Ehlers-Danlos syndrome, kyphoscoliotic type, 2

Summary

Ehlers-Danlos syndrome, kyphoscoliotic type, 2 (MONDO:0013800) is a disease caused by FKBP14 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FKBP14 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 188
• Phenotypes (HPO): 23

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		9	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0000407	Sensorineural hearing impairment	Very frequent (80-99%)
HP:0000974	Hyperextensible skin	Very frequent (80-99%)
HP:0001270	Motor delay	Very frequent (80-99%)
HP:0001382	Joint hypermobility	Very frequent (80-99%)
HP:0001763	Pes planus	Very frequent (80-99%)
HP:0002421	Poor head control	Very frequent (80-99%)
HP:0002751	Kyphoscoliosis	Very frequent (80-99%)
HP:0003198	Myopathy	Very frequent (80-99%)
HP:0003202	Skeletal muscle atrophy	Very frequent (80-99%)
HP:0006829	Severe muscular hypotonia	Very frequent (80-99%)
HP:0007502	Follicular hyperkeratosis	Very frequent (80-99%)
HP:0000545	Myopia	Frequent (30-79%)
HP:0000938	Osteopenia	Frequent (30-79%)
HP:0000978	Bruising susceptibility	Frequent (30-79%)
HP:0001075	Atrophic scars	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0003236	Elevated circulating creatine kinase concentration	Frequent (30-79%)
HP:0003388	Easy fatigability	Frequent (30-79%)
HP:0100790	Hernia	Frequent (30-79%)
HP:0012372	Abnormal eye morphology	Occasional (5-29%)
HP:0025019	Arterial rupture	Occasional (5-29%)
HP:0000482	Microcornea	Very rare (<1-4%)
HP:0001519	Disproportionate tall stature	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Ehlers-Danlos syndrome, kyphoscoliotic type, 2
Mondo ID	MONDO:0013800
OMIM	614557
Orphanet	300179
SNOMED CT	720859009
UMLS	C3281160
MedGen	482790
GARD	0017361
Is cancer (heuristic)	no

Also known as: EDS with progressive kyphoscoliosis, myopathy, and deafness · EDS with progressive kyphoscoliosis, myopathy, and hearing loss · EDS, kyphoscoliotic and hearing loss type · EDSKMH · EDSKSCL2 · Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and deafness · Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss · Ehlers-Danlos syndrome, kyphoscoliotic and deafness type · Ehlers-Danlos syndrome, kyphoscoliotic and hearing loss type · Ehlers-Danlos syndrome, kyphoscoliotic type, 2

Data availability: 188 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Ehlers-Danlos syndrome › Ehlers-Danlos syndrome, kyphoscoliotic type, 2

Related subtypes (24): Ehlers-Danlos syndrome, classic type, Ehlers-Danlos syndrome, hypermobility type, Ehlers-Danlos syndrome, arthrochalasia type, Ehlers-Danlos syndrome, spondylodysplastic type, Ehlers-Danlos syndrome, periodontitis type, Ehlers-Danlos syndrome, autosomal dominant, type unspecified, joint laxity, familial, Ehlers-Danlos syndrome, fibronectinemic type, Ehlers-Danlos syndrome, dermatosparaxis type, brittle cornea syndrome, X-linked Ehlers-Danlos syndrome, Ehlers-Danlos syndrome, musculocontractural type, Ehlers-Danlos syndrome due to tenascin-X deficiency, Ehlers-Danlos syndrome, Beasley-Cohen type, Ehlers-Danlos syndrome, kyphoscoliotic type 1, Ehlers-Danlos syndrome, vascular-like type, Ehlers-Danlos/osteogenesis imperfecta syndrome, Ehlers-Danlos syndrome, vascular type, spondylodysplastic Ehlers-Danlos syndrome, Bethlem myopathy 2, Ehlers-Danlos syndrome, classic-like, 2, COL1A1-related Ehlers-Danlos syndrome, COL1A2-related Ehlers-Danlos syndrome, Ehlers-Danlos syndrome, classic-like, 3

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

188 retrieved; paginated sample, class counts are floors:

