Schwannomatosis

Summary

Schwannomatosis (MONDO:0008075) is a disease caused by LZTR1 (GenCC Definitive), with 3 cohort genes and 6 clinical trials. Top therapeutic interventions include erenumab, siltuximab, and tanezumab.

At a glance

• Prevalence: <1 / 1 000 000 (Finland) [Orphanet-validated]
• Causal gene: LZTR1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 33
• Phenotypes (HPO): 21
• Clinical trials: 6

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	<1 / 1 000 000	0.058	Finland	Validated

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO ID	Term	Frequency
HP:0100008	Schwannoma	Obligate (100%)
HP:0009593	Peripheral schwannoma	Frequent (30-79%)
HP:0010302	Spinal cord tumor	Frequent (30-79%)
HP:0012531	Pain	Frequent (30-79%)
HP:0000131	Uterine leiomyoma	Occasional (5-29%)
HP:0000360	Tinnitus	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0001324	Muscle weakness	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002664	Neoplasm	Occasional (5-29%)
HP:0003401	Paresthesia	Occasional (5-29%)
HP:0012032	Lipoma	Occasional (5-29%)
HP:0410275	Lumbosacral hemangioma	Occasional (5-29%)
HP:0009589	Bilateral vestibular schwannoma	Excluded (0%)
HP:0001250	Seizure	Very rare (<1-4%)
HP:0001621	Weak voice	Very rare (<1-4%)
HP:0002380	Fasciculations	Very rare (<1-4%)
HP:0002858	Meningioma	Very rare (<1-4%)
HP:0011750	Neoplasm of the anterior pituitary	Very rare (<1-4%)
HP:0033748	Hypoesthesia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	schwannomatosis
Mondo ID	MONDO:0008075
OMIM	162091
Orphanet	93921
DOID	DOID:3204
ICD-10-CM	Q85.03
NCIT	C6557
UMLS	C1335929
MedGen	234775
GARD	0004768
Is cancer (heuristic)	no

Also known as: congenital cutaneous neurilemmomatosis · neurilemmomatosis · neurilemmomatosis congenital cutaneous · neurinoma · Neurinomatosis · neurofibromatosis type 3 · NF3 · Schwannomatosis · schwannomatosis · schwannomatosis, NEC · schwannomatosis, NOS

Data availability: 33 ClinVar variants · 2 GenCC gene-disease records · 6 cell lines.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › skin neoplasm › schwannomatosis

Related subtypes (16): dermoid cyst of skin, eyelid neoplasm, epidermal appendage tumor, dermis tumor, skin cancer, benign dermal neurilemmoma, actinic keratosis, familial Dupuytren contracture, familial multiple discoid fibromas, Maffucci syndrome, hemangiopericytoma of skin, benign neoplasm of skin, melanocytic skin neoplasm, epithelial skin neoplasm, calcifying epithelial odontogenic tumor, familial hyperphosphatemic tumoral calcinosis/hyperphosphatemic hyperostosis syndrome

Subtypes (4): neurofibromatosis, type III, mixed central and peripheral, LZTR1-related schwannomatosis, SMARCB1-related schwannomatosis, 22q-related schwannomatosis

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

33 retrieved; paginated sample, class counts are floors:

