Spastic paraplegia, intellectual disability, nystagmus, and obesity

Summary

Spastic paraplegia, intellectual disability, nystagmus, and obesity (MONDO:0015007) is a disease caused by KIDINS220 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: KIDINS220 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 71
• Phenotypes (HPO): 14

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

14 HPO clinical features (Orphanet curated; top 14 by frequency):

HPO ID	Term	Frequency
HP:0000490	Deeply set eye	Frequent (30-79%)
HP:0000540	Hypermetropia	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001357	Plagiocephaly	Frequent (30-79%)
HP:0001513	Obesity	Frequent (30-79%)
HP:0002079	Hypoplasia of the corpus callosum	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0002194	Delayed gross motor development	Frequent (30-79%)
HP:0007020	Progressive spastic paraplegia	Frequent (30-79%)
HP:0011220	Prominent forehead	Frequent (30-79%)
HP:0011400	Abnormal CNS myelination	Frequent (30-79%)
HP:0025312	Esophoria	Frequent (30-79%)
HP:0001561	Polyhydramnios	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spastic paraplegia, intellectual disability, nystagmus, and obesity
Mondo ID	MONDO:0015007
OMIM	617296
Orphanet	521390
UMLS	C4284592
MedGen	924883
GARD	0017957
Is cancer (heuristic)	no

Also known as: SINO · spastic paraplegia, intellectual disability, nystagmus, and obesity

Data availability: 71 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 dominant disease › autosomal dominant complex spastic paraplegia › spastic paraplegia, intellectual disability, nystagmus, and obesity

Related subtypes (12): spastic paraplegia-epilepsy-intellectual disability syndrome, spastic paraplegia-nephritis-deafness syndrome, spastic paraplegia-neuropathy-poikiloderma syndrome, spastic paraplegia-precocious puberty syndrome, hereditary spastic paraplegia 17, hereditary spastic paraplegia 29, hereditary spastic paraplegia 38, hereditary spastic paraplegia 36, autosomal dominant spastic paraplegia type 9, spastic paraplegia-facial-cutaneous lesions syndrome, spastic paraplegia-Paget disease of bone syndrome, spastic paraplegia 18a, autosomal dominant

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

71 retrieved; paginated sample, class counts are floors:

