5q35 microduplication syndrome

Summary

5q35 microduplication syndrome (MONDO:0016461) is a disease with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 3
• Phenotypes (HPO): 9

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		30	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

9 HPO clinical features (Orphanet curated; top 9 by frequency):

HPO ID	Term	Frequency
HP:0000252	Microcephaly	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001328	Specific learning disability	Very frequent (80-99%)
HP:0001510	Growth delay	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0000545	Myopia	Frequent (30-79%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0002750	Delayed skeletal maturation	Frequent (30-79%)
HP:0001250	Seizure	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	5q35 microduplication syndrome
Mondo ID	MONDO:0016461
Orphanet	228415
SNOMED CT	719665003
UMLS	C4304526
MedGen	930195
GARD	0020595
Is cancer (heuristic)	no

Also known as: dup(5)(q35) · trisomy 5q35

Data availability: 3 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › chromosomal disorder › syndrome caused by partial chromosomal duplication › partial trisomy/tetrasomy of chromosome 5 › partial trisomy of the long arm of chromosome 5 › 5q35 microduplication syndrome

Related subtypes (2): adult-onset autosomal dominant demyelinating leukodystrophy, distal trisomy 5q

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

3 retrieved; paginated sample, class counts are floors:

3 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
981214	GRCh37/hg19 5q35.1-35.3(chr5:170805664-180719789)x3	ADAMTS2	Pathogenic	no assertion criteria provided
1707460	Single allele	CDHR2	Pathogenic	criteria provided, single submitter
830214	NC_000005.10:g.(177090796_177094455)_(177346090_177352856)dup	FGFR4	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ADAMTS2	Orphanet:1901	Dermatosparaxis Ehlers-Danlos syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CDHR2	HGNC:18231	ENSG00000074276	Q9BYE9	Cadherin-related family member 2	clinvar
ADAMTS2	HGNC:218	ENSG00000087116	O95450	A disintegrin and metalloproteinase with thrombospondin motifs 2	clinvar
FGFR4	HGNC:3691	ENSG00000160867	P22455	Fibroblast growth factor receptor 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CDHR2	Cadherin-related family member 2	Intermicrovillar adhesion molecule that forms, via its extracellular domain, calcium-dependent heterophilic complexes with CDHR5 on adjacent microvilli.
ADAMTS2	A disintegrin and metalloproteinase with thrombospondin motifs 2	Cleaves the propeptides of type I and II collagen prior to fibril assembly.
FGFR4	Fibroblast growth factor receptor 4	Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays a role in the regulation of cell proliferation, differentiation and migration, and in regulation of lipid metabolism, bile acid biosynthes…

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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
Protease	1	12.2×	0.157
Kinase	1	9.2×	0.157
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CDHR2	Other/Unknown	no		Cadherin-like_dom, Cadherin-like_sf, Cadherin_CS
ADAMTS2	Protease	yes	3.4.24.14	TSP1_rpt, Peptidase_M12B, Peptidase_M12B_N
FGFR4	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
duodenum	1
ileal mucosa	1
jejunal mucosa	1
adipose tissue	1
stromal cell of endometrium	1
subcutaneous adipose tissue	1
right lobe of liver	1
right lung	1
upper lobe of left lung	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CDHR2	176	tissue_specific	marker	jejunal mucosa, ileal mucosa, duodenum
ADAMTS2	139	ubiquitous	marker	stromal cell of endometrium, subcutaneous adipose tissue, adipose tissue
FGFR4	185	broad	marker	right lobe of liver, upper lobe of left lung, right lung

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FGFR4	2,721
ADAMTS2	1,478
CDHR2	931

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FGFR4	P22455	52
CDHR2	Q9BYE9	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ADAMTS2	O95450	71.59

