Chromosome 16p11.2 duplication syndrome

Summary

Chromosome 16p11.2 duplication syndrome (MONDO:0013847) is a disease with 8 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 8
• ClinVar variants: 17
• Phenotypes (HPO): 38
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		21	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

38 HPO clinical features (Orphanet curated; top 38 by frequency):

HPO ID	Term	Frequency
HP:0000219	Thin upper lip vermilion	Very frequent (80-99%)
HP:0000252	Microcephaly	Very frequent (80-99%)
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0000319	Smooth philtrum	Very frequent (80-99%)
HP:0000490	Deeply set eye	Very frequent (80-99%)
HP:0000653	Sparse eyelashes	Very frequent (80-99%)
HP:0000750	Delayed speech and language development	Very frequent (80-99%)
HP:0001166	Arachnodactyly	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001265	Hyporeflexia	Very frequent (80-99%)
HP:0001270	Motor delay	Very frequent (80-99%)
HP:0001337	Tremor	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0008551	Microtia	Very frequent (80-99%)
HP:0009088	Speech articulation difficulties	Very frequent (80-99%)
HP:0012368	Flat face	Very frequent (80-99%)
HP:0012751	Abnormal basal ganglia MRI signal intensity	Very frequent (80-99%)
HP:0045075	Sparse eyebrow	Very frequent (80-99%)
HP:0045082	Decreased body mass index	Very frequent (80-99%)
HP:0000722	Compulsive behaviors	Frequent (30-79%)
HP:0000729	Autistic behavior	Frequent (30-79%)
HP:0000739	Anxiety	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0007018	Attention deficit hyperactivity disorder	Frequent (30-79%)
HP:0030800	Abnormal visual accommodation	Frequent (30-79%)
HP:0000717	Autism	Occasional (5-29%)
HP:0000776	Congenital diaphragmatic hernia	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0002007	Frontal bossing	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0007302	Bipolar affective disorder	Occasional (5-29%)
HP:0009553	Abnormality of the hairline	Occasional (5-29%)
HP:0009891	Underdeveloped supraorbital ridges	Occasional (5-29%)
HP:0100753	Schizophrenia	Occasional (5-29%)
HP:0000054	Micropenis	Very rare (<1-4%)
HP:0002937	Hemivertebrae	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	chromosome 16p11.2 duplication syndrome
Mondo ID	MONDO:0013847
OMIM	614671
Orphanet	370079
DOID	DOID:0060430
SNOMED CT	765142003
UMLS	C3553407
MedGen	766321
GARD	0012388
Is cancer (heuristic)	no

Also known as: 16p11.2 duplication · 16p11.2 duplication syndrome · 16p11.2 microduplication · AUTS14B · chromosome 16p11.2 duplication syndrome · proximal 16p11.2 microduplication syndrome · proximal dup(16)(p11.2) · proximal trisomy 16p11.2 · susceptibility to autism, 14B

Data availability: 17 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 16 › partial duplication of the short arm of chromosome 16 › chromosome 16p11.2 duplication syndrome

Related subtypes (5): congenital cataracts-facial dysmorphism-neuropathy syndrome, chromosome 16p13.3 duplication syndrome, 16p11.2p12.2 microduplication syndrome, 16p13.11 microduplication syndrome, 16p12.1p12.3 triplication 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

ClinVar germline variants

17 retrieved; paginated sample, class counts are floors:

