Chromosome 1q21.1 deletion syndrome

Summary

Chromosome 1q21.1 deletion syndrome (MONDO:0012914) is a disease with 5 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 5
• ClinVar variants: 20
• Phenotypes (HPO): 47

Clinical features

Signs & symptoms

Clinical features (HPO)

47 HPO clinical features (Orphanet curated; top 47 by frequency):

HPO ID	Term	Frequency
HP:0000218	High palate	Frequent (30-79%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000286	Epicanthus	Frequent (30-79%)
HP:0000343	Long philtrum	Frequent (30-79%)
HP:0000414	Bulbous nose	Frequent (30-79%)
HP:0000431	Wide nasal bridge	Frequent (30-79%)
HP:0000490	Deeply set eye	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0002007	Frontal bossing	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0000023	Inguinal hernia	Occasional (5-29%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000076	Vesicoureteral reflux	Occasional (5-29%)
HP:0000126	Hydronephrosis	Occasional (5-29%)
HP:0000238	Hydrocephalus	Occasional (5-29%)
HP:0000407	Sensorineural hearing impairment	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0000568	Microphthalmia	Occasional (5-29%)
HP:0000612	Iris coloboma	Occasional (5-29%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000717	Autism	Occasional (5-29%)
HP:0000739	Anxiety	Occasional (5-29%)
HP:0001161	Hand polydactyly	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001274	Agenesis of corpus callosum	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0001511	Intrauterine growth retardation	Occasional (5-29%)
HP:0001643	Patent ductus arteriosus	Occasional (5-29%)
HP:0001671	Abnormal cardiac septum morphology	Occasional (5-29%)
HP:0001762	Talipes equinovarus	Occasional (5-29%)
HP:0001770	Toe syndactyly	Occasional (5-29%)
HP:0001773	Short foot	Occasional (5-29%)
HP:0001829	Foot polydactyly	Occasional (5-29%)
HP:0002360	Sleep abnormality	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0004209	Clinodactyly of the 5th finger	Occasional (5-29%)
HP:0007018	Attention deficit hyperactivity disorder	Occasional (5-29%)
HP:0008499	High hypermetropia	Occasional (5-29%)
HP:0010059	Broad hallux phalanx	Occasional (5-29%)
HP:0010296	Ankyloglossia	Occasional (5-29%)
HP:0011304	Broad thumb	Occasional (5-29%)
HP:0011611	Interrupted aortic arch	Occasional (5-29%)
HP:0100753	Schizophrenia	Occasional (5-29%)
HP:0001382	Joint hypermobility	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	chromosome 1q21.1 deletion syndrome
Mondo ID	MONDO:0012914
MeSH	C567291
OMIM	612474
Orphanet	250989
DOID	DOID:0060411
SNOMED CT	699305004
UMLS	C2675897
MedGen	393913
GARD	0010813
Is cancer (heuristic)	no

Also known as: 1q21.1 microdeletion · 1q21.1 microdeletion syndrome · 1q21.1 recurrent microdeletion (susceptibility locus for neurodevelopmental disorders) · chromosome 1q21.1 deletion syndrome, isolated cases · chromosome 1q21.1 microdeletion syndrome · Del(1)(q21) · monosomy 1q21.1

Data availability: 20 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 deletion › partial deletion of chromosome 1 › chromosome 1q deletion › chromosome 1q21.1 deletion syndrome

Related subtypes (3): chromosome 1q41-q42 deletion syndrome, 1q44 microdeletion syndrome, distal monosomy 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

20 retrieved; paginated sample, class counts are floors:

