Short-rib thoracic dysplasia 15 with polydactyly

Summary

Short-rib thoracic dysplasia 15 with polydactyly (MONDO:0014907) is a disease caused by DYNC2LI1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: DYNC2LI1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 24

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	short-rib thoracic dysplasia 15 with polydactyly
Mondo ID	MONDO:0014907
OMIM	617088
UMLS	C4310724
MedGen	934691
GARD	0016185
Is cancer (heuristic)	no

Also known as: short-rib thoracic dysplasia 15 with polydactyly · short-rib thoracic dysplasia 15 with polydactyly; SRTD15 · SRTD15

Data availability: 24 ClinVar variants · 3 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 15 with 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 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 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

24 retrieved; paginated sample, class counts are floors:

10 pathogenic, 5 uncertain significance, 3 pathogenic/likely pathogenic, 2 likely pathogenic, 2 likely benign, 1 benign, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
212767	NM_016008.4(DYNC2LI1):c.1000G>T (p.Glu334Ter)	ABCG5	Pathogenic	no assertion criteria provided
30485	NM_022436.3(ABCG5):c.1336C>T (p.Arg446Ter)	ABCG5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1106719	NM_016008.4(DYNC2LI1):c.18_19del (p.Trp7fs)	DYNC2LI1	Pathogenic	no assertion criteria provided
212764	NM_016008.4(DYNC2LI1):c.993+1G>A	DYNC2LI1	Pathogenic	criteria provided, single submitter
212765	NM_016008.4(DYNC2LI1):c.349C>G (p.Leu117Val)	DYNC2LI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
212766	NM_016008.4(DYNC2LI1):c.372G>A (p.Trp124Ter)	DYNC2LI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
212768	NM_016008.4(DYNC2LI1):c.993+3A>G	DYNC2LI1	Pathogenic	no assertion criteria provided
253218	NM_016008.4(DYNC2LI1):c.619C>T (p.Arg207Ter)	DYNC2LI1	Pathogenic	criteria provided, single submitter
253219	NM_016008.4(DYNC2LI1):c.659C>T (p.Thr220Ile)	DYNC2LI1	Pathogenic	criteria provided, single submitter
518437	NM_016008.4(DYNC2LI1):c.2T>C (p.Met1Thr)	DYNC2LI1	Pathogenic	criteria provided, single submitter
518438	NM_016008.4(DYNC2LI1):c.420del (p.Lys140_Val141insTer)	DYNC2LI1	Pathogenic	criteria provided, single submitter
518439	NM_016008.4(DYNC2LI1):c.123_124insA (p.Gly42fs)	DYNC2LI1	Pathogenic	no assertion criteria provided
518440	NM_016008.4(DYNC2LI1):c.655-9del	DYNC2LI1	Pathogenic	no assertion criteria provided
2584572	NM_022436.3(ABCG5):c.576del (p.Ile193fs)	ABCG5	Likely pathogenic	criteria provided, single submitter
3629470	NM_016008.4(DYNC2LI1):c.1008C>A (p.Tyr336Ter)	ABCG5	Likely pathogenic	criteria provided, single submitter
764830	NM_016008.4(DYNC2LI1):c.389T>C (p.Leu130Pro)	DYNC2LI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2584573	NM_022436.3(ABCG5):c.1340C>T (p.Ala447Val)	ABCG5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1806184	NM_016008.4(DYNC2LI1):c.764T>C (p.Leu255Pro)	DYNC2LI1	Uncertain significance	criteria provided, single submitter
1806344	NM_016008.4(DYNC2LI1):c.127-8A>G	DYNC2LI1	Uncertain significance	criteria provided, single submitter
2441079	NM_016008.4(DYNC2LI1):c.326T>A (p.Phe109Tyr)	DYNC2LI1	Uncertain significance	criteria provided, single submitter
2441080	NM_016008.4(DYNC2LI1):c.930C>A (p.Asp310Glu)	DYNC2LI1	Uncertain significance	criteria provided, single submitter
1255528	NM_016008.4(DYNC2LI1):c.98T>C (p.Phe33Ser)	DYNC2LI1	Benign	criteria provided, multiple submitters, no conflicts
4820042	NM_016008.4(DYNC2LI1):c.488A>C (p.Asn163Thr)	DYNC2LI1	Likely benign	criteria provided, single submitter
719316	NM_016008.4(DYNC2LI1):c.16C>T (p.Leu6Phe)	DYNC2LI1	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 4 · 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
DYNC2LI1	Definitive	Autosomal recessive	short-rib thoracic dysplasia 15 with polydactyly	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DYNC2LI1	Orphanet:289	Ellis Van Creveld syndrome
DYNC2LI1	Orphanet:474	Jeune syndrome
ABCG5	Orphanet:2882	Sitosterolemia
ABCG5	Orphanet:391665	Homozygous familial hypercholesterolemia

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
DYNC2LI1	HGNC:24595	ENSG00000138036	Q8TCX1	Cytoplasmic dynein 2 light intermediate chain 1	gencc,clinvar
ABCG5	HGNC:13886	ENSG00000138075	Q9H222	ATP-binding cassette sub-family G member 5	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DYNC2LI1	Cytoplasmic dynein 2 light 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…
ABCG5	ATP-binding cassette sub-family G member 5	ABCG5 and ABCG8 form an obligate heterodimer that mediates Mg(2+)- and ATP-dependent sterol transport across the cell membrane.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Transporter	1	38.9×	0.051
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DYNC2LI1	Other/Unknown	no		Dynein_light_int_chain, P-loop_NTPase, DYNC2LI1
ABCG5	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC2_TM

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
bronchial epithelial cell	1
mucosa of paranasal sinus	1
right uterine tube	1
duodenum	1
jejunal mucosa	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DYNC2LI1	293	ubiquitous	marker	right uterine tube, bronchial epithelial cell, mucosa of paranasal sinus
ABCG5	61	tissue_specific	marker	jejunal mucosa, right lobe of liver, duodenum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ABCG5	1,996
DYNC2LI1	852

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ABCG5	Q9H222	8
DYNC2LI1	Q8TCX1	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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
Defective ABCG8 causes GBD4 and sitosterolemia	1	2855.0×	0.002	ABCG5
Defective ABCG5 causes sitosterolemia	1	2855.0×	0.002	ABCG5
ABC transporters in lipid homeostasis	1	300.5×	0.013	ABCG5
ABC transporter disorders	1	219.6×	0.013	ABCG5
NR1H2 and NR1H3-mediated signaling	1	196.9×	0.013	ABCG5
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux	1	154.3×	0.014	ABCG5
Intraflagellar transport	1	100.2×	0.018	DYNC2LI1
Disorders of transmembrane transporters	1	69.6×	0.023	ABCG5
ABC-family protein mediated transport	1	60.7×	0.024	ABCG5
Signaling by Nuclear Receptors	1	51.0×	0.025	ABCG5
Transport of small molecules	1	12.6×	0.092	ABCG5
Disease	1	6.5×	0.159	ABCG5
Signal Transduction	1	5.1×	0.187	ABCG5

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
negative regulation of intestinal phytosterol absorption	1	4213.0×	0.002	ABCG5
negative regulation of intestinal cholesterol absorption	1	4213.0×	0.002	ABCG5
sterol transport	1	1404.3×	0.003	ABCG5
intraciliary transport involved in cilium assembly	1	1203.7×	0.003	DYNC2LI1
intestinal cholesterol absorption	1	702.2×	0.005	ABCG5
intraciliary retrograde transport	1	561.7×	0.005	DYNC2LI1
regulation of cilium assembly	1	300.9×	0.007	DYNC2LI1
response to muscle activity	1	290.6×	0.007	ABCG5
cholesterol efflux	1	263.3×	0.007	ABCG5
triglyceride homeostasis	1	240.7×	0.007	ABCG5
response to ionizing radiation	1	205.5×	0.007	ABCG5
response to nutrient	1	147.8×	0.009	ABCG5
determination of left/right symmetry	1	127.7×	0.010	DYNC2LI1
transmembrane transport	1	84.3×	0.014	ABCG5
cholesterol homeostasis	1	78.0×	0.014	ABCG5
response to xenobiotic stimulus	1	34.5×	0.029	ABCG5

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 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
DYNC2LI1	0	0
ABCG5	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	1	ABCG5
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	DYNC2LI1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DYNC2LI1	0	—
ABCG5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.