Chromosome 1q21.1 duplication syndrome

Summary

Chromosome 1q21.1 duplication syndrome (MONDO:0012915) is a disease with 7 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 7
• ClinVar variants: 15
• Phenotypes (HPO): 25
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		46	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

25 HPO clinical features (Orphanet curated; top 25 by frequency):

HPO ID	Term	Frequency
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0000256	Macrocephaly	Frequent (30-79%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0002007	Frontal bossing	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000047	Hypospadias	Occasional (5-29%)
HP:0000238	Hydrocephalus	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000501	Glaucoma	Occasional (5-29%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0000717	Autism	Occasional (5-29%)
HP:0000738	Hallucinations	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001276	Hypertonia	Occasional (5-29%)
HP:0001385	Hip dysplasia	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0001636	Tetralogy of Fallot	Occasional (5-29%)
HP:0001762	Talipes equinovarus	Occasional (5-29%)
HP:0002020	Gastroesophageal reflux	Occasional (5-29%)
HP:0002804	Arthrogryposis multiplex congenita	Occasional (5-29%)
HP:0002827	Hip dislocation	Occasional (5-29%)
HP:0007018	Attention deficit hyperactivity disorder	Occasional (5-29%)
HP:0100753	Schizophrenia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	chromosome 1q21.1 duplication syndrome
Mondo ID	MONDO:0012915
MeSH	C567290
OMIM	612475
Orphanet	250994
DOID	DOID:0060435
UMLS	C2675891
MedGen	382715
GARD	0010591
Is cancer (heuristic)	no

Also known as: 1q21.1 microduplication syndrome · 1q21.1 recurrent microduplication (possible susceptibility locus for neurodevelopmental disorders) · chromosome 1q21.1 duplication syndrome · chromosome 1q21.1 duplication syndrome, isolated cases · dup(1)(q21.1) · trisomy 1q21.1

Data availability: 15 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 duplication of chromosome 1 › partial duplication of the long arm of chromosome 1 › chromosome 1q21.1 duplication syndrome

Related subtypes (1): trisomy 1q

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

15 retrieved; paginated sample, class counts are floors:

15 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1690369	NC_000001.11:g.(146472798_148439081)dup		Pathogenic	criteria provided, single submitter
1330159	GRCh37/hg19 1q21.1-21.2(chr1:146022474-147599371)x3	ACP6	Pathogenic	criteria provided, single submitter
1679693	Single allele	ACP6	Pathogenic	criteria provided, single submitter
1703633	GRCh37/hg19 1q21.1-21.2(chr1:145768022-148020154)	ACP6	Pathogenic	no assertion criteria provided
1703634	GRCh37/hg19 1q21.1-21.2(chr1:145808308-147819294)	ACP6	Pathogenic	no assertion criteria provided
3242445	GRCh38/hg38 1q21.1-21.2(chr1:146387442-148577050)x3	ACP6	Pathogenic	criteria provided, single submitter
625536	GRCh37/hg19 1q21.1-21.2(chr1:145015937-147416122)	ACP6	Pathogenic	criteria provided, single submitter
625538	GRCh37/hg19 1q21.1-21.2(chr1:145765424-147142037)	ACP6	Pathogenic	criteria provided, single submitter
1703635	GRCh37/hg19 1q21.1-21.2(chr1:146043713-147830830)	BCL9	Pathogenic	no assertion criteria provided
2506525	GRCh37/hg19 1q21.1-21.2(chr1:146465878-147416212)	BCL9	Pathogenic	criteria provided, single submitter
2580317	GRCh37/hg19 1q12-23.1(chr1:142535935-157648813)x3	ENSA	Pathogenic	criteria provided, single submitter
625537	GRCh37/hg19 1q21.1-21.2(chr1:145103956-147220326)	FMO5	Pathogenic	criteria provided, single submitter
666434	GRCh37/hg19 1q21.1-21.2(chr1:145804679-147735815)x3	GPHRB	Pathogenic	criteria provided, single submitter
625818	GRCh37/hg19 1q21.1-21.2(chr1:145740598-147825678)	NBPF12	Pathogenic	criteria provided, single submitter
225520	GRCh37/hg19 1q21.1-21.3(chr1:144927578-153223600)x3	SPRR1B	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