38 uncertain significance, 11 pathogenic, 8 conflicting classifications of pathogenicity, 5 likely pathogenic, 4 benign/likely benign, 3 benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
16168	NM_002055.5(GFAP):c.716G>A (p.Arg239His)	GFAP	Pathogenic	criteria provided, multiple submitters, no conflicts
1217311	NM_020738.4(KIDINS220):c.4389_4390del (p.Val1465fs)	KIDINS220	Pathogenic	no assertion criteria provided
1333866	NM_020738.4(KIDINS220):c.3991G>T (p.Glu1331Ter)	KIDINS220	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685907	NM_020738.4(KIDINS220):c.3415-4A>G	KIDINS220	Pathogenic	criteria provided, single submitter
1804954	NM_020738.4(KIDINS220):c.3395dup (p.His1133fs)	KIDINS220	Pathogenic	criteria provided, single submitter
1895452	NM_020738.4(KIDINS220):c.4412delinsAAG (p.Ser1471Ter)	KIDINS220	Pathogenic	criteria provided, single submitter
3602731	NM_020738.4(KIDINS220):c.3991delinsAGCCCTACACACTCAAC (p.Glu1331fs)	KIDINS220	Pathogenic	criteria provided, single submitter
374908	NM_020738.4(KIDINS220):c.4050G>A (p.Trp1350Ter)	KIDINS220	Pathogenic	no assertion criteria provided
374909	NM_020738.4(KIDINS220):c.4096C>T (p.Gln1366Ter)	KIDINS220	Pathogenic	no assertion criteria provided
374910	NM_020738.4(KIDINS220):c.4520dup (p.Leu1507fs)	KIDINS220	Pathogenic	no assertion criteria provided
3893243	NM_020738.4(KIDINS220):c.4177C>T (p.Gln1393Ter)	KIDINS220	Pathogenic	criteria provided, single submitter
4685503	NM_020738.4(KIDINS220):c.535C>T (p.Arg179Ter)	KIDINS220	Pathogenic	criteria provided, single submitter
817641	NM_020738.4(KIDINS220):c.4417dup (p.Leu1473fs)	KIDINS220	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1526161	NM_020738.4(KIDINS220):c.4388C>A (p.Ser1463Ter)	KIDINS220	Likely pathogenic	criteria provided, single submitter
2585019	NM_020738.4(KIDINS220):c.876T>G (p.Tyr292Ter)	KIDINS220	Likely pathogenic	criteria provided, single submitter
2672131	NM_020738.4(KIDINS220):c.4213_4216dup (p.Ile1406fs)	KIDINS220	Likely pathogenic	criteria provided, single submitter
3362459	NM_020738.4(KIDINS220):c.856C>T (p.Arg286Ter)	KIDINS220	Likely pathogenic	criteria provided, single submitter
431718	NM_020738.4(KIDINS220):c.4138C>T (p.Gln1380Ter)	KIDINS220	Likely pathogenic	criteria provided, single submitter
1525138	NM_020738.4(KIDINS220):c.2569G>A (p.Val857Ile)	KIDINS220	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2146522	NM_020738.4(KIDINS220):c.4835C>A (p.Ala1612Glu)	KIDINS220	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2388180	NM_020738.4(KIDINS220):c.346C>T (p.Arg116Cys)	KIDINS220	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2388181	NM_020738.4(KIDINS220):c.517C>T (p.Pro173Ser)	KIDINS220	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2903472	NM_020738.4(KIDINS220):c.3334G>A (p.Ala1112Thr)	KIDINS220	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2979344	NM_020738.4(KIDINS220):c.4269del (p.Gly1425fs)	KIDINS220	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
441104	NM_020738.4(KIDINS220):c.974A>G (p.Asn325Ser)	KIDINS220	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
729662	NM_020738.4(KIDINS220):c.4947C>G (p.Asp1649Glu)	KIDINS220	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1012049	NM_020738.4(KIDINS220):c.1012C>T (p.Pro338Ser)	KIDINS220	Uncertain significance	criteria provided, multiple submitters, no conflicts
1030723	NM_020738.4(KIDINS220):c.4549C>T (p.Gln1517Ter)	KIDINS220	Uncertain significance	criteria provided, multiple submitters, no conflicts
1032091	NM_020738.4(KIDINS220):c.207+3A>G	KIDINS220	Uncertain significance	criteria provided, multiple submitters, no conflicts
1032092	NM_020738.4(KIDINS220):c.2428A>G (p.Ile810Val)	KIDINS220	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
KIDINS220	Strong	Autosomal dominant	spastic paraplegia, intellectual disability, nystagmus, and obesity	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KIDINS220	Orphanet:521390	Spastic paraplegia-intellectual disability-nystagmus-obesity syndrome
LRBA	Orphanet:445018	Syndromic autoimmune enteropathy due to LRBA deficiency
GFAP	Orphanet:363717	Alexander disease type I
GFAP	Orphanet:363722	Alexander disease type II

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
KIDINS220	HGNC:29508	ENSG00000134313	Q9ULH0	Kinase D-interacting substrate of 220 kDa	gencc,clinvar
LRBA	HGNC:1742	ENSG00000198589	P50851	Lipopolysaccharide-responsive and beige-like anchor protein	clinvar
GFAP	HGNC:4235	ENSG00000131095	P14136	Glial fibrillary acidic protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KIDINS220	Kinase D-interacting substrate of 220 kDa	Promotes a prolonged MAP-kinase signaling by neurotrophins through activation of a Rap1-dependent mechanism.
LRBA	Lipopolysaccharide-responsive and beige-like anchor protein	Involved in coupling signal transduction and vesicle trafficking to enable polarized secretion and/or membrane deposition of immune effector molecules.
GFAP	Glial fibrillary acidic protein	GFAP, a class-III intermediate filament, is a cell-specific marker that, during the development of the central nervous system, distinguishes astrocytes from other glial cells.