13 pathogenic, 4 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1703600	GRCh37/hg19 16p11.2(chr16:29628661-30306955)	ALDOA	Pathogenic	no assertion criteria provided
1703603	GRCh37/hg19 16p11.2(chr16:29591078-30177240)	ALDOA	Pathogenic	no assertion criteria provided
4279101	GRCh37/hg19 16p11.2(chr16:29690418-30200285)x2	ALDOA	Pathogenic	criteria provided, single submitter
4686714	GRCh37/hg19 16p11.2(chr16:29498472-30199909)x3	ALDOA	Pathogenic	criteria provided, single submitter
4279102	GRCh37/hg19 16p12.1-11.2(chr16:27078317-29001333)x2	APOBR	Pathogenic	criteria provided, single submitter
625608	GRCh37/hg19 16p11.2(chr16:29727054-29969912)	ASPHD1	Pathogenic	criteria provided, single submitter
1330201	GRCh37/hg19 16p11.2(chr16:29808153-30750270)x3	C16orf92	Pathogenic	criteria provided, single submitter
625604	GRCh37/hg19 16p11.2(chr16:29595483-30199713)	C16orf92	Pathogenic	criteria provided, single submitter
625610	GRCh37/hg19 16p11.2(chr16:29827174-30198041)	CDIPT	Pathogenic	criteria provided, single submitter
1703233	Single allele	KCTD13-DT	Pathogenic	criteria provided, single submitter
625603	GRCh37/hg19 16p11.2(chr16:29532264-30271237)	KIF22	Pathogenic	criteria provided, single submitter
4529470	GRCh38/hg38 16p11.2(chr16:29617341-30158191)x3	LOC130058782	Pathogenic	criteria provided, single submitter
625607	GRCh37/hg19 16p11.2(chr16:29678569-30199578)	MVP	Pathogenic	criteria provided, single submitter
1339950	GRCh37/hg19 16p11.2(chr16:29567295-30320307)x1	ALDOA	not provided	no classification provided
1810304	GRCh37/hg19 16p11.2(chr16:29670770-30207956)x3	ALDOA	not provided	no classification provided
4074287	GRCh37/hg19 16p11.2(chr16:29597822-30177240)x3	ALDOA	not provided	no classification provided
1339949	GRCh37/hg19 16p11.2(chr16:29591078-30177240)x3	C16orf92	not provided	no classification provided

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
ALDOA	Orphanet:57	Glycogen storage disease due to aldolase A deficiency
KIF22	Orphanet:93360	Spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type

Cohort genes → proteins

8 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CDIPT	HGNC:1769	ENSG00000103502	O14735	CDP-diacylglycerol–inositol 3-phosphatidyltransferase	clinvar
APOBR	HGNC:24087	ENSG00000184730	Q0VD83	Apolipoprotein B receptor	clinvar
FIMP1	HGNC:26346	ENSG00000167194	Q96LL3	Fertilization-influencing membrane protein	clinvar
ASPHD1	HGNC:27380	ENSG00000174939	Q5U4P2	Aspartate beta-hydroxylase domain-containing protein 1	clinvar
ALDOA	HGNC:414	ENSG00000149925	P04075	Fructose-bisphosphate aldolase A	clinvar
KCTD13-DT	HGNC:55585	ENSG00000247735		KCTD13 divergent transcript	clinvar
KIF22	HGNC:6391	ENSG00000079616	Q14807	Kinesin-like protein KIF22	clinvar
MVP	HGNC:7531	ENSG00000013364	Q14764	Major vault protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CDIPT	CDP-diacylglycerol–inositol 3-phosphatidyltransferase	Catalyzes the biosynthesis of phosphatidylinositol (PtdIns) as well as PtdIns:inositol exchange reaction.
APOBR	Apolipoprotein B receptor	Macrophage receptor that binds to the apolipoprotein B48 (APOB) of dietary triglyceride (TG)-rich lipoproteins (TRL) or to a like domain of APOB in hypertriglyceridemic very low density lipoprotein (HTG-VLDL).
FIMP1	Fertilization-influencing membrane protein	May play a role in sperm-oocyte fusion during fertilization.
ALDOA	Fructose-bisphosphate aldolase A	Catalyzes the reversible conversion of beta-D-fructose 1,6-bisphosphate (FBP) into two triose phosphate and plays a key role in glycolysis and gluconeogenesis.
KIF22	Kinesin-like protein KIF22	Kinesin family member that is involved in spindle formation and the movements of chromosomes during mitosis and meiosis.
MVP	Major vault protein	Required for normal vault structure.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 6 · Druggable fraction: 0.25

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
Enzyme (other)	2	3.0×	0.234
Other/Unknown	6	1.3×	0.234

