Macrocephaly/megalencephaly syndrome, autosomal recessive

Summary

Macrocephaly/megalencephaly syndrome, autosomal recessive (MONDO:0009544) is a disease caused by TBC1D7 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: TBC1D7 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 6

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	macrocephaly/megalencephaly syndrome, autosomal recessive
Mondo ID	MONDO:0009544
MeSH	C537453
OMIM	248000
UMLS	C3806412
MedGen	812742
GARD	0024680
Is cancer (heuristic)	no

Also known as: Fryns Dereymaeker Haegeman syndrome · intellectual disability, macrocephaly, short stature and craniofacial dysmorphism · macrocephaly/megalencephaly syndrome, autosomal recessive · mental retardation, macrocephaly, short stature and craniofacial dysmorphism · MGCPH

Data availability: 6 ClinVar variants · 4 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 › megalencephaly › macrocephaly/megalencephaly syndrome, autosomal recessive

Related subtypes (3): megalencephaly, autosomal dominant, isolated megalencephaly, bagatelle Cassidy syndrome

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

6 retrieved; paginated sample, class counts are floors:

3 pathogenic, 2 benign, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
144034	NM_016495.6(TBC1D7):c.18_21del (p.Arg7fs)	TBC1D7	Pathogenic	no assertion criteria provided
2062902	NM_016495.6(TBC1D7):c.322dup (p.Tyr108fs)	TBC1D7	Pathogenic	criteria provided, multiple submitters, no conflicts
89031	NM_016495.6(TBC1D7):c.538del (p.Tyr180fs)	TBC1D7-LOC100130357	Pathogenic	no assertion criteria provided
1033329	NM_016495.6(TBC1D7):c.381+143C>T	TBC1D7	Uncertain significance	criteria provided, single submitter
1289943	NM_016495.6(TBC1D7):c.665+8G>A	LOC126859592	Benign	criteria provided, multiple submitters, no conflicts
1231415	NM_016495.6(TBC1D7):c.193+47G>A	TBC1D7	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
TBC1D7	Strong	Autosomal recessive	macrocephaly/megalencephaly syndrome, autosomal recessive	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TBC1D7	Orphanet:2477	Isolated megalencephaly

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
TBC1D7	HGNC:21066	ENSG00000145979	Q9P0N9	TBC1 domain family member 7	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TBC1D7	TBC1 domain family member 7	Non-catalytic component of the TSC-TBC complex, a multiprotein complex that acts as a negative regulator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolec…

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)
TBC1D7	Other/Unknown	no		Rab-GAP-TBC_dom, Rab-GAP_TBC_sf, TBC1D7

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	1
ganglionic eminence	1
oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TBC1D7	242	ubiquitous	marker	cortical plate, oocyte, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TBC1D7	952

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TBC1D7	Q9P0N9	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Rab regulation of trafficking	1	368.4×	0.008	TBC1D7
TBC/RABGAPs	1	259.6×	0.008	TBC1D7
Membrane Trafficking	1	37.1×	0.029	TBC1D7
Vesicle-mediated transport	1	34.8×	0.029	TBC1D7

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
response to growth factor	1	1404.3×	0.004	TBC1D7
negative regulation of cilium assembly	1	802.5×	0.004	TBC1D7
activation of GTPase activity	1	732.7×	0.004	TBC1D7
negative regulation of TOR signaling	1	561.7×	0.004	TBC1D7
negative regulation of TORC1 signaling	1	324.1×	0.005	TBC1D7
positive regulation of GTPase activity	1	276.3×	0.005	TBC1D7
positive regulation of protein ubiquitination	1	213.3×	0.005	TBC1D7
cellular response to starvation	1	193.7×	0.005	TBC1D7

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
TBC1D7	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	1	TBC1D7

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)
TBC1D7	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.