SIX1

protein-coding

SIX homeobox 1, the group of SINE class homeoboxes

Gene summary

The protein encoded by this gene is a homeobox protein that is similar to the Drosophila 'sine oculis' gene product. This gene is found in a cluster of related genes on chromosome 14 and is thought to be involved in limb development. Defects in this gene are a cause of autosomal dominant deafness type 23 (DFNA23) and branchiootic syndrome type 3 (BOS3). [provided by RefSeq, Jul 2008]

Previous symbols:

DFNA23

MANE transcript

NM_005982.4

Inheritance

ClinVar variants

P:40U:152B:53

Top phenotype

Deafness, autosomal dominant 23; Branchiootorenal syndrome 3; Branchiootic syndrome 3

gnomAD constraint

pLI —, LoF o/e 0.17

Max pathogenic AF

—

Genomic locus

chr14:60,643,421-60,658,259

External References & Databases

Ensembl (ENSG00000126778)

Transcript & Mutation Effects

hg38 • Region Span ~14.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal dominant nonsyndromic hearing loss 23STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011519

Submitter: PanelApp Australia

branchiootic syndrome 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012025

Submitter: Labcorp Genetics (formerly Invitae)

craniosynostosisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0015469

Submitter: G2P

branchiootic syndrome 3DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012025

Submitter: G2P

branchio-oto-renal syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007029

Submitter: Ambry Genetics

autosomal dominant nonsyndromic hearing loss 23DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011519

Submitter: G2P

branchio-oto-renal syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007029

Submitter: Orphanet

branchiootic syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018878

Submitter: Orphanet

branchio-oto-renal syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007029

Submitter: ClinGen

The association between the SIX1 gene and autosomal dominant branchio-oto-renal syndrome (AD BOR) has been classified as Definitive using the ClinGen Cllinical Validity Framework as of 11/21/16. The first case was published in 2004 by Ruf et al. Some affected individuals do not have any renal phenotype, and are sometimes considered to have branchio-otic syndrome. Mutai 2013 reported a mother and child with the p.Arg110Trp variant in SIX1, which was previously reported in a family with BOR syndrome, who did not have any other clinical features of BOR other than hearing loss. The association with nonsyndromic hearing loss, however, has not been replicated. In a family reported by Salam et al. 2000 with linkage to a novel autosomal dominant nonsyndromic hearing loss locus DFNA23, Ruf 2004 later identified a missense variant in SIX1, but also that an affected individual had progressive renal failure, indicating this family may have actually had BOR syndrome. Functional studies indicate that SIX1 interacts with EYA1, the most common cause of BOR syndrome, and that pathogenic variants in SIX1 impair the protein's ability to bind EYA1 or to bind DNA (Ruf et al. 2004, Patrick et al. 2009) and two mouse models of BOR syndrome have been generated (Zheng et al. 2003, Bosman et al. 2009). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern for BOR and autosomal dominant nonsyndromic hearing loss. Therefore, all of the disease entitites have been lumped into one disease entity, AD BOR. In summary, SIX1 is definitively associated with AD BOR. This classification was approved by the ClinGen Hearing Loss Working Group on 6/22/2017.

branchiootic syndrome 3LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0012025

Submitter: PanelApp Australia

autosomal dominant nonsyndromic hearing lossSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019587

Submitter: Orphanet

Clinical Genomic Database (CGD)

Deafness, autosomal dominant 23; Branchiootorenal syndrome 3; Branchiootic syndrome 3AD

Manifestation: Audiologic/Otolaryngologic; Craniofacial; Renal

Intervention: Audiologic/Otolaryngologic; Renal

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; In BOR, surveillance and treatment/prophylaxis related to vesicoureteral reflux can be beneficial

Comments: Individuals can have characteristic aural anomalies, but these may not be readily ascertained

Refs: 10777717; 15141091; 16652090; 17637804; 18330911; 20301554

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SIX1 variants in ClinVar

16 Conditions Cataloged

Branchiootic syndrome 3Total: 154

Autosomal dominant nonsyndromic hearing loss 23Total: 142

not providedTotal: 100

SIX1-related disorderTotal: 30

Inborn genetic diseasesTotal: 27

not specifiedTotal: 18

Branchiootorenal syndrome 1Total: 7

Hearing impairmentTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005982.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	45 clinvar	1 clinvar	49
missense	3 clinvar	23 clinvar	130 clinvar	6 clinvar		162
nonsense	2 clinvar	6 clinvar	4 clinvar			12
start loss			1 clinvar	1 clinvar		2
frameshift	2 clinvar	3 clinvar	12 clinvar			17
splice donor/acceptor (+/-2bp)		1 clinvar	2 clinvar			3
Total	7	33	152	52	1	245

