Permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome

Summary

Permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome (MONDO:0012192) is a disease caused by variants in PTF1A and NEUROD1, with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal genes: PTF1A (GenCC Definitive), NEUROD1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 36
• Phenotypes (HPO): 7

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

7 HPO clinical features (Orphanet curated; top 7 by frequency):

HPO ID	Term	Frequency
HP:0000325	Triangular face	Very frequent (80-99%)
HP:0000331	Short chin	Very frequent (80-99%)
HP:0000369	Low-set ears	Very frequent (80-99%)
HP:0000609	Optic nerve hypoplasia	Very frequent (80-99%)
HP:0000857	Neonatal insulin-dependent diabetes mellitus	Very frequent (80-99%)
HP:0001321	Cerebellar hypoplasia	Very frequent (80-99%)
HP:0100800	Aplasia/Hypoplasia of the pancreas	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome
Mondo ID	MONDO:0012192
MeSH	C563796
OMIM	609069
Orphanet	65288
UMLS	C1836780
MedGen	332288
GARD	0016670
Is cancer (heuristic)	no

Also known as: paca · pancreatic and cerebellar agenesis

Data availability: 36 ClinVar variants · 7 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome

Related subtypes (56): Neu-Laxova syndrome, inborn mitochondrial metabolism disorder, Ehlers-Danlos syndrome, spondylodysplastic type, MGAT2-congenital disorder of glycosylation, ALDH18A1-related de Barsy syndrome, classic homocystinuria, Larsen-like syndrome, B3GAT3 type, Nijmegen breakage syndrome, Peters plus syndrome, Wiedemann-Rautenstrauch syndrome, 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency, SHORT syndrome, mucosulfatidosis, CHIME syndrome, creatine transporter deficiency, multiple congenital anomalies-hypotonia-seizures syndrome 2, SLC35A2-congenital disorder of glycosylation, SSR4-congenital disorder of glycosylation, Fabry disease, occipital horn syndrome, Ehlers-Danlos syndrome, musculocontractural type, temtamy preaxial brachydactyly syndrome, B4GALT1-congenital disorder of glycosylation, AICA-ribosiduria, COG7-congenital disorder of glycosylation, Al-Gazali syndrome, COG1-congenital disorder of glycosylation, RFT1-congenital disorder of glycosylation, Nijmegen breakage syndrome-like disorder, multiple congenital anomalies-hypotonia-seizures syndrome 1, multiple congenital anomalies-hypotonia-seizures syndrome 3, autism spectrum disorder - epilepsy - arthrogryposis syndrome, cutis laxa, autosomal dominant 3, SLC39A8-CDG, transketolase deficiency, mucopolysaccharidosis-plus syndrome, Cockayne syndrome, pontocerebellar hypoplasia type 1, mandibuloacral dysplasia, hyperphosphatasia-intellectual disability syndrome, arthrogryposis-renal dysfunction-cholestasis syndrome, CADDS, XYLT1-congenital disorder of glycosylation, hypophosphatasia, sterol biosynthesis disorder, mucolipidosis, mucopolysaccharidosis, oligosaccharidosis, encephalopathy due to sulfite oxidase deficiency, Fanconi anemia, autosomal recessive cutis laxa type 2, Zellweger spectrum disorders, pseudohypoparathyroidism, developmental and epileptic encephalopathy, 77, glycosylphosphatidylinositol biosynthesis defect 15, progressive hypotonia-intellectual disability-facial dysmorphism syndrome due to FYVE-defective RBSN

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

36 retrieved; paginated sample, class counts are floors:

