Megalencephaly-severe kyphoscoliosis-overgrowth syndrome

Summary

Megalencephaly-severe kyphoscoliosis-overgrowth syndrome (MONDO:0018710) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• Phenotypes (HPO): 54

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

54 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000276	Long face	Very frequent (80-99%)
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0001166	Arachnodactyly	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001548	Overgrowth	Very frequent (80-99%)
HP:0010864	Intellectual disability, severe	Very frequent (80-99%)
HP:0011220	Prominent forehead	Very frequent (80-99%)
HP:0011229	Broad eyebrow	Very frequent (80-99%)
HP:0045075	Sparse eyebrow	Very frequent (80-99%)
HP:0001355	Megalencephaly	Frequent (30-79%)
HP:0001519	Disproportionate tall stature	Frequent (30-79%)
HP:0001520	Large for gestational age	Frequent (30-79%)
HP:0001533	Slender build	Frequent (30-79%)
HP:0001833	Long foot	Frequent (30-79%)
HP:0001999	Abnormal facial shape	Frequent (30-79%)
HP:0002066	Gait ataxia	Frequent (30-79%)
HP:0002069	Bilateral tonic-clonic seizure	Frequent (30-79%)
HP:0002307	Drooling	Frequent (30-79%)
HP:0002751	Kyphoscoliosis	Frequent (30-79%)
HP:0000218	High palate	Frequent (30-79%)
HP:0000256	Macrocephaly	Frequent (30-79%)
HP:0000303	Mandibular prognathia	Frequent (30-79%)
HP:0000358	Posteriorly rotated ears	Frequent (30-79%)
HP:0000400	Macrotia	Frequent (30-79%)
HP:0000494	Downslanted palpebral fissures	Frequent (30-79%)
HP:0000520	Proptosis	Frequent (30-79%)
HP:0000582	Upslanted palpebral fissure	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001344	Absent speech	Frequent (30-79%)
HP:0000054	Micropenis	Occasional (5-29%)
HP:0000272	Malar flattening	Occasional (5-29%)
HP:0000297	Facial hypotonia	Occasional (5-29%)
HP:0000325	Triangular face	Occasional (5-29%)
HP:0000426	Prominent nasal bridge	Occasional (5-29%)
HP:0000472	Long neck	Occasional (5-29%)
HP:0000586	Shallow orbits	Occasional (5-29%)
HP:0001321	Cerebellar hypoplasia	Occasional (5-29%)
HP:0001334	Communicating hydrocephalus	Occasional (5-29%)
HP:0001376	Limitation of joint mobility	Occasional (5-29%)
HP:0001382	Joint hypermobility	Occasional (5-29%)
HP:0001555	Asymmetry of the thorax	Occasional (5-29%)
HP:0001763	Pes planus	Occasional (5-29%)
HP:0001998	Neonatal hypoglycemia	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)
HP:0002120	Cerebral cortical atrophy	Occasional (5-29%)
HP:0002808	Kyphosis	Occasional (5-29%)
HP:0002938	Lumbar hyperlordosis	Occasional (5-29%)
HP:0006863	Severe expressive language delay	Occasional (5-29%)
HP:0007074	Thick corpus callosum	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	megalencephaly-severe kyphoscoliosis-overgrowth syndrome
Mondo ID	MONDO:0018710
Orphanet	457359
UMLS	C5681123
MedGen	1814470
GARD	0017805
Is cancer (heuristic)	no

Data availability: 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › macrocephaly, dysmorphic facies, and psychomotor retardation › megalencephaly-severe kyphoscoliosis-overgrowth 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

No tiered GWAS variants or ClinVar records for this disease.

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
HERC1	Supportive	Autosomal recessive	megalencephaly-severe kyphoscoliosis-overgrowth syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HERC1	Orphanet:457359	Megalencephaly-severe kyphoscoliosis-overgrowth syndrome

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
HERC1	HGNC:4867	ENSG00000103657	Q15751	Probable E3 ubiquitin-protein ligase HERC1	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HERC1	Probable E3 ubiquitin-protein ligase HERC1	Involved in membrane trafficking via some guanine nucleotide exchange factor (GEF) activity and its ability to bind clathrin.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Scaffold/PPI	1	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HERC1	Scaffold/PPI	no		Reg_chr_condens, HECT_dom, WD40_rpt

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
Brodmann (1909) area 23	1
cortical plate	1
middle temporal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HERC1	285	ubiquitous	marker	cortical plate, middle temporal gyrus, Brodmann (1909) area 23

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HERC1	1,563

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HERC1	Q15751	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Antigen processing: Ubiquitination & Proteasome degradation	1	37.2×	0.027	HERC1

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
cerebellar Purkinje cell differentiation	1	1053.2×	0.004	HERC1
bone remodeling	1	936.2×	0.004	HERC1
corpus callosum development	1	842.6×	0.004	HERC1
neuromuscular process controlling balance	1	330.4×	0.006	HERC1
bone mineralization	1	271.8×	0.006	HERC1
negative regulation of autophagy	1	259.3×	0.006	HERC1
neuron projection development	1	122.1×	0.011	HERC1
autophagy	1	110.1×	0.011	HERC1
gene expression	1	79.9×	0.014	HERC1
protein ubiquitination	1	41.4×	0.024	HERC1

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
HERC1	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	HERC1

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)
HERC1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.