Lichtenstein-Knorr syndrome

Summary

Lichtenstein-Knorr syndrome (MONDO:0014572) is a disease caused by SLC9A1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SLC9A1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 12

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		13	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Lichtenstein-Knorr syndrome
Mondo ID	MONDO:0014572
OMIM	616291
Orphanet	448251
DOID	DOID:0080065
UMLS	C4225383
MedGen	898996
GARD	0017780
Is cancer (heuristic)	no

Also known as: autosomal recessive spinocerebellar ataxia type 19 · Lichtenstein-Knorr syndrome · LIKNS · progressive autosomal recessive ataxia-sensorineural hearing loss syndrome · SCAR19 · SLC9A1-related spinocerebellar ataxia syndrome · spinocerebellar ataxia, autosomal recessive 19

Data availability: 12 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › autosomal recessive cerebellar ataxia › Lichtenstein-Knorr syndrome

Related subtypes (28): Charlevoix-Saguenay spastic ataxia, infantile-onset autosomal recessive nonprogressive cerebellar ataxia, autosomal recessive spinocerebellar ataxia 7, autosomal recessive ataxia, Beauce type, RIDDLE syndrome, autosomal recessive ataxia due to ubiquinone deficiency, autosomal recessive spinocerebellar ataxia 10, ataxia with oculomotor apraxia type 3, autosomal recessive spinocerebellar ataxia 14, autosomal recessive spinocerebellar ataxia 16, autosomal recessive spinocerebellar ataxia 20, spinocerebellar ataxia, autosomal recessive 22, spinocerebellar ataxia, autosomal recessive 24, autosomal recessive cerebellar ataxia - epilepsy - intellectual disability syndrome, autosomal recessive congenital cerebellar ataxia, autosomal recessive metabolic cerebellar ataxia, autosomal recessive degenerative and progressive cerebellar ataxia, autosomal recessive syndromic cerebellar ataxia, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy, spinocerebellar ataxia, autosomal recessive 29, spinocerebellar ataxia, autosomal recessive 30, spinocerebellar ataxia, autosomal recessive 31, spinocerebellar ataxia, autosomal recessive 27, spinocerebellar ataxia, autosomal recessive 28, spinocerebellar ataxia, autosomal recessive 25, spinocerebellar ataxia, autosomal recessive 26, spinocerebellar ataxia, autosomal recessive 32, spinocerebellar ataxia, autosomal recessive 33

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

12 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
978078	NM_003047.5(SLC9A1):c.862del (p.Ile288fs)	SLC9A1	Pathogenic	no assertion criteria provided
1331440	NM_003047.5(SLC9A1):c.1048_1052dup (p.Gly352fs)	SLC9A1	Likely pathogenic	criteria provided, single submitter
189315	NM_003047.5(SLC9A1):c.913G>A (p.Gly305Arg)	SLC9A1	Likely pathogenic	criteria provided, single submitter
1683602	NM_003047.5(SLC9A1):c.2031G>A (p.Glu677=)	SLC9A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2441715	NM_003047.5(SLC9A1):c.176A>T (p.Asp59Val)	SLC9A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2690036	NM_003047.5(SLC9A1):c.644G>A (p.Gly215Asp)	SLC9A1	Uncertain significance	criteria provided, single submitter
3064996	NM_003047.5(SLC9A1):c.1273C>T (p.Arg425Cys)	SLC9A1	Uncertain significance	criteria provided, single submitter
638455	NM_003047.5(SLC9A1):c.856G>A (p.Val286Met)	SLC9A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1253772	NM_003047.5(SLC9A1):c.69T>C (p.Val23=)	SLC9A1	Benign	criteria provided, multiple submitters, no conflicts
1333120	NM_003047.5(SLC9A1):c.*2A>G	SLC9A1	Benign	criteria provided, multiple submitters, no conflicts
1333121	NM_003047.5(SLC9A1):c.2205A>G (p.Glu735=)	SLC9A1	Benign	criteria provided, multiple submitters, no conflicts
713880	NM_003047.5(SLC9A1):c.1821G>A (p.Gln607=)	SLC9A1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
SLC9A1	Strong	Autosomal recessive	Lichtenstein-Knorr syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC9A1	Orphanet:448251	Progressive autosomal recessive ataxia-deafness syndrome

