Distal 16p11.2 microdeletion syndrome

Summary

Distal 16p11.2 microdeletion syndrome (MONDO:0013267) is a disease with 6 cohort genes. The dominant Reactome pathway is Hemostasis (3 cohort genes).

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 6
• ClinVar variants: 19
• Phenotypes (HPO): 26

Clinical features

Signs & symptoms

Clinical features (HPO)

26 HPO clinical features (Orphanet curated; top 26 by frequency):

HPO ID	Term	Frequency
HP:0000160	Narrow mouth	Very frequent (80-99%)
HP:0000294	Low anterior hairline	Very frequent (80-99%)
HP:0000300	Oval face	Very frequent (80-99%)
HP:0000426	Prominent nasal bridge	Very frequent (80-99%)
HP:0000510	Rod-cone dystrophy	Very frequent (80-99%)
HP:0000556	Retinal dystrophy	Very frequent (80-99%)
HP:0000750	Delayed speech and language development	Very frequent (80-99%)
HP:0001166	Arachnodactyly	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001319	Neonatal hypotonia	Very frequent (80-99%)
HP:0007018	Attention deficit hyperactivity disorder	Very frequent (80-99%)
HP:0000076	Vesicoureteral reflux	Frequent (30-79%)
HP:0000077	Abnormality of the kidney	Frequent (30-79%)
HP:0000093	Proteinuria	Frequent (30-79%)
HP:0000104	Renal agenesis	Frequent (30-79%)
HP:0000729	Autistic behavior	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001513	Obesity	Frequent (30-79%)
HP:0002149	Hyperuricemia	Frequent (30-79%)
HP:0002251	Aganglionic megacolon	Frequent (30-79%)
HP:0011351	Moderate receptive language delay	Frequent (30-79%)
HP:0012450	Chronic constipation	Frequent (30-79%)
HP:0012622	Chronic kidney disease	Frequent (30-79%)
HP:0002076	Migraine	Occasional (5-29%)
HP:0002808	Kyphosis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	distal 16p11.2 microdeletion syndrome
Mondo ID	MONDO:0013267
OMIM	613444
Orphanet	261222
DOID	DOID:0060398
SNOMED CT	733521003
UMLS	C3150701
MedGen	462051
GARD	0017244
Is cancer (heuristic)	no

Also known as: body mass index QTL16 · chromosome 16p11.2 deletion syndrome, type 220kb · distal 16p11.2 microdeletion syndrome · distal del(16)(p11.2) · distal monosomy 16p11.2

Data availability: 19 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 16 › partial deletion of the short arm of chromosome 16 › distal 16p11.2 microdeletion syndrome

Related subtypes (8): chromosome 16p12.1 deletion syndrome, 520kb, alpha thalassemia-intellectual disability syndrome type 1, autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis, proximal 16p11.2 microdeletion syndrome, chromosome 16p12.2-p11.2 deletion syndrome, 16p13.11 microdeletion syndrome, chromosome 16p13.3 deletion syndrome, Hao-Fountain syndrome due to 16p13.2 microdeletion

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

19 retrieved; paginated sample, class counts are floors:

