Developmental delay with short stature, dysmorphic facial features, and sparse hair 1

Summary

Developmental delay with short stature, dysmorphic facial features, and sparse hair 1 (MONDO:0800438) is a disease caused by DPH1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DPH1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 22
• Phenotypes (HPO): 40

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		8	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

40 HPO clinical features (Orphanet curated; top 40 by frequency):

HPO ID	Term	Frequency
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001999	Abnormal facial shape	Very frequent (80-99%)
HP:0002209	Sparse scalp hair	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0011220	Prominent forehead	Very frequent (80-99%)
HP:0045075	Sparse eyebrow	Very frequent (80-99%)
HP:0000077	Abnormality of the kidney	Frequent (30-79%)
HP:0000238	Hydrocephalus	Frequent (30-79%)
HP:0000243	Trigonocephaly	Frequent (30-79%)
HP:0001305	Dandy-Walker malformation	Frequent (30-79%)
HP:0001320	Cerebellar vermis hypoplasia	Frequent (30-79%)
HP:0001763	Pes planus	Frequent (30-79%)
HP:0001800	Hypoplastic toenails	Frequent (30-79%)
HP:0005280	Depressed nasal bridge	Frequent (30-79%)
HP:0007291	Posterior fossa cyst	Frequent (30-79%)
HP:0012385	Camptodactyly	Frequent (30-79%)
HP:0000023	Inguinal hernia	Occasional (5-29%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000248	Brachycephaly	Occasional (5-29%)
HP:0000286	Epicanthus	Occasional (5-29%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0000369	Low-set ears	Occasional (5-29%)
HP:0000494	Downslanted palpebral fissures	Occasional (5-29%)
HP:0000687	Widely spaced teeth	Occasional (5-29%)
HP:0000739	Anxiety	Occasional (5-29%)
HP:0000805	Enuresis	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001274	Agenesis of corpus callosum	Occasional (5-29%)
HP:0001631	Atrial septal defect	Occasional (5-29%)
HP:0001650	Aortic valve stenosis	Occasional (5-29%)
HP:0001970	Tubulointerstitial nephritis	Occasional (5-29%)
HP:0004442	Sagittal craniosynostosis	Occasional (5-29%)
HP:0004482	Relative macrocephaly	Occasional (5-29%)
HP:0007018	Attention deficit hyperactivity disorder	Occasional (5-29%)
HP:0007598	Bilateral single transverse palmar creases	Occasional (5-29%)
HP:0010535	Sleep apnea	Occasional (5-29%)
HP:0012712	Mild hearing impairment	Occasional (5-29%)
HP:0030799	Scaphocephaly	Occasional (5-29%)
HP:0200055	Small hand	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental delay with short stature, dysmorphic facial features, and sparse hair 1
Mondo ID	MONDO:0800438
OMIM	616901
Orphanet	459061
DOID	DOID:0070477
GARD	0017814
Is cancer (heuristic)	no

Also known as: DEDSSH1 · developmental delay with short stature, dysmorphic facial features, and sparse hair · developmental delay with short stature, dysmorphic features, and sparse hair 1 · developmental delay-short stature-dysmorphic features-sparse hair syndrome · diphtamide deficiency syndrome

Data availability: 22 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › developmental delay with short stature, dysmorphic facial features, and sparse hair › developmental delay with short stature, dysmorphic facial features, and sparse hair 1

Related subtypes (1): developmental delay with short stature, dysmorphic facial features, and sparse hair 2

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

22 retrieved; paginated sample, class counts are floors:

10 uncertain significance, 4 pathogenic, 3 pathogenic/likely pathogenic, 3 conflicting classifications of pathogenicity, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
183359	NM_001383.6(DPH1):c.686T>C (p.Leu229Pro)	DPH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
218949	NM_001383.6(DPH1):c.2T>A (p.Met1Lys)	DPH1	Pathogenic/Likely pathogenic	no assertion criteria provided
2682284	NM_001383.6(DPH1):c.103G>T (p.Glu35Ter)	DPH1	Pathogenic	criteria provided, single submitter
3339380	NM_001383.6(DPH1):c.919C>T (p.Arg307Ter)	DPH1	Pathogenic	criteria provided, single submitter
664140	NM_001383.6(DPH1):c.274del (p.Glu92fs)	DPH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
997985	NM_001383.6(DPH1):c.476T>C (p.Leu159Pro)	DPH1	Pathogenic	no assertion criteria provided
997988	NM_001383.6(DPH1):c.320A>G (p.Tyr107Cys)	DPH1	Pathogenic	criteria provided, single submitter
1324291	NM_001383.6(DPH1):c.652C>T (p.Arg218Ter)	DPH1	Likely pathogenic	criteria provided, single submitter
4277948	NM_001383.6(DPH1):c.400+1G>A	DPH1	Likely pathogenic	criteria provided, single submitter
2637694	NM_001383.6(DPH1):c.1086+2dup	DPH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2691774	NM_001383.6(DPH1):c.749+39G>A	DPH1	Conflicting classifications of pathogenicity	no assertion criteria provided
521028	NM_001383.6(DPH1):c.359T>C (p.Leu120Pro)	DPH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2363993	NM_001383.6(DPH1):c.139C>T (p.Arg47Trp)	DPH1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2441023	NM_001383.6(DPH1):c.65G>A (p.Arg22Gln)	DPH1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2442231	NM_001383.6(DPH1):c.155A>G (p.Asn52Ser)	DPH1	Uncertain significance	criteria provided, single submitter
2501780	NM_001383.6(DPH1):c.400+5G>T	DPH1	Uncertain significance	criteria provided, single submitter
2582411	NM_001383.6(DPH1):c.322G>A (p.Gly108Arg)	DPH1	Uncertain significance	criteria provided, single submitter
2582416	NM_001383.6(DPH1):c.1256C>G (p.Ser419Trp)	DPH1	Uncertain significance	criteria provided, single submitter
2637692	NM_001383.6(DPH1):c.786_788del (p.Tyr263del)	DPH1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3065620	NM_001383.6(DPH1):c.-13G>A	DPH1	Uncertain significance	criteria provided, single submitter
3068255	NM_001383.6(DPH1):c.1228-1G>A	DPH1	Uncertain significance	criteria provided, single submitter
3382880	NM_001383.6(DPH1):c.693T>G (p.Asp231Glu)	DPH1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
DPH1	Strong	Autosomal recessive	developmental delay with short stature, dysmorphic facial features, and sparse hair 1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DPH1	Orphanet:459061	Craniofacial dysplasia-short stature-ectodermal anomalies-intellectual disability 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
DPH1	HGNC:3003	ENSG00000108963	Q9BZG8	2-(3-amino-3-carboxypropyl)histidine synthase subunit 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DPH1	2-(3-amino-3-carboxypropyl)histidine synthase subunit 1	Catalyzes the first step of diphthamide biosynthesis, a post-translational modification of histidine which occurs in elongation factor 2.

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)
DPH1	Other/Unknown	no		DPH1/DPH2, DPH1/DPH2_1, DPH1/DPH2_2

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
adenohypophysis	1
pituitary gland	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DPH1	140	ubiquitous	marker	pituitary gland, right hemisphere of cerebellum, adenohypophysis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DPH1	1,593

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DPH1	Q9BZG8	87.00

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Synthesis of diphthamide-EEF2	1	1427.5×	7e-04	DPH1

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
protein histidyl modification to diphthamide	1	2407.4×	8e-04	DPH1
fibroblast proliferation	1	391.9×	0.003	DPH1

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
DPH1	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	DPH1

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)
DPH1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.