BHLHA9

Chr 17AR

basic helix-loop-helix family member a9

Also known as: BHLHF42, CCSPD

NCBI Gene: 727857ENSG00000205899UniProt: Q7RTU4

This gene is a member of the basic helix-loop-helix family. The encoded protein is a transcription factor involved in limb development. Mutations in this gene have been associated with mesoaxial synostotic syndactyly Malik-Percin type (MSSD). Copy number variation of a locus containing this gene has been linked to a form of split-hand/foot malformation with long bone deficiency (SHFLD3). [provided by RefSeq, Mar 2015]

Primary Disease Associations & Inheritance

?Camptosynpolydactyly, complexMIM #607539
AR
Syndactyly, mesoaxial synostotic, with phalangeal reductionMIM #609432
AR
UniProtSplit-hand/foot malformation with long bone deficiency 3
227
ClinVar variants
112
Pathogenic / LP
0.30
pLI score
0
Active trials
Clinical Summary— BHLHA9
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.00) despite low pLI — interpret in context.
📋
ClinVar Variants
112 Pathogenic / Likely Pathogenic· 80 VUS of 227 total submissions
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esummary.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
1.89LOEUF
pLI 0.296
Z-score 0.35
OE 0.00 (0.00–1.89)
Tolerant

Highly tolerant — LoF variants common in population

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.
0.02Z-score
OE missense 0.98 (0.65–1.53)
14 obs / 14.2 exp
Tolerant

Mild missense constraint

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.0.00 (0.00–1.89)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.98 (0.65–1.53)
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.1.55
0≤1.21.6
LoF obs/exp: 0 / 0.1Missense obs/exp: 14 / 14.2Syn Z: -1.16

ClinVar Variant Classifications

227 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic90
Likely Pathogenic22
VUS80
Likely Benign28
Benign3
Conflicting2
90
Pathogenic
22
Likely Pathogenic
80
VUS
28
Likely Benign
3
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
2
88
0
90
Likely Pathogenic
0
2
20
0
22
VUS
0
54
25
1
80
Likely Benign
0
4
8
16
28
Benign
0
0
1
2
3
Conflicting
—2
Total06214219225

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

View in ClinVar →

Protein Context — Lollipop Plot

BHLHA9 · protein map & ClinVar variants

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

Gene2Phenotype Curations

BHLHA9-related split hand and foot malformation

definitive
ADUndeterminedIncreased Gene Product Level
Dev. DisordersSkeletal
G2P ↗

BHLHA9-related mesoaxial synostotic syndactyly with phalangeal reduction, Malik-Percin type

definitive
ARDominant NegativeAltered Gene Product Structure
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Camptosynpolydactyly, complex

MIM #607539

Molecular basis of disorder known

Autosomal recessive

Syndactyly, mesoaxial synostotic, with phalangeal reduction

MIM #609432

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The duplication 17p13.3 phenotype: analysis of 21 families delineates developmental, behavioral and brain abnormalities, and rare variant phenotypes.
Curry CJ et al.·Am J Med Genet A
2013Case report
Genetic regulatory pathways of split-hand/foot malformation.
Kantaputra PN et al.·Clin Genet
2019Review
Bhlha9 regulates apical ectodermal ridge formation during limb development.
Kataoka K et al.·J Bone Miner Metab
2018
Japanese founder duplications/triplications involving BHLHA9 are associated with split-hand/foot malformation with or without long bone deficiency and Gollop-Wolfgang complex.
Nagata E et al.·Orphanet J Rare Dis
2014
A novel frameshift variant in BHLHA9 underlies mesoaxial synostotic syndactyly associated with postaxial polydactyly.
Khan F et al.·Eur J Med Genet
2019
SHFLD3 phenotypes caused by 17p13.3 triplication/ duplication encompassing Fingerin (BHLHA9) invariably.
Bukowska-Olech E et al.·Orphanet J Rare Dis
2022Case report
Identification of a rare 17p13.3 duplication including the BHLHA9 and YWHAE genes in a family with developmental delay and behavioural problems.
Capra V et al.·BMC Med Genet
2012Case report
A novel insertion and deletion mutation in the BHLHA9 underlies polydactyly and mesoaxial synostotic syndactyly with phalangeal reduction.
Ullah A et al.·Eur J Med Genet
2019Case report
Duplications of BHLHA9 are associated with ectrodactyly and tibia hemimelia inherited in non-Mendelian fashion.
Klopocki E et al.·J Med Genet
2012
BHLHA9 homozygous duplication in a consanguineous family: A challenge for genetic counseling.
Chouery E et al.·Am J Med Genet A
2023Case report
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools