I1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 459

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	short-rib thoracic dysplasia 8 with or without polydactyly
Mondo ID	MONDO:0014214
OMIM	615503
DOID	DOID:0110094
UMLS	C3809691
MedGen	816021
GARD	0015975
Is cancer (heuristic)	no

Also known as: short-rib thoracic dysplasia 8 with or without polydactyly · SRPS6 · SRTD8

Data availability: 459 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 8 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 10 with or without polydactyly, short-rib thoracic dysplasia 11 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

459 retrieved; paginated sample, class counts are floors:

218 likely benign, 155 uncertain significance, 42 benign, 18 pathogenic, 14 conflicting classifications of pathogenicity, 10 likely pathogenic, 1 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1076069	NM_018051.5(DYNC2I1):c.975dup (p.Asp326fs)	DYNC2I1	Pathogenic	criteria provided, single submitter
1680624	NC_000007.13:g.(?158677235)(158677330_?)del	DYNC2I1	Pathogenic	criteria provided, single submitter
1680649	NM_018051.5(DYNC2I1):c.682C>T (p.Arg228Ter)	DYNC2I1	Pathogenic	criteria provided, single submitter
1680698	NM_018051.5(DYNC2I1):c.1924C>T (p.Arg642Ter)	DYNC2I1	Pathogenic	criteria provided, single submitter
2000055	NM_018051.5(DYNC2I1):c.527_528del (p.Asp175_Ser176insTer)	DYNC2I1	Pathogenic	criteria provided, single submitter
2025330	NM_018051.5(DYNC2I1):c.378_381del (p.Asp126fs)	DYNC2I1	Pathogenic	criteria provided, single submitter
2162517	NM_018051.5(DYNC2I1):c.712_715del (p.Glu238fs)	DYNC2I1	Pathogenic	criteria provided, single submitter
2186983	NM_018051.5(DYNC2I1):c.562C>T (p.Arg188Ter)	DYNC2I1	Pathogenic	criteria provided, single submitter
2706914	NM_018051.5(DYNC2I1):c.2378dup (p.Gly794fs)	DYNC2I1	Pathogenic	criteria provided, single submitter
2873339	NM_018051.5(DYNC2I1):c.778C>T (p.Arg260Ter)	DYNC2I1	Pathogenic	criteria provided, single submitter
3245816	NC_000007.13:g.(?158649427)(158738470_?)del	DYNC2I1	Pathogenic	criteria provided, single submitter
446629	NM_018051.5(DYNC2I1):c.2284C>T (p.Arg762Ter)	DYNC2I1	Pathogenic	criteria provided, multiple submitters, no conflicts
4719191	NM_018051.5(DYNC2I1):c.2651_2652dup (p.Ile885fs)	DYNC2I1	Pathogenic	criteria provided, single submitter
4719425	NM_018051.5(DYNC2I1):c.671del (p.Asp224fs)	DYNC2I1	Pathogenic	criteria provided, single submitter
4723080	NM_018051.5(DYNC2I1):c.1647dup (p.Glu550fs)	DYNC2I1	Pathogenic	criteria provided, single submitter
577342	NM_018051.5(DYNC2I1):c.1321C>T (p.Arg441Ter)	DYNC2I1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
88644	NM_018051.5(DYNC2I1):c.1891C>T (p.Gln631Ter)	DYNC2I1	Pathogenic	no assertion criteria provided
88645	NM_018051.5(DYNC2I1):c.2246C>T (p.Thr749Met)	DYNC2I1	Pathogenic	criteria provided, single submitter
88646	NM_018051.5(DYNC2I1):c.1703-3T>A	DYNC2I1	Pathogenic	no assertion criteria provided
2690779	NM_018051.5(DYNC2I1):c.898C>T (p.Arg300Ter)	DYNC2I1	Likely pathogenic	criteria provided, single submitter
3649821	NM_018051.5(DYNC2I1):c.490+1G>A	DYNC2I1	Likely pathogenic	criteria provided, single submitter
3780797	NM_018051.5(DYNC2I1):c.1358-2A>G	DYNC2I1	Likely pathogenic	criteria provided, single submitter
3906974	NM_018051.5(DYNC2I1):c.265_268del (p.Gln89fs)	DYNC2I1	Likely pathogenic	criteria provided, single submitter
4292405	NM_018051.5(DYNC2I1):c.1566_1578del (p.Asn522fs)	DYNC2I1	Likely pathogenic	criteria provided, single submitter
437277	NM_018051.5(DYNC2I1):c.1162del (p.Cys388fs)	DYNC2I1	Likely pathogenic	criteria provided, single submitter
4740024	NM_018051.5(DYNC2I1):c.935+1G>C	DYNC2I1	Likely pathogenic	criteria provided, single submitter
4811326	NM_018051.5(DYNC2I1):c.1703-1G>A	DYNC2I1	Likely pathogenic	criteria provided, single submitter
917969	NM_018051.5(DYNC2I1):c.772_775del (p.Glu258fs)	DYNC2I1	Likely pathogenic	no assertion criteria provided
917970	NM_018051.5(DYNC2I1):c.899G>T (p.Arg300Leu)	DYNC2I1	Likely pathogenic	no assertion criteria provided
1039216	NM_018051.5(DYNC2I1):c.389G>A (p.Arg130Gln)	DYNC2I1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · 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
DYNC2I1	Definitive	Autosomal recessive	short-rib thoracic dysplasia 8 with or without polydactyly	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DYNC2I1	Orphanet:474	Jeune syndrome
DYNC2I1	Orphanet:93271	Short rib-polydactyly syndrome, Verma-Naumoff type

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
DYNC2I1	HGNC:21862	ENSG00000126870	Q8WVS4	Cytoplasmic dynein 2 intermediate chain 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DYNC2I1	Cytoplasmic dynein 2 intermediate chain 1	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…

Protein-family classification

Druggable: 0 · Difficult: 1 · 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	1	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DYNC2I1	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_dom_sf

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
right uterine tube	1
sperm	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DYNC2I1	269	ubiquitous	marker	sural nerve, right uterine tube, sperm

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DYNC2I1	955

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DYNC2I1	Q8WVS4	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Intraflagellar transport	1	200.3×	0.005	DYNC2I1

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
intraciliary retrograde transport	1	1123.5×	0.003	DYNC2I1
embryonic skeletal system morphogenesis	1	391.9×	0.004	DYNC2I1
cilium assembly	1	73.6×	0.014	DYNC2I1

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
DYNC2I1	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	DYNC2I1

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)
DYNC2I1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.