11 pathogenic, 10 pathogenic/likely pathogenic, 6 likely pathogenic, 3 conflicting classifications of pathogenicity, 3 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
101034	NM_006767.4(LZTR1):c.264-13G>A	LZTR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
101038	NM_006767.4(LZTR1):c.1397G>A (p.Arg466Gln)	LZTR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1433138	NM_006767.4(LZTR1):c.352del (p.Arg118fs)	LZTR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457076	NM_006767.4(LZTR1):c.2284C>T (p.Gln762Ter)	LZTR1	Pathogenic	criteria provided, multiple submitters, no conflicts
2501186	NM_006767.4(LZTR1):c.2258del (p.Asn753fs)	LZTR1	Pathogenic	criteria provided, single submitter
2506334	NM_006767.4(LZTR1):c.1753_1754del (p.Ser585fs)	LZTR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3233815	NM_006767.4(LZTR1):c.495G>A (p.Trp165Ter)	LZTR1	Pathogenic	criteria provided, multiple submitters, no conflicts
3629816	NC_000022.10:g.(?21336585)(21353322_?)del	LZTR1	Pathogenic	criteria provided, single submitter
450845	NM_006767.4(LZTR1):c.1733_1734del (p.Asn578fs)	LZTR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
488877	NM_006767.4(LZTR1):c.1018C>T (p.Arg340Ter)	LZTR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
872339	NM_006767.4(LZTR1):c.791+1G>A	LZTR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
917601	NM_006767.4(LZTR1):c.372_385del (p.Val125fs)	LZTR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
917763	NM_006767.4(LZTR1):c.824_921dup (p.Pro308fs)	LZTR1	Pathogenic	criteria provided, single submitter
917769	NM_006767.4(LZTR1):c.714_783dup (p.Asp262delinsGlnAspValCysIleLeuTrpAlaLysArgSerGlnAsnAsnGlnGlnProLeuProValTer)	LZTR1	Pathogenic	criteria provided, single submitter
918099	NM_006767.4(LZTR1):c.11dup (p.Ser6fs)	LZTR1	Pathogenic	criteria provided, single submitter
928947	NM_006767.4(LZTR1):c.1496_1590dup (p.Asp531fs)	LZTR1	Pathogenic	criteria provided, single submitter
955623	NM_006767.4(LZTR1):c.482del (p.Gln161fs)	LZTR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
996239	NM_006767.4(LZTR1):c.658C>T (p.Gln220Ter)	LZTR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076272	NM_003073.5(SMARCB1):c.364G>T (p.Glu122Ter)	SMARCB1	Pathogenic	criteria provided, single submitter
1192514	NM_003073.5(SMARCB1):c.500+883T>G	SMARCB1	Pathogenic	criteria provided, single submitter
1192515	NM_003073.5(SMARCB1):c.500+887G>A	SMARCB1	Pathogenic	criteria provided, single submitter
1343619	NM_006767.4(LZTR1):c.320+1G>A	LZTR1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1479453	NM_006767.4(LZTR1):c.401-1G>C	LZTR1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1770635	NM_006767.4(LZTR1):c.1353+1G>A	LZTR1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
289969	NM_006767.4(LZTR1):c.1084C>T (p.Arg362Ter)	LZTR1	Likely pathogenic	reviewed by expert panel
4813644	NM_006767.4(LZTR1):c.2259_2260del (p.Asn753fs)	LZTR1	Likely pathogenic	criteria provided, single submitter
521702	NM_006767.4(LZTR1):c.400+1G>C	LZTR1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
101035	NM_006767.4(LZTR1):c.365C>T (p.Ser122Leu)	LZTR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
101036	NM_006767.4(LZTR1):c.2062C>T (p.Arg688Cys)	LZTR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
809328	NM_006767.4(LZTR1):c.370GTC[1] (p.Val125del)	LZTR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 31 · Orphanet: 11 · 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
LZTR1	Definitive	Autosomal dominant	LZTR1-related schwannomatosis	15
SMARCB1	Definitive	Autosomal dominant	SMARCB1-related schwannomatosis	16

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SMARCB1	Orphanet:1465	Coffin-Siris syndrome
SMARCB1	Orphanet:231108	Rhabdoid tumor predisposition syndrome
SMARCB1	Orphanet:2495	Meningioma
SMARCB1	Orphanet:263662	Familial multiple meningioma
SMARCB1	Orphanet:93921	Full schwannomatosis
SMARCB1	Orphanet:99966	Atypical teratoid rhabdoid tumor
LZTR1	Orphanet:251576	Gliosarcoma
LZTR1	Orphanet:251579	Giant cell glioblastoma
LZTR1	Orphanet:2678	Familial isolated café-au-lait macules
LZTR1	Orphanet:648	Noonan syndrome
LZTR1	Orphanet:93921	Full schwannomatosis

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SMARCB1	HGNC:11103	ENSG00000099956	Q12824	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1	gencc,clinvar
LZTR1	HGNC:6742	ENSG00000099949	Q8N653	Leucine-zipper-like transcriptional regulator 1	gencc,clinvar
DERL3	HGNC:14236	ENSG00000099958	Q96Q80	Derlin-3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMARCB1	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1	Core component of the BAF (hSWI/SNF) complex.
LZTR1	Leucine-zipper-like transcriptional regulator 1	Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex that mediates ubiquitination of Ras (K-Ras/KRAS, N-Ras/NRAS and H-Ras/HRAS).
DERL3	Derlin-3	Functional component of endoplasmic reticulum-associated degradation (ERAD) for misfolded lumenal glycoproteins, but not that of misfolded nonglycoproteins.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SMARCB1	Other/Unknown	no		SNF5, Sfh1/SNF5, INI1_DNA-bd
LZTR1	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf
DERL3	Other/Unknown	no		DER1, Rhomboid-like_sf

Expression context

Cohort genes with no expression data: 0.

3 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
cortical plate	1
embryo	1
ganglionic eminence	1
adenohypophysis	1
pituitary gland	1
sural nerve	1
bone marrow cell	1
duodenum	1
tonsil	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMARCB1	214	ubiquitous	marker	embryo, ganglionic eminence, cortical plate
LZTR1	134	ubiquitous	marker	sural nerve, pituitary gland, adenohypophysis
DERL3	135	ubiquitous	marker	bone marrow cell, duodenum, tonsil

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMARCB1	5,083
LZTR1	1,562
DERL3	1,156

Intra-cohort edges

A	B	Sources
LZTR1	SMARCB1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SMARCB1	Q12824	17
LZTR1	Q8N653	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DERL3	Q96Q80	84.33