13 pathogenic, 3 not provided, 2 uncertain significance, 1 likely benign, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1703630	GRCh37/hg19 1q21.1-21.2(chr1:146101790-147831000)	ACP6	Pathogenic	no assertion criteria provided
1703631	GRCh37/hg19 1q21.1-21.2(chr1:146145424-147929323)	ACP6	Pathogenic	no assertion criteria provided
1703632	GRCh37/hg19 1q21.1-21.2(chr1:146101790-147832190)	ACP6	Pathogenic	no assertion criteria provided
2580296	GRCh37/hg19 1q21.1-21.2(chr1:146474687-147415708)x1	ACP6	Pathogenic	criteria provided, single submitter
2580307	GRCh37/hg19 1q21.1-21.2(chr1:145883619-147594599)x1	ACP6	Pathogenic	criteria provided, single submitter
2580347	GRCh37/hg19 1q21.1-21.2(chr1:145883619-147817082)x3	ACP6	Pathogenic	criteria provided, single submitter
374371	Single allele	ACP6	Pathogenic	no assertion criteria provided
4528902	GRCh38/hg38 1q21.1-21.2(chr1:146231513-148358701)x3	ACP6	Pathogenic	criteria provided, single submitter
625652	GRCh37/hg19 1q21.1-21.2(chr1:146618988-147825678)	ACP6	Pathogenic	criteria provided, single submitter
625685	GRCh37/hg19 1q21.1-21.2(chr1:146560564-147416122)	ACP6	Pathogenic	criteria provided, single submitter
666433	GRCh37/hg19 1q21.1-21.2(chr1:146521698-147721869)x1	ACP6	Pathogenic	criteria provided, single submitter
2574675	GRCh37/hg19 1q21.1(chr1:145382123-145792051)	ANKRD34A	Pathogenic	no assertion criteria provided
2580306	GRCh37/hg19 1q21.1(chr1:145365275-145826979)x3	ANKRD34A	Pathogenic	criteria provided, single submitter
292448	NM_181703.4(GJA5):c.995G>A (p.Arg332His)	GJA5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
539329	NM_181703.4(GJA5):c.365C>T (p.Ser122Phe)	GJA5	Uncertain significance	criteria provided, multiple submitters, no conflicts
931889	NM_005267.5(GJA8):c.1033G>A (p.Glu345Lys)	GJA8	Uncertain significance	criteria provided, single submitter
217323	NM_005267.5(GJA8):c.658A>G (p.Asn220Asp)	GJA8	Likely benign	criteria provided, multiple submitters, no conflicts
684447	Single allele	ACP6	not provided	no classification provided
4279955	GRCh37/hg19 1q21.1(chr1:143983211-145985385)x3	ANKRD34A	not provided	no classification provided
1810322	GRCh37/hg19 1q21.1-21.2(chr1:146542843-147857135)x1	PRKAB2	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 8 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GJA5	Orphanet:3303	Tetralogy of Fallot
GJA5	Orphanet:334	Hereditary atrial fibrillation
GJA8	Orphanet:1377	Cataract-microcornea syndrome
GJA8	Orphanet:91490	Isolated congenital sclerocornea
GJA8	Orphanet:98984	Pulverulent cataract
GJA8	Orphanet:98985	Early-onset sutural cataract
GJA8	Orphanet:98991	Early-onset nuclear cataract
GJA8	Orphanet:98994	Total early-onset cataract

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ANKRD34A	HGNC:27639	ENSG00000272031	Q69YU3	Ankyrin repeat domain-containing protein 34A	clinvar
ACP6	HGNC:29609	ENSG00000162836	Q9NPH0	Lysophosphatidic acid phosphatase type 6	clinvar
GJA5	HGNC:4279	ENSG00000265107	P36382	Gap junction alpha-5 protein	clinvar
GJA8	HGNC:4281	ENSG00000121634	P48165	Gap junction alpha-8 protein	clinvar
PRKAB2	HGNC:9379	ENSG00000131791	O43741	5’-AMP-activated protein kinase subunit beta-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACP6	Lysophosphatidic acid phosphatase type 6	Hydrolyzes lysophosphatidic acid (LPA) containing a medium length fatty acid chain to the corresponding monoacylglycerol.
GJA5	Gap junction alpha-5 protein	One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.
GJA8	Gap junction alpha-8 protein	Structural component of eye lens gap junctions.
PRKAB2	5’-AMP-activated protein kinase subunit beta-2	Non-catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.4

