Branchiootic syndrome 3

Summary

Branchiootic syndrome 3 (MONDO:0012025) is a disease caused by SIX1 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: SIX1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 186

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	branchiootic syndrome 3
Mondo ID	MONDO:0012025
MeSH	C564248
OMIM	608389
DOID	DOID:0061210
UMLS	C1842124
MedGen	333995
GARD	0015430
Is cancer (heuristic)	no

Also known as: BOS3 · branchiootic syndrome 3 · branchiootic syndrome caused by mutation in SIX1 · branchiootic syndrome type 3 · SIX1 branchiootic syndrome

Data availability: 186 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › branchiootic syndrome › branchiootic syndrome 3

Related subtypes (2): branchiootic syndrome 2, branchiootic syndrome 1

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

186 retrieved; paginated sample, class counts are floors:

99 uncertain significance, 32 likely benign, 16 conflicting classifications of pathogenicity, 13 benign/likely benign, 9 likely pathogenic, 7 pathogenic, 5 benign, 3 not provided, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
208361	NM_005982.4(SIX1):c.373G>A (p.Glu125Lys)	SIX1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2503043	NM_005982.4(SIX1):c.307dup (p.Leu103fs)	SIX1	Pathogenic	criteria provided, single submitter
2953157	NM_005982.4(SIX1):c.340A>G (p.Lys114Glu)	SIX1	Pathogenic	criteria provided, single submitter
3757320	NM_005982.4(SIX1):c.337C>T (p.Arg113Ter)	SIX1	Pathogenic	criteria provided, single submitter
420132	NM_005982.4(SIX1):c.329G>A (p.Arg110Gln)	SIX1	Pathogenic	criteria provided, multiple submitters, no conflicts
8308	NM_005982.4(SIX1):c.386A>G (p.Tyr129Cys)	SIX1	Pathogenic	criteria provided, multiple submitters, no conflicts
8309	NM_005982.4(SIX1):c.328C>T (p.Arg110Trp)	SIX1	Pathogenic	criteria provided, multiple submitters, no conflicts
8310	NM_005982.4(SIX1):c.397_399del (p.Glu133del)	SIX1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8311	NM_005982.4(SIX1):c.364T>A (p.Trp122Arg)	SIX1	Pathogenic	no assertion criteria provided
1202646	NM_005982.4(SIX1):c.316G>A (p.Val106Met)	SIX1	Likely pathogenic	criteria provided, single submitter
1517704	NM_005982.4(SIX1):c.329G>T (p.Arg110Leu)	SIX1	Likely pathogenic	criteria provided, single submitter
189222	NM_005982.4(SIX1):c.560+1G>C	SIX1	Likely pathogenic	no assertion criteria provided
2503044	NM_005982.4(SIX1):c.386_391del (p.Tyr129_Cys130del)	SIX1	Likely pathogenic	criteria provided, single submitter
3066285	NM_005982.4(SIX1):c.421G>T (p.Glu141Ter)	SIX1	Likely pathogenic	criteria provided, single submitter
3068253	NM_005982.4(SIX1):c.733A>G (p.Asn245Asp)	SIX1	Likely pathogenic	criteria provided, single submitter
3382037	NM_005982.4(SIX1):c.385T>C (p.Tyr129His)	SIX1	Likely pathogenic	criteria provided, single submitter
417916	NM_005982.4(SIX1):c.460A>T (p.Lys154Ter)	SIX1	Likely pathogenic	no assertion criteria provided
974692	NM_005982.4(SIX1):c.416T>G (p.Leu139Arg)	SIX1	Likely pathogenic	criteria provided, single submitter
1175856	NM_005982.4(SIX1):c.510C>G (p.Asn170Lys)	MIR9718	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1305847	NM_005982.4(SIX1):c.524G>A (p.Arg175Gln)	MIR9718	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
880804	NM_005982.4(SIX1):c.495C>T (p.Thr165=)	MIR9718	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1687607	NM_005982.4(SIX1):c.501G>C (p.Gln167His)	SIX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1710698	NM_005982.4(SIX1):c.385T>A (p.Tyr129Asn)	SIX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1723302	NM_005982.4(SIX1):c.597G>A (p.Lys199=)	SIX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1989481	NM_005982.4(SIX1):c.321C>T (p.Gly107=)	SIX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
313465	NM_005982.4(SIX1):c.578A>T (p.Asn193Ile)	SIX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
444331	NM_005982.4(SIX1):c.191G>A (p.Arg64His)	SIX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
493144	NM_005982.4(SIX1):c.690G>C (p.Ser230=)	SIX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
497389	NM_005982.4(SIX1):c.402G>A (p.Lys134=)	SIX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
497460	NM_005982.4(SIX1):c.330G>A (p.Arg110=)	SIX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · 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
SIX1	Definitive	Autosomal dominant	branchiootic syndrome 3	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SIX1	Orphanet:107	BOR syndrome
SIX1	Orphanet:52429	Branchiootic syndrome
SIX1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SIX1	HGNC:10887	ENSG00000126778	Q15475	Homeobox protein SIX1	gencc,clinvar
SIX4	HGNC:10890	ENSG00000100625	Q9UIU6	Homeobox protein SIX4	clinvar
MIR9718	HGNC:53988			microRNA 9718	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SIX1	Homeobox protein SIX1	Transcription factor that is involved in the regulation of cell proliferation, apoptosis and embryonic development.
SIX4	Homeobox protein SIX4	Transcriptional regulator which can act as both a transcriptional repressor and activator by binding a DNA sequence on these target genes and is involved in processes like cell differentiation, cell migration and cell survival.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 1 · 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	2	5.5×	0.081
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SIX1	Transcription factor	no		HD, KN_HD, Homeodomain-like_sf
SIX4	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
MIR9718	Other/Unknown	no

Expression context

Cohort genes with no expression data: 1.

2 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)	2
unknown	1

Top tissues across cohort

Tissue	Cohort genes
biceps brachii	1
parotid gland	1
skeletal muscle tissue of biceps brachii	1
bronchial epithelial cell	1
quadriceps femoris	1
vastus lateralis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SIX1	188	ubiquitous	marker	skeletal muscle tissue of biceps brachii, biceps brachii, parotid gland
SIX4	205	ubiquitous	marker	bronchial epithelial cell, vastus lateralis, quadriceps femoris
MIR9718

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SIX1	1,977
SIX4	1,056
MIR9718	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SIX1	Q15475	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SIX4	Q9UIU6	50.19

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 3 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Kidney development	1	815.7×	0.003	SIX1
Formation of the ureteric bud	1	496.5×	0.003	SIX1
Developmental Biology	1	14.5×	0.069	SIX1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
fungiform papilla morphogenesis	2	8426.0×	5e-07	SIX1, SIX4
olfactory placode formation	2	5617.3×	5e-07	SIX1, SIX4
regulation of branch elongation involved in ureteric bud branching	2	5617.3×	5e-07	SIX1, SIX4
myotome development	2	4213.0×	6e-07	SIX1, SIX4
trigeminal ganglion development	2	4213.0×	6e-07	SIX1, SIX4
positive regulation of ureteric bud formation	2	2808.7×	1e-06	SIX1, SIX4
metanephric mesenchyme development	2	2407.4×	2e-06	SIX1, SIX4
myoblast migration	2	1872.4×	2e-06	SIX1, SIX4
regulation of synaptic assembly at neuromuscular junction	2	1685.2×	3e-06	SIX1, SIX4
generation of neurons	2	1532.0×	3e-06	SIX1, SIX4
regulation of epithelial cell proliferation	2	936.2×	7e-06	SIX1, SIX4
pharyngeal system development	2	802.5×	8e-06	SIX1, SIX4
positive regulation of branching involved in ureteric bud morphogenesis	2	802.5×	8e-06	SIX1, SIX4
embryonic cranial skeleton morphogenesis	2	581.1×	1e-05	SIX1, SIX4
protein localization to nucleus	2	351.1×	4e-05	SIX1, SIX4
thymus development	2	337.0×	4e-05	SIX1, SIX4
inner ear morphogenesis	2	300.9×	5e-05	SIX1, SIX4
skeletal muscle tissue development	2	290.6×	5e-05	SIX1, SIX4
regulation of protein localization	2	205.5×	9e-05	SIX1, SIX4
negative regulation of neuron apoptotic process	2	110.9×	3e-04	SIX1, SIX4
mesonephric tubule formation	1	8426.0×	4e-04	SIX1
mesenchymal cell proliferation involved in ureter development	1	8426.0×	4e-04	SIX1
regulation of skeletal muscle cell proliferation	1	4213.0×	6e-04	SIX1
facial nerve morphogenesis	1	4213.0×	6e-04	SIX1
cellular response to 3,3’,5-triiodo-L-thyronine	1	4213.0×	6e-04	SIX1
positive regulation of mesenchymal cell proliferation involved in ureter development	1	4213.0×	6e-04	SIX1
ureter smooth muscle cell differentiation	1	2808.7×	9e-04	SIX1
positive regulation of secondary heart field cardioblast proliferation	1	2808.7×	9e-04	SIX1
male sex differentiation	1	2106.5×	0.001	SIX4
negative regulation of satellite cell differentiation	1	1685.2×	0.001	SIX4

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SIX1	0	0
SIX4	0	0
MIR9718	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SIX1	12	Binding:12

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	3	SIX1, SIX4, MIR9718

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SIX1	12	—
SIX4	0	—
MIR9718	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.