Hereditary spastic paraplegia 15

Summary

Hereditary spastic paraplegia 15 (MONDO:0010044) is a disease caused by ZFYVE26 (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ZFYVE26 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 478
• Phenotypes (HPO): 38
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

38 HPO clinical features (Orphanet curated; top 38 by frequency):

HPO ID	Term	Frequency
HP:0002079	Hypoplasia of the corpus callosum	Very frequent (80-99%)
HP:0000009	Functional abnormality of the bladder	Frequent (30-79%)
HP:0000580	Pigmentary retinopathy	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001258	Spastic paraplegia	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001317	Abnormal cerebellum morphology	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0002061	Lower limb spasticity	Frequent (30-79%)
HP:0002071	Abnormality of extrapyramidal motor function	Frequent (30-79%)
HP:0002395	Lower limb hyperreflexia	Frequent (30-79%)
HP:0002500	Abnormal cerebral white matter morphology	Frequent (30-79%)
HP:0003477	Peripheral axonal neuropathy	Frequent (30-79%)
HP:0003484	Upper limb muscle weakness	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0006986	Upper limb spasticity	Frequent (30-79%)
HP:0007024	Pseudobulbar paralysis	Frequent (30-79%)
HP:0007108	Demyelinating peripheral neuropathy	Frequent (30-79%)
HP:0008969	Leg muscle stiffness	Frequent (30-79%)
HP:0012045	Retinal flecks	Frequent (30-79%)
HP:0030506	Yellow/white lesions of the retina	Frequent (30-79%)
HP:0030892	Deep cerebral white matter hyperdensities	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)
HP:0000496	Abnormality of eye movement	Occasional (5-29%)
HP:0000708	Atypical behavior	Occasional (5-29%)
HP:0000726	Dementia	Occasional (5-29%)
HP:0000819	Diabetes mellitus	Occasional (5-29%)
HP:0001152	Saccadic smooth pursuit	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001328	Specific learning disability	Occasional (5-29%)
HP:0001761	Pes cavus	Occasional (5-29%)
HP:0002145	Frontotemporal dementia	Occasional (5-29%)
HP:0002378	Hand tremor	Occasional (5-29%)
HP:0002495	Impaired vibratory sensation	Occasional (5-29%)
HP:0003693	Distal amyotrophy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 15
Mondo ID	MONDO:0010044
MeSH	C536642
OMIM	270700
Orphanet	100996
DOID	DOID:0110768
SNOMED CT	709417000
UMLS	C1849128
MedGen	341387
GARD	0009581
Is cancer (heuristic)	no

Also known as: autosomal recessive complex spastic paraplegia caused by mutation in ZFYVE26 · autosomal recessive spastic paraplegia type 15 · hereditary spastic paraparesis type 15 · hereditary spastic paraplegia 15 · hereditary spastic paraplegia type 15 · Kjellin syndrome · recessive spastic paraplegia with retinal degeneration · spastic paraplegia 15 · spastic paraplegia 15, autosomal recessive · spastic paraplegia and retinal degeneration · spastic paraplegia-retinal degeneration syndrome · SPG15 · ZFYVE26 autosomal recessive complex spastic paraplegia

Data availability: 478 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › complex hereditary spastic paraplegia › hereditary spastic paraplegia 15