16 pathogenic, 2 likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1330158	GRCh37/hg19 16p11.2(chr16:29675000-30199844)x1	ALDOA	Pathogenic	criteria provided, single submitter
1330166	GRCh37/hg19 16p11.2(chr16:29511270-30200335)x1	ALDOA	Pathogenic	criteria provided, single submitter
1330167	GRCh37/hg19 16p11.2(chr16:29464904-30233799)x3	ALDOA	Pathogenic	criteria provided, single submitter
1330182	GRCh37/hg19 16p11.2(chr16:29511270-30199844)x1	ALDOA	Pathogenic	criteria provided, single submitter
1330208	GRCh37/hg19 16p11.2(chr16:29675000-30200335)x3	ALDOA	Pathogenic	criteria provided, single submitter
2580320	GRCh37/hg19 16p11.2(chr16:29517464-30200058)x3	ALDOA	Pathogenic	criteria provided, single submitter
2580331	GRCh37/hg19 16p11.2(chr16:29517464-30199839)x1	ALDOA	Pathogenic	criteria provided, single submitter
2580337	GRCh37/hg19 16p11.2(chr16:29517464-30200058)x1	ALDOA	Pathogenic	criteria provided, single submitter
3765501	NC_000016.10:g.29663719_30188586del	ALDOA	Pathogenic	no assertion criteria provided
1703567	GRCh37/hg19 16p11.2(chr16:28349949-29342589)	APOBR	Pathogenic	no assertion criteria provided
1330187	GRCh37/hg19 16p11.2(chr16:28784627-29230353)x1	ATP2A1	Pathogenic	criteria provided, single submitter
1679691	Single allele	ATP2A1	Pathogenic	criteria provided, single submitter
1703523	GRCh37/hg19 16p11.2(chr16:28689085-29051191)	ATP2A1	Pathogenic	no assertion criteria provided
2580325	GRCh37/hg19 16p11.2(chr16:28834531-29001678)x1	ATP2A1	Pathogenic	criteria provided, single submitter
625600	GRCh37/hg19 16p11.2(chr16:28529940-28906458)	ATP2A1	Pathogenic	criteria provided, single submitter
625601	GRCh37/hg19 16p11.2(chr16:28734571-29043450)	ATXN2L	Pathogenic	criteria provided, single submitter
1330173	GRCh37/hg19 16p11.2(chr16:28353878-29478115)x3	APOBR	Likely pathogenic	criteria provided, single submitter
1330157	GRCh37/hg19 16p11.2(chr16:29974415-30596982)x1	HIRIP3	Likely pathogenic	criteria provided, single submitter
929780	NM_001387430.1(SH2B1):c.1846T>C (p.Ser616Pro)	SH2B1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SH2B1	Orphanet:261197	Proximal 16p11.2 microdeletion syndrome
SH2B1	Orphanet:261222	Distal 16p11.2 microdeletion syndrome
SH2B1	Orphanet:329249	Severe early-onset obesity-insulin resistance syndrome due to SH2B1 deficiency
ALDOA	Orphanet:57	Glycogen storage disease due to aldolase A deficiency
ATP2A1	Orphanet:53347	Brody myopathy

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
APOBR	HGNC:24087	ENSG00000184730	Q0VD83	Apolipoprotein B receptor	clinvar
SH2B1	HGNC:30417	ENSG00000178188	Q9NRF2	SH2B adapter protein 1	clinvar
ATXN2L	HGNC:31326	ENSG00000168488	Q8WWM7	Ataxin-2-like protein	clinvar
ALDOA	HGNC:414	ENSG00000149925	P04075	Fructose-bisphosphate aldolase A	clinvar
HIRIP3	HGNC:4917	ENSG00000149929	Q9BW71	HIRA-interacting protein 3	clinvar
ATP2A1	HGNC:811	ENSG00000196296	O14983	Sarcoplasmic/endoplasmic reticulum calcium ATPase 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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).
SH2B1	SH2B adapter protein 1	Adapter protein for several members of the tyrosine kinase receptor family.
ATXN2L	Ataxin-2-like protein	Involved in the regulation of stress granule and P-body formation.
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.
HIRIP3	HIRA-interacting protein 3	Histone chaperone that carries a H2A-H2B histone complex and facilitates its deposition onto chromatin.
ATP2A1	Sarcoplasmic/endoplasmic reticulum calcium ATPase 1	Key regulator of striated muscle performance by acting as the major Ca(2+) ATPase responsible for the reuptake of cytosolic Ca(2+) into the sarcoplasmic reticulum.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 3 · Druggable fraction: 0.17

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
Scaffold/PPI	1	2.9×	0.719
Enzyme (other)	1	2.0×	0.719
Transcription factor	1	1.4×	0.719
Other/Unknown	3	0.9×	0.758