19 uncertain significance, 8 conflicting classifications of pathogenicity, 3 benign/likely benign, 3 pathogenic, 1 benign, 1 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
30651	NM_178161.3(PTF1A):c.437_460del (p.Ala146_Arg154delinsGly)	PTF1A	Pathogenic	no assertion criteria provided
3425	NM_178161.3(PTF1A):c.886C>T (p.Arg296Ter)	PTF1A	Pathogenic	no assertion criteria provided
3426	NM_178161.3(PTF1A):c.705dup (p.Pro236fs)	PTF1A	Pathogenic	no assertion criteria provided
800794	NM_178161.3(PTF1A):c.571C>A (p.Pro191Thr)	PTF1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
130054	NM_178161.3(PTF1A):c.269G>C (p.Gly90Ala)	PTF1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
130055	NM_178161.3(PTF1A):c.787T>C (p.Ser263Pro)	PTF1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
299622	NM_178161.3(PTF1A):c.162C>T (p.Ser54=)	PTF1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
299626	NM_178161.3(PTF1A):c.654C>A (p.Leu218=)	PTF1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
436444	NM_178161.3(PTF1A):c.499G>A (p.Ala167Thr)	PTF1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
451673	NM_178161.3(PTF1A):c.44C>T (p.Ala15Val)	PTF1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
877721	NM_178161.3(PTF1A):c.462G>T (p.Arg154=)	PTF1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
880488	NM_178161.3(PTF1A):c.201C>T (p.Cys67=)	PTF1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1803846	NM_178161.3(PTF1A):c.987A>G (p.Ter329Trp)	PTF1A	Uncertain significance	criteria provided, single submitter
2179361	NM_178161.3(PTF1A):c.703_720del (p.Gly235_Gly240del)	PTF1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
2502253	NM_178161.3(PTF1A):c.673T>G (p.Leu225Val)	PTF1A	Uncertain significance	criteria provided, single submitter
299623	NM_178161.3(PTF1A):c.263G>A (p.Gly88Asp)	PTF1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
299625	NM_178161.3(PTF1A):c.617G>T (p.Arg206Leu)	PTF1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
299627	NM_178161.3(PTF1A):c.960C>A (p.Asn320Lys)	PTF1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
299629	NM_178161.3(PTF1A):c.*117A>G	PTF1A	Uncertain significance	criteria provided, single submitter
299633	NM_178161.3(PTF1A):c.*265A>G	PTF1A	Uncertain significance	criteria provided, single submitter
299634	NM_178161.3(PTF1A):c.*306C>G	PTF1A	Uncertain significance	criteria provided, single submitter
4279826	NM_178161.3(PTF1A):c.878A>C (p.Asn293Thr)	PTF1A	Uncertain significance	criteria provided, single submitter
549537	NM_178161.3(PTF1A):c.265C>A (p.Leu89Ile)	PTF1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
877718	NM_178161.3(PTF1A):c.341C>T (p.Ser114Leu)	PTF1A	Uncertain significance	criteria provided, single submitter
877719	NM_178161.3(PTF1A):c.362G>A (p.Cys121Tyr)	PTF1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
877720	NM_178161.3(PTF1A):c.446C>T (p.Ala149Val)	PTF1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
879345	NM_178161.3(PTF1A):c.*272G>A	PTF1A	Uncertain significance	criteria provided, single submitter
879346	NM_178161.3(PTF1A):c.*283T>C	PTF1A	Uncertain significance	criteria provided, single submitter
879347	NM_178161.3(PTF1A):c.*316T>C	PTF1A	Uncertain significance	criteria provided, single submitter
880486	NM_178161.3(PTF1A):c.8C>T (p.Ala3Val)	PTF1A	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 22 · 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
PTF1A	Definitive	Autosomal recessive	permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome	12
NEUROD1	Strong	Autosomal recessive	permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PTF1A	Orphanet:2805	Partial pancreatic agenesis
PTF1A	Orphanet:65288	Permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome
NEUROD1	Orphanet:552	MODY

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
PTF1A	HGNC:23734	ENSG00000168267	Q7RTS3	Pancreas transcription factor 1 subunit alpha	gencc,clinvar
NEUROD1	HGNC:7762	ENSG00000162992	Q13562	Neurogenic differentiation factor 1	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PTF1A	Pancreas transcription factor 1 subunit alpha	Transcription factor implicated in the cell fate determination in various organs.
NEUROD1	Neurogenic differentiation factor 1	Acts as a transcriptional activator: mediates transcriptional activation by binding to E box-containing promoter consensus core sequences 5’-CANNTG-3'.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 0 · 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
Transcription factor	2	8.3×	0.015

