Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination

Summary

Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination (MONDO:0044306) is a disease caused by NACC1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: NACC1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 19
• Phenotypes (HPO): 23

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		6	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0000737	Irritability	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0008872	Feeding difficulties in infancy	Very frequent (80-99%)
HP:0008947	Floppy infant	Very frequent (80-99%)
HP:0012171	Stereotypical hand wringing	Very frequent (80-99%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0002187	Intellectual disability, profound	Frequent (30-79%)
HP:0002360	Sleep abnormality	Frequent (30-79%)
HP:0002521	Hypsarrhythmia	Frequent (30-79%)
HP:0010864	Intellectual disability, severe	Frequent (30-79%)
HP:0000455	Broad nasal tip	Occasional (5-29%)
HP:0001118	Juvenile cataract	Occasional (5-29%)
HP:0001257	Spasticity	Occasional (5-29%)
HP:0001371	Flexion contracture	Occasional (5-29%)
HP:0002059	Cerebral atrophy	Occasional (5-29%)
HP:0002376	Developmental regression	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0005949	Apneic episodes in infancy	Occasional (5-29%)
HP:0012430	Cerebral white matter hypoplasia	Occasional (5-29%)
HP:0012448	Delayed myelination	Occasional (5-29%)
HP:0040288	Nasogastric tube feeding	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination
Mondo ID	MONDO:0044306
OMIM	617393
Orphanet	500545
UMLS	C4479333
MedGen	1377894
GARD	0017930
Is cancer (heuristic)	no

Also known as: NECFM · neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination

Data availability: 19 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › epilepsy › monogenic epilepsy › neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination

Related subtypes (17): Mowat-Wilson syndrome, developmental and epileptic encephalopathy, 2, severe neonatal-onset encephalopathy with microcephaly, familial infantile myoclonic epilepsy, neuronal ceroid lipofuscinosis 8 northern epilepsy variant, polyhydramnios, megalencephaly, and symptomatic epilepsy, neonatal-onset encephalopathy with rigidity and seizures, developmental and epileptic encephalopathy, 23, spastic paraplegia-severe developmental delay-epilepsy syndrome, X-linked intellectual disability-epilepsy syndrome, focal epilepsy-intellectual disability-cerebro-cerebellar malformation, infantile-onset mesial temporal lobe epilepsy with severe cognitive regression, autosomal recessive cerebellar ataxia - epilepsy - intellectual disability syndrome, developmental and epileptic encephalopathy, 73, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, epilepsy, X-linked, with or without impaired intellectual development and dysmorphic features, neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphism

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

19 retrieved; paginated sample, class counts are floors:

11 uncertain significance, 5 conflicting classifications of pathogenicity, 1 likely pathogenic, 1 benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
417784	NM_052876.4(NACC1):c.892C>T (p.Arg298Trp)	NACC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1320157	NM_052876.4(NACC1):c.1384G>A (p.Asp462Asn)	NACC1	Likely pathogenic	criteria provided, single submitter
1389649	NM_052876.4(NACC1):c.125A>G (p.Lys42Arg)	NACC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1439640	NM_052876.4(NACC1):c.503C>T (p.Thr168Met)	NACC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1502121	NM_052876.4(NACC1):c.1303C>T (p.Arg435Cys)	NACC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1695571	NM_052876.4(NACC1):c.1010G>A (p.Arg337Gln)	NACC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
978132	NM_052876.4(NACC1):c.1537G>A (p.Ala513Thr)	NACC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1251943	NM_052876.4(NACC1):c.1406G>A (p.Arg469His)	NACC1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1342358	NM_052876.4(NACC1):c.1042A>G (p.Ile348Val)	NACC1	Uncertain significance	criteria provided, single submitter
1359243	NM_052876.4(NACC1):c.476C>T (p.Pro159Leu)	NACC1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1393113	NM_052876.4(NACC1):c.1003C>T (p.Arg335Trp)	NACC1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2434017	NM_052876.4(NACC1):c.947C>T (p.Ala316Val)	NACC1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2434018	NM_052876.4(NACC1):c.1414C>T (p.Arg472Cys)	NACC1	Uncertain significance	criteria provided, single submitter
2434019	NM_052876.4(NACC1):c.673G>C (p.Ala225Pro)	NACC1	Uncertain significance	criteria provided, single submitter
2663927	NM_052876.4(NACC1):c.1079A>G (p.Tyr360Cys)	NACC1	Uncertain significance	criteria provided, single submitter
931073	NM_052876.4(NACC1):c.1325-14A>C	NACC1	Uncertain significance	criteria provided, single submitter
931635	NM_052876.4(NACC1):c.1038A>C (p.Glu346Asp)	NACC1	Uncertain significance	criteria provided, single submitter
931953	NM_052876.4(NACC1):c.1325-4A>C	NACC1	Uncertain significance	criteria provided, single submitter
1321835	NM_052876.4(NACC1):c.*24A>G	NACC1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
NACC1	Strong	Autosomal dominant	neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NACC1	Orphanet:500545	Severe neurodevelopmental disorder with feeding difficulties-stereotypic hand movement-bilateral cataract

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
NACC1	HGNC:20967	ENSG00000160877	Q96RE7	Nucleus accumbens-associated protein 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NACC1	Nucleus accumbens-associated protein 1	Functions as a transcriptional repressor.

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)
NACC1	Other/Unknown	no		BTB/POZ_dom, SKP1/BTB/POZ_sf, BEN_domain

Expression context

Cohort genes with no expression data: 0.

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
nasal cavity epithelium	1
pancreatic ductal cell	1
upper arm skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NACC1	259	ubiquitous	yes	pancreatic ductal cell, nasal cavity epithelium, upper arm skin

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NACC1	1,719

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NACC1	Q96RE7	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
positive regulation of cell population proliferation	1	33.6×	0.048	NACC1
negative regulation of DNA-templated transcription	1	31.6×	0.048	NACC1
regulation of transcription by RNA polymerase II	1	11.7×	0.086	NACC1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
NACC1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NACC1	6	Binding:6

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	NACC1

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)
NACC1	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.