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	16.8×	0.233
Kinase	1	5.5×	0.336
Scaffold/PPI	1	3.5×	0.344
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ANKRD34A	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf, AN34A/B/C
ACP6	Phosphatase	yes	3.1.3.106	His_Pase_clade-2, His_PPase_superfam, Acid_Pase_AS
GJA5	Other/Unknown	no		Connexin, Connexin40, Connexin_N
GJA8	Other/Unknown	no		Connexin, Connexin50_C, Connexin_N
PRKAB2	Kinase	yes	2.7.11.31	ASC_dom, Ig-like_fold, Ig_E-set

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)	1
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar hemisphere	1
prefrontal cortex	1
right hemisphere of cerebellum	1
mucosa of stomach	1
pancreatic ductal cell	1
right uterine tube	1
left coronary artery	1
placenta	1
right coronary artery	1
buccal mucosa cell	1
frontal pole	1
paraflocculus	1
biceps brachii	1
jejunal mucosa	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ANKRD34A	168	ubiquitous	yes	prefrontal cortex, right hemisphere of cerebellum, cerebellar hemisphere
ACP6	257	ubiquitous	marker	right uterine tube, pancreatic ductal cell, mucosa of stomach
GJA5	190	broad	marker	placenta, right coronary artery, left coronary artery
GJA8	17	tissue_specific	yes	buccal mucosa cell, frontal pole, paraflocculus
PRKAB2	274	ubiquitous	marker	jejunal mucosa, biceps brachii, skeletal muscle tissue of rectus abdominis

Protein interactions among cohort

Intra-cohort edges: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRKAB2	2,793
GJA5	1,476
ANKRD34A	1,162
GJA8	1,149
ACP6	785

Intra-cohort edges

A	B	Sources
ACP6	ANKRD34A	string_interaction
ACP6	GJA5	string_interaction
ACP6	GJA8	string_interaction
ACP6	PRKAB2	string_interaction
GJA5	PRKAB2	string_interaction
GJA8	PRKAB2	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PRKAB2	O43741	17
ACP6	Q9NPH0	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GJA5	P36382	70.35
GJA8	P48165	65.85
ANKRD34A	Q69YU3	57.86

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 35. Enrichment computed across 5 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
Gap junction assembly	2	146.4×	0.002	GJA5, GJA8
AMPK inhibits chREBP transcriptional activation activity	1	356.9×	0.031	PRKAB2
Lipophagy	1	317.2×	0.031	PRKAB2
Activation of PPARGC1A (PGC-1alpha) by phosphorylation	1	285.5×	0.031	PRKAB2
Carnitine shuttle	1	190.3×	0.037	PRKAB2
Energy dependent regulation of mTOR by LKB1-AMPK	1	98.5×	0.052	PRKAB2
Activation of AMPK downstream of NMDARs	1	95.2×	0.052	PRKAB2
Synthesis of PA	1	73.2×	0.052	ACP6
Selective autophagy	1	69.6×	0.052	PRKAB2
MTOR signalling	1	66.4×	0.052	PRKAB2
Post NMDA receptor activation events	1	51.0×	0.053	PRKAB2
AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)	1	48.4×	0.053	PRKAB2
Activation of NMDA receptors and postsynaptic events	1	46.0×	0.053	PRKAB2
Integration of energy metabolism	1	43.9×	0.053	PRKAB2
Mitochondrial biogenesis	1	42.0×	0.053	PRKAB2
Translocation of SLC2A4 (GLUT4) to the plasma membrane	1	38.6×	0.053	PRKAB2
Autophagy	1	37.1×	0.053	PRKAB2
Regulation of TP53 Activity	1	33.2×	0.053	PRKAB2
Fatty acid metabolism	1	32.8×	0.053	PRKAB2
TP53 Regulates Metabolic Genes	1	32.4×	0.053	PRKAB2
Regulation of TP53 Activity through Phosphorylation	1	29.4×	0.054	PRKAB2
Macroautophagy	1	28.8×	0.054	PRKAB2
Neurotransmitter receptors and postsynaptic signal transmission	1	25.0×	0.060	PRKAB2
Transmission across Chemical Synapses	1	19.0×	0.075	PRKAB2
Organelle biogenesis and maintenance	1	16.5×	0.083	PRKAB2
Transcriptional Regulation by TP53	1	15.5×	0.085	PRKAB2
Neuronal System	1	11.1×	0.113	PRKAB2
Membrane Trafficking	1	9.3×	0.130	PRKAB2
Vesicle-mediated transport	1	8.7×	0.133	PRKAB2
Metabolism of lipids	1	7.9×	0.141	PRKAB2