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CDIPT	Enzyme (other)	yes	2.7.8.11	CDP-OH_P_trans, CDP_diag_ino_3_P_euk, CDP-OH_PTrfase_TM_dom
APOBR	Other/Unknown	no		ApolipoprotB_rcpt
FIMP1	Other/Unknown	no		FIMP
ASPHD1	Other/Unknown	no		Asp/Arg/Pro-Hydrxlase, IPNS-like_sf, Asp/Asn_beta-hydroxylase
ALDOA	Enzyme (other)	yes	4.1.2.13	FBA_I, Aldolase_TIM, Aldolase_I_AS
KCTD13-DT	Other/Unknown	no
KIF22	Other/Unknown	no		Kinesin_motor_dom, Hlx-hairpin-Hlx_DNA-bd_motif, RuvA_2-like
MVP	Other/Unknown	no		Vault_N, MVP_shoulder, Band_7/SPFH_dom_sf

Expression context

Cohort genes with no expression data: 0.

5 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)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	2
cervix squamous epithelium	1
endothelial cell	1
parotid gland	1
granulocyte	1
monocyte	1
mononuclear cell	1
left testis	1
right testis	1
C1 segment of cervical spinal cord	1
putamen	1
right frontal lobe	1
gastrocnemius	1
hindlimb stylopod muscle	1
skeletal muscle tissue	1
buccal mucosa cell	1
pancreatic ductal cell	1
ganglionic eminence	1
right lobe of thyroid gland	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CDIPT	299	ubiquitous	marker	parotid gland, endothelial cell, cervix squamous epithelium
APOBR	160	broad	marker	monocyte, mononuclear cell, granulocyte
FIMP1	114		yes	right testis, left testis, male germ line stem cell (sensu Vertebrata) in testis
ASPHD1	205	ubiquitous	yes	C1 segment of cervical spinal cord, putamen, right frontal lobe
ALDOA	134	ubiquitous	marker	skeletal muscle tissue, gastrocnemius, hindlimb stylopod muscle
KCTD13-DT	151		yes	buccal mucosa cell, male germ line stem cell (sensu Vertebrata) in testis, pancreatic ductal cell
KIF22	242	ubiquitous	marker	ventricular zone, ganglionic eminence, right lobe of thyroid gland
MVP	265	ubiquitous	marker	mucosa of transverse colon, right adrenal gland, left adrenal gland

Protein interactions among cohort

Intra-cohort edges: 5.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALDOA	3,591
CDIPT	3,399
KIF22	2,097
MVP	1,435
APOBR	1,258
ASPHD1	603
FIMP1	317
KCTD13-DT	0

Intra-cohort edges

A	B	Sources
ASPHD1	CDIPT	string_interaction
ASPHD1	FIMP1	string_interaction
ASPHD1	KIF22	string_interaction
CDIPT	KIF22	string_interaction
FIMP1	KIF22	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 4 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MVP	Q14764	20
ALDOA	P04075	8
KIF22	Q14807	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CDIPT	O14735	90.02
ASPHD1	Q5U4P2	76.01
FIMP1	Q96LL3	65.84
APOBR	Q0VD83	41.14

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 29. Enrichment computed across 8 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Synthesis of PI	1	456.8×	0.038	CDIPT
VLDL clearance	1	380.7×	0.038	APOBR
Immune System	3	7.8×	0.039	ALDOA, KIF22, MVP
Glucose metabolism	1	175.7×	0.041	ALDOA
Hemostasis	2	14.4×	0.042	ALDOA, KIF22
Plasma lipoprotein clearance	1	95.2×	0.046	APOBR
Gluconeogenesis	1	87.8×	0.046	ALDOA
Glycerophospholipid biosynthesis	1	67.2×	0.046	CDIPT
Glycolysis	1	57.1×	0.046	ALDOA
Innate Immune System	2	10.2×	0.046	ALDOA, MVP
Neutrophil degranulation	2	9.2×	0.046	ALDOA, MVP
Plasma lipoprotein assembly, remodeling, and clearance	1	45.7×	0.052	APOBR
Phospholipid metabolism	1	40.1×	0.055	CDIPT
Kinesins	1	35.7×	0.057	KIF22
Response to elevated platelet cytosolic Ca2+	1	32.6×	0.059	ALDOA
Golgi-to-ER retrograde transport	1	26.6×	0.067	KIF22
Metabolism of carbohydrates and carbohydrate derivatives	1	24.0×	0.068	ALDOA
COPI-dependent Golgi-to-ER retrograde traffic	1	22.2×	0.068	KIF22
Platelet activation, signaling and aggregation	1	21.1×	0.068	ALDOA
Intra-Golgi and retrograde Golgi-to-ER traffic	1	20.9×	0.068	KIF22
MHC class II antigen presentation	1	17.8×	0.073	KIF22
Platelet degranulation	1	17.6×	0.073	ALDOA
Metabolism	2	4.7×	0.078	CDIPT, ALDOA
Factors involved in megakaryocyte development and platelet production	1	13.3×	0.088	KIF22
Membrane Trafficking	1	7.4×	0.148	KIF22
Vesicle-mediated transport	1	7.0×	0.151	KIF22
Metabolism of lipids	1	6.3×	0.160	CDIPT
Adaptive Immune System	1	6.0×	0.162	KIF22
Transport of small molecules	1	5.0×	0.184	APOBR

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
CDP-diacylglycerol metabolic process	1	2808.7×	0.006	CDIPT
protein activation cascade	1	2808.7×	0.006	MVP
foam cell differentiation	1	1404.3×	0.008	APOBR
ERBB signaling pathway	1	561.7×	0.015	MVP
fructose 1,6-bisphosphate metabolic process	1	351.1×	0.019	ALDOA
fructose metabolic process	1	280.9×	0.020	ALDOA
metaphase chromosome alignment	1	175.5×	0.023	KIF22
ATP biosynthetic process	1	165.2×	0.023	ALDOA
striated muscle contraction	1	140.4×	0.023	ALDOA
sister chromatid cohesion	1	127.7×	0.023	KIF22
negative regulation of epidermal growth factor receptor signaling pathway	1	127.7×	0.023	MVP
canonical glycolysis	1	117.0×	0.023	ALDOA
muscle cell cellular homeostasis	1	108.0×	0.023	ALDOA
fusion of sperm to egg plasma membrane involved in single fertilization	1	93.6×	0.025	FIMP1
triglyceride metabolic process	1	73.9×	0.027	APOBR
binding of sperm to zona pellucida	1	70.2×	0.027	ALDOA
glycolytic process	1	63.8×	0.027	ALDOA
mitotic metaphase chromosome alignment	1	63.8×	0.027	KIF22
positive regulation of insulin secretion involved in cellular response to glucose stimulus	1	62.4×	0.027	ALDOA
phosphatidylinositol biosynthetic process	1	61.1×	0.027	CDIPT
fertilization	1	52.0×	0.030	FIMP1
microtubule-based movement	1	49.3×	0.030	KIF22
lipid transport	1	43.9×	0.031	APOBR
mRNA transport	1	43.9×	0.031	MVP
protein homotetramerization	1	39.6×	0.033	ALDOA
cholesterol metabolic process	1	32.7×	0.038	APOBR
mitotic cell cycle	1	22.3×	0.054	KIF22
regulation of cell shape	1	20.5×	0.056	ALDOA
actin filament organization	1	19.8×	0.056	ALDOA
cell population proliferation	1	17.1×	0.063	MVP

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 7

Druggability breadth: 3 of 8 evidence-associated genes (38%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ALDOA	1	2
CDIPT	0	0
APOBR	0	0
FIMP1	0	0
ASPHD1	0	0
KCTD13-DT	0	0
KIF22	0	0
MVP	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	ALDOA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
ALDOA	9	Binding:9
KIF22	4	Binding:4
CDIPT	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CDIPT	2.7.8.11	CDP-diacylglycerol-inositol 3-phosphatidyltransferase
ALDOA	4.1.2.13	fructose-bisphosphate aldolase

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)
MOLIBRESIB	2	ALDOA

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	ALDOA
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	CDIPT
E	Difficult family or no structure, no drug	6	APOBR, FIMP1, ASPHD1, KCTD13-DT, KIF22, MVP

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CDIPT	1	—
APOBR	0	—
FIMP1	0	—
ASPHD1	0	—
KCTD13-DT	0	—
KIF22	4	—
MVP	0	—

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