Shwachman-Diamond syndrome 1

Summary

Shwachman-Diamond syndrome 1 (MONDO:0044204) is a disease caused by SBDS (GenCC Definitive), with 5 cohort genes. The dominant Reactome pathway is SRP-dependent cotranslational protein targeting to membrane (3 cohort genes).

At a glance

• Causal gene: SBDS (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 76

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Shwachman-Diamond syndrome 1
Mondo ID	MONDO:0044204
OMIM	260400
UMLS	C4692625
MedGen	1640046
GARD	0015221
Is cancer (heuristic)	no

Also known as: SBDS-related Shwachman Diamond syndrome · SDS1 · Shwachman-Diamond syndrome 1

Data availability: 76 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Shwachman-Diamond syndrome › Shwachman-Diamond syndrome 1

Related subtypes (2): Shwachman-Diamond syndrome 2, DNAJC21-related Shwachman Diamond 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

76 retrieved; paginated sample, class counts are floors:

20 uncertain significance, 20 pathogenic, 10 conflicting classifications of pathogenicity, 8 likely pathogenic, 8 pathogenic/likely pathogenic, 5 benign, 4 benign/likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
222066	NM_001012339.3(DNAJC21):c.983+1G>A	DNAJC21	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1033391	NM_016038.2(SBDS):c.625-1delG	SBDS	Pathogenic	criteria provided, single submitter
21538	NM_016038.4(SBDS):c.258+1G>C	SBDS	Pathogenic	criteria provided, multiple submitters, no conflicts
21539	NM_016038.4(SBDS):c.297_300del (p.Glu99fs)	SBDS	Pathogenic	criteria provided, multiple submitters, no conflicts
21542	NM_016038.4(SBDS):c.624+1G>C	SBDS	Pathogenic	criteria provided, single submitter
21545	NM_016038.4(SBDS):c.652C>T (p.Arg218Ter)	SBDS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
219289	NM_016038.4(SBDS):c.98A>C (p.Lys33Thr)	SBDS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2498197	NC_000007.14:g.66971410_66990307del	SBDS	Pathogenic	no assertion criteria provided
2498198	NM_016038.4(SBDS):c.258+347_459+223del	SBDS	Pathogenic	no assertion criteria provided
265256	NM_016038.4(SBDS):c.120del (p.Ser41fs)	SBDS	Pathogenic	criteria provided, multiple submitters, no conflicts
2678592	NM_016038.4(SBDS):c.107del (p.Val36fs)	SBDS	Pathogenic	criteria provided, multiple submitters, no conflicts
2678598	NM_016038.4(SBDS):c.307_308del (p.Gln103fs)	SBDS	Pathogenic	criteria provided, multiple submitters, no conflicts
3195	NM_016038.4(SBDS):c.183_184delinsCT (p.Lys62Ter)	SBDS	Pathogenic	criteria provided, multiple submitters, no conflicts
3196	NM_016038.4(SBDS):c.258+2T>C	SBDS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3198	NM_016038.4(SBDS):c.101dup (p.Asn34fs)	SBDS	Pathogenic	no assertion criteria provided
3382997	NM_016038.4(SBDS):c.160dup (p.His54fs)	SBDS	Pathogenic	criteria provided, single submitter
3776902	NM_016038.4(SBDS):c.129-2A>G	SBDS	Pathogenic	criteria provided, single submitter
3776903	NM_016038.4(SBDS):c.123del (p.Ser41fs)	SBDS	Pathogenic	criteria provided, single submitter
4076140	NM_016038.4(SBDS):c.356G>A (p.Cys119Tyr)	SBDS	Pathogenic	no assertion criteria provided
449094	NM_016038.4(SBDS):c.13del (p.Thr5fs)	SBDS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
449095	NM_016038.4(SBDS):c.184A>T (p.Lys62Ter)	SBDS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
807486	NM_016038.4(SBDS):c.18del (p.Thr7fs)	SBDS	Pathogenic	criteria provided, multiple submitters, no conflicts
929404	NM_016038.4(SBDS):c.460-1G>A	SBDS	Pathogenic	criteria provided, single submitter
810839	NM_003135.3(SRP19):c.189+5G>A	SRP19	Pathogenic	no assertion criteria provided
430850	NM_003136.4(SRP54):c.677G>A (p.Gly226Glu)	SRP54	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
430851	NM_003136.4(SRP54):c.343A>G (p.Thr115Ala)	SRP54	Pathogenic	no assertion criteria provided
430852	NM_003136.4(SRP54):c.343ACA[2] (p.Thr117del)	SRP54	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
810840	NM_003139.4(SRPRA):c.1390C>G (p.Gln464Glu)	SRPRA	Pathogenic	no assertion criteria provided
1339526	NM_016038.4(SBDS):c.629G>A (p.Cys210Tyr)	SBDS	Likely pathogenic	criteria provided, single submitter
2431953	NM_016038.4(SBDS):c.478C>T (p.Gln160Ter)	SBDS	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 6 · 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
SBDS	Definitive	Autosomal recessive	Shwachman-Diamond syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SBDS	Orphanet:622934	SBDS-related severe neonatal spondylometaphyseal dysplasia
SBDS	Orphanet:811	Shwachman-Diamond syndrome
SBDS	Orphanet:88	Idiopathic aplastic anemia
SRP19	Orphanet:486	Autosomal dominant severe congenital neutropenia
SRP54	Orphanet:675767	Severe congenital neutropenia-developmental delay syndrome due to SRP54 deficiency
DNAJC21	Orphanet:811	Shwachman-Diamond syndrome