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. 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
Formation of the canonical BAF (cBAF) complex	1	317.2×	0.024	SMARCB1
Formation of the polybromo-BAF (pBAF) complex	1	317.2×	0.024	SMARCB1
Formation of the embryonic stem cell BAF (esBAF) complex	1	300.5×	0.024	SMARCB1
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	1	228.4×	0.024	SMARCB1
Regulation of endogenous retroelements	1	184.2×	0.024	SMARCB1
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	1	150.3×	0.024	SMARCB1
Regulation of MITF-M-dependent genes involved in pigmentation	1	132.8×	0.024	SMARCB1
Defective CFTR causes cystic fibrosis	1	109.8×	0.024	DERL3
AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)	1	96.8×	0.024	DERL3
MITF-M-dependent gene expression	1	90.6×	0.024	SMARCB1
RMTs methylate histone arginines	1	73.2×	0.025	SMARCB1
Transcriptional regulation by RUNX1	1	73.2×	0.025	SMARCB1
ABC-family protein mediated transport	1	60.7×	0.026	DERL3
Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)	1	58.9×	0.026	SMARCB1
MITF-M-regulated melanocyte development	1	57.1×	0.026	SMARCB1
Chromatin organization	1	40.8×	0.034	SMARCB1
Chromatin modifying enzymes	1	36.1×	0.034	SMARCB1
Epigenetic regulation of gene expression	1	35.7×	0.034	SMARCB1
RNA Polymerase II Transcription	1	11.3×	0.101	SMARCB1
Gene expression (Transcription)	1	8.9×	0.120	SMARCB1
Generic Transcription Pathway	1	7.5×	0.134	SMARCB1
Developmental Biology	1	7.2×	0.134	SMARCB1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
single stranded viral RNA replication via double stranded DNA intermediate	1	5617.3×	0.005	SMARCB1
positive regulation of glucose mediated signaling pathway	1	1872.4×	0.008	SMARCB1
RNA polymerase I preinitiation complex assembly	1	1123.5×	0.009	SMARCB1
DNA integration	1	702.2×	0.010	SMARCB1
negative regulation of retrograde protein transport, ER to cytosol	1	624.1×	0.010	DERL3
positive regulation of transcription of nucleolar large rRNA by RNA polymerase I	1	510.7×	0.010	SMARCB1
hepatocyte differentiation	1	401.2×	0.011	SMARCB1
host-mediated activation of viral transcription	1	295.6×	0.011	SMARCB1
nucleosome disassembly	1	267.5×	0.011	SMARCB1
obsolete protein N-linked glycosylation via asparagine	1	224.7×	0.011	DERL3
negative regulation of Ras protein signal transduction	1	224.7×	0.011	LZTR1
regulation of G0 to G1 transition	1	224.7×	0.011	SMARCB1
regulation of nucleotide-excision repair	1	200.6×	0.011	SMARCB1
blastocyst hatching	1	181.2×	0.012	SMARCB1
regulation of mitotic metaphase/anaphase transition	1	165.2×	0.012	SMARCB1
positive regulation of T cell differentiation	1	151.8×	0.012	SMARCB1
transcription initiation-coupled chromatin remodeling	1	127.7×	0.013	SMARCB1
positive regulation of myoblast differentiation	1	122.1×	0.013	SMARCB1
positive regulation of stem cell population maintenance	1	114.6×	0.013	SMARCB1
positive regulation of double-strand break repair	1	114.6×	0.013	SMARCB1
regulation of G1/S transition of mitotic cell cycle	1	102.1×	0.014	SMARCB1
endoplasmic reticulum unfolded protein response	1	98.5×	0.014	DERL3
positive regulation of cell differentiation	1	89.2×	0.015	SMARCB1
ERAD pathway	1	60.4×	0.021	DERL3
chromatin remodeling	1	24.3×	0.049	SMARCB1
nervous system development	1	15.3×	0.074	SMARCB1
negative regulation of cell population proliferation	1	14.0×	0.076	SMARCB1
protein ubiquitination	1	13.8×	0.076	LZTR1
positive regulation of transcription by RNA polymerase II	1	5.0×	0.195	SMARCB1
regulation of transcription by RNA polymerase II	1	3.9×	0.236	SMARCB1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SMARCB1	0	0
LZTR1	0	0
DERL3	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
SMARCB1	7	Binding:7

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	3	SMARCB1, LZTR1, DERL3

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)
SMARCB1	7	—
LZTR1	0	—
DERL3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	4
PHASE2	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05684692	PHASE2	RECRUITING	Screening Trial for Pain Relief in Schwannomatosis (STARFISH)
NCT04163419	PHASE2	UNKNOWN	Phase 2 Study of Tanezumab in Subjects With Moderate to Severe Pain Due to Schwannomatosis
NCT01885767	Not specified	RECRUITING	Neurofibromatosis (NF) Registry Portal
NCT01951365	Not specified	COMPLETED	Assessment of Volumetric Growth Rates of Spinal Intradural Extramedullary Schwannoma
NCT02298270	Not specified	COMPLETED	Resiliency Training for Patients With Neurofibromatosis Via Videoconferencing With Skype
NCT03406208	Not specified	COMPLETED	Resiliency Training for Adults With Neurofibromatosis Via Live Videoconferencing

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ERENUMAB	4	1
SILTUXIMAB	4	1
TANEZUMAB	3	1