Mast syndrome

Summary

Mast syndrome (MONDO:0009568) is a disease caused by SPG21 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SPG21 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 106
• Phenotypes (HPO): 19

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		35	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

19 HPO clinical features (Orphanet curated; top 19 by frequency):

HPO ID	Term	Frequency
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0000726	Dementia	Very frequent (80-99%)
HP:0007256	Abnormal pyramidal sign	Very frequent (80-99%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001268	Mental deterioration	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002079	Hypoplasia of the corpus callosum	Frequent (30-79%)
HP:0002186	Apraxia	Frequent (30-79%)
HP:0002476	Primitive reflex	Frequent (30-79%)
HP:0003134	Abnormality of peripheral nerve conduction	Frequent (30-79%)
HP:0006892	Frontotemporal cerebral atrophy	Frequent (30-79%)
HP:0007340	Lower limb muscle weakness	Frequent (30-79%)
HP:0010526	Dysgraphia	Frequent (30-79%)
HP:0012075	Personality disorder	Frequent (30-79%)
HP:0001317	Abnormal cerebellum morphology	Occasional (5-29%)
HP:0002071	Abnormality of extrapyramidal motor function	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	mast syndrome
Mondo ID	MONDO:0009568
MeSH	C565409
OMIM	248900
Orphanet	101001
DOID	DOID:0060245
SNOMED CT	764734003
UMLS	C1855346
MedGen	343325
GARD	0016939
Is cancer (heuristic)	no

Also known as: autosomal recessive spastic paraplegia type 21 · Mast syndrome · mast syndrome · SPG21

Data availability: 106 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › palsy › paraplegia › hereditary spastic paraplegia › mast syndrome

Related subtypes (44): hereditary spastic paraplegia 3A, hereditary spastic paraplegia 4, hereditary spastic paraplegia 5A, hereditary spastic paraplegia 16, hereditary spastic paraplegia 2, macrocephaly-spastic paraplegia-dysmorphism syndrome, Charcot-Marie-Tooth disease type 5, hereditary spastic paraplegia 6, hereditary spastic paraplegia 10, hereditary spastic paraplegia 14, hereditary spastic paraplegia 13, hereditary spastic paraplegia 7, hereditary spastic paraplegia 33, hereditary spastic paraplegia 31, hereditary spastic paraplegia 30, hereditary spastic paraplegia 35, hereditary spastic paraplegia 50, hereditary spastic paraplegia 48, hereditary spastic paraplegia 51, hereditary spastic paraplegia 47, hereditary spastic paraplegia 52, hereditary spastic paraplegia 56, early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, hereditary spastic paraplegia 77, pure hereditary spastic paraplegia, complex hereditary spastic paraplegia, pure or complex hereditary spastic paraplegia, spastic paraplegia 87, autosomal recessive, spastic paraplegia 80, autosomal dominant, spastic paraplegia 81, autosomal recessive, spastic paraplegia 82, autosomal recessive, spastic paraplegia 83, autosomal recessive, spastic paraplegia 88, autosomal dominant, spastic paraplegia 79A, autosomal dominant, with ataxia, spastic paraplegia 89, autosomal recessive, spastic paraplegia 90A, autosomal dominant, spastic paraplegia 90B, autosomal recessive, spastic paraplegia 91, autosomal dominant, with or without cerebellar ataxia, spastic paraplegia 72b, autosomal recessive, spastic paraplegia 92, autosomal recessive, spastic paraplegia 93, autosomal recessive, IFIH1-related hereditary spastic paraplegia, RNASEH2B-related hereditary spastic paraplegia, ADAR-related hereditary spastic paraplegia

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

106 retrieved; paginated sample, class counts are floors:

39 uncertain significance, 36 likely benign, 13 conflicting classifications of pathogenicity, 6 pathogenic, 4 benign, 3 pathogenic/likely pathogenic, 3 likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
127082	NM_016630.7(SPG21):c.322G>C (p.Ala108Pro)	SPG21	Pathogenic	no assertion criteria provided
1285233	NM_016630.7(SPG21):c.118C>T (p.Arg40Ter)	SPG21	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1326870	NM_016630.7(SPG21):c.487del (p.Lys162_Ile163insTer)	SPG21	Pathogenic	no assertion criteria provided
2490	NM_016630.7(SPG21):c.601dup (p.Thr201fs)	SPG21	Pathogenic	criteria provided, multiple submitters, no conflicts
2500987	NM_016630.7(SPG21):c.118del (p.Arg40fs)	SPG21	Pathogenic	no assertion criteria provided
2720153	NM_016630.7(SPG21):c.137_138del (p.Leu46fs)	SPG21	Pathogenic	criteria provided, single submitter
372515	NM_016630.7(SPG21):c.736C>T (p.Arg246Ter)	SPG21	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
573980	NM_016630.7(SPG21):c.119dup (p.Ser41fs)	SPG21	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
989200	NM_016630.7(SPG21):c.345_346del (p.Gln116fs)	SPG21	Pathogenic	criteria provided, single submitter
1325118	NM_016630.7(SPG21):c.153del (p.Val52fs)	SPG21	Likely pathogenic	criteria provided, single submitter
1805260	NM_016630.7(SPG21):c.226-1G>A	SPG21	Likely pathogenic	criteria provided, single submitter
837857	NM_016630.7(SPG21):c.452+2T>C	SPG21	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1030573	NM_016630.7(SPG21):c.141A>G (p.Ile47Met)	SPG21	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1344110	NM_016630.7(SPG21):c.153T>C (p.Pro51=)	SPG21	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1344113	NM_016630.7(SPG21):c.243T>C (p.Tyr81=)	SPG21	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1344118	NM_016630.7(SPG21):c.64A>G (p.Ile22Val)	SPG21	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
215896	NM_016630.7(SPG21):c.846G>A (p.Ala282=)	SPG21	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2578742	NM_016630.7(SPG21):c.306+6T>A	SPG21	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
316719	NM_016630.7(SPG21):c.670-13G>T	SPG21	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
316720	NM_016630.7(SPG21):c.538G>A (p.Ala180Thr)	SPG21	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
316721	NM_016630.7(SPG21):c.360A>G (p.Glu120=)	SPG21	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
316730	NM_016630.7(SPG21):c.-241G>C	SPG21	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
696703	NM_016630.7(SPG21):c.771A>C (p.Pro257=)	SPG21	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
887277	NM_016630.7(SPG21):c.321C>T (p.Gly107=)	SPG21	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
887279	NM_016630.7(SPG21):c.177T>C (p.Phe59=)	SPG21	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1397004	NM_016630.7(SPG21):c.569G>A (p.Ser190Asn)	SPG21	Uncertain significance	criteria provided, multiple submitters, no conflicts
1411087	NM_016630.7(SPG21):c.810+3A>G	SPG21	Uncertain significance	criteria provided, multiple submitters, no conflicts
1416990	NM_016630.7(SPG21):c.367C>T (p.His123Tyr)	SPG21	Uncertain significance	criteria provided, single submitter
188225	NM_016630.7(SPG21):c.526A>G (p.Met176Val)	SPG21	Uncertain significance	criteria provided, single submitter
1925006	NM_016630.7(SPG21):c.810+4A>C	SPG21	Uncertain significance	criteria provided, single submitter

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
SPG21	Strong	Autosomal recessive	mast syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SPG21	Orphanet:101001	Autosomal recessive spastic paraplegia type 21

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
SPG21	HGNC:20373	ENSG00000090487	Q9NZD8	Maspardin	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SPG21	Maspardin	May play a role as a negative regulatory factor in CD4-dependent T-cell activation.

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)
SPG21	Other/Unknown	no		AB_hydrolase_1, Maspardin, AB_hydrolase_fold

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
corpus epididymis	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SPG21	286	ubiquitous	marker	corpus epididymis, monocyte, mononuclear cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SPG21	1,776

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SPG21	Q9NZD8	93.02

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
response to epidermal growth factor	1	3370.4×	0.002	SPG21
antigen receptor-mediated signaling pathway	1	2808.7×	0.002	SPG21
collateral sprouting	1	1203.7×	0.002	SPG21
neuron maturation	1	802.5×	0.003	SPG21
neuromuscular process	1	526.6×	0.003	SPG21
limb development	1	411.0×	0.004	SPG21
epidermal growth factor receptor signaling pathway	1	247.8×	0.005	SPG21
locomotory behavior	1	179.3×	0.006	SPG21
gene expression	1	79.9×	0.013	SPG21

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
SPG21	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	1	SPG21

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)
SPG21	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.