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
SLC9A1	HGNC:11071	ENSG00000090020	P19634	Sodium/hydrogen exchanger 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC9A1	Sodium/hydrogen exchanger 1	Electroneutral Na(+) /H(+) antiporter that extrudes Na(+) in exchange for external protons driven by the inward sodium ion chemical gradient, protecting cells from acidification that occurs from metabolism.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC9A1	Other/Unknown	no		NHE-1-like, NaH_exchanger, Cation/H_exchanger_TM

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
mucosa of transverse colon	1
oocyte	1
parotid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC9A1	273	ubiquitous	marker	parotid gland, mucosa of transverse colon, oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC9A1	2,023

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC9A1	P19634	20

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. 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
Sodium/Proton exchangers	1	1268.9×	0.004	SLC9A1
Hyaluronan metabolism	1	951.7×	0.004	SLC9A1
Hyaluronan degradation	1	713.8×	0.004	SLC9A1
Glycosaminoglycan metabolism	1	219.6×	0.010	SLC9A1
R-HSA-425393	1	129.8×	0.012	SLC9A1
Metabolism of carbohydrates and carbohydrate derivatives	1	120.2×	0.012	SLC9A1
SLC-mediated transmembrane transport	1	59.2×	0.022	SLC9A1
Transport of small molecules	1	25.1×	0.045	SLC9A1
Metabolism	1	11.6×	0.086	SLC9A1

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
positive regulation of mitochondrial membrane permeability	1	8426.0×	0.002	SLC9A1
regulation of the force of heart contraction by cardiac conduction	1	8426.0×	0.002	SLC9A1
positive regulation of the force of heart contraction	1	3370.4×	0.002	SLC9A1
maintenance of cell polarity	1	2407.4×	0.002	SLC9A1
cellular response to antibiotic	1	2407.4×	0.002	SLC9A1
regulation of cardiac muscle cell membrane potential	1	2407.4×	0.002	SLC9A1
positive regulation of action potential	1	2106.5×	0.002	SLC9A1
cardiac muscle cell contraction	1	1685.2×	0.002	SLC9A1
regulation of pH	1	1404.3×	0.002	SLC9A1
response to acidic pH	1	1296.3×	0.002	SLC9A1
regulation of cardiac muscle contraction by calcium ion signaling	1	1296.3×	0.002	SLC9A1
cellular response to electrical stimulus	1	1296.3×	0.002	SLC9A1
cellular response to epinephrine stimulus	1	1296.3×	0.002	SLC9A1
sodium ion export across plasma membrane	1	1053.2×	0.002	SLC9A1
cellular response to cold	1	1053.2×	0.002	SLC9A1
hyaluronan catabolic process	1	991.3×	0.002	SLC9A1
regulation of stress fiber assembly	1	991.3×	0.002	SLC9A1
positive regulation of calcineurin-NFAT signaling cascade	1	802.5×	0.002	SLC9A1
intracellular sodium ion homeostasis	1	766.0×	0.002	SLC9A1
response to muscle stretch	1	766.0×	0.002	SLC9A1
positive regulation of cardiac muscle hypertrophy	1	732.7×	0.002	SLC9A1
cellular response to acidic pH	1	732.7×	0.002	SLC9A1
protein complex oligomerization	1	674.1×	0.002	SLC9A1
cardiac muscle cell differentiation	1	674.1×	0.002	SLC9A1
sodium ion import across plasma membrane	1	624.1×	0.002	SLC9A1
regulation of intracellular pH	1	601.9×	0.002	SLC9A1
regulation of focal adhesion assembly	1	601.9×	0.002	SLC9A1
proton transmembrane transport	1	312.1×	0.004	SLC9A1
stem cell differentiation	1	300.9×	0.004	SLC9A1
cellular response to mechanical stimulus	1	216.1×	0.006	SLC9A1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
SLC9A1	AMILORIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC9A1	6	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AMILORIDE	4	SLC9A1
SABIPORIDE	2	SLC9A1
RIMEPORIDE	2	SLC9A1
ZONIPORIDE	2	SLC9A1
CARIPORIDE	2	SLC9A1
ENIPORIDE	2	SLC9A1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SLC9A1	36	Binding:28, Functional:7, ADMET:1

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

6 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)
AMILORIDE	4	SLC9A1
SABIPORIDE	2	SLC9A1
RIMEPORIDE	2	SLC9A1
ZONIPORIDE	2	SLC9A1
CARIPORIDE	2	SLC9A1
ENIPORIDE	2	SLC9A1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SLC9A1
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.