Macroglossia

Summary

Macroglossia (MONDO:0015496) is a disease with 2 cohort genes and 3 clinical trials. Top therapeutic interventions include isatuximab.

At a glance

• Cohort genes: 2
• ClinVar variants: 2
• Clinical trials: 3

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	macroglossia
Mondo ID	MONDO:0015496
MeSH	D008260
Orphanet	156207
ICD-11	670519908
UMLS	C0024421
MedGen	44236
GARD	0003342
MedDRA	10025391
Is cancer (heuristic)	no

Also known as: enlarged tongue · giant tongue

Data availability: 2 ClinVar variants · 1 cell line.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › developmental defect during embryogenesis › macroglossia

Related subtypes (51): disorder of sexual differentiation, hereditary neurocutaneous angioma, nevoid basal cell carcinoma syndrome, angioosteohypertrophic syndrome, Larsen syndrome, schwannomatosis, linear nevus sebaceous syndrome, lethal Larsen-like syndrome, pseudodiastrophic dysplasia, focal dermal hypoplasia, microtia, neurofibromatosis-Noonan syndrome, Becker nevus syndrome, Legius syndrome, bone fragility with contractures, arterial rupture, and deafness, blindness - scoliosis - arachnodactyly syndrome, cutis laxa - Marfanoid syndrome, Maffucci syndrome, hydrops fetalis, ankyloblepharon filiforme-imperforate anus syndrome, developmental anomaly of metabolic origin, progeroid syndrome, facial cleft, Desbuquois dysplasia, cysts and fistulae of the face and oral cavity, middle ear anomaly, cleft palate, cutis laxa, infectious embryofetopathy, toxic or drug-related embryofetopathy, hemihyperplasia-multiple lipomatosis syndrome, phakomatosis pigmentokeratotica, phakomatosis pigmentovascularis, PTEN hamartoma tumor syndrome, marfanoid habitus-inguinal hernia-advanced bone age syndrome, neurofibromatosis type 1, multiple congenital anomalies/dysmorphic syndrome, congenital limb malformation, hereditary hemorrhagic telangiectasia, urogenital tract malformation, congenital anomaly of kidney and urinary tract, anotia, central nervous system malformation, Ehlers-Danlos syndrome, X-linked external auditory canal atresia-dilated internal auditory canal-facial dysmorphism syndrome, joint laxity, short stature, and myopia, diaphragmatic malformation, abdominal wall malformation, port-wine nevi-mega cisterna magna-hydrocephalus syndrome, conjoined twins, TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations

Subtypes (1): congenital macroglossia

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

2 retrieved; paginated sample, class counts are floors:

1 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1299338	NM_020791.4(TAOK1):c.1303C>T (p.Arg435Ter)	TAOK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
638278	NM_001042424.3(NSD2):c.3295G>A (p.Glu1099Lys)	NSD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NSD2	Orphanet:280	Wolf-Hirschhorn syndrome
TAOK1	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NSD2	HGNC:12766	ENSG00000109685	O96028	Histone-lysine N-methyltransferase NSD2	clinvar
TAOK1	HGNC:29259	ENSG00000160551	Q7L7X3	Serine/threonine-protein kinase TAO1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NSD2	Histone-lysine N-methyltransferase NSD2	Histone methyltransferase which specifically dimethylates nucleosomal histone H3 at ‘Lys-36’ (H3K36me2).
TAOK1	Serine/threonine-protein kinase TAO1	Serine/threonine-protein kinase involved in various processes such as p38/MAPK14 stress-activated MAPK cascade, DNA damage response and regulation of cytoskeleton stability.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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
Kinase	1	13.9×	0.142
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NSD2	Transcription factor	no	2.1.1.356	PWWP_dom, SET_dom, Znf_RING
TAOK1	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	1
ganglionic eminence	1
ventricular zone	1
corpus callosum	1
globus pallidus	1
medial globus pallidus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NSD2	281	ubiquitous	marker	ventricular zone, ganglionic eminence, cortical plate
TAOK1	274	ubiquitous	marker	corpus callosum, globus pallidus, medial globus pallidus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NSD2	3,530
TAOK1	1,325