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PTF1A	Transcription factor	no		bHLH_dom, HLH_DNA-bd_sf, E-box_TF_Regulators
NEUROD1	Transcription factor	no		bHLH_dom, TF_bHLH_NeuroD, NeuroD_DUF

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
body of pancreas	1
islet of Langerhans	1
pancreas	1
cerebellar vermis	1
cerebellum	1
paraflocculus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PTF1A	96	tissue_specific	marker	body of pancreas, pancreas, islet of Langerhans
NEUROD1	115	broad	marker	paraflocculus, cerebellar vermis, cerebellum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NEUROD1	2,901
PTF1A	1,213

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NEUROD1	Q13562	62.39
PTF1A	Q7RTS3	61.81

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
Regulation of gene expression in endocrine-committed (NEUROG3+) progenitor cells	1	1142.0×	0.004	NEUROD1
Regulation of gene expression in early pancreatic precursor cells	1	713.8×	0.004	PTF1A
Regulation of beta-cell development	1	356.9×	0.006	NEUROD1
Regulation of gene expression in beta cells	1	259.6×	0.006	NEUROD1
Developmental Lineage of Pancreatic Acinar Cells	1	150.3×	0.008	PTF1A
Developmental Biology	1	7.2×	0.134	NEUROD1

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
amacrine cell differentiation	2	1532.0×	2e-05	PTF1A, NEUROD1
cerebellum development	2	358.6×	2e-04	PTF1A, NEUROD1
regulation of intestinal epithelial structure maintenance	1	8426.0×	0.002	NEUROD1
pancreatic A cell fate commitment	1	4213.0×	0.002	NEUROD1
pancreatic PP cell fate commitment	1	4213.0×	0.002	NEUROD1
transcription by RNA polymerase II	2	70.5×	0.002	PTF1A, NEUROD1
regulation of neural retina development	1	2808.7×	0.002	PTF1A
enteroendocrine cell differentiation	1	2106.5×	0.002	NEUROD1
embryonic organ morphogenesis	1	2106.5×	0.002	NEUROD1
negative regulation of type B pancreatic cell apoptotic process	1	1053.2×	0.004	NEUROD1
tissue development	1	936.2×	0.004	PTF1A
exocrine pancreas development	1	842.6×	0.004	PTF1A
endocrine pancreas development	1	468.1×	0.006	NEUROD1
negative regulation of receptor signaling pathway via JAK-STAT	1	443.5×	0.006	NEUROD1
neuron fate commitment	1	401.2×	0.006	PTF1A
signal transduction involved in regulation of gene expression	1	351.1×	0.006	NEUROD1
sensory organ development	1	337.0×	0.006	NEUROD1
pancreas development	1	337.0×	0.006	PTF1A
developmental process	1	337.0×	0.006	PTF1A
retina layer formation	1	324.1×	0.006	PTF1A
retinoic acid receptor signaling pathway	1	324.1×	0.006	PTF1A
dentate gyrus development	1	312.1×	0.006	NEUROD1
cellular response to glucocorticoid stimulus	1	312.1×	0.006	NEUROD1
obsolete positive regulation of DNA-binding transcription factor activity	1	300.9×	0.006	NEUROD1
axon development	1	227.7×	0.007	NEUROD1
insulin secretion	1	216.1×	0.007	NEUROD1
regulation of insulin secretion	1	195.9×	0.008	NEUROD1
inner ear development	1	187.2×	0.008	NEUROD1
cell surface receptor signaling pathway via JAK-STAT	1	145.3×	0.010	NEUROD1
positive regulation of cell differentiation	1	133.8×	0.010	NEUROD1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 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
PTF1A	0	0
NEUROD1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	PTF1A, NEUROD1

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)
PTF1A	0	—
NEUROD1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.