Related subtypes (49): hereditary sensory and autonomic neuropathy with spastic paraplegia, hereditary spastic paraplegia 23, spastic paraplegia-glaucoma-intellectual disability syndrome, Troyer syndrome, MASA syndrome, hereditary spastic paraplegia 11, hereditary spastic paraplegia 24, hereditary spastic paraplegia 25, hereditary spastic paraplegia 27, hereditary spastic paraplegia 26, spastic paraplegia, optic atropy, and neuropathy, hereditary spastic paraplegia 18, hereditary spastic paraplegia 32, spastic ataxia 2, hereditary spastic paraplegia 39, hereditary spastic paraplegia 45, hereditary spastic paraplegia 44, hereditary spastic paraplegia 46, hereditary spastic paraplegia 53, hereditary spastic paraplegia 49, hereditary spastic paraplegia 54, hereditary spastic paraplegia 55, hereditary spastic paraplegia 43, hereditary spastic paraplegia 57, hereditary spastic paraplegia 64, hereditary spastic paraplegia 61, hereditary spastic paraplegia 63, glutamate pyruvate transaminase 2 deficiency, hereditary spastic paraplegia 74, autosomal recessive complex spastic paraplegia type 9B, hereditary spastic paraplegia 75, spastic paraplegia-severe developmental delay-epilepsy syndrome, autosomal recessive spastic paraplegia type 76, autosomal recessive spastic paraplegia type 78, autosomal dominant complex spastic paraplegia, maternally-inherited spastic paraplegia, fatty acid hydroxylase-associated neurodegeneration, autosomal recessive spastic paraplegia type 59, autosomal recessive spastic paraplegia type 60, autosomal recessive spastic paraplegia type 66, autosomal recessive spastic paraplegia type 67, autosomal recessive spastic paraplegia type 68, autosomal recessive spastic paraplegia type 69, autosomal recessive spastic paraplegia type 70, spastic paraplegia 84, autosomal recessive, spastic paraplegia 85, autosomal recessive, spastic paraplegia 86, autosomal recessive, kyphoscoliosis-lateral tongue atrophy-hereditary spastic paraplegia syndrome, autosomal recessive complex spastic paraplegia due to kennedy pathway dysfunction

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

478 retrieved; paginated sample, class counts are floors:

