HECW2

Chr 2AD

HECT, C2 and WW domain containing E3 ubiquitin protein ligase 2

Also known as: NDHSAL, NEDL2

NCBI Gene: 57520ENSG00000138411UniProt: Q9P2P5

This gene encodes a member of a family of E3 ubiquitin ligases which plays an important role in the proliferation, migration and differentiation of neural crest cells as a regulator of glial cell line-derived neurotrophic factor (GDNF)/Ret signaling. This gene also plays an important role in angiogenesis through stabilization of endothelial cell-to-cell junctions as a regulator of angiomotin-like 1 stability. The encoded protein contains an N-terminal calcium/lipid-binding (C2) domain involved in membrane targeting, two-four WW domains responsible for cellular localization and substrate recognition, and a C-terminal homologous with E6-associated protein C-terminus (HECT) catalytic domain. Naturally occurring mutations in this gene are associated with neurodevelopmental delay, hypotonia, and epilepsy. The decreased expression of this gene in the aganglionic colon is associated with Hirschsprung's disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2017]

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with hypotonia, seizures, and absent languageMIM #617268
AD
563
ClinVar variants
70
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— HECW2
🧬
Gene-Disease Validity (ClinGen)
complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
70 Pathogenic / Likely Pathogenic· 314 VUS of 563 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.26LOEUF
pLI 1.000
Z-score 6.98
OE 0.16 (0.10–0.26)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
3.31Z-score
OE missense 0.69 (0.65–0.74)
625 obs / 904.8 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.16 (0.10–0.26)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.69 (0.65–0.74)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.95
0≤1.21.6
LoF obs/exp: 13 / 80.6Missense obs/exp: 625 / 904.8Syn Z: 0.78

ClinVar Variant Classifications

563 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic41
Likely Pathogenic29
VUS314
Likely Benign133
Benign28
Conflicting18
41
Pathogenic
29
Likely Pathogenic
314
VUS
133
Likely Benign
28
Benign
18
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
6
34
0
41
Likely Pathogenic
0
27
2
0
29
VUS
10
274
25
5
314
Likely Benign
0
65
16
52
133
Benign
0
8
8
12
28
Conflicting
—18
Total113808569563

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

HECW2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

HECW2-related neurodevelopmental disorder (biallelic)

limited
ARUndeterminedDecreased Gene Product Level
Dev. Disorders
G2P ↗

HECW2-related neurodevelopmental disorder (monoallelic)

definitive
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Neurodevelopmental disorder with hypotonia, seizures, and absent language

MIM #617268

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Delineating the genotypic and phenotypic spectrum of HECW2-related neurodevelopmental disorders.
Acharya A et al.·J Med Genet
2022Review
Association of HECW2 variants with developmental and epileptic encephalopathy and knockdown of zebrafish hecw2a.
Lu Q et al.·Am J Med Genet A
2021Functional
A homozygous nonsense HECW2 variant is associated with neurodevelopmental delay and intellectual disability.
Krami AM et al.·Eur J Med Genet
2022Case report
First splicing variant in HECW2 with an autosomal recessive pattern of inheritance and associated with NDHSAL.
Rodríguez-García ME et al.·Hum Mutat
2022Case report
Mechanism of Circ_HECW2 regulating osteoblast apoptosis in osteoporosis by attenuating the maturation of miR-1224-5p.
Zhang C et al.·J Orthop Surg Res
2024Functional
A De Novo HECW2 Variant in a Patient with Acetazolamide-Responsive Episodic Ataxia.
Tedesco Silva LM et al.·Cerebellum
2023Case report
Mutations in HECW2 are associated with intellectual disability and epilepsy.
Halvardson J et al.·J Med Genet
2016
A novel likely pathogenic heterozygous HECW2 missense variant in a family with variable expressivity of neurodevelopmental delay, hypotonia, and epileptiform EEG patterns.
Heide EC et al.·Am J Med Genet A
2021Case report
HECW2-related disorder in four Japanese patients.
Yanagishita T et al.·Am J Med Genet A
2021Cohort
De novo missense variants in HECW2 are associated with neurodevelopmental delay and hypotonia.
Berko ER et al.·J Med Genet
2017
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10

External Resources

Links to major genomics databases and tools