Keppen-Lubinsky syndrome

Summary

Keppen-Lubinsky syndrome (MONDO:0013572) is a disease caused by KCNJ6 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: KCNJ6 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 13
• Phenotypes (HPO): 42

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

42 HPO clinical features (Orphanet curated; top 42 by frequency):

HPO ID	Term	Frequency
HP:0005328	Progeroid facial appearance	Obligate (100%)
HP:0009059	Congenital generalized lipodystrophy	Obligate (100%)
HP:0000194	Open mouth	Very frequent (80-99%)
HP:0000252	Microcephaly	Very frequent (80-99%)
HP:0000322	Short philtrum	Very frequent (80-99%)
HP:0000347	Micrognathia	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001347	Hyperreflexia	Very frequent (80-99%)
HP:0100678	Premature skin wrinkling	Very frequent (80-99%)
HP:0000212	Gingival overgrowth	Frequent (30-79%)
HP:0000218	High palate	Frequent (30-79%)
HP:0000290	Abnormality of the forehead	Frequent (30-79%)
HP:0000292	Loss of facial adipose tissue	Frequent (30-79%)
HP:0000298	Mask-like facies	Frequent (30-79%)
HP:0000430	Underdeveloped nasal alae	Frequent (30-79%)
HP:0000446	Narrow nasal bridge	Frequent (30-79%)
HP:0000496	Abnormality of eye movement	Frequent (30-79%)
HP:0000520	Proptosis	Frequent (30-79%)
HP:0000586	Shallow orbits	Frequent (30-79%)
HP:0001090	Abnormally large globe	Frequent (30-79%)
HP:0001276	Hypertonia	Frequent (30-79%)
HP:0001285	Spastic tetraparesis	Frequent (30-79%)
HP:0001371	Flexion contracture	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001561	Polyhydramnios	Frequent (30-79%)
HP:0002093	Respiratory insufficiency	Frequent (30-79%)
HP:0002094	Dyspnea	Frequent (30-79%)
HP:0002179	Opisthotonus	Frequent (30-79%)
HP:0002187	Intellectual disability, profound	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0002781	Upper airway obstruction	Frequent (30-79%)
HP:0005274	Prominent nasal tip	Frequent (30-79%)
HP:0006532	Recurrent pneumonia	Frequent (30-79%)
HP:0008734	Decreased testicular size	Frequent (30-79%)
HP:0008897	Postnatal growth retardation	Frequent (30-79%)
HP:0009125	Lipodystrophy	Frequent (30-79%)
HP:0009933	Narrow naris	Frequent (30-79%)
HP:0010751	Chin dimple	Frequent (30-79%)
HP:0010804	Tented upper lip vermilion	Frequent (30-79%)
HP:0011344	Severe global developmental delay	Frequent (30-79%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0002659	Increased susceptibility to fractures	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Keppen-Lubinsky syndrome
Mondo ID	MONDO:0013572
OMIM	614098
Orphanet	435628
UMLS	C3279800
MedGen	481430
GARD	0017716
Is cancer (heuristic)	no

Also known as: generalised lipodystrophy-progeroid features-severe intellectual disability syndrome · generalized lipodystrophy-progeroid features-severe intellectual disability syndrome · Keppen-Lubinsky syndrome · KPLBS

Data availability: 13 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › lipodystrophy › hereditary lipodystrophy › Keppen-Lubinsky syndrome

Related subtypes (10): congenital generalized lipodystrophy, lipodystrophy due to peptidic growth factors deficiency, Wiedemann-Rautenstrauch syndrome, SHORT syndrome, lipodystrophy-intellectual disability-deafness syndrome, severe neurodegenerative syndrome with lipodystrophy, lipoatrophy with diabetes, leukomelanodermic papules, liver steatosis, and hypertrophic cardiomyopathy, mandibuloacral dysplasia, Berardinelli-Seip congenital lipodystrophy, familial partial lipodystrophy

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

13 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 2 benign, 2 likely pathogenic, 1 pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
189254	NM_002240.5(KCNJ6):c.452CCA[1] (p.Thr152del)	KCNJ6	Pathogenic	no assertion criteria provided
189255	NM_002240.5(KCNJ6):c.460G>A (p.Gly154Ser)	KCNJ6	Likely pathogenic	criteria provided, single submitter
431712	NM_002240.5(KCNJ6):c.512T>G (p.Leu171Arg)	KCNJ6-AS1	Likely pathogenic	criteria provided, single submitter
1342550	NM_002240.5(KCNJ6):c.25+11980A>G	KCNJ6	Uncertain significance	criteria provided, single submitter
2431874	NM_002240.5(KCNJ6):c.22A>G (p.Met8Val)	KCNJ6	Uncertain significance	criteria provided, single submitter
3376147	NM_002240.5(KCNJ6):c.329T>A (p.Ile110Asn)	KCNJ6	Uncertain significance	criteria provided, single submitter
3587679	NM_002240.5(KCNJ6):c.371T>A (p.Ile124Lys)	KCNJ6	Uncertain significance	criteria provided, single submitter
3891447	NM_002240.5(KCNJ6):c.1003C>T (p.Arg335Trp)	KCNJ6	Uncertain significance	criteria provided, single submitter
4291128	NM_002240.5(KCNJ6):c.868T>C (p.Trp290Arg)	KCNJ6	Uncertain significance	criteria provided, single submitter
1232299	NM_002240.5(KCNJ6):c.191A>G (p.Asn64Ser)	KCNJ6-AS1	Uncertain significance	criteria provided, single submitter
1165658	NM_002240.5(KCNJ6):c.495A>G (p.Pro165=)	KCNJ6	Benign	criteria provided, multiple submitters, no conflicts
1170806	NM_002240.5(KCNJ6):c.1032C>T (p.Asp344=)	KCNJ6-AS1	Benign	criteria provided, multiple submitters, no conflicts
585052	NM_002240.5(KCNJ6):c.8A>T (p.Lys3Met)	KCNJ6	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · 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
KCNJ6	Strong	Autosomal dominant	Keppen-Lubinsky syndrome	5
MYH6	Moderate	Autosomal dominant	Keppen-Lubinsky syndrome	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KCNJ6	Orphanet:435628	Keppen-Lubinsky syndrome
MYH6	Orphanet:154	Familial isolated dilated cardiomyopathy
MYH6	Orphanet:166282	Hereditary sick sinus syndrome
MYH6	Orphanet:99103	Atrial septal defect, ostium secundum type

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
KCNJ6	HGNC:6267	ENSG00000157542	P48051	G protein-activated inward rectifier potassium channel 2	gencc,clinvar
MYH6	HGNC:7576	ENSG00000197616	P13533	Myosin-6	gencc
KCNJ6-AS1	HGNC:41352	ENSG00000233213		KCNJ6 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KCNJ6	G protein-activated inward rectifier potassium channel 2	Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it.
MYH6	Myosin-6	Muscle contraction.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · 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
Ion channel	1	37.2×	0.080
Scaffold/PPI	1	5.8×	0.246
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KCNJ6	Ion channel	yes		K_chnl_inward-rec_Kir3.2, K_chnl_inward-rec_Kir_cyto, Ig_E-set
MYH6	Scaffold/PPI	no		Myosin_head_motor_dom-like, Myosin_tail, SH3_Myosin
KCNJ6-AS1	Other/Unknown	no

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
middle temporal gyrus	1
substantia nigra pars compacta	1
substantia nigra pars reticulata	1
cardiac atrium	1
cardiac muscle of right atrium	1
vena cava	1
gall bladder	1
primordial germ cell in gonad	1
skeletal muscle tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KCNJ6	108	tissue_specific	marker	substantia nigra pars reticulata, substantia nigra pars compacta, middle temporal gyrus
MYH6	154	tissue_specific	yes	cardiac muscle of right atrium, cardiac atrium, vena cava
KCNJ6-AS1	89		yes	primordial germ cell in gonad, skeletal muscle tissue, gall bladder

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MYH6	3,119
KCNJ6	1,757
KCNJ6-AS1	0

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KCNJ6	P48051	83.83
MYH6	P13533	74.91

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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
G protein gated Potassium channels	1	571.0×	0.011	KCNJ6
Inwardly rectifying K+ channels	1	356.9×	0.011	KCNJ6
Activation of GABAB receptors	1	300.5×	0.011	KCNJ6
GABA B receptor activation	1	271.9×	0.011	KCNJ6
Activation of G protein gated Potassium channels	1	196.9×	0.011	KCNJ6
Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits	1	196.9×	0.011	KCNJ6
GABA receptor activation	1	158.6×	0.011	KCNJ6
Striated Muscle Contraction	1	154.3×	0.011	MYH6
Potassium Channels	1	67.2×	0.021	KCNJ6
Neurotransmitter receptors and postsynaptic signal transmission	1	50.1×	0.026	KCNJ6
Muscle contraction	1	38.6×	0.028	MYH6
Transmission across Chemical Synapses	1	38.1×	0.028	KCNJ6
Neuronal System	1	22.1×	0.045	KCNJ6

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
visceral muscle development	1	8426.0×	0.003	MYH6
regulation of heart growth	1	4213.0×	0.003	MYH6
atrial cardiac muscle tissue morphogenesis	1	1203.7×	0.006	MYH6
adult heart development	1	601.9×	0.006	MYH6
myofibril assembly	1	561.7×	0.006	MYH6
cardiac muscle hypertrophy in response to stress	1	526.6×	0.006	MYH6
muscle filament sliding	1	526.6×	0.006	MYH6
regulation of the force of heart contraction	1	495.6×	0.006	MYH6
striated muscle contraction	1	421.3×	0.006	MYH6
regulation of monoatomic ion transmembrane transport	1	366.4×	0.006	KCNJ6
ventricular cardiac muscle tissue morphogenesis	1	351.1×	0.006	MYH6
cardiac muscle cell development	1	312.1×	0.006	MYH6
regulation of heart contraction	1	247.8×	0.006	MYH6
regulation of heart rate	1	234.1×	0.006	MYH6
ATP metabolic process	1	234.1×	0.006	MYH6
cardiac muscle contraction	1	200.6×	0.007	MYH6
sarcomere organization	1	191.5×	0.007	MYH6
potassium ion import across plasma membrane	1	183.2×	0.007	KCNJ6
regulation of blood pressure	1	110.9×	0.010	MYH6
muscle contraction	1	104.0×	0.011	MYH6
potassium ion transport	1	95.8×	0.011	KCNJ6
in utero embryonic development	1	36.0×	0.028	MYH6

Therapeutics

Drug target analysis

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

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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNJ6	0	0
MYH6	0	0
KCNJ6-AS1	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
KCNJ6	25	Binding:25

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	0
D	Druggable family + AlphaFold only, no drug	1	KCNJ6
E	Difficult family or no structure, no drug	2	MYH6, KCNJ6-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
KCNJ6	25	—
MYH6	0	—
KCNJ6-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.