Schimke immuno-osseous dysplasia

Summary

Schimke immuno-osseous dysplasia (MONDO:0009458) is a disease caused by SMARCAL1 (GenCC Definitive), with 1 cohort gene and 2 clinical trials. Top therapeutic interventions include fludarabine phosphate.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SMARCAL1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 1,219
• Phenotypes (HPO): 73
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		133	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

73 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000093	Proteinuria	Very frequent (80-99%)
HP:0000097	Focal segmental glomerulosclerosis	Very frequent (80-99%)
HP:0000112	Nephropathy	Very frequent (80-99%)
HP:0001511	Intrauterine growth retardation	Very frequent (80-99%)
HP:0003368	Abnormality of the femoral head	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0031409	Abnormal lymphocyte physiology	Very frequent (80-99%)
HP:0011840	Abnormality of T cell physiology	Frequent (30-79%)
HP:0000455	Broad nasal tip	Frequent (30-79%)
HP:0000691	Microdontia	Frequent (30-79%)
HP:0000707	Abnormality of the nervous system	Frequent (30-79%)
HP:0000822	Hypertension	Frequent (30-79%)
HP:0000926	Platyspondyly	Frequent (30-79%)
HP:0001003	Multiple lentigines	Frequent (30-79%)
HP:0001034	Hypermelanotic macule	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001297	Stroke	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001622	Premature birth	Frequent (30-79%)
HP:0001875	Decreased total neutrophil count	Frequent (30-79%)
HP:0001888	Lymphopenia	Frequent (30-79%)
HP:0001903	Anemia	Frequent (30-79%)
HP:0001999	Abnormal facial shape	Frequent (30-79%)
HP:0002315	Headache	Frequent (30-79%)
HP:0002621	Atherosclerosis	Frequent (30-79%)
HP:0002637	Cerebral ischemia	Frequent (30-79%)
HP:0002655	Spondyloepiphyseal dysplasia	Frequent (30-79%)
HP:0002719	Recurrent infections	Frequent (30-79%)
HP:0002926	Abnormality of thyroid physiology	Frequent (30-79%)
HP:0002938	Lumbar hyperlordosis	Frequent (30-79%)
HP:0003077	Hyperlipidemia	Frequent (30-79%)
HP:0003182	Shallow acetabular fossae	Frequent (30-79%)
HP:0003270	Abdominal distention	Frequent (30-79%)
HP:0003300	Ovoid vertebral bodies	Frequent (30-79%)
HP:0003521	Disproportionate short-trunk short stature	Frequent (30-79%)
HP:0005352	Severe T-cell immunodeficiency	Frequent (30-79%)
HP:0008784	Wide capital femoral epiphyses	Frequent (30-79%)
HP:0008839	Hypoplastic pelvis	Frequent (30-79%)
HP:0012593	Nephrotic range proteinuria	Frequent (30-79%)
HP:0410373	Abnormal proportion of naive CD4 T cells	Frequent (30-79%)
HP:0410377	Reduced proportion of naive CD8 T cells	Frequent (30-79%)
HP:0000470	Short neck	Occasional (5-29%)
HP:0000668	Hypodontia	Occasional (5-29%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0001269	Hemiparesis	Occasional (5-29%)
HP:0001324	Muscle weakness	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0001518	Small for gestational age	Occasional (5-29%)
HP:0001635	Congestive heart failure	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Schimke immuno-osseous dysplasia
Mondo ID	MONDO:0009458
MeSH	C536629
OMIM	242900
Orphanet	1830
DOID	DOID:0060490
ICD-11	2002226225
NCIT	C135087
SNOMED CT	723995003
UMLS	C0877024
MedGen	164078
GARD	0004984
MedDRA	10048699
NORD	1691
Is cancer (heuristic)	no

Also known as: Schimke immuno-osseous dysplasia · Schimke immunoosseous dysplasia · Schimke syndrome · SIOD · spondyloepiphyseal dysplasia - nephrotic syndrome · spondyloepiphyseal dysplasia nephrotic syndrome · spondyloepiphyseal dysplasia-nephrotic syndrome

Data availability: 1,219 ClinVar variants · 5 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › immuno-osseous dysplasia › Schimke immuno-osseous dysplasia

Related subtypes (3): cartilage-hair hypoplasia, skeletal dysplasia-T-cell immunodeficiency-developmental delay syndrome, congenital progressive bone marrow failure-B-cell immunodeficiency-skeletal dysplasia syndrome

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

600 retrieved; paginated sample, class counts are floors:

345 likely benign, 171 uncertain significance, 39 pathogenic, 17 conflicting classifications of pathogenicity, 9 benign, 8 pathogenic/likely pathogenic, 7 likely pathogenic, 4 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1064696	NM_014140.4(SMARCAL1):c.1027_1034del (p.Phe343fs)	SMARCAL1	Pathogenic	no assertion criteria provided
1068979	NM_014140.4(SMARCAL1):c.1544_1569del (p.Gly515fs)	SMARCAL1	Pathogenic	criteria provided, single submitter
1069037	NM_014140.4(SMARCAL1):c.1517del (p.Pro506fs)	SMARCAL1	Pathogenic	criteria provided, single submitter
1069134	NM_014140.4(SMARCAL1):c.1263dup (p.Glu422fs)	SMARCAL1	Pathogenic	criteria provided, single submitter
1070110	NM_014140.4(SMARCAL1):c.2424del (p.Val810fs)	SMARCAL1	Pathogenic	criteria provided, single submitter
1071628	NM_014140.4(SMARCAL1):c.609del (p.Asn203fs)	SMARCAL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073208	NM_014140.4(SMARCAL1):c.1000C>T (p.Arg334Ter)	SMARCAL1	Pathogenic	criteria provided, multiple submitters, no conflicts
1073209	NM_014140.4(SMARCAL1):c.1191del (p.Thr399fs)	SMARCAL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073210	NM_014140.4(SMARCAL1):c.2070+2dup	SMARCAL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074171	NM_014140.4(SMARCAL1):c.641dup (p.Thr215fs)	SMARCAL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074524	NM_014140.4(SMARCAL1):c.409C>T (p.Gln137Ter)	SMARCAL1	Pathogenic	criteria provided, single submitter
1325104	NM_014140.4(SMARCAL1):c.1934G>A (p.Arg645His)	SMARCAL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1344879	NM_014140.4(SMARCAL1):c.1940A>C (p.Lys647Thr)	SMARCAL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1358943	NM_014140.4(SMARCAL1):c.2507del (p.Gly836fs)	SMARCAL1	Pathogenic	criteria provided, single submitter
1359407	NM_014140.4(SMARCAL1):c.1399C>T (p.Gln467Ter)	SMARCAL1	Pathogenic	criteria provided, single submitter
1360533	NM_014140.4(SMARCAL1):c.1632del (p.Val545fs)	SMARCAL1	Pathogenic	criteria provided, single submitter
1408052	NM_014140.4(SMARCAL1):c.622del (p.His208fs)	SMARCAL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1410646	NM_014140.4(SMARCAL1):c.416T>A (p.Leu139Ter)	SMARCAL1	Pathogenic	criteria provided, single submitter
1418313	NM_014140.4(SMARCAL1):c.1727del (p.Ile576fs)	SMARCAL1	Pathogenic	criteria provided, single submitter
1434068	NM_014140.4(SMARCAL1):c.1426del (p.Arg476fs)	SMARCAL1	Pathogenic	criteria provided, single submitter
1452431	NM_014140.4(SMARCAL1):c.1810dup (p.Gln604fs)	SMARCAL1	Pathogenic	criteria provided, single submitter
1453416	NM_014140.4(SMARCAL1):c.1859G>A (p.Trp620Ter)	SMARCAL1	Pathogenic	criteria provided, single submitter
1453865	NM_014140.4(SMARCAL1):c.1612C>T (p.Gln538Ter)	SMARCAL1	Pathogenic	criteria provided, single submitter
1455796	NM_014140.4(SMARCAL1):c.1222C>T (p.Gln408Ter)	SMARCAL1	Pathogenic	criteria provided, single submitter
1457631	NM_014140.4(SMARCAL1):c.1931G>A (p.Arg644Gln)	SMARCAL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458113	NM_014140.4(SMARCAL1):c.1437dup (p.Pro480fs)	SMARCAL1	Pathogenic	criteria provided, multiple submitters, no conflicts
1458384	NM_014140.4(SMARCAL1):c.1625del (p.Pro542fs)	SMARCAL1	Pathogenic	criteria provided, single submitter
1458389	NM_014140.4(SMARCAL1):c.1921dup (p.Val641fs)	SMARCAL1	Pathogenic	criteria provided, multiple submitters, no conflicts
1488622	NM_014140.4(SMARCAL1):c.2141+5G>A	SMARCAL1	Pathogenic	criteria provided, single submitter
1683463	NM_014140.4(SMARCAL1):c.996del (p.Arg334fs)	SMARCAL1	Pathogenic	criteria provided, single submitter

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
SMARCAL1	Definitive	Autosomal recessive	Schimke immuno-osseous dysplasia	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SMARCAL1	Orphanet:1830	Schimke immuno-osseous dysplasia

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
SMARCAL1	HGNC:11102	ENSG00000138375	Q9NZC9	SNF2 related chromatin remodeling annealing helicase 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMARCAL1	SNF2 related chromatin remodeling annealing helicase 1	ATP-dependent annealing helicase that binds selectively to fork DNA relative to ssDNA or dsDNA and catalyzes the rewinding of the stably unwound DNA.

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)
SMARCAL1	Other/Unknown	no		SNF2_N, Helicase_C-like, HARP_dom

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
primordial germ cell in gonad	1
stromal cell of endometrium	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMARCAL1	264	ubiquitous	marker	primordial germ cell in gonad, stromal cell of endometrium, sural nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMARCAL1	2,899

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SMARCAL1	Q9NZC9	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
t-circle formation	1	1404.3×	0.004	SMARCAL1
double-strand break repair via nonhomologous end joining	1	421.3×	0.005	SMARCAL1
replication fork processing	1	421.3×	0.005	SMARCAL1
DNA repair	1	63.8×	0.022	SMARCAL1
DNA damage response	1	53.5×	0.022	SMARCAL1
regulation of transcription by RNA polymerase II	1	11.7×	0.086	SMARCAL1

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
SMARCAL1	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	SMARCAL1

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)
SMARCAL1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1/PHASE2	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05508009	PHASE1/PHASE2	RECRUITING	Early Trial of Allogeneic Hematopoietic Stem Cell Transplantation for Patients Who Will Receive a Kidney Transplant From the Same Donor
NCT06769191	EARLY_PHASE1	RECRUITING	Clinical Study on the Safety and Efficacy of CD7 CAR-T Cell Sequential Allo-HSCT and Kidney Transplantation in the Treatment of SIOD

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
FLUDARABINE PHOSPHATE	4	1