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SBDS	HGNC:19440	ENSG00000126524	Q9Y3A5	Ribosome maturation protein SBDS	gencc,clinvar
SRP19	HGNC:11300	ENSG00000153037	P09132	Signal recognition particle 19 kDa protein	clinvar
SRP54	HGNC:11301	ENSG00000100883	P61011	Signal recognition particle subunit SRP54	clinvar
SRPRA	HGNC:11307	ENSG00000182934	P08240	Signal recognition particle receptor subunit alpha	clinvar
DNAJC21	HGNC:27030	ENSG00000168724	Q5F1R6	DnaJ homolog subfamily C member 21	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SBDS	Ribosome maturation protein SBDS	Required for the assembly of mature ribosomes and ribosome biogenesis.
SRP19	Signal recognition particle 19 kDa protein	Component of the signal recognition particle (SRP) complex, a ribonucleoprotein complex that mediates the cotranslational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER).
SRP54	Signal recognition particle subunit SRP54	Component of the signal recognition particle (SRP) complex, a ribonucleoprotein complex that mediates the cotranslational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER).
SRPRA	Signal recognition particle receptor subunit alpha	Component of the signal recognition particle (SRP) complex receptor (SR).
DNAJC21	DnaJ homolog subfamily C member 21	May act as a co-chaperone for HSP70.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.2

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
Enzyme (other)	1	2.4×	0.608
Transcription factor	1	1.6×	0.608
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SBDS	Other/Unknown	no		Sdo1/SBDS, Ribosome_mat_SBDS_CS, SDO1/SBDS_central
SRP19	Other/Unknown	no		Signal_recog_particle_SRP19, SRP19-like_sf
SRP54	Other/Unknown	no		SRP54_GTPase_dom, AAA+_ATPase, Signal_recog_particle_SRP54_M
SRPRA	Enzyme (other)	yes	3.6.5.4	SRP54_GTPase_dom, AAA+_ATPase, SRPRA_N
DNAJC21	Transcription factor	no		DnaJ_domain, Matrin/U1-like-C_Znf_C2H2, Znf_C2H2_type

Expression context

Cohort genes with no expression data: 0.