79 uncertain significance, 72 likely benign, 10 pathogenic, 9 benign/likely benign, 7 conflicting classifications of pathogenicity, 6 likely pathogenic, 3 pathogenic/likely pathogenic, 1 benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068632	NM_017946.4(FKBP14):c.95_96del (p.Leu32fs)	FKBP14	Pathogenic	criteria provided, single submitter
1433477	NM_017946.4(FKBP14):c.206dup (p.His69fs)	FKBP14	Pathogenic	criteria provided, single submitter
1898707	NM_017946.4(FKBP14):c.428C>G (p.Ser143Ter)	FKBP14	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2739931	NM_017946.4(FKBP14):c.264G>A (p.Trp88Ter)	FKBP14	Pathogenic	criteria provided, single submitter
279809	NM_017946.4(FKBP14):c.362dup (p.Glu122fs)	FKBP14	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4722553	NM_017946.4(FKBP14):c.364G>T (p.Glu122Ter)	FKBP14	Pathogenic	criteria provided, single submitter
567476	NM_017946.4(FKBP14):c.156T>A (p.Tyr52Ter)	FKBP14	Pathogenic	criteria provided, single submitter
599393	NM_017946.4(FKBP14):c.570AGA[1] (p.Glu191del)	FKBP14	Pathogenic	no assertion criteria provided
657045	NM_017946.4(FKBP14):c.34_35del (p.Leu12fs)	FKBP14	Pathogenic	criteria provided, single submitter
807418	NM_017946.4(FKBP14):c.636G>C (p.Ter212Tyr)	FKBP14	Pathogenic	criteria provided, single submitter
1800565	NM_017946.4(FKBP14):c.34dup (p.Leu12fs)	FKBP14-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31198	NM_017946.4(FKBP14):c.42_60del (p.Val14_Thr15insTer)	FKBP14-AS1	Pathogenic	no assertion criteria provided
3689717	NM_017946.4(FKBP14):c.36_37del (p.Phe13fs)	FKBP14-AS1	Pathogenic	criteria provided, single submitter
161456	NM_017946.4(FKBP14):c.197+5_197+8del	FKBP14	Likely pathogenic	criteria provided, single submitter
2501231	NM_017946.4(FKBP14):c.52_55del (p.Ile18fs)	FKBP14	Likely pathogenic	criteria provided, single submitter
3654395	NM_017946.4(FKBP14):c.349+1G>A	FKBP14	Likely pathogenic	criteria provided, single submitter
944682	NM_017946.4(FKBP14):c.197+1G>A	FKBP14	Likely pathogenic	criteria provided, single submitter
3775211	NM_017946.4(FKBP14):c.523dup (p.Val175fs)	FKBP14-AS1	Likely pathogenic	criteria provided, single submitter
800533	NM_017946.4(FKBP14):c.207_208del (p.His69fs)	FKBP14-AS1	Likely pathogenic	criteria provided, single submitter
432050	NM_017946.4(FKBP14):c.568_570del (p.Lys190del)	FKBP14	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
432169	NM_017946.4(FKBP14):c.493AAG[1] (p.Lys166del)	FKBP14	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
681733	NM_017946.4(FKBP14):c.525G>T (p.Val175=)	FKBP14	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
966849	NM_017946.4(FKBP14):c.477+1G>A	FKBP14	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1036143	NM_017946.4(FKBP14):c.518C>T (p.Ala173Val)	FKBP14-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1143605	NM_017946.4(FKBP14):c.350-5G>A	FKBP14-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
521060	NM_017946.4(FKBP14):c.467_468del (p.Leu155_Ser156insTer)	FKBP14-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1002303	NM_017946.4(FKBP14):c.25G>A (p.Val9Ile)	FKBP14	Uncertain significance	criteria provided, multiple submitters, no conflicts
1020959	NM_017946.4(FKBP14):c.349+6A>C	FKBP14	Uncertain significance	criteria provided, single submitter
1030616	NM_017946.4(FKBP14):c.340G>A (p.Glu114Lys)	FKBP14	Uncertain significance	criteria provided, single submitter
1035149	NM_017946.4(FKBP14):c.179G>A (p.Gly60Asp)	FKBP14	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
FKBP14	Definitive	Autosomal recessive	Ehlers-Danlos syndrome, kyphoscoliotic type, 2	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FKBP14	Orphanet:300179	Kyphoscoliotic Ehlers-Danlos syndrome due to FKBP22 deficiency

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FKBP14	HGNC:18625	ENSG00000106080	Q9NWM8	Peptidyl-prolyl cis-trans isomerase FKBP14	gencc,clinvar
NOD1	HGNC:16390	ENSG00000106100	Q9Y239	Nucleotide-binding oligomerization domain-containing protein 1	clinvar
FKBP14-AS1	HGNC:40990	ENSG00000227014		FKBP14 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FKBP14	Peptidyl-prolyl cis-trans isomerase FKBP14	PPIase which accelerates the folding of proteins during protein synthesis.
NOD1	Nucleotide-binding oligomerization domain-containing protein 1	Pattern recognition receptor (PRR) that detects bacterial peptidoglycan fragments and other danger signals and thus participates in both innate and adaptive immune responses.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Enzyme (other)	1	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FKBP14	Enzyme (other)	yes	5.2.1.8	PPIase_FKBP_dom, EF_hand_dom, EF-hand-dom_pair
NOD1	Other/Unknown	no		CARD, Leu-rich_rpt, NACHT_NTPase
FKBP14-AS1	Other/Unknown	no