Protein-family classification

Druggable: 0 · Difficult: 2 · 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
Scaffold/PPI	2	11.5×	0.019
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KIDINS220	Scaffold/PPI	no		Ankyrin_rpt, KAP_P-loop, SAM/pointed_sf
LRBA	Scaffold/PPI	no		BEACH_dom, WD40_rpt, NBEA-like_DUF1088
GFAP	Other/Unknown	no		Intermed_filament_DNA-bd, IF_conserved, IF_rod_dom

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
middle frontal gyrus	1
paraflocculus	1
bronchial epithelial cell	1
epithelium of bronchus	1
upper leg skin	1
dorsal motor nucleus of vagus nerve	1
inferior olivary complex	1
medulla oblongata	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KIDINS220	299	ubiquitous	marker	middle frontal gyrus, cortical plate, paraflocculus
LRBA	274	ubiquitous	marker	upper leg skin, bronchial epithelial cell, epithelium of bronchus
GFAP	210	broad	marker	medulla oblongata, inferior olivary complex, dorsal motor nucleus of vagus nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GFAP	6,997
KIDINS220	2,084
LRBA	1,331

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KIDINS220	Q9ULH0	1
LRBA	P50851	1
GFAP	P14136	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. 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
ARMS-mediated activation	1	815.7×	0.010	KIDINS220
Prolonged ERK activation events	1	713.8×	0.010	KIDINS220
Signalling to ERKs	1	300.5×	0.014	KIDINS220
Chaperone Mediated Autophagy	1	248.3×	0.014	GFAP
Nuclear signaling by ERBB4	1	173.0×	0.015	GFAP
RND1 GTPase cycle	1	132.8×	0.015	KIDINS220
RND2 GTPase cycle	1	129.8×	0.015	KIDINS220
Signaling by NTRK1 (TRKA)	1	98.5×	0.017	KIDINS220
Signaling by NTRKs	1	90.6×	0.017	KIDINS220
RHO GTPase cycle	1	30.1×	0.046	KIDINS220
Signaling by Receptor Tyrosine Kinases	1	25.8×	0.049	KIDINS220
Signaling by Rho GTPases	1	17.1×	0.063	KIDINS220
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	16.7×	0.063	KIDINS220
Signal Transduction	1	5.1×	0.187	KIDINS220

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
positive regulation of Schwann cell proliferation	1	5617.3×	0.004	GFAP
Schwann cell proliferation	1	1872.4×	0.004	GFAP
regulation of neurotransmitter uptake	1	1872.4×	0.004	GFAP
neuron projection regeneration	1	1404.3×	0.004	GFAP
D-aspartate import across plasma membrane	1	1123.5×	0.004	GFAP
regulation of chaperone-mediated autophagy	1	1123.5×	0.004	GFAP
Bergmann glial cell differentiation	1	510.7×	0.007	GFAP
nerve growth factor signaling pathway	1	432.1×	0.007	KIDINS220
astrocyte development	1	374.5×	0.007	GFAP
protein localization to phagophore assembly site	1	330.4×	0.007	LRBA
enteric nervous system development	1	330.4×	0.007	GFAP
regulation of protein-containing complex assembly	1	244.2×	0.009	GFAP
cellular response to nerve growth factor stimulus	1	156.0×	0.012	KIDINS220
dendrite morphogenesis	1	144.0×	0.012	KIDINS220
neural crest cell migration	1	112.3×	0.015	GFAP
mitophagy	1	106.0×	0.015	LRBA
long-term synaptic potentiation	1	93.6×	0.016	GFAP
intermediate filament organization	1	80.2×	0.017	GFAP
negative regulation of neuron projection development	1	79.1×	0.017	GFAP
positive regulation of neuron projection development	1	45.7×	0.027	KIDINS220
extracellular matrix organization	1	40.7×	0.029	GFAP
intracellular protein localization	1	34.9×	0.032	LRBA
gene expression	1	26.6×	0.040	GFAP
in utero embryonic development	1	24.0×	0.043	KIDINS220
intracellular protein transport	1	21.6×	0.046	GFAP

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
KIDINS220	0	0
LRBA	0	0
GFAP	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
LRBA	1	Binding:1

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	KIDINS220, LRBA, GFAP

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)
KIDINS220	0	—
LRBA	1	—
GFAP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.