5 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of pancreas	3
islet of Langerhans	2
calcaneal tendon	1
popliteal artery	1
tibial artery	1
adenohypophysis	1
pancreas	1
parotid gland	1
type B pancreatic cell	1
epithelial cell of pancreas	1
left testis	1
tibialis anterior	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SBDS	144	ubiquitous	marker	popliteal artery, tibial artery, calcaneal tendon
SRP19	169	ubiquitous	marker	adenohypophysis, body of pancreas, islet of Langerhans
SRP54	296	ubiquitous	marker	body of pancreas, pancreas, islet of Langerhans
SRPRA	290	ubiquitous	marker	parotid gland, body of pancreas, type B pancreatic cell
DNAJC21	255	ubiquitous	marker	epithelial cell of pancreas, tibialis anterior, left testis

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SRPRA	3,014
SBDS	2,110
SRP19	2,099
DNAJC21	1,048
SRP54	299

Intra-cohort edges

A	B	Sources
DNAJC21	SBDS	string_interaction
SRP19	SRP54	biogrid_interaction
SRP19	SRPRA	string_interaction
SRP54	SRPRA	intact

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SRP19	P09132	9
SRP54	P61011	9
SBDS	Q9Y3A5	6
SRPRA	P08240	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DNAJC21	Q5F1R6	72.10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 5 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
SRP-dependent cotranslational protein targeting to membrane	3	100.2×	8e-06	SRP19, SRP54, SRPRA
Translation	3	62.1×	2e-05	SRP19, SRP54, SRPRA
Metabolism of proteins	3	12.4×	0.001	SRP19, SRP54, SRPRA
IRE1alpha activates chaperones	1	173.0×	0.012	SRPRA
Unfolded Protein Response (UPR)	1	119.0×	0.013	SRPRA
XBP1(S) activates chaperone genes	1	71.8×	0.018	SRPRA
Cellular responses to stress	1	12.3×	0.091	SRPRA
Cellular responses to stimuli	1	10.5×	0.092	SRPRA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
SRP-dependent cotranslational protein targeting to membrane, signal sequence recognition	3	2527.8×	9e-10	SRP19, SRP54, SRPRA
cotranslational protein targeting to membrane	2	674.1×	3e-05	SRP19, SRPRA
protein targeting to ER	2	449.4×	4e-05	SRP54, SRPRA
cytosolic ribosome assembly	1	481.5×	0.007	SBDS
SRP-dependent cotranslational protein targeting to membrane	1	421.3×	0.007	SRP54
SRP-dependent cotranslational protein targeting to membrane, translocation	1	421.3×	0.007	SRP54
exocrine pancreas development	1	337.0×	0.007	SRP54
bone marrow development	1	306.4×	0.007	SBDS
granulocyte differentiation	1	240.7×	0.008	SRP54
leukocyte chemotaxis	1	210.7×	0.008	SBDS
inner cell mass cell proliferation	1	198.3×	0.008	SBDS
neutrophil chemotaxis	1	57.1×	0.023	SRP54
mitotic spindle organization	1	54.4×	0.023	SBDS
bone mineralization	1	54.4×	0.023	SBDS
hematopoietic progenitor cell differentiation	1	47.5×	0.025	SBDS
rRNA processing	1	28.3×	0.039	SBDS
protein folding	1	20.7×	0.050	DNAJC21
intracellular protein transport	1	13.0×	0.075	SRPRA

Therapeutics

Drug target analysis

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

Druggability breadth: 4 of 5 evidence-associated genes (80%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SRPRA	1	2
SBDS	0	0
SRP19	0	0
SRP54	0	0
DNAJC21	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ENMD-2076	2	SRPRA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
SRP19	2	Binding:2
SRP54	2	Binding:2
SRPRA	2	Binding:2
SBDS	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SRPRA	3.6.5.4	signal-recognition-particle GTPase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 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.

Compound	Max phase	Cohort target (bioactivity)
ENMD-2076	2	SRPRA

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	1	SRPRA
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	SBDS, SRP19, SRP54, DNAJC21

Undrugged target profiles

4 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SBDS	1	—
SRP19	2	—
SRP54	2	—
DNAJC21	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.