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
APOBR	Other/Unknown	no		ApolipoprotB_rcpt
SH2B1	Scaffold/PPI	no		SH2, PH_domain, PH-like_dom_sf
ATXN2L	Other/Unknown	no		LsmAD_domain, PAM2_motif, SM_dom_ATX
ALDOA	Enzyme (other)	yes	4.1.2.13	FBA_I, Aldolase_TIM, Aldolase_I_AS
HIRIP3	Other/Unknown	no		Histone_chaperone_domain_CHZ, HIRIP3
ATP2A1	Transcription factor	no		P_typ_ATPase, ATPase_P-typ_cation-transptr_N, P-type_ATPase_IIA

Expression context

Cohort genes with no expression data: 0.

6 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right hemisphere of cerebellum	2
left testis	2
right testis	2
hindlimb stylopod muscle	2
granulocyte	1
monocyte	1
mononuclear cell	1
cerebellar cortex	1
cerebellar hemisphere	1
gastrocnemius	1
skeletal muscle tissue	1
oocyte	1
diaphragm	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
APOBR	160	broad	marker	monocyte, mononuclear cell, granulocyte
SH2B1	253	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
ATXN2L	273	ubiquitous	marker	left testis, right testis, right hemisphere of cerebellum
ALDOA	134	ubiquitous	marker	skeletal muscle tissue, gastrocnemius, hindlimb stylopod muscle
HIRIP3	278	ubiquitous	marker	oocyte, left testis, right testis
ATP2A1	185	tissue_specific	marker	hindlimb stylopod muscle, skeletal muscle tissue of rectus abdominis, diaphragm

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALDOA	3,591
ATP2A1	2,809
ATXN2L	2,427
APOBR	1,258
SH2B1	1,123
HIRIP3	778

Intra-cohort edges

A	B	Sources
APOBR	ATXN2L	string_interaction
APOBR	SH2B1	string_interaction
ATP2A1	ATXN2L	string_interaction
ATXN2L	SH2B1	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ALDOA	P04075	8
SH2B1	Q9NRF2	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ATP2A1	O14983	88.65
HIRIP3	Q9BW71	60.04
ATXN2L	Q8WWM7	49.52
APOBR	Q0VD83	41.14

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 32. Enrichment computed across 6 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
Hemostasis	3	27.0×	0.003	SH2B1, ALDOA, ATP2A1
VLDL clearance	1	475.8×	0.024	APOBR
Signaling by Leptin	1	259.6×	0.024	SH2B1
Reduction of cytosolic Ca++ levels	1	237.9×	0.024	ATP2A1
Glucose metabolism	1	219.6×	0.024	ALDOA
Prolactin receptor signaling	1	190.3×	0.024	SH2B1
Platelet calcium homeostasis	1	178.4×	0.024	ATP2A1
Pre-NOTCH Processing in Golgi	1	158.6×	0.024	ATP2A1
Plasma lipoprotein clearance	1	119.0×	0.024	APOBR
Growth hormone receptor signaling	1	119.0×	0.024	SH2B1
Gluconeogenesis	1	109.8×	0.024	ALDOA
Transport of small molecules	2	12.6×	0.024	APOBR, ATP2A1
Pre-NOTCH Expression and Processing	1	92.1×	0.027	ATP2A1
Glycolysis	1	71.4×	0.030	ALDOA
Platelet homeostasis	1	69.6×	0.030	ATP2A1
Plasma lipoprotein assembly, remodeling, and clearance	1	57.1×	0.035	APOBR
Ion transport by P-type ATPases	1	51.9×	0.035	ATP2A1
Ion homeostasis	1	51.0×	0.035	ATP2A1
Signaling by NOTCH	1	43.9×	0.038	ATP2A1
Response to elevated platelet cytosolic Ca2+	1	40.8×	0.039	ALDOA
Metabolism of carbohydrates and carbohydrate derivatives	1	30.1×	0.050	ALDOA
Cardiac conduction	1	27.2×	0.052	ATP2A1
Platelet activation, signaling and aggregation	1	26.4×	0.052	ALDOA
Ion channel transport	1	24.0×	0.055	ATP2A1
Platelet degranulation	1	22.0×	0.057	ALDOA
Muscle contraction	1	19.3×	0.063	ATP2A1
Factors involved in megakaryocyte development and platelet production	1	16.6×	0.070	SH2B1
Innate Immune System	1	6.4×	0.169	ALDOA
Neutrophil degranulation	1	5.8×	0.179	ALDOA
Immune System	1	3.2×	0.293	ALDOA