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. Enrichment computed across 3 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
FGFR4 mutant receptor activation	1	5710.0×	0.005	FGFR4
betaKlotho-mediated ligand binding	1	1903.3×	0.007	FGFR4
Signaling by FGFR4 in disease	1	475.8×	0.013	FGFR4
FGFR4 ligand binding and activation	1	407.9×	0.013	FGFR4
Phospholipase C-mediated cascade; FGFR4	1	380.7×	0.013	FGFR4
PI-3K cascade:FGFR4	1	285.5×	0.013	FGFR4
SHC-mediated cascade:FGFR4	1	271.9×	0.013	FGFR4
FRS-mediated FGFR4 signaling	1	248.3×	0.013	FGFR4
Collagen formation	1	228.4×	0.013	ADAMTS2
Negative regulation of FGFR4 signaling	1	203.9×	0.013	FGFR4
Defective B3GALTL causes PpS	1	154.3×	0.014	ADAMTS2
O-glycosylation of TSR domain-containing proteins	1	150.3×	0.014	ADAMTS2
PI3K Cascade	1	135.9×	0.015	FGFR4
Diseases associated with O-glycosylation of proteins	1	107.7×	0.017	ADAMTS2
Collagen biosynthesis and modifying enzymes	1	85.2×	0.020	ADAMTS2
O-linked glycosylation	1	72.3×	0.022	ADAMTS2
Diseases of glycosylation	1	65.6×	0.023	ADAMTS2
Constitutive Signaling by Aberrant PI3K in Cancer	1	63.4×	0.023	FGFR4
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	1	48.4×	0.028	FGFR4
Diseases of metabolism	1	40.2×	0.032	ADAMTS2
PIP3 activates AKT signaling	1	33.4×	0.037	FGFR4
Extracellular matrix organization	1	31.6×	0.037	ADAMTS2
RAF/MAP kinase cascade	1	30.5×	0.037	FGFR4
Post-translational protein modification	1	9.6×	0.110	ADAMTS2
Disease	1	6.5×	0.153	ADAMTS2
Metabolism of proteins	1	6.2×	0.155	ADAMTS2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
intermicrovillar adhesion	1	2808.7×	0.006	CDHR2
regulation of extracellular matrix disassembly	1	1123.5×	0.006	FGFR4
negative regulation of cell growth involved in contact inhibition	1	1123.5×	0.006	CDHR2
regulation of bile acid biosynthetic process	1	936.2×	0.006	FGFR4
regulation of microvillus length	1	802.5×	0.006	CDHR2
positive regulation of catalytic activity	1	802.5×	0.006	FGFR4
brush border assembly	1	802.5×	0.006	CDHR2
positive regulation of DNA biosynthetic process	1	374.5×	0.010	FGFR4
phosphate ion homeostasis	1	351.1×	0.010	FGFR4
positive regulation of proteolysis	1	267.5×	0.012	FGFR4
skin development	1	147.8×	0.016	ADAMTS2
regulation of lipid metabolic process	1	144.0×	0.016	FGFR4
peptidyl-tyrosine phosphorylation	1	140.4×	0.016	FGFR4
cell-cell adhesion mediated by cadherin	1	137.0×	0.016	CDHR2
collagen catabolic process	1	130.6×	0.016	ADAMTS2
fibroblast growth factor receptor signaling pathway	1	95.2×	0.021	FGFR4
collagen fibril organization	1	74.9×	0.025	ADAMTS2
lung development	1	66.1×	0.027	ADAMTS2
epithelial cell differentiation	1	58.5×	0.028	CDHR2
protein processing	1	56.7×	0.028	ADAMTS2
axonogenesis	1	53.5×	0.028	CDHR2
cholesterol homeostasis	1	52.0×	0.028	FGFR4
protein autophosphorylation	1	48.4×	0.028	FGFR4
homophilic cell-cell adhesion	1	46.8×	0.028	CDHR2
glucose homeostasis	1	43.5×	0.029	FGFR4
extracellular matrix organization	1	40.7×	0.030	ADAMTS2
positive regulation of ERK1 and ERK2 cascade	1	28.4×	0.041	FGFR4
cell migration	1	20.5×	0.055	FGFR4
positive regulation of gene expression	1	12.9×	0.083	FGFR4
spermatogenesis	1	11.7×	0.087	ADAMTS2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
FGFR4	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FGFR4	47	4
CDHR2	0	0
ADAMTS2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	FGFR4
PEMIGATINIB	4	FGFR4
NINTEDANIB	4	FGFR4
FEDRATINIB	4	FGFR4
LENVATINIB	4	FGFR4
INFIGRATINIB PHOSPHATE	4	FGFR4
INFIGRATINIB	4	FGFR4
CERITINIB	4	FGFR4
VANDETANIB	4	FGFR4
NINTEDANIB ESYLATE	4	FGFR4
BRIGATINIB	4	FGFR4
ERDAFITINIB	4	FGFR4
FUTIBATINIB	4	FGFR4
PAZOPANIB	4	FGFR4
SUNITINIB	4	FGFR4
LINIFANIB	3	FGFR4
SEMAXANIB	3	FGFR4
BRIVANIB	3	FGFR4
CEDIRANIB	3	FGFR4
DOVITINIB	3	FGFR4
MOTESANIB	3	FGFR4
LESTAURTINIB	3	FGFR4
TANDUTINIB	2	FGFR4
DORAMAPIMOD	2	FGFR4
SU-014813	2	FGFR4
REBASTINIB	2	FGFR4
R-343	2	FGFR4
OSI-632	2	FGFR4
FEXAGRATINIB	2	FGFR4
E-7090	2	FGFR4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
FGFR4	900	Binding:891, Functional:9

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ADAMTS2	3.4.24.14	procollagen N-endopeptidase
FGFR4	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
FGFR4	900

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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)
PONATINIB	4	FGFR4
PEMIGATINIB	4	FGFR4
NINTEDANIB	4	FGFR4
FEDRATINIB	4	FGFR4
LENVATINIB	4	FGFR4
INFIGRATINIB PHOSPHATE	4	FGFR4
INFIGRATINIB	4	FGFR4
CERITINIB	4	FGFR4
VANDETANIB	4	FGFR4
NINTEDANIB ESYLATE	4	FGFR4
BRIGATINIB	4	FGFR4
ERDAFITINIB	4	FGFR4
FUTIBATINIB	4	FGFR4
PAZOPANIB	4	FGFR4
SUNITINIB	4	FGFR4
LINIFANIB	3	FGFR4
SEMAXANIB	3	FGFR4
BRIVANIB	3	FGFR4
CEDIRANIB	3	FGFR4
DOVITINIB	3	FGFR4
MOTESANIB	3	FGFR4
LESTAURTINIB	3	FGFR4
TANDUTINIB	2	FGFR4
DORAMAPIMOD	2	FGFR4
SU-014813	2	FGFR4
REBASTINIB	2	FGFR4
R-343	2	FGFR4
OSI-632	2	FGFR4
FEXAGRATINIB	2	FGFR4
E-7090	2	FGFR4

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	FGFR4
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	ADAMTS2
E	Difficult family or no structure, no drug	1	CDHR2

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)
CDHR2	0	—
ADAMTS2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.