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mitral valve development	1	4213.0×	0.002	GJA5
septum primum development	1	4213.0×	0.002	GJA5
atrial ventricular junction remodeling	1	4213.0×	0.002	GJA5
positive regulation of cell communication by chemical coupling	1	4213.0×	0.002	GJA5
atrial cardiac muscle cell to AV node cell communication by electrical coupling	1	4213.0×	0.002	GJA5
Purkinje myocyte to ventricular cardiac muscle cell communication by electrical coupling	1	4213.0×	0.002	GJA5
regulation of Purkinje myocyte action potential	1	4213.0×	0.002	GJA5
regulation of renin secretion into blood stream	1	4213.0×	0.002	GJA5
vasomotion	1	4213.0×	0.002	GJA5
pulmonary valve formation	1	2106.5×	0.002	GJA5
cell communication by chemical coupling	1	2106.5×	0.002	GJA5
foramen ovale closure	1	2106.5×	0.002	GJA5
SA node cell to atrial cardiac muscle cell communication by electrical coupling	1	2106.5×	0.002	GJA5
AV node cell to bundle of His cell communication by electrical coupling	1	2106.5×	0.002	GJA5
bundle of His cell to Purkinje myocyte communication by electrical coupling	1	2106.5×	0.002	GJA5
regulation of bundle of His cell action potential	1	2106.5×	0.002	GJA5
lysobisphosphatidic acid metabolic process	1	2106.5×	0.002	ACP6
regulation of AV node cell action potential	1	1404.3×	0.002	GJA5
regulation of atrial cardiac muscle cell action potential	1	1404.3×	0.002	GJA5
negative regulation of glomerular filtration	1	1053.2×	0.003	GJA5
regulation of membrane depolarization during cardiac muscle cell action potential	1	1053.2×	0.003	GJA5
cell-cell signaling	2	34.8×	0.003	GJA5, GJA8
regulation of ventricular cardiac muscle cell membrane depolarization	1	702.2×	0.003	GJA5
SA node cell action potential	1	702.2×	0.003	GJA5
gap junction-mediated intercellular transport	1	702.2×	0.003	GJA8
regulation of cell communication by electrical coupling	1	601.9×	0.004	GJA5
atrial septum development	1	526.6×	0.004	GJA5
gap junction assembly	1	526.6×	0.004	GJA5
regulation of atrial cardiac muscle cell membrane depolarization	1	468.1×	0.004	GJA5
cell communication by electrical coupling involved in cardiac conduction	1	351.1×	0.006	GJA5

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 5 evidence-associated genes (20%) 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
PRKAB2	ADENOSINE PHOSPHATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRKAB2	2	4
ANKRD34A	0	0
ACP6	0	0
GJA5	0	0
GJA8	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ADENOSINE PHOSPHATE	4	PRKAB2
NARAZACICLIB	2	PRKAB2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PRKAB2	322	Binding:321, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ACP6	3.1.3.106	2-lysophosphatidate phosphatase
PRKAB2	2.7.11.31	[hydroxymethylglutaryl-CoA reductase (NADPH)] kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PRKAB2	322

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

2 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)
ADENOSINE PHOSPHATE	4	PRKAB2
NARAZACICLIB	2	PRKAB2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PRKAB2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ACP6
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	ANKRD34A, GJA5, GJA8

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ACP6	0	PRKAB2
ANKRD34A	0	—
GJA5	0	—
GJA8	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.