Microcephaly 18, primary, autosomal dominant

Summary

Microcephaly 18, primary, autosomal dominant (MONDO:0054593) is a disease caused by WDFY3 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: WDFY3 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 85

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	microcephaly 18, primary, autosomal dominant
Mondo ID	MONDO:0054593
OMIM	617520
DOID	DOID:0070295
UMLS	C4479608
MedGen	1391110
GARD	0016233
Is cancer (heuristic)	no

Also known as: MCPH18 · microcephaly 18, primary, autosomal dominant

Data availability: 85 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › autosomal dominant primary microcephaly › microcephaly 18, primary, autosomal dominant

Related subtypes (2): microcephaly 26, primary, autosomal dominant, microcephaly 27, primary, autosomal dominant

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

85 retrieved; paginated sample, class counts are floors:

44 uncertain significance, 18 likely pathogenic, 8 conflicting classifications of pathogenicity, 6 pathogenic, 3 likely benign, 2 benign, 2 benign/likely benign, 1 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1174114	NM_014991.6(WDFY3):c.4063-1G>T	WDFY3	Pathogenic	no assertion criteria provided
1334627	NM_014991.6(WDFY3):c.9496C>T (p.Arg3166Ter)	WDFY3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3236646	NM_014991.6(WDFY3):c.7297_7298insC (p.Val2433fs)	WDFY3	Pathogenic	criteria provided, single submitter
4081929	NM_014991.6(WDFY3):c.6913C>T (p.Gln2305Ter)	WDFY3	Pathogenic	no assertion criteria provided
446237	NM_014991.6(WDFY3):c.7909C>T (p.Arg2637Trp)	WDFY3	Pathogenic	criteria provided, multiple submitters, no conflicts
4688604	NC_000004.11:g.(85717906_85719148)_(85723018_85724442)del	WDFY3	Pathogenic	criteria provided, single submitter
975777	NM_014991.6(WDFY3):c.2459_2460del (p.Pro820fs)	WDFY3	Pathogenic	criteria provided, single submitter
1029337	NM_014991.6(WDFY3):c.8287C>T (p.Arg2763Ter)	WDFY3	Likely pathogenic	criteria provided, single submitter
1172659	NM_014991.6(WDFY3):c.5114_5115del (p.Lys1705fs)	WDFY3	Likely pathogenic	criteria provided, single submitter
1709645	NM_014991.6(WDFY3):c.2785C>T (p.Arg929Ter)	WDFY3	Likely pathogenic	criteria provided, single submitter
1803494	NM_014991.6(WDFY3):c.8017C>T (p.Arg2673Ter)	WDFY3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2434617	NM_014991.6(WDFY3):c.8693del (p.Leu2898fs)	WDFY3	Likely pathogenic	criteria provided, single submitter
2442018	NM_014991.6(WDFY3):c.5825C>T (p.Ser1942Leu)	WDFY3	Likely pathogenic	criteria provided, single submitter
2672154	NM_014991.6(WDFY3):c.8901+1G>A	WDFY3	Likely pathogenic	criteria provided, single submitter
3066117	NM_014991.6(WDFY3):c.290C>G (p.Ser97Ter)	WDFY3	Likely pathogenic	criteria provided, single submitter
3068450	NM_014991.6(WDFY3):c.7304dup (p.Tyr2435Ter)	WDFY3	Likely pathogenic	criteria provided, single submitter
3777168	NM_014991.6(WDFY3):c.941_945del (p.Cys314fs)	WDFY3	Likely pathogenic	criteria provided, single submitter
4076311	NM_014991.6(WDFY3):c.1409T>A (p.Leu470Ter)	WDFY3	Likely pathogenic	criteria provided, single submitter
4076312	NM_014991.6(WDFY3):c.2064_2065del (p.Phe689fs)	WDFY3	Likely pathogenic	criteria provided, single submitter
4076314	NM_014991.6(WDFY3):c.4037T>A (p.Leu1346Ter)	WDFY3	Likely pathogenic	criteria provided, single submitter
4076316	NM_014991.6(WDFY3):c.5929_5932del (p.Thr1977fs)	WDFY3	Likely pathogenic	criteria provided, single submitter
4076317	NM_014991.6(WDFY3):c.7987dup (p.Thr2663fs)	WDFY3	Likely pathogenic	criteria provided, single submitter
4292086	NM_014991.6(WDFY3):c.1471_1483del (p.Arg491fs)	WDFY3	Likely pathogenic	criteria provided, single submitter
975778	NM_014991.6(WDFY3):c.1670T>C (p.Leu557Pro)	WDFY3	Likely pathogenic	no assertion criteria provided
982381	NM_014991.6(WDFY3):c.957-2A>G	WDFY3	Likely pathogenic	criteria provided, single submitter
1033721	NM_014991.6(WDFY3):c.10486C>T (p.Arg3496Cys)	WDFY3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1325748	NM_014991.6(WDFY3):c.5242C>T (p.Arg1748Ter)	WDFY3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1695095	NM_014991.6(WDFY3):c.9304G>A (p.Val3102Met)	WDFY3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2438562	NM_014991.6(WDFY3):c.10114A>C (p.Ile3372Leu)	WDFY3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2438563	NM_014991.6(WDFY3):c.3172C>G (p.Leu1058Val)	WDFY3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
WDFY3	Strong	Autosomal dominant	microcephaly 18, primary, autosomal dominant	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
WDFY3	Orphanet:528084	Non-specific syndromic intellectual disability

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
WDFY3	HGNC:20751	ENSG00000163625	Q8IZQ1	WD repeat and FYVE domain-containing protein 3	gencc,clinvar
WDFY3-AS1	HGNC:40935	ENSG00000251260		WDFY3 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
WDFY3	WD repeat and FYVE domain-containing protein 3	Required for selective macroautophagy (aggrephagy).

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
WDFY3	Transcription factor	no		Znf_FYVE, BEACH_dom, WD40_rpt
WDFY3-AS1	Other/Unknown	no

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
corpus callosum	1
sural nerve	1
male germ line stem cell (sensu Vertebrata) in testis	1
skeletal muscle tissue	1
tonsil	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
WDFY3	293	ubiquitous	marker	sural nerve, calcaneal tendon, corpus callosum
WDFY3-AS1	97		yes	male germ line stem cell (sensu Vertebrata) in testis, tonsil, skeletal muscle tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
WDFY3	1,780
WDFY3-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
WDFY3	Q8IZQ1	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 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
aggrephagy	1	1685.2×	6e-04	WDFY3

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
WDFY3	0	0
WDFY3-AS1	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	2	WDFY3, WDFY3-AS1

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)
WDFY3	0	—
WDFY3-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.