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
maintenance of mitochondrion location	1	2808.7×	0.005	ATP2A1
positive regulation of fast-twitch skeletal muscle fiber contraction	1	1404.3×	0.005	ATP2A1
foam cell differentiation	1	1404.3×	0.005	APOBR
positive regulation of ATPase-coupled calcium transmembrane transporter activity	1	1404.3×	0.005	ATP2A1
positive regulation of calcium ion import into sarcoplasmic reticulum	1	1404.3×	0.005	ATP2A1
positive regulation of endoplasmic reticulum calcium ion concentration	1	936.2×	0.005	ATP2A1
negative regulation of striated muscle contraction	1	936.2×	0.005	ATP2A1
relaxation of skeletal muscle	1	936.2×	0.005	ATP2A1
positive regulation of cardiac muscle cell contraction	1	936.2×	0.005	ATP2A1
calcium ion import into sarcoplasmic reticulum	1	936.2×	0.005	ATP2A1
negative regulation of endoplasmic reticulum calcium ion concentration	1	468.1×	0.009	ATP2A1
regulation of striated muscle contraction	1	351.1×	0.010	ATP2A1
fructose 1,6-bisphosphate metabolic process	1	351.1×	0.010	ALDOA
regulation of DNA biosynthetic process	1	312.1×	0.010	SH2B1
fructose metabolic process	1	280.9×	0.010	ALDOA
mRNA metabolic process	1	280.9×	0.010	ATXN2L
positive regulation of mitochondrial calcium ion concentration	1	280.9×	0.010	ATP2A1
ATP biosynthetic process	1	165.2×	0.015	ALDOA
apoptotic mitochondrial changes	1	147.8×	0.016	ATP2A1
striated muscle contraction	1	140.4×	0.016	ALDOA
regulation of cardiac conduction	1	140.4×	0.016	ATP2A1
calcium ion import	1	133.8×	0.016	ATP2A1
canonical glycolysis	1	117.0×	0.017	ALDOA
muscle cell cellular homeostasis	1	108.0×	0.018	ALDOA
stress granule assembly	1	100.3×	0.018	ATXN2L
positive regulation of mitotic nuclear division	1	90.6×	0.019	SH2B1
intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	1	80.2×	0.021	ATP2A1
triglyceride metabolic process	1	73.9×	0.021	APOBR
lamellipodium assembly	1	73.9×	0.021	SH2B1
binding of sperm to zona pellucida	1	70.2×	0.022	ALDOA

Therapeutics

Drug target analysis

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

Druggability breadth: 4 of 6 evidence-associated genes (67%) 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
HIRIP3	1	2
APOBR	0	0
SH2B1	0	0
ATXN2L	0	0
ATP2A1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	ALDOA, HIRIP3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ALDOA	9	Binding:9
HIRIP3	7	Binding:7
ATP2A1	6	Binding:6
ATXN2L	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALDOA	4.1.2.13	fructose-bisphosphate aldolase

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; 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, HIRIP3

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	2	ALDOA, HIRIP3
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	APOBR, SH2B1, ATXN2L, ATP2A1

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)
APOBR	0	—
SH2B1	0	—
ATXN2L	1	—
ATP2A1	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.