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cartilage tissue	1
corpus epididymis	1
tibia	1
left ovary	1
right lobe of thyroid gland	1
sural nerve	1
bone marrow	1
bone marrow cell	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FKBP14	260	ubiquitous	marker	tibia, corpus epididymis, cartilage tissue
NOD1	220	ubiquitous	marker	sural nerve, left ovary, right lobe of thyroid gland
FKBP14-AS1	129		yes	male germ line stem cell (sensu Vertebrata) in testis, bone marrow cell, bone marrow

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FKBP14	2,296
NOD1	2,067
FKBP14-AS1	0

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NOD1	Q9Y239	6
FKBP14	Q9NWM8	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 3 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
JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1	1	259.6×	0.011	NOD1
activated TAK1 mediates p38 MAPK activation	1	248.3×	0.011	NOD1
NOD1/2 Signaling Pathway	1	158.6×	0.011	NOD1
TAK1-dependent IKK and NF-kappa-B activation	1	150.3×	0.011	NOD1
Ovarian tumor domain proteases	1	139.3×	0.011	NOD1
XBP1(S) activates chaperone genes	1	107.7×	0.012	FKBP14
Interleukin-1 signaling	1	62.1×	0.018	NOD1
SARS-CoV-2 activates/modulates innate and adaptive immune responses	1	44.6×	0.022	NOD1

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
detection of biotic stimulus	1	4213.0×	0.003	NOD1
nucleotide-binding oligomerization domain containing 1 signaling pathway	1	3370.4×	0.003	NOD1
positive regulation of dendritic cell antigen processing and presentation	1	2407.4×	0.003	NOD1
xenophagy	1	2407.4×	0.003	NOD1
positive regulation of xenophagy	1	2106.5×	0.003	NOD1
cellular response to muramyl dipeptide	1	1685.2×	0.003	NOD1
detection of bacterium	1	1404.3×	0.003	NOD1
pattern recognition receptor signaling pathway	1	991.3×	0.004	NOD1
positive regulation of stress-activated MAPK cascade	1	802.5×	0.004	NOD1
positive regulation of macrophage cytokine production	1	732.7×	0.004	NOD1
stress-activated MAPK cascade	1	702.2×	0.004	NOD1
ERK1 and ERK2 cascade	1	318.0×	0.008	NOD1
JNK cascade	1	271.8×	0.008	NOD1
positive regulation of interleukin-1 beta production	1	259.3×	0.008	NOD1
positive regulation of non-canonical NF-kappaB signal transduction	1	255.3×	0.008	NOD1
positive regulation of interleukin-8 production	1	244.2×	0.008	NOD1
defense response	1	216.1×	0.009	NOD1
obsolete positive regulation of NF-kappaB transcription factor activity	1	205.5×	0.009	NOD1
defense response to Gram-negative bacterium	1	168.5×	0.009	NOD1
positive regulation of interleukin-6 production	1	166.8×	0.009	NOD1
response to endoplasmic reticulum stress	1	166.8×	0.009	NOD1
positive regulation of JNK cascade	1	163.6×	0.009	NOD1
positive regulation of tumor necrosis factor production	1	153.2×	0.009	NOD1
defense response to Gram-positive bacterium	1	127.7×	0.011	NOD1
defense response to bacterium	1	108.0×	0.012	NOD1
positive regulation of ERK1 and ERK2 cascade	1	85.1×	0.015	NOD1
positive regulation of canonical NF-kappaB signal transduction	1	72.6×	0.017	NOD1
positive regulation of apoptotic process	1	56.7×	0.021	NOD1
intracellular signal transduction	1	38.1×	0.029	NOD1
inflammatory response	1	37.7×	0.029	NOD1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
NOD1	GEFITINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FKBP14	1	2
NOD1	1	4
FKBP14-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
GEFITINIB	4	NOD1
CYCLOHEXIMIDE	2	FKBP14

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
NOD1	111	Binding:100, Functional:11
FKBP14	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FKBP14	5.2.1.8	peptidylprolyl isomerase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
NOD1	111

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

2 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)
GEFITINIB	4	NOD1
CYCLOHEXIMIDE	2	FKBP14

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	NOD1
B	Phased (≥1) drug, not yet approved	1	FKBP14
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	FKBP14-AS1

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)
FKBP14-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.