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NSD2	O96028	22

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TAOK1	Q7L7X3	77.36

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 24. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Dengue virus modulates apoptosis	1	356.9×	0.039	TAOK1
Amplification of signal from the kinetochores	1	98.5×	0.039	TAOK1
Nonhomologous End-Joining (NHEJ)	1	84.0×	0.039	NSD2
PKMTs methylate histone lysines	1	80.4×	0.039	NSD2
Mitotic Spindle Checkpoint	1	79.3×	0.039	TAOK1
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	1	73.2×	0.039	NSD2
G2/M DNA damage checkpoint	1	60.1×	0.039	NSD2
Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal	1	58.3×	0.039	TAOK1
Processing of DNA double-strand break ends	1	57.1×	0.039	NSD2
Mitotic Metaphase and Anaphase	1	48.4×	0.039	TAOK1
Mitotic Anaphase	1	48.4×	0.039	TAOK1
EML4 and NUDC in mitotic spindle formation	1	46.4×	0.039	TAOK1
Cell Cycle Checkpoints	1	44.3×	0.039	TAOK1
Resolution of Sister Chromatid Cohesion	1	43.3×	0.039	TAOK1
RHO GTPases Activate Formins	1	38.8×	0.040	TAOK1
Mitotic Prometaphase	1	34.6×	0.040	TAOK1
RHO GTPase Effectors	1	34.0×	0.040	TAOK1
M Phase	1	33.0×	0.040	TAOK1
Separation of Sister Chromatids	1	30.4×	0.041	TAOK1
Cell Cycle, Mitotic	1	24.1×	0.049	TAOK1
Cell Cycle	1	18.0×	0.061	TAOK1
Signaling by Rho GTPases	1	17.1×	0.061	TAOK1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	16.7×	0.061	TAOK1
Signal Transduction	1	5.1×	0.187	TAOK1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
atrial septum secundum morphogenesis	1	4213.0×	0.004	NSD2
atrial septum primum morphogenesis	1	1685.2×	0.004	NSD2
regulation of double-strand break repair via nonhomologous end joining	1	1685.2×	0.004	NSD2
positive regulation of isotype switching to IgA isotypes	1	1404.3×	0.004	NSD2
regulation of establishment of protein localization	1	1203.7×	0.004	NSD2
membranous septum morphogenesis	1	842.6×	0.005	NSD2
central nervous system neuron development	1	401.2×	0.007	TAOK1
positive regulation of stress-activated MAPK cascade	1	401.2×	0.007	TAOK1
execution phase of apoptosis	1	383.0×	0.007	TAOK1
regulation of cytoskeleton organization	1	324.1×	0.007	TAOK1
regulation of microtubule cytoskeleton organization	1	271.8×	0.008	TAOK1
negative regulation of microtubule depolymerization	1	247.8×	0.008	TAOK1
neuron cellular homeostasis	1	227.7×	0.008	TAOK1
mitotic G2 DNA damage checkpoint signaling	1	221.7×	0.008	TAOK1
bone development	1	138.1×	0.012	NSD2
double-strand break repair	1	101.5×	0.015	NSD2
methylation	1	85.1×	0.016	NSD2
positive regulation of JNK cascade	1	81.8×	0.016	TAOK1
regulation of actin cytoskeleton organization	1	78.8×	0.016	TAOK1
microtubule cytoskeleton organization	1	60.6×	0.020	TAOK1
DNA repair	1	31.9×	0.036	TAOK1
DNA damage response	1	26.8×	0.040	TAOK1
regulation of DNA-templated transcription	1	15.8×	0.065	NSD2
negative regulation of transcription by RNA polymerase II	1	8.9×	0.110	NSD2

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 evidence-associated genes (100%) 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
NSD2	VENETOCLAX
TAOK1	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TAOK1	58	4
NSD2	8	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VENETOCLAX	4	NSD2
MITOXANTRONE	4	NSD2
FEDRATINIB	4	TAOK1
SORAFENIB	4	TAOK1
RUXOLITINIB	4	TAOK1
PALBOCICLIB	4	TAOK1
ENTRECTINIB	4	TAOK1
PACRITINIB	4	TAOK1
NILOTINIB	4	TAOK1
BOSUTINIB	4	TAOK1
ABEMACICLIB	4	TAOK1
BRIGATINIB	4	TAOK1
PAZOPANIB	4	TAOK1
SUNITINIB	4	TAOK1
DASATINIB	4	TAOK1
CRIZOTINIB	4	TAOK1
IMATINIB	4	TAOK1
SURAMIN	3	NSD2
DINACICLIB	3	TAOK1
CRENOLANIB	3	TAOK1
LINIFANIB	3	TAOK1
DEFACTINIB	3	TAOK1
ALVOCIDIB	3	TAOK1
CEDIRANIB	3	TAOK1
LESTAURTINIB	3	TAOK1
RUBOXISTAURIN	3	TAOK1
SINEFUNGIN	2	NSD2
MOLIBRESIB	2	NSD2
HOMIDIUM BROMIDE	2	NSD2
SILMITASERTIB	2	TAOK1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
NSD2	264	Binding:256, Functional:8
TAOK1	231	Binding:230, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NSD2	2.1.1.356, 2.1.1.357, 2.1.1.359	[histone H3]-lysine27 N-trimethyltransferase, [histone H3]-lysine36 N-dimethyltransferase, [histone H3]-lysine36 N-trimethyltransferase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
NSD2	264
TAOK1	231

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
VENETOCLAX	4	NSD2
MITOXANTRONE	4	NSD2
FEDRATINIB	4	TAOK1
SORAFENIB	4	TAOK1
RUXOLITINIB	4	TAOK1
PALBOCICLIB	4	TAOK1
ENTRECTINIB	4	TAOK1
PACRITINIB	4	TAOK1
NILOTINIB	4	TAOK1
BOSUTINIB	4	TAOK1
ABEMACICLIB	4	TAOK1
BRIGATINIB	4	TAOK1
PAZOPANIB	4	TAOK1
SUNITINIB	4	TAOK1
DASATINIB	4	TAOK1
CRIZOTINIB	4	TAOK1
IMATINIB	4	TAOK1
SURAMIN	3	NSD2
DINACICLIB	3	TAOK1
CRENOLANIB	3	TAOK1
LINIFANIB	3	TAOK1
DEFACTINIB	3	TAOK1
ALVOCIDIB	3	TAOK1
CEDIRANIB	3	TAOK1
LESTAURTINIB	3	TAOK1
RUBOXISTAURIN	3	TAOK1
SINEFUNGIN	2	NSD2
MOLIBRESIB	2	NSD2
HOMIDIUM BROMIDE	2	NSD2
SILMITASERTIB	2	TAOK1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	NSD2, TAOK1
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03499808	PHASE2	COMPLETED	S1702 Isatuximab in Treating Patients With Relapsed or Refractory Primary Amyloidosis
NCT01457443	Not specified	WITHDRAWN	Biomarker for Pompe Disease (BioPompe)
NCT01458613	Not specified	WITHDRAWN	Biomarker for Maroteaux-Lamy Disease (BioMaroteaux)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ISATUXIMAB	4	1