Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1

Summary

Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1 (MONDO:8000012) is a disease caused by PTRH2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PTRH2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 8
• Phenotypes (HPO): 48

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

48 HPO clinical features (Orphanet curated; top 48 by frequency):

HPO ID	Term	Frequency
HP:0000407	Sensorineural hearing impairment	Very frequent (80-99%)
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001270	Motor delay	Very frequent (80-99%)
HP:0001738	Exocrine pancreatic insufficiency	Very frequent (80-99%)
HP:0001999	Abnormal facial shape	Very frequent (80-99%)
HP:0002342	Intellectual disability, moderate	Very frequent (80-99%)
HP:0003693	Distal amyotrophy	Very frequent (80-99%)
HP:0000219	Thin upper lip vermilion	Frequent (30-79%)
HP:0000248	Brachycephaly	Frequent (30-79%)
HP:0000309	Abnormal midface morphology	Frequent (30-79%)
HP:0000577	Exotropia	Frequent (30-79%)
HP:0000819	Diabetes mellitus	Frequent (30-79%)
HP:0001155	Abnormality of the hand	Frequent (30-79%)
HP:0001310	Dysmetria	Frequent (30-79%)
HP:0001319	Neonatal hypotonia	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001530	Mild postnatal growth retardation	Frequent (30-79%)
HP:0001760	Abnormal foot morphology	Frequent (30-79%)
HP:0001771	Achilles tendon contracture	Frequent (30-79%)
HP:0002353	EEG abnormality	Frequent (30-79%)
HP:0002460	Distal muscle weakness	Frequent (30-79%)
HP:0005484	Secondary microcephaly	Frequent (30-79%)
HP:0009623	Proximal placement of thumb	Frequent (30-79%)
HP:0010628	Facial palsy	Frequent (30-79%)
HP:0100307	Cerebellar hemisphere hypoplasia	Frequent (30-79%)
HP:0100807	Long fingers	Frequent (30-79%)
HP:0000049	Shawl scrotum	Occasional (5-29%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0000821	Hypothyroidism	Occasional (5-29%)
HP:0000823	Delayed puberty	Occasional (5-29%)
HP:0001374	Congenital hip dislocation	Occasional (5-29%)
HP:0001558	Decreased fetal movement	Occasional (5-29%)
HP:0001772	Talipes equinovalgus	Occasional (5-29%)
HP:0001844	Abnormal hallux morphology	Occasional (5-29%)
HP:0002123	Generalized myoclonic seizure	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0003431	Decreased motor nerve conduction velocity	Occasional (5-29%)
HP:0003448	Decreased sensory nerve conduction velocity	Occasional (5-29%)
HP:0006276	Hyperechogenic pancreas	Occasional (5-29%)
HP:0008366	Foot joint contracture	Occasional (5-29%)
HP:0009463	Ulnar deviation of the 3rd finger	Occasional (5-29%)
HP:0009464	Ulnar deviation of the 2nd finger	Occasional (5-29%)
HP:0009473	Joint contracture of the hand	Occasional (5-29%)
HP:0012418	Hypoxemia	Occasional (5-29%)
HP:0030146	Abnormal liver parenchyma morphology	Occasional (5-29%)
HP:0030951	Skeletal muscle fibrosis	Occasional (5-29%)
HP:0100800	Aplasia/Hypoplasia of the pancreas	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1
Mondo ID	MONDO:8000012
OMIM	616263
Orphanet	456312
UMLS	C4015728
MedGen	864165
GARD	0017791
Is cancer (heuristic)	no

Also known as: IMNEPD · infantile-onset multisystem neurologic, endocrine, and pancreatic disease · neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset

Data availability: 8 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset › neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1

Related subtypes (1): neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 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

8 retrieved; paginated sample, class counts are floors:

3 likely pathogenic, 2 pathogenic, 2 uncertain significance, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
183428	NM_016077.5(PTRH2):c.269_270del (p.Ala90fs)	CLTC	Pathogenic	criteria provided, multiple submitters, no conflicts
183332	NM_016077.5(PTRH2):c.254A>C (p.Gln85Pro)	PTRH2	Pathogenic	criteria provided, multiple submitters, no conflicts
695110	NM_016077.5(PTRH2):c.324G>A (p.Trp108Ter)	PTRH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048079	NM_016077.5(PTRH2):c.127dup (p.Ser43fs)	PTRH2	Likely pathogenic	criteria provided, single submitter
3896966	NM_016077.5(PTRH2):c.92G>A (p.Trp31Ter)	PTRH2	Likely pathogenic	criteria provided, single submitter
4814177	NM_016077.5(PTRH2):c.100C>T (p.Arg34Ter)	PTRH2	Likely pathogenic	criteria provided, single submitter
2412752	NM_016077.5(PTRH2):c.515_516del (p.Val172fs)	PTRH2	Uncertain significance	criteria provided, single submitter
2570662	NM_016077.5(PTRH2):c.535dup (p.Tyr179fs)	PTRH2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 5 · 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
PTRH2	Definitive	Autosomal recessive	neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PTRH2	Orphanet:456312	Infantile multisystem neurologic-endocrine-pancreatic disease
CLTC	Orphanet:178342	Inflammatory myofibroblastic tumor
CLTC	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
CLTC	Orphanet:319308	MiT family translocation renal cell carcinoma
CLTC	Orphanet:442835	Non-specific early-onset epileptic encephalopathy