150 likely pathogenic, 143 uncertain significance, 74 conflicting classifications of pathogenicity, 38 pathogenic, 26 benign, 22 pathogenic/likely pathogenic, 21 benign/likely benign, 4 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1027980	NM_015346.4(ZFYVE26):c.886+1G>C	ZFYVE26	Pathogenic	criteria provided, single submitter
1031907	NM_015346.4(ZFYVE26):c.1564C>T (p.Gln522Ter)	ZFYVE26	Pathogenic	criteria provided, single submitter
1071110	NM_015346.4(ZFYVE26):c.6144C>A (p.Tyr2048Ter)	ZFYVE26	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074144	NM_015346.4(ZFYVE26):c.2114dup (p.Pro705_Glu706insTer)	ZFYVE26	Pathogenic	criteria provided, multiple submitters, no conflicts
1323783	NM_015346.4(ZFYVE26):c.5428dup (p.Val1810fs)	ZFYVE26	Pathogenic	criteria provided, single submitter
1354728	NM_015346.4(ZFYVE26):c.3256C>T (p.Gln1086Ter)	ZFYVE26	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1442056	NM_015346.4(ZFYVE26):c.6390del (p.Thr2131fs)	ZFYVE26	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452504	NM_015346.4(ZFYVE26):c.961A>T (p.Lys321Ter)	ZFYVE26	Pathogenic	criteria provided, multiple submitters, no conflicts
1705922	NM_015346.4(ZFYVE26):c.1254dup (p.Cys419fs)	ZFYVE26	Pathogenic	criteria provided, single submitter
1724121	NM_015346.4(ZFYVE26):c.2830C>T (p.Gln944Ter)	ZFYVE26	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1725288	NM_015346.4(ZFYVE26):c.5690C>A (p.Ser1897Ter)	ZFYVE26	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1725395	NM_015346.4(ZFYVE26):c.7270C>T (p.Gln2424Ter)	ZFYVE26	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1805297	NM_015346.4(ZFYVE26):c.517del (p.Glu173fs)	ZFYVE26	Pathogenic	criteria provided, single submitter
209210	NM_015346.4(ZFYVE26):c.4181G>A (p.Trp1394Ter)	ZFYVE26	Pathogenic	criteria provided, multiple submitters, no conflicts
224987	NM_015346.4(ZFYVE26):c.7195C>T (p.Gln2399Ter)	ZFYVE26	Pathogenic	criteria provided, multiple submitters, no conflicts
2783888	NM_015346.4(ZFYVE26):c.5941C>T (p.Gln1981Ter)	ZFYVE26	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2841993	NM_015346.4(ZFYVE26):c.1558C>T (p.Gln520Ter)	ZFYVE26	Pathogenic	criteria provided, multiple submitters, no conflicts
2865368	NM_015346.4(ZFYVE26):c.1093del (p.Leu365fs)	ZFYVE26	Pathogenic	criteria provided, multiple submitters, no conflicts
2878461	NM_015346.4(ZFYVE26):c.5729G>A (p.Trp1910Ter)	ZFYVE26	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30932	NM_015346.4(ZFYVE26):c.5036del (p.Leu1679fs)	ZFYVE26	Pathogenic	criteria provided, single submitter
30933	NM_015346.4(ZFYVE26):c.5422C>T (p.Gln1808Ter)	ZFYVE26	Pathogenic	criteria provided, multiple submitters, no conflicts
372839	NM_015346.4(ZFYVE26):c.2254C>T (p.Gln752Ter)	ZFYVE26	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4081833	NM_015346.4(ZFYVE26):c.4764del (p.Leu1588_Leu1589insTer)	ZFYVE26	Pathogenic	criteria provided, single submitter
424005	NM_015346.4(ZFYVE26):c.7041C>A (p.Cys2347Ter)	ZFYVE26	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
424650	NM_015346.4(ZFYVE26):c.6296dup (p.Asn2100fs)	ZFYVE26	Pathogenic	criteria provided, multiple submitters, no conflicts
430412	NM_015346.4(ZFYVE26):c.2450del (p.Leu817fs)	ZFYVE26	Pathogenic	criteria provided, multiple submitters, no conflicts
458283	NM_015346.4(ZFYVE26):c.4132C>T (p.Arg1378Ter)	ZFYVE26	Pathogenic	criteria provided, multiple submitters, no conflicts
4687969	NM_015346.4(ZFYVE26):c.2283_2284dup (p.Arg762fs)	ZFYVE26	Pathogenic	criteria provided, single submitter
488743	NM_015346.4(ZFYVE26):c.2554-1G>C	ZFYVE26	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
527985	NM_015346.4(ZFYVE26):c.4114_4115insGAAGGGC (p.Ala1372fs)	ZFYVE26	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
ZFYVE26	Definitive	Autosomal recessive	hereditary spastic paraplegia 15	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ZFYVE26	Orphanet:100996	Kjellin 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
ZFYVE26	HGNC:20761	ENSG00000072121	Q68DK2	Zinc finger FYVE domain-containing protein 26	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ZFYVE26	Zinc finger FYVE domain-containing protein 26	Phosphatidylinositol 3-phosphate-binding protein required for the abscission step in cytokinesis: recruited to the midbody during cytokinesis and acts as a regulator of abscission.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ZFYVE26	Transcription factor	no		Znf_FYVE, Znf_FYVE_PHD, Znf_RING/FYVE/PHD

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
endothelial cell	1
sural nerve	1
visceral pleura	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ZFYVE26	287	ubiquitous	marker	sural nerve, endothelial cell, visceral pleura

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ZFYVE26	1,139

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ZFYVE26	Q68DK2	1

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
autophagosome organization	1	3370.4×	0.001	ZFYVE26
regulation of cytokinesis	1	421.3×	0.005	ZFYVE26
lysosome organization	1	306.4×	0.005	ZFYVE26
mitotic cytokinesis	1	259.3×	0.005	ZFYVE26
double-strand break repair via homologous recombination	1	156.0×	0.006	ZFYVE26

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
ZFYVE26	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	ZFYVE26

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)
ZFYVE26	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04712812	Not specified	RECRUITING	Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia