Mesoaxial synostotic syndactyly with phalangeal reduction

Summary

Mesoaxial synostotic syndactyly with phalangeal reduction (MONDO:0012271) is a disease caused by BHLHA9 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: BHLHA9 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 6
• Phenotypes (HPO): 12

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		6	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

12 HPO clinical features (Orphanet curated; top 12 by frequency):

HPO ID	Term	Frequency
HP:0001770	Toe syndactyly	Very frequent (80-99%)
HP:0004209	Clinodactyly of the 5th finger	Very frequent (80-99%)
HP:0004279	Short palm	Very frequent (80-99%)
HP:0004691	2-3 toe syndactyly	Very frequent (80-99%)
HP:0006101	Finger syndactyly	Very frequent (80-99%)
HP:0008362	Aplasia/Hypoplasia of the hallux	Very frequent (80-99%)
HP:0009701	Metacarpal synostosis	Very frequent (80-99%)
HP:0009773	Symphalangism affecting the phalanges of the hand	Very frequent (80-99%)
HP:0009778	Short thumb	Very frequent (80-99%)
HP:0009843	Aplasia/Hypoplasia of the middle phalanges of the hand	Very frequent (80-99%)
HP:0010109	Short hallux	Very frequent (80-99%)
HP:0005048	Synostosis of carpal bones	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	mesoaxial synostotic syndactyly with phalangeal reduction
Mondo ID	MONDO:0012271
MeSH	C563721
OMIM	609432
Orphanet	157801
SNOMED CT	724170007
UMLS	C1836206
MedGen	324459
GARD	0010590
Is cancer (heuristic)	no

Also known as: MSSD · syndactyly Malik-Percin type · syndactyly mesoaxial synostotic with phalangeal reduction · syndactyly type 9 · syndactyly, Malik-Percin type · syndactyly, mesoaxial synostotic, with phalangeal reduction

Data availability: 6 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › syndactyly › non-syndromic syndactyly › mesoaxial synostotic syndactyly with phalangeal reduction

Related subtypes (7): non-syndromic synpolydactyly, syndactyly type 1, syndactyly type 3, syndactyly type 4, syndactyly type 5, syndactyly type 8, syndactyly type 6

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

6 retrieved; paginated sample, class counts are floors:

2 pathogenic, 2 likely pathogenic, 1 benign, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
162065	NM_001164405.2(BHLHA9):c.211A>G (p.Asn71Asp)	BHLHA9	Pathogenic	no assertion criteria provided
162067	NM_001164405.2(BHLHA9):c.224G>T (p.Arg75Leu)	BHLHA9	Pathogenic	no assertion criteria provided
162066	NM_001164405.2(BHLHA9):c.218G>C (p.Arg73Pro)	BHLHA9	Likely pathogenic	criteria provided, single submitter
3065871	NM_001164405.2(BHLHA9):c.218G>T (p.Arg73Leu)	BHLHA9	Likely pathogenic	criteria provided, single submitter
1202456	NM_001164405.2(BHLHA9):c.475A>G (p.Ser159Gly)	BHLHA9	Uncertain significance	criteria provided, multiple submitters, no conflicts
1185322	NM_001164405.2(BHLHA9):c.237A>G (p.Leu79=)	BHLHA9	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
BHLHA9	Definitive	Autosomal recessive	mesoaxial synostotic syndactyly with phalangeal reduction	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BHLHA9	Orphanet:157801	Mesoaxial synostotic syndactyly with phalangeal reduction
BHLHA9	Orphanet:1986	Gollop-Wolfgang complex
BHLHA9	Orphanet:3329	Tibial aplasia-ectrodactyly syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BHLHA9	HGNC:35126	ENSG00000205899	Q7RTU4	Class A basic helix-loop-helix protein 9	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BHLHA9	Class A basic helix-loop-helix protein 9	Transcription factor, which play a role in limb development.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BHLHA9	Transcription factor	no		bHLH_dom, HLH_DNA-bd_sf, E-box_TF_Regulators

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 9	1
dorsolateral prefrontal cortex	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BHLHA9	28	tissue_specific	yes	primordial germ cell in gonad, Brodmann (1909) area 9, dorsolateral prefrontal cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BHLHA9	405

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
BHLHA9	Q7RTU4	66.46

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
developmental process	1	674.1×	0.003	BHLHA9
regulation of transcription by RNA polymerase II	1	11.7×	0.086	BHLHA9

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BHLHA9	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

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	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	BHLHA9

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
BHLHA9	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.