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PTRH2	HGNC:24265	ENSG00000141378	Q9Y3E5	Peptidyl-tRNA hydrolase 2, mitochondrial	gencc,clinvar
CLTC	HGNC:2092	ENSG00000141367	Q00610	Clathrin heavy chain 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PTRH2	Peptidyl-tRNA hydrolase 2, mitochondrial	Peptidyl-tRNA hydrolase which releases tRNAs from the ribosome during protein synthesis.
CLTC	Clathrin heavy chain 1	Clathrin is the major protein of the polyhedral coat of coated pits and vesicles.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PTRH2	Enzyme (other)	yes	3.1.1.29	PTH2, Pep_tRNA_hydro_II_dom_sf
CLTC	Other/Unknown	no		Clathrin_H-chain/VPS_repeat, TPR-like_helical_dom_sf, Clathrin_H-chain_linker_core

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cervix squamous epithelium	1
endothelial cell	1
islet of Langerhans	1
Brodmann (1909) area 46	1
lateral nuclear group of thalamus	1
pons	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PTRH2	283	ubiquitous	marker	cervix squamous epithelium, islet of Langerhans, endothelial cell
CLTC	305	ubiquitous	marker	pons, lateral nuclear group of thalamus, Brodmann (1909) area 46

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CLTC	5,550
PTRH2	1,933

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CLTC	Q00610	10
PTRH2	Q9Y3E5	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Entry of Influenza Virion into Host Cell via Endocytosis	1	2855.0×	0.007	CLTC
Formation of annular gap junctions	1	519.1×	0.007	CLTC
Gap junction degradation	1	475.8×	0.007	CLTC
ALK mutants bind TKIs	1	475.8×	0.007	CLTC
WNT5A-dependent internalization of FZD2, FZD5 and ROR2	1	439.2×	0.007	CLTC
Retrograde neurotrophin signalling	1	407.9×	0.007	CLTC
WNT5A-dependent internalization of FZD4	1	380.7×	0.007	CLTC
VLDLR internalisation and degradation	1	356.9×	0.007	CLTC
LDL clearance	1	271.9×	0.008	CLTC
Lysosome Vesicle Biogenesis	1	163.1×	0.012	CLTC
RHOV GTPase cycle	1	142.8×	0.012	CLTC
RHOU GTPase cycle	1	139.3×	0.012	CLTC
Recycling pathway of L1	1	112.0×	0.013	CLTC
EPH-ephrin mediated repulsion of cells	1	109.8×	0.013	CLTC
Golgi Associated Vesicle Biogenesis	1	100.2×	0.013	CLTC
Signaling by ALK fusions and activated point mutants	1	75.1×	0.017	CLTC
Cargo recognition for clathrin-mediated endocytosis	1	52.4×	0.022	CLTC
MHC class II antigen presentation	1	44.6×	0.025	CLTC
Clathrin-mediated endocytosis	1	42.6×	0.025	CLTC
Ub-specific processing proteases	1	26.6×	0.037	PTRH2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
clathrin coat disassembly	1	2106.5×	0.005	CLTC
negative regulation of hyaluronan biosynthetic process	1	2106.5×	0.005	CLTC
amyloid-beta clearance by transcytosis	1	1203.7×	0.005	CLTC
positive regulation of anoikis	1	936.2×	0.005	PTRH2
transferrin transport	1	766.0×	0.005	CLTC
clathrin coat assembly	1	443.5×	0.006	CLTC
negative regulation of anoikis	1	443.5×	0.006	PTRH2
regulation of mitotic spindle organization	1	421.3×	0.006	CLTC
negative regulation of protein localization to plasma membrane	1	312.1×	0.007	CLTC
clathrin-dependent endocytosis	1	290.6×	0.007	CLTC
receptor internalization	1	162.0×	0.011	CLTC
receptor-mediated endocytosis	1	110.9×	0.015	CLTC
retrograde transport, endosome to Golgi	1	102.8×	0.015	CLTC
mitotic cell cycle	1	66.9×	0.021	CLTC
osteoblast differentiation	1	60.6×	0.022	CLTC
autophagy	1	55.1×	0.023	CLTC
negative regulation of gene expression	1	34.5×	0.034	PTRH2
intracellular protein transport	1	32.4×	0.034	CLTC
cell division	1	23.1×	0.045	CLTC
apoptotic process	1	14.3×	0.068	PTRH2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PTRH2	0	0
CLTC	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CLTC	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PTRH2	3.1.1.29	peptidyl-tRNA hydrolase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	1	PTRH2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CLTC

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PTRH2	0	—
CLTC	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.