Highest pathogenic variant AF is 0.0000075249795

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005982.4	RefSeq	NP_005973.1	2	MANE Select
ENST00000645694.3	Ensembl	ENSP00000494686.1	2	MANE Select
NM_001425142.1	RefSeq	NP_001412071.1	2	Standard
ENST00000554986.2	Ensembl	ENSP00000452700.2	2	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
six1a	Danio rerio	Structure: fast muscle cell Quality: decreased process quality abnormal

Gene / Model

Organism

Observed Phenotype

six1a

Danio rerio

Structure: fast muscle cell

Quality: decreased process quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Transcriptional misregulation in cancer - Homo sapiens (human)

Biological Process

negative regulation of transcription by RNA polymerase II
ureteric bud development
branching involved in ureteric bud morphogenesis
organ induction
kidney development

Molecular Function

transcription regulatory region sequence-specific DNA binding
RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
transcription coactivator binding
DNA-binding transcription activator activity, RNA polymerase II-specific

Cellular Component

nucleus
transcription factor complex
nucleolus
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000247182
Coding exons: 2
Length: 14845
Individuals with no LoFs: 125741
Homozygous LoFs: 0
Heterozygous LoFs: 6
Defined: 125747
p: 0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.19	119	162	0.736	0.00000718	1828
Missense (PolyPhen)		11	44.919	0.24488		517
Synonymous	-0.905	85	75.0	1.13	0.00000352	589
Loss of Function	2.69	2	12.1	0.166	5.29e-7	119

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcription factor that is involved in the regulation of cell proliferation, apoptosis and embryonic development. Plays an important role in the development of several organs, including kidney, muscle and inner ear. Depending on context, functions as transcriptional repressor or activator. Lacks an activation domain, and requires interaction with EYA family members for transcription activation. Mediates nuclear translocation of EYA1 and EYA2. Binds the 5'-TCA[AG][AG]TTNC-3' motif present in the MEF3 element in the MYOG promoter. Regulates the expression of numerous genes, including MYC, CCND1 and EZR. Acts as activator of the IGFBP5 promoter, probably coactivated by EYA2. Repression of precursor cell proliferation in myoblasts is switched to activation through recruitment of EYA3 to the SIX1-DACH1 complex. During myogenesis, seems to act together with EYA2 and DACH2 (By similarity). Regulates the expression of CCNA1. {ECO:0000250, ECO:0000269|PubMed:15123840, ECO:0000269|PubMed:15141091, ECO:0000269|PubMed:19497856, ECO:0000269|PubMed:23435380}.;
Disease: DISEASE: Deafness, autosomal dominant, 23 (DFNA23) [MIM:605192]: A form of non-syndromic deafness characterized by prelingual, bilateral, symmetric hearing loss with a conductive component present in some but not all patients. {ECO:0000269|PubMed:15141091, ECO:0000269|PubMed:19497856, ECO:0000269|PubMed:23435380}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Branchiootic syndrome 3 (BOS3) [MIM:608389]: A syndrome characterized by usually bilateral branchial cleft fistulas or cysts, sensorineural and/or conductive hearing loss, pre-auricular pits, and structural defects of the outer, middle or inner ear. Otic defects include malformed and hypoplastic pinnae, a narrowed external ear canal, bulbous internal auditory canal, stapes fixation, malformed and hypoplastic cochlea. Branchial and otic anomalies overlap with those seen in individuals with the branchiootorenal syndrome. However renal anomalies are absent in branchiootic syndrome patients. {ECO:0000269|PubMed:15141091, ECO:0000269|PubMed:17637804, ECO:0000269|PubMed:18330911, ECO:0000269|PubMed:19497856, ECO:0000269|PubMed:21280147, ECO:0000269|PubMed:23435380}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in SIX1 could be a cause of branchiootorenal syndrome (BOR). BOR is an autosomal dominant disorder manifested by various combinations of preauricular pits, branchial fistulae or cysts, lacrimal duct stenosis, hearing loss, structural defects of the outer, middle, or inner ear, and renal dysplasia. Associated defects include asthenic habitus, long narrow facies, constricted palate, deep overbite, and myopia. Hearing loss may be due to mondini type cochlear defect and stapes fixation. Penetrance of BOR syndrome is high, although expressivity can be extremely variable. {ECO:0000305|PubMed:15141091, ECO:0000305|PubMed:19497856}.;

Recessive Scores

pRec: 0.235

Intolerance Scores

RVIS EVS: -0.3
RVIS percentile EVS: 32.62

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.860

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium