Syndromic complex neurodevelopmental disorder

Summary

Syndromic complex neurodevelopmental disorder (MONDO:0800439) is a disease caused by variants in RNU4-2 and ZFHX3, with 8 cohort genes.

At a glance

• Causal genes: RNU4-2 (GenCC Strong), ZFHX3 (GenCC Strong)
• Cohort genes: 8
• ClinVar variants: 9

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	syndromic complex neurodevelopmental disorder
Mondo ID	MONDO:0800439
GARD	0027071
Is cancer (heuristic)	no

Data availability: 9 ClinVar variants · 4 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › complex neurodevelopmental disorder › syndromic complex neurodevelopmental disorder

Related subtypes (14): pervasive developmental disorder, Prader-Willi syndrome, intellectual disability, autosomal dominant 29, neurodevelopmental disorder with language impairment and behavioral abnormalities, neurodevelopmental disorder with severe motor impairment and absent language, X-linked complex neurodevelopmental disorder, neonatal encephalopathy with non-epileptic myoclonus, complex neurodevelopmental disorder with or without congenital anomalies, complex neurodevelopmental disorder with motor features, AFG2B-related complex neurodevelopmental disorder with motor features and hearing loss, developmental and epileptic encephalopathy, DEAF1-associated neurodevelopmental disorder, NACC1-related neurodevelopmental disorder with epilepsy, cataracts and episodic irritability, GRIN-related complex neurodevelopmental disorder

Subtypes (2): HMGB1-related brachyphalangy, polydactyly and tibial aplasia syndrome, X-linked syndromic complex neurodevelopmental disorder

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

9 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 2 conflicting classifications of pathogenicity, 2 likely benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
203529	NM_145207.3(AFG2A):c.1574_1578del (p.Asn525fs)	AFG2A	Pathogenic	criteria provided, multiple submitters, no conflicts
203526	NM_145207.3(AFG2A):c.1964G>A (p.Arg655Gln)	AFG2A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
475726	NM_145207.3(AFG2A):c.2321G>A (p.Arg774His)	AFG2A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3780078	NM_018489.3(ASH1L):c.7270C>T (p.Arg2424Trp)	ASH1L	Uncertain significance	criteria provided, single submitter
2413110	NM_001190737.2(NFIB):c.2T>C (p.Met1Thr)	NFIB	Uncertain significance	criteria provided, single submitter
3385351	NM_016539.4(SIRT6):c.701G>A (p.Gly234Asp)	SIRT6	Uncertain significance	criteria provided, single submitter
3385352	NM_016539.4(SIRT6):c.615-8G>A	SIRT6	Uncertain significance	criteria provided, single submitter
2387376	NM_018489.3(ASH1L):c.1589C>T (p.Pro530Leu)	ASH1L	Likely benign	criteria provided, multiple submitters, no conflicts
3130338	NM_018489.3(ASH1L):c.851C>T (p.Thr284Ile)	ASH1L	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 6 · 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
ZFHX3	Definitive	Autosomal dominant	complex neurodevelopmental disorder	7
FBRSL1	Strong	Autosomal dominant	syndromic disease	3
RNU4-2	Strong	Autosomal dominant	neurodevelopmental disorder with hypotonia, brain anomalies, distinctive facies, and absent language	4
THAP12	Limited	Autosomal recessive	syndromic complex neurodevelopmental disorder

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RNU4-2	Orphanet:686488	RNU4-2-related autosomal dominant neurodevelopmental disorder
SIRT6	Orphanet:580933	Lethal brain and heart developmental defects
AFG2A	Orphanet:457351	Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome
ASH1L	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
NFIB	Orphanet:714407	Developmental delay-macrocephaly-corpus callosum dysgenesis-intellectual disability syndrome due to NFIB mutation
NFIB	Orphanet:714413	9p23p22.2 microdeletion syndrome

Cohort genes → proteins

8 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RNU4-2	HGNC:10193	ENSG00000202538		RNA, U4 small nuclear 2	gencc
FBRSL1	HGNC:29308	ENSG00000112787	Q9HCM7	Fibrosin-1-like protein	gencc
ZFHX3	HGNC:777	ENSG00000140836	Q15911	Zinc finger homeobox protein 3	gencc
THAP12	HGNC:9440	ENSG00000137492	O43422	52 kDa repressor of the inhibitor of the protein kinase	gencc
SIRT6	HGNC:14934	ENSG00000077463	Q8N6T7	NAD-dependent protein deacylase sirtuin-6	clinvar
AFG2A	HGNC:18119	ENSG00000145375	Q8NB90	ATPase family gene 2 protein homolog A	clinvar
ASH1L	HGNC:19088	ENSG00000116539	Q9NR48	Histone-lysine N-methyltransferase ASH1L	clinvar
NFIB	HGNC:7785	ENSG00000147862	O00712	Nuclear factor 1 B-type	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ZFHX3	Zinc finger homeobox protein 3	Transcriptional regulator which can act as an activator or a repressor.
THAP12	52 kDa repressor of the inhibitor of the protein kinase	Upstream regulator of interferon-induced serine/threonine protein kinase R (PKR).
SIRT6	NAD-dependent protein deacylase sirtuin-6	NAD-dependent protein deacetylase, deacylase and mono-ADP-ribosyltransferase that plays an essential role in DNA damage repair, telomere maintenance, metabolic homeostasis, inflammation, tumorigenesis and aging.
AFG2A	ATPase family gene 2 protein homolog A	ATP-dependent chaperone part of the 55LCC heterohexameric ATPase complex which is chromatin-associated and promotes replisome proteostasis to maintain replication fork progression and genome stability.
ASH1L	Histone-lysine N-methyltransferase ASH1L	Histone methyltransferase specifically trimethylating ‘Lys-36’ of histone H3 forming H3K36me3.
NFIB	Nuclear factor 1 B-type	Transcriptional activator of GFAP, essential for proper brain development.

Protein-family classification

Druggable: 1 · Difficult: 3 · Unknown: 4 · Druggable fraction: 0.12

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	3	3.1×	0.187
Enzyme (other)	1	1.5×	0.753
Other/Unknown	4	0.9×	0.755

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RNU4-2	Other/Unknown	no
FBRSL1	Other/Unknown	no		AUTS2
ZFHX3	Transcription factor	no		HD, Matrin/U1-like-C_Znf_C2H2, Homeodomain-like_sf
THAP12	Transcription factor	no		THAP_Znf, HATC_C_dom, RNaseH-like_sf
SIRT6	Enzyme (other)	yes	2.3.1.B41	Sirtuin, Ssirtuin_cat_dom, DHS-like_NAD/FAD-binding_dom
AFG2A	Other/Unknown	no		AAA+_ATPase, ATPase_AAA_core, ATPase_AAA_CS
ASH1L	Transcription factor	no	2.1.1.357	BAH_dom, SET_dom, Bromodomain
NFIB	Other/Unknown	no		CTF/NFI, MAD_homology1_Dwarfin-type, CTF/NFI_DNA-bd_N

Expression context

Cohort genes with no expression data: 0.

8 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)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	2
adrenal tissue	1
corpus callosum	1
sural nerve	1
cortical plate	1
oviduct epithelium	1
pancreatic ductal cell	1
buccal mucosa cell	1
saphenous vein	1
synovial joint	1
corpus epididymis	1
skeletal muscle tissue of biceps brachii	1
granulocyte	1
mucosa of transverse colon	1
transverse colon	1
tendon	1
tendon of biceps brachii	1
Brodmann (1909) area 23	1
cardia of stomach	1
pylorus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RNU4-2	110	ubiquitous	marker	adrenal tissue, sural nerve, corpus callosum
FBRSL1	248	ubiquitous	marker	pancreatic ductal cell, oviduct epithelium, cortical plate
ZFHX3	274	ubiquitous	marker	saphenous vein, buccal mucosa cell, synovial joint
THAP12	290	ubiquitous	marker	calcaneal tendon, skeletal muscle tissue of biceps brachii, corpus epididymis
SIRT6	208	ubiquitous	marker	mucosa of transverse colon, transverse colon, granulocyte
AFG2A	211	ubiquitous	marker	tendon of biceps brachii, calcaneal tendon, tendon
ASH1L	267	ubiquitous	marker	Brodmann (1909) area 23, pylorus, cardia of stomach
NFIB	292	ubiquitous	marker	pericardium, epithelium of mammary gland, mammary duct

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SIRT6	3,599
AFG2A	3,394
ASH1L	2,789
NFIB	2,496
ZFHX3	1,649
THAP12	1,090
FBRSL1	1,068
RNU4-2	0

Structural data

PDB: 5 · AlphaFold-only: 2 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SIRT6	Q8N6T7	45
ASH1L	Q9NR48	16
ZFHX3	Q15911	3
AFG2A	Q8NB90	2
NFIB	O00712	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
THAP12	O43422	83.91
FBRSL1	Q9HCM7	46.19

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 8 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RUNX3 regulates CDKN1A transcription	1	407.9×	0.034	ZFHX3
RNA Polymerase III Transcription Termination	1	124.1×	0.034	NFIB
Pre-NOTCH Expression and Processing	1	92.1×	0.034	SIRT6
Homology Directed Repair	1	77.2×	0.034	SIRT6
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1	77.2×	0.034	SIRT6
RNA Polymerase III Abortive And Retractive Initiation	1	69.6×	0.034	NFIB
DNA Double-Strand Break Repair	1	62.1×	0.034	SIRT6
Signaling by NOTCH	1	43.9×	0.041	SIRT6
PKMTs methylate histone lysines	1	40.2×	0.041	ASH1L
Pre-NOTCH Transcription and Translation	1	30.7×	0.047	SIRT6
Processing of DNA double-strand break ends	1	28.6×	0.047	SIRT6
DNA Repair	1	24.6×	0.050	SIRT6
Chromatin organization	1	20.4×	0.056	ASH1L
Chromatin modifying enzymes	1	18.1×	0.058	ASH1L
Signal Transduction	1	2.5×	0.339	SIRT6

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regeneration	1	2808.7×	0.006	NFIB
ketone biosynthetic process	1	2808.7×	0.006	SIRT6
lung ciliated cell differentiation	1	2808.7×	0.006	NFIB
tarsal gland development	1	2808.7×	0.006	ASH1L
uterine gland development	1	2808.7×	0.006	ASH1L
negative regulation of epithelial cell proliferation involved in lung morphogenesis	1	2808.7×	0.006	NFIB
circadian regulation of gene expression	2	78.0×	0.006	SIRT6, ZFHX3
cell differentiation involved in salivary gland development	1	1404.3×	0.008	NFIB
regulation of locomotor rhythm	1	1404.3×	0.008	ZFHX3
negative regulation of mesenchymal cell proliferation involved in lung development	1	1404.3×	0.008	NFIB
principal sensory nucleus of trigeminal nerve development	1	936.2×	0.010	NFIB
positive regulation of protein localization to chromatin	1	936.2×	0.010	SIRT6
glial cell fate specification	1	702.2×	0.011	NFIB
regulation of lipid catabolic process	1	702.2×	0.011	SIRT6
pericentric heterochromatin formation	1	561.7×	0.011	SIRT6
protein delipidation	1	561.7×	0.011	SIRT6
club cell differentiation	1	561.7×	0.011	NFIB
salivary gland cavitation	1	561.7×	0.011	NFIB
uterus morphogenesis	1	468.1×	0.012	ASH1L
positive regulation of blood vessel branching	1	468.1×	0.012	SIRT6
negative regulation of acute inflammatory response	1	401.2×	0.012	ASH1L
anterior commissure morphogenesis	1	401.2×	0.012	NFIB
brain development	2	26.5×	0.012	AFG2A, NFIB
glandular epithelial cell differentiation	1	351.1×	0.012	NFIB
type II pneumocyte differentiation	1	351.1×	0.012	NFIB
protein deacetylation	1	312.1×	0.012	SIRT6
response to transforming growth factor beta	1	312.1×	0.012	ZFHX3
positive regulation of chondrocyte proliferation	1	312.1×	0.012	SIRT6
negative regulation of transcription by RNA polymerase II	3	8.9×	0.012	SIRT6, ZFHX3, NFIB
subtelomeric heterochromatin formation	1	255.3×	0.013	SIRT6

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 7

Druggability breadth: 3 of 8 evidence-associated genes (38%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SIRT6	NIACINAMIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SIRT6	7	4
RNU4-2	0	0
FBRSL1	0	0
ZFHX3	0	0
THAP12	0	0
AFG2A	0	0
ASH1L	0	0
NFIB	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NIACINAMIDE	4	SIRT6
FLUVASTATIN	4	SIRT6
QUERCETIN	3	SIRT6
LUTEOLIN	2	SIRT6
LINOLEIC ACID	2	SIRT6
OLEIC ACID	2	SIRT6
TRICHOSTATIN	1	SIRT6

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
SIRT6	244	Binding:240, Functional:4
ASH1L	65	Binding:63, ADMET:1, Functional:1
AFG2A	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SIRT6	2.3.1.B41
ASH1L	2.1.1.357	[histone H3]-lysine36 N-dimethyltransferase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
SIRT6	244

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

7 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.

Compound	Max phase	Cohort target (bioactivity)
NIACINAMIDE	4	SIRT6
FLUVASTATIN	4	SIRT6
QUERCETIN	3	SIRT6
LUTEOLIN	2	SIRT6
LINOLEIC ACID	2	SIRT6
OLEIC ACID	2	SIRT6
TRICHOSTATIN	1	SIRT6

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SIRT6
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	7	RNU4-2, FBRSL1, ZFHX3, THAP12, AFG2A, ASH1L, NFIB

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RNU4-2	0	—
FBRSL1	0	—
ZFHX3	0	—
THAP12	0	—
AFG2A	2	—
ASH1L	65	—
NFIB	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.