short stature-optic atrophy-Pelger-Huët anomaly syndrome

Summary

short stature-optic atrophy-Pelger-Huët anomaly syndrome (MONDO:0013889) is a disease caused by NBAS (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: NBAS (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 104

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		39	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	short stature-optic atrophy-Pelger-Huët anomaly syndrome
Mondo ID	MONDO:0013889
OMIM	614800
Orphanet	391677
UMLS	C3541319
MedGen	762020
GARD	0010945
Is cancer (heuristic)	no

Also known as: short stature with optic atrophy and Pelger-Huët anomaly syndrome · short stature, optic nerve atrophy, and Pelger-Huet anomaly · short stature-optic atrophy-Pelger-Huët anomaly syndrome · soph syndrome

Data availability: 104 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › osteochondrodysplasia › osteogenesis imperfecta › osteogenesis imperfecta and a reduction of bone mineral density. › short stature-optic atrophy-Pelger-Huët anomaly syndrome

Related subtypes (32): Cole-Carpenter syndrome 1, calvarial doughnut lesions-bone fragility syndrome, osteogenesis imperfecta type 1, osteogenesis imperfecta type 2, osteogenesis imperfecta type 4, gnathodiaphyseal dysplasia, geroderma osteodysplastica, osteogenesis imperfecta type 3, osteogenesis imperfecta type 9, osteoporosis-pseudoglioma syndrome, Wiedemann-Rautenstrauch syndrome, spondylo-ocular syndrome, Bruck syndrome 2, osteogenesis imperfecta type 7, osteogenesis imperfecta type 8, osteogenesis imperfecta type 5, osteogenesis imperfecta type 11, autosomal recessive cutis laxa type 2B, osteogenesis imperfecta type 10, osteogenesis imperfecta type 12, osteogenesis imperfecta type 6, osteogenesis imperfecta type 14, osteogenesis imperfecta type 15, osteogenesis imperfecta type 16, Cole-Carpenter syndrome 2, Singleton-Merten syndrome 2, osteogenesis imperfecta type 17, autosomal recessive cutis laxa type 2A, Ehlers-Danlos syndrome, spondylodysplastic type, 1, Singleton-Merten syndrome 1, osteogenesis imperfecta, type 18, osteogenesis imperfecta, type 19

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

104 retrieved; paginated sample, class counts are floors:

21 pathogenic/likely pathogenic, 20 conflicting classifications of pathogenicity, 20 likely pathogenic, 17 uncertain significance, 14 benign, 9 pathogenic, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1442652	NM_015909.4(NBAS):c.1A>C (p.Met1Leu)	LOC129933155	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
838205	NM_015909.4(NBAS):c.17C>A (p.Ser6Ter)	LOC129933155	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076261	NM_015909.4(NBAS):c.2827G>T (p.Glu943Ter)	NBAS	Pathogenic	criteria provided, multiple submitters, no conflicts
1333991	NM_015909.4(NBAS):c.513+2T>C	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1373796	NM_015909.4(NBAS):c.2389C>T (p.Arg797Ter)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1427718	NM_015909.4(NBAS):c.1366C>T (p.Arg456Ter)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1441232	NM_015909.4(NBAS):c.3842dup (p.Gln1282fs)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1448431	NM_015909.4(NBAS):c.169C>T (p.Arg57Ter)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456602	NM_015909.4(NBAS):c.4336C>T (p.Arg1446Ter)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457346	NM_015909.4(NBAS):c.3316C>T (p.Gln1106Ter)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1693290	NM_015909.4(NBAS):c.3010C>T (p.Arg1004Ter)	NBAS	Pathogenic	criteria provided, multiple submitters, no conflicts
1699908	NM_015909.4(NBAS):c.5104del (p.Phe1701_Met1702insTer)	NBAS	Pathogenic	criteria provided, single submitter
1723648	NM_015909.4(NBAS):c.4753C>T (p.Arg1585Ter)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1942208	NM_015909.4(NBAS):c.4332_4333insT (p.Leu1445fs)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1946443	NM_015909.4(NBAS):c.5176del (p.Leu1726fs)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2163359	NM_015909.4(NBAS):c.5983C>T (p.Arg1995Ter)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2441821	NM_015909.4(NBAS):c.4255del (p.Ser1419fs)	NBAS	Pathogenic	criteria provided, multiple submitters, no conflicts
2988958	NM_015909.4(NBAS):c.3706C>T (p.Arg1236Ter)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3584473	NM_015909.4(NBAS):c.6448_6449del (p.Asp2149_Ile2150insTer)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3584475	NM_015909.4(NBAS):c.5883_5884dup (p.Leu1962fs)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3584486	NM_015909.4(NBAS):c.2591dup (p.Leu864fs)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3584489	NM_015909.4(NBAS):c.425dup (p.Tyr142Ter)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
37042	NM_015909.4(NBAS):c.5741G>A (p.Arg1914His)	NBAS	Pathogenic	criteria provided, multiple submitters, no conflicts
3901226	NM_015909.4(NBAS):c.2032C>T (p.Gln678Ter)	NBAS	Pathogenic	no assertion criteria provided
3901228	NBAS, ARG1585TER	NBAS	Pathogenic	no assertion criteria provided
421958	NM_015909.4(NBAS):c.6316del (p.Arg2106fs)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
430659	NM_015909.4(NBAS):c.586C>T (p.Gln196Ter)	NBAS	Pathogenic	criteria provided, multiple submitters, no conflicts
501319	NM_015909.4(NBAS):c.2950del (p.Ile984fs)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
617879	NM_015909.4(NBAS):c.6840G>A (p.Thr2280=)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
976858	NM_015909.4(NBAS):c.1741C>T (p.Arg581Ter)	NBAS	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 3 · 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
NBAS	Definitive	Autosomal recessive	short stature-optic atrophy-Pelger-Huët anomaly syndrome	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NBAS	Orphanet:391677	Short stature-optic atrophy-Pelger-Huët anomaly syndrome
NBAS	Orphanet:464724	Fever-associated acute infantile liver failure syndrome
PTPRO	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome

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
NBAS	HGNC:15625	ENSG00000151779	A2RRP1	NBAS subunit of NRZ tethering complex	gencc,clinvar
PTPRO	HGNC:9678	ENSG00000151490	Q16827	Receptor-type tyrosine-protein phosphatase O	clinvar
PTPRU	HGNC:9683	ENSG00000060656	Q92729	Receptor-type tyrosine-protein phosphatase U	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NBAS	NBAS subunit of NRZ tethering complex	Involved in Golgi-to-endoplasmic reticulum (ER) retrograde transport; the function is proposed to depend on its association in the NRZ complex which is believed to play a role in SNARE assembly at the ER.
PTPRO	Receptor-type tyrosine-protein phosphatase O	Possesses tyrosine phosphatase activity.
PTPRU	Receptor-type tyrosine-protein phosphatase U	Tyrosine-protein phosphatase which dephosphorylates CTNNB1.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.67

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
Phosphatase	2	55.9×	8e-04
Scaffold/PPI	1	5.8×	0.164

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NBAS	Scaffold/PPI	no		Quino_amine_DH_bsu, Sec39_domain, WD40/YVTN_repeat-like_dom_sf
PTPRO	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, Tyr_Pase_cat
PTPRU	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, MAM_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
calcaneal tendon	1
primordial germ cell in gonad	1
ventricular zone	1
cortical plate	1
metanephric glomerulus	1
renal glomerulus	1
ectocervix	1
endocervix	1
olfactory segment of nasal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NBAS	293	ubiquitous	marker	calcaneal tendon, primordial germ cell in gonad, ventricular zone
PTPRO	214	broad	marker	renal glomerulus, metanephric glomerulus, cortical plate
PTPRU	239	ubiquitous	marker	endocervix, olfactory segment of nasal mucosa, ectocervix

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PTPRO	1,520
NBAS	1,134
PTPRU	206

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PTPRO	Q16827	2
PTPRU	Q92729	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NBAS	A2RRP1	74.42

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 3 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
Signaling by NTRK3 (TRKC)	1	380.7×	0.018	PTPRO
Signaling by SCF-KIT	1	82.8×	0.040	PTPRU
Golgi-to-ER retrograde transport	1	44.3×	0.040	NBAS
COPI-dependent Golgi-to-ER retrograde traffic	1	37.0×	0.040	NBAS
Intra-Golgi and retrograde Golgi-to-ER traffic	1	34.9×	0.040	NBAS
Membrane Trafficking	1	12.4×	0.084	NBAS
Vesicle-mediated transport	1	11.6×	0.084	NBAS

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
slit diaphragm assembly	1	2808.7×	0.004	PTPRO
negative regulation of retinal ganglion cell axon guidance	1	2808.7×	0.004	PTPRO
negative regulation of canonical Wnt signaling pathway	2	78.6×	0.004	PTPRO, PTPRU
regulation of glomerular filtration	1	1404.3×	0.004	PTPRO
negative regulation of glomerular filtration	1	1404.3×	0.004	PTPRO
cell surface receptor protein tyrosine phosphatase signaling pathway	1	702.2×	0.006	PTPRU
negative regulation of nuclear-transcribed mRNA catabolic process, nonsense-mediated decay	1	624.1×	0.006	NBAS
homotypic cell-cell adhesion	1	561.7×	0.006	PTPRU
podocyte differentiation	1	468.1×	0.006	PTPRO
glomerulus development	1	432.1×	0.006	PTPRO
positive regulation of cell-cell adhesion mediated by cadherin	1	432.1×	0.006	PTPRU
negative regulation of cell-substrate adhesion	1	351.1×	0.007	PTPRO
nuclear-transcribed mRNA catabolic process	1	255.3×	0.009	NBAS
regulation of synapse organization	1	216.1×	0.010	PTPRO
animal organ regeneration	1	200.6×	0.010	PTPRU
monocyte chemotaxis	1	193.7×	0.010	PTPRO
protein localization to cell surface	1	165.2×	0.011	PTPRU
lamellipodium assembly	1	147.8×	0.011	PTPRO
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	1	112.3×	0.014	NBAS
response to glucocorticoid	1	108.0×	0.014	PTPRU
negative regulation of neuron projection development	1	79.1×	0.018	PTPRO
protein dephosphorylation	1	73.9×	0.018	PTPRU
cell morphogenesis	1	52.5×	0.025	PTPRO
neuron projection development	1	40.7×	0.030	PTPRU
negative regulation of cell migration	1	37.2×	0.032	PTPRU
axon guidance	1	30.2×	0.038	PTPRO
protein transport	1	14.6×	0.074	NBAS
negative regulation of cell population proliferation	1	14.0×	0.075	PTPRU
cell adhesion	1	12.5×	0.081	PTPRU
signal transduction	1	5.3×	0.176	PTPRU

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 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
NBAS	0	0
PTPRO	0	0
PTPRU	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PTPRO	7	Binding:7
NBAS	1	Binding:1
PTPRU	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PTPRO	3.1.3.48	protein-tyrosine-phosphatase
PTPRU	3.1.3.48	protein-tyrosine-phosphatase

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	2	PTPRO, PTPRU
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	NBAS

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)
NBAS	1	—
PTPRO	7	—
PTPRU	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.