HMX1

protein-coding

H6 family homeobox 1, the group of NKL subclass homeoboxes and pseudogenes

Gene summary

This gene encodes a transcription factor that belongs to the H6 family of homeobox proteins. This protein can bind a 5'-CAAG-3' core DNA sequence, and it is involved in the development of craniofacial structures. Mutations in this gene cause oculoauricular syndrome, a disorder of the eye and external ear. [provided by RefSeq, Oct 2009]

MANE transcript

NM_018942.3

Inheritance

AR, AD

ClinVar variants

P:3U:224B:140

Top phenotype

Oculoauricular syndrome

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr4:8,846,076-8,871,839

External References & Databases

Ensembl (ENSG00000215612)

Transcript & Mutation Effects

hg38 • Region Span ~25.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

oculoauricular syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012802

Submitter: Labcorp Genetics (formerly Invitae)

oculoauricular syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012802

Submitter: G2P

oculoauricular syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012802

Submitter: ClinGen

Oculoauricular syndrome, sometimes referred to as Schorderet-Munier-Franceschetti syndrome, is an autosomal recessive disorder characterized by ocular anomalies (microphthalmia, cataract, ocular coloboma, anterior segment dysgenesis, and early onset retinal dystrophy) and external ear anomalies (lobule aplasia and abnormal external ear appearance with typical hearing). In some cases, additional features have been reported, most commonly orodental anomalies. Eye and ear anomalies with oculoauricular syndrome are apparent at birth/in infancy. The HMX1 gene (NKX5-3) is part of the NKL subclass of ANTP homeobox genes on 4p16.1. It has a highly conserved 60 amino acid homeodomain. HMX1 is involved in DNA binding. Gene targets include EPHA6, which is a gene implicated in retinal axon guidance (Marcelli et al. 2014, PMID: 24945320). Three families have been reported in the literature with both the eye and ear phenotype. A consanguineous family with oculoauricular syndrome was first described by Franseschetti & Valerio in 1945. In 2008 Schorderet et al. (PMID: 18423520) reported additional information and family members for the original family and provided the first report of a homozygous HMX1 frameshift variant as the putative cause of disease. In this case, ERG evaluation of the proband revealed progressive rod-cone dystrophy. Since then, 2 additional consanguineous families with oculoauricular syndrome with homozygous HMX1 variants have been reported (Gillespie et al. 2015, PMID: 25574057; Abdel-Salam et al. 2018, PMID: 29140751). In addition, a 4th family, with two affected siblings, both with a homozygous nonsense variant, was identified (PMID: 35946463). In this curation, 4 probands, one from each family reported in the literature, were curated. This gene-disease relationship is supported by zebrafish, mouse, and human expression data as well as morpholino and zinc-finger-nuclease knockdown/rescue studies in zebrafish (Schorderet et al. 2008, PMID: 18423520; Boisset et al. 2012, PMID: 23068565). Functional alternation studies indicate that an HMX1 mutant failed to activate transcription of reporter constructs (Gillespie et al. 2015, PMID: 25574057). In addition, the Dumbo mouse (dmbo), created in a forward mutagenesis screen, with large/protruding ears and microphthalmia, was found to have a nonsense variant in exon 1 of HMX1 (Munroe et al.2009, PMID: 19379485). In summary, there is a definitive association between HMX1 and oculoauricular syndrome. This has been demonstrated multiple times over several years with experimental and genetic evidence. This classification was approved by the ClinGen Retina gene Curation expert panel on May 6, 2021 (SOP Version 8).

oculoauricular syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012802

Submitter: Orphanet

oculoauricular syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012802

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Oculoauricular syndromeAD

Manifestation: Craniofacial; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 18423520; 21417677; 25574057

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HMX1 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 335

Inborn genetic diseasesTotal: 90

not specifiedTotal: 54

HMX1-related disorderTotal: 7

Retinal dystrophyTotal: 4

Oculoauricular syndromeTotal: 4

Isolated microphthalmia 6Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018942.3. 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				125 clinvar	1 clinvar	126
missense	1 clinvar		215 clinvar	12 clinvar	2 clinvar	230
nonsense			2 clinvar			2
start loss			1 clinvar			1
frameshift	2 clinvar		6 clinvar			8
splice donor/acceptor (+/-2bp)						0
Total	3	0	224	137	3	367

Highest pathogenic variant AF is 7.304495e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 6 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018942.3	RefSeq	NP_061815.2	2	MANE Select
ENST00000400677.5	Ensembl	ENSP00000383516.3	2	MANE Select
NM_001306142.2	RefSeq	NP_001293071.1	2	Standard
ENST00000506970.2	Ensembl	ENSP00000446997.2	2	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
hmx1	Danio rerio	Structure: solid lens vesicle Quality: decreased occurrence abnormal

Gene / Model

Organism

Observed Phenotype

hmx1

Danio rerio

Structure: solid lens vesicle

Quality: decreased occurrence

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

negative regulation of transcription by RNA polymerase II
multicellular organism development
negative regulation of transcription, DNA-templated

Molecular Function

RNA polymerase II regulatory region sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription repressor activity, RNA polymerase II-specific
DNA binding

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000400677
Coding exons: 2
Length: 25742
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.102	73	70.6	1.03	0.00000348	2057
Missense (PolyPhen)		18	24.658	0.72999		467
Synonymous	-0.460	36	32.7	1.10	0.00000175	816
Loss of Function	1.92	0	4.28	0.00	1.90e-7	87

Population LoF Frequency

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

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: DNA-binding protein that binds to the 5'-CAAG-3' core sequence. May function as a transcriptional repressor. Seems to act as a transcriptional antagonist of NKX2-5. May play an important role in the development of craniofacial structures such as the eye and ear. {ECO:0000269|PubMed:10206974}.;
Disease: DISEASE: Oculoauricular syndrome (OCACS) [MIM:612109]: A syndrome characterized by microphthalmia, microcornea, anterior segment dysgenesis, cataract, ocular coloboma, retinal pigment epithelium abnormalities, rod-cone dystrophy, and anomalies of the external ear. {ECO:0000269|PubMed:18423520}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.283

Gene Damage Prediction

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