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

Cohort genes → proteins

7 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BCL9	HGNC:1008	ENSG00000116128	O00512	B-cell CLL/lymphoma 9 protein	clinvar
SPRR1B	HGNC:11260	ENSG00000169469	P22528	Cornifin-B	clinvar
GPHRB	HGNC:13840	ENSG00000188092	P0CG08	Golgi pH regulator B	clinvar
NBPF12	HGNC:24297	ENSG00000268043	Q5TAG4	NBPF family member NBPF12	clinvar
ACP6	HGNC:29609	ENSG00000162836	Q9NPH0	Lysophosphatidic acid phosphatase type 6	clinvar
ENSA	HGNC:3360	ENSG00000143420	O43768	Alpha-endosulfine	clinvar
FMO5	HGNC:3773	ENSG00000131781	P49326	Flavin-containing monooxygenase 5	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BCL9	B-cell CLL/lymphoma 9 protein	Involved in signal transduction through the Wnt pathway.
SPRR1B	Cornifin-B	Cross-linked envelope protein of keratinocytes.
GPHRB	Golgi pH regulator B	Voltage-gated channel that enables the transfer of anions such as iodide, chloride, bromide and fluoride which may function in counter-ion conductance and participates in Golgi acidification.
ACP6	Lysophosphatidic acid phosphatase type 6	Hydrolyzes lysophosphatidic acid (LPA) containing a medium length fatty acid chain to the corresponding monoacylglycerol.
ENSA	Alpha-endosulfine	Protein phosphatase inhibitor that specifically inhibits protein phosphatase 2A (PP2A) during mitosis.
FMO5	Flavin-containing monooxygenase 5	Acts as a Baeyer-Villiger monooxygenase on a broad range of substrates.

Protein-family classification

Druggable: 3 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.43

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
Phosphatase	1	12.0×	0.403
GPCR	1	3.4×	0.646
Enzyme (other)	1	1.7×	0.744
Transcription factor	1	1.2×	0.744
Other/Unknown	3	0.8×	0.858

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BCL9	Transcription factor	no		Znf_RING/FYVE/PHD, Bcl-9/Bcl-9l, BCL9_beta-catenin-bd_dom
SPRR1B	Other/Unknown	no
GPHRB	GPCR	yes		GPHR/GTG, Golgi_pH-regulator_cons_dom, ABA_GPCR_dom
NBPF12	Other/Unknown	no		Olduvai_dom, NBPF
ACP6	Phosphatase	yes	3.1.3.106	His_Pase_clade-2, His_PPase_superfam, Acid_Pase_AS
ENSA	Other/Unknown	no		Endosulphine
FMO5	Enzyme (other)	yes	1.14.13.8	Flavin_mOase, Flavin_mOase_5, Flavin_mOase-like

Expression context

Cohort genes with no expression data: 0.

7 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cervix squamous epithelium	2
cortical plate	1
ganglionic eminence	1
ventricular zone	1
amniotic fluid	1
gingiva	1
corpus callosum	1
duodenum	1
male germ line stem cell (sensu Vertebrata) in testis	1
body of stomach	1
stomach	1
sural nerve	1
mucosa of stomach	1
pancreatic ductal cell	1
right uterine tube	1
esophagus squamous epithelium	1
tongue squamous epithelium	1
liver	1
rectum	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BCL9	198	ubiquitous	marker	cortical plate, ganglionic eminence, ventricular zone
SPRR1B	175	broad	marker	amniotic fluid, gingiva, cervix squamous epithelium
GPHRB	134	not_expressed	marker	male germ line stem cell (sensu Vertebrata) in testis, duodenum, corpus callosum
NBPF12	134	broad	marker	sural nerve, body of stomach, stomach
ACP6	257	ubiquitous	marker	right uterine tube, pancreatic ductal cell, mucosa of stomach
ENSA	303	ubiquitous	marker	cervix squamous epithelium, esophagus squamous epithelium, tongue squamous epithelium
FMO5	211	broad	marker	right lobe of liver, liver, rectum

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FMO5	1,768
ENSA	1,146
BCL9	963
ACP6	785
SPRR1B	685
NBPF12	349
GPHRB	308

Intra-cohort edges

A	B	Sources
ACP6	BCL9	string_interaction
ACP6	FMO5	string_interaction
ACP6	NBPF12	string_interaction
BCL9	FMO5	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 5 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BCL9	O00512	8
ACP6	Q9NPH0	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FMO5	P49326	95.03
GPHRB	P0CG08	82.78
SPRR1B	P22528	70.02
ENSA	O43768	67.74
NBPF12	Q5TAG4	45.84

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 7 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
MASTL Facilitates Mitotic Progression	1	285.5×	0.035	ENSA
Synthesis of PA	1	73.2×	0.057	ACP6
Deactivation of the beta-catenin transactivating complex	1	58.3×	0.057	BCL9
Formation of the beta-catenin:TCF transactivating complex	1	30.1×	0.059	BCL9
TCF dependent signaling in response to WNT	1	29.4×	0.059	BCL9
Signaling by WNT	1	28.0×	0.059	BCL9
Formation of the cornified envelope	1	22.0×	0.064	SPRR1B
Keratinization	1	13.9×	0.087	SPRR1B
Developmental Biology	1	3.6×	0.277	SPRR1B
Signal Transduction	1	2.5×	0.339	BCL9

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
lysobisphosphatidic acid metabolic process	1	1404.3×	0.019	ACP6
myotube differentiation involved in skeletal muscle regeneration	1	561.7×	0.023	BCL9
peptide cross-linking	1	234.1×	0.028	SPRR1B
intracellular pH reduction	1	200.6×	0.028	GPHRB
regulation of cholesterol metabolic process	1	187.2×	0.028	FMO5
myoblast differentiation	1	140.4×	0.031	BCL9
phosphatidic acid biosynthetic process	1	85.1×	0.039	ACP6
regulation of insulin secretion	1	65.3×	0.039	ENSA
T cell differentiation	1	63.8×	0.039	GPHRB
phospholipid metabolic process	1	57.3×	0.039	ACP6
skeletal muscle cell differentiation	1	57.3×	0.039	BCL9
G2/M transition of mitotic cell cycle	1	52.0×	0.039	ENSA
response to nutrient	1	49.3×	0.039	ENSA
keratinocyte differentiation	1	41.3×	0.039	SPRR1B
somatic stem cell population maintenance	1	41.3×	0.039	BCL9
hematopoietic progenitor cell differentiation	1	39.6×	0.039	ACP6
keratinization	1	39.0×	0.039	SPRR1B
epidermis development	1	35.1×	0.041	SPRR1B
canonical Wnt signaling pathway	1	25.5×	0.051	BCL9
xenobiotic metabolic process	1	24.9×	0.051	FMO5
mitotic cell cycle	1	22.3×	0.055	ENSA
lipid metabolic process	1	15.3×	0.075	FMO5
transcription by RNA polymerase II	1	11.8×	0.093	BCL9
cell division	1	7.7×	0.133	ENSA
protein transport	1	7.3×	0.134	GPHRB
positive regulation of transcription by RNA polymerase II	1	2.5×	0.341	BCL9

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 6

Druggability breadth: 2 of 7 evidence-associated genes (29%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BCL9	1	3
SPRR1B	0	0
GPHRB	0	0
NBPF12	0	0
ACP6	0	0
ENSA	0	0
FMO5	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
QUERCETIN	3	BCL9

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
BCL9	125	Binding:125
FMO5	14	ADMET:14

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ACP6	3.1.3.106	2-lysophosphatidate phosphatase
FMO5	1.14.13.8	flavin-containing monooxygenase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
BCL9	125

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
QUERCETIN	3	BCL9

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	1	BCL9
C	Druggable family + PDB, no drug	1	ACP6
D	Druggable family + AlphaFold only, no drug	2	GPHRB, FMO5
E	Difficult family or no structure, no drug	3	SPRR1B, NBPF12, ENSA

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SPRR1B	0	—
GPHRB	0	—
NBPF12	0	—
ACP6	0	—
ENSA	0	—
FMO5	14	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01238250	Not specified	RECRUITING	Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight