Short-limb skeletal dysplasia with severe combined immunodeficiency

Summary

Short-limb skeletal dysplasia with severe combined immunodeficiency (MONDO:0008704) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 1
• Phenotypes (HPO): 18

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		19	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0000944	Abnormal metaphysis morphology	Very frequent (80-99%)
HP:0001888	Lymphopenia	Very frequent (80-99%)
HP:0002205	Recurrent respiratory infections	Very frequent (80-99%)
HP:0004430	Severe combined immunodeficiency	Very frequent (80-99%)
HP:0005374	Cellular immunodeficiency	Very frequent (80-99%)
HP:0002213	Fine hair	Frequent (30-79%)
HP:0004349	Reduced bone mineral density	Frequent (30-79%)
HP:0004422	Biparietal narrowing	Frequent (30-79%)
HP:0004432	Agammaglobulinemia	Frequent (30-79%)
HP:0000023	Inguinal hernia	Occasional (5-29%)
HP:0000767	Pectus excavatum	Occasional (5-29%)
HP:0001732	Abnormality of the pancreas	Occasional (5-29%)
HP:0001903	Anemia	Occasional (5-29%)
HP:0002024	Malabsorption	Occasional (5-29%)
HP:0002251	Aganglionic megacolon	Occasional (5-29%)
HP:0003085	Long fibula	Occasional (5-29%)
HP:0011364	White hair	Occasional (5-29%)
HP:0100543	Cognitive impairment	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	short-limb skeletal dysplasia with severe combined immunodeficiency
Mondo ID	MONDO:0008704
MeSH	C565984
OMIM	200900
Orphanet	935
ICD-11	469016488
UMLS	C1860168
MedGen	348040
GARD	0002988
Is cancer (heuristic)	no

Also known as: achondroplasia and severe combined immunodeficiency · achondroplasia and Swiss type agammaglobulinemia · achondroplasia and Swiss-type agammaglobulinemia · achondroplasia so-called and severe combined immunodeficiency · achondroplasia-SCID syndrome · achondroplasia-severe combined immunodeficiency syndrome · achondroplasia-Swiss type agammaglobulinemia syndrome · agammaglobulinemia and achondroplasia · immunodeficiency-short limb dwarfism syndrome · short limb skeletal dysplasia with SCID · short-limb skeletal dysplasia with severe combined immunodeficiency · SLSD with SCID

Data availability: 1 ClinVar variant.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › combined immunodeficiency › severe combined immunodeficiency › T-B- severe combined immunodeficiency › short-limb skeletal dysplasia with severe combined immunodeficiency

Related subtypes (15): severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency, combined immunodeficiency with skin granulomas, reticular dysgenesis, severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, severe combined immunodeficiency due to DCLRE1C deficiency, Omenn syndrome, DNA ligase IV deficiency, neutrophil immunodeficiency syndrome, combined immunodeficiency due to partial RAG1 deficiency, Cernunnos-XLF deficiency, severe combined immunodeficiency due to LCK deficiency, severe combined immunodeficiency due to DNA-PKcs deficiency, immunodeficiency 73b with defective neutrophil chemotaxis and lymphopenia, immunodeficiency 73c with defective neutrophil chemotaxis and hypogammaglobulinemia, reticular dysgenesis-like severe combined immunodeficiency

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

1 retrieved; paginated sample, class counts are floors:

1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1339122	NM_198525.3(KIF7):c.733G>A (p.Val245Ile)	KIF7	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KIF7	Orphanet:166024	Multiple epiphyseal dysplasia-macrocephaly-facial dysmorphism syndrome
KIF7	Orphanet:2189	Hydrolethalus
KIF7	Orphanet:2754	Orofaciodigital syndrome type 6
KIF7	Orphanet:36	Acrocallosal 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
KIF7	HGNC:30497	ENSG00000166813	Q2M1P5	Kinesin-like protein KIF7	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KIF7	Kinesin-like protein KIF7	Essential for hedgehog signaling regulation: acts both as a negative and positive regulator of sonic hedgehog (Shh) and Indian hedgehog (Ihh) pathways, acting downstream of SMO, through both SUFU-dependent and -independent mechanisms.

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)
KIF7	Other/Unknown	no		Kinesin_motor_dom, Kinesin_motor_CS, P-loop_NTPase

Expression context

Cohort genes with no expression data: 0.

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
cardiac muscle of right atrium	1
kidney epithelium	1
left ventricle myocardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KIF7	165	ubiquitous	yes	kidney epithelium, cardiac muscle of right atrium, left ventricle myocardium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KIF7	1,655

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KIF7	Q2M1P5	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Signaling by Hedgehog	1	184.2×	0.008	KIF7
Hedgehog ‘off’ state	1	178.4×	0.008	KIF7
Hedgehog ‘on’ state	1	158.6×	0.008	KIF7
Signal Transduction	1	10.2×	0.098	KIF7

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
negative regulation of smoothened signaling pathway	1	455.5×	0.003	KIF7
positive regulation of smoothened signaling pathway	1	421.3×	0.003	KIF7
microtubule-based movement	1	295.6×	0.003	KIF7

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KIF7	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
KIF7	5	Binding:5

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	KIF7

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)
KIF7	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.