PAX1

protein-coding

paired box 1, the group of Paired boxes

Gene summary

This gene is a member of the paired box (PAX) family of transcription factors. Members of the PAX family typically contain a paired box domain and a paired-type homeodomain. These genes play critical roles during fetal development. This gene plays a role in pattern formation during embryogenesis and may be essential for development of the vertebral column. This gene is silenced by methylation in ovarian and cervical cancers and may be a tumor suppressor gene. Mutations in this gene are also associated with vertebral malformations. [provided by RefSeq, Mar 2012]

MANE transcript

NM_001257096.2

Inheritance

AR, AD

ClinVar variants

P:30U:205B:159

Top phenotype

Otofaciocervical syndrome 2, with T-cell deficiency

gnomAD constraint

pLI —, LoF o/e 0.16

Max pathogenic AF

—

Genomic locus

chr20:21,705,659-21,718,481

External References & Databases

Ensembl (ENSG00000125813)

Transcript & Mutation Effects

hg38 • Region Span ~12.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

otofaciocervical syndrome 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014254

Submitter: ClinGen

Biallelic PAX1 germline loss-of-function (LOF) variants were first reported in association to otofaciocervical syndrome type 2 (OTFCS2), with other groups later identifying a subset of patients with severe combined immunodeficiency (SCID) (PMID: 32111619, 28657137, 29681087). OTFCS2 is characterized by facial dysmorphism, external ear anomalies with preauricular pits, hearing impairment, hypoparathyroidism, anomalies of the vertebrae and shoulder, and mild intellectual disability. OTFCS2 patients that present with SCID demonstrate thymic aplasia/hypoplasia and T-B+NK+ SCID. 13 variants were curated and are composed of missense, nonsense and frameshift mutations. Evidence supporting this gene-disease relationship includes case-level and experimental data. Heterozygous carriers have been identified that show full penetrance of the OTFCS2 phenotype with variable expressivity without signs of immunodeficiency, though the immune system has not been extensively studied in these patients (PMID: 35879406). The maximum score for genetic evidence has been reached for this curation (12 pts). PAX1 is a member of the paired box-containing (PAX) family of transcription factors and plays a role in pattern formation during embryogenesis. It is primarily expressed in the third pharyngeal pouch that generates the thymus, thyroid, parathyroid and middle ear during human development (PMID: 36393845). PAX1 is essential for the development of the thymus, is expressed in thymic epithelial cells during embryogenesis and into adulthood (PMID:2453291). Mice with different LOF mutations in PAX1 demonstrate impacts in the cellularity of the thymus as well as thymocyte development and maturation (PMID:8565834). This is most likely due to the impact of PAX1 on thymic epithelial cells, as cell culture model systems have shown altered thymic stromal cell transcriptomes following induced pluripotent stem cell differentiation (PMID: 32111619). In patients with OTFCS2, thymic transplant has shown promise in patients presenting with immunodeficiency, while HSCT has been less successful (PMID: 37060484, 33987750). Not all reports of OTFCS2 have reported patients with SCID phenotypes. It is currently unclear if this is due to reduced penetrance, the type or location of the mutation in PAX1 or other genetic modifiers. Further study is required to elucidate this finding. In summary, there is definitive evidence to support this gene-disease relationship. This association has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen SCID-CID Working Group on 11/16/2023 (SOP Version 9).

otofaciocervical syndrome 2LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0014254

Submitter: Ambry Genetics

otofaciocervical syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014254

Submitter: G2P

otofaciocervical syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014254

Submitter: PanelApp Australia

otofaciocervical syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014254

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Otofaciocervical syndrome 2, with T-cell deficiencyAR

Manifestation: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Craniofacial; Musculoskeletal; Neurologic

Intervention: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; The condition has been described as including thymic anomalies and T-cell immunodeficiency associated with severe infections, and awareness may allow preventative measures and early and aggressive management of infections

Refs: 23851939; 28657137; 29681087; 32111619

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PAX1 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 378

Inborn genetic diseasesTotal: 87

Otofaciocervical syndrome 2Total: 24

not specifiedTotal: 22

PAX1-related disorderTotal: 12

PAX1-related disordersTotal: 2

Primary ciliary dyskinesiaTotal: 2

Craniofacial microsomiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001257096.2. 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			8 clinvar	139 clinvar	3 clinvar	150
missense	2 clinvar	1 clinvar	195 clinvar	17 clinvar		215
nonsense	3 clinvar	6 clinvar	1 clinvar			10
start loss						0
frameshift	8 clinvar	8 clinvar	1 clinvar			17
splice donor/acceptor (+/-2bp)		2 clinvar				2
Total	13	17	205	156	3	394

Highest pathogenic variant AF is 0.0003927273

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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_001257096.2	RefSeq	NP_001244025.1	5	MANE Select
ENST00000613128.5	Ensembl	ENSP00000481334.1	5	MANE Select
NM_006192.5	RefSeq	NP_006183.2	5	Standard
ENST00000398485.6	Ensembl	ENSP00000381499.2	5	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
pax1b	Danio rerio	Structure: fin bud Quality: hypoplastic abnormal

Gene / Model

Organism

Observed Phenotype

pax1b

Danio rerio

Structure: fin bud

Quality: hypoplastic

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

skeletal system development
somitogenesis
transcription by RNA polymerase II
cell population proliferation
CD4-positive, alpha-beta T cell differentiation

Molecular Function

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

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000398485
Coding exons: 5
Length: 10324
Individuals with no LoFs: 125571
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125575
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.758	305	270	1.13	0.0000129	3303
Missense (PolyPhen)		83	95.948	0.86505		1136
Synonymous	-2.44	154	120	1.28	0.00000593	1203
Loss of Function	2.77	2	12.6	0.158	5.51e-7	152

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	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0	0.0	absent
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: This protein is a transcriptional activator. It may play a role in the formation of segmented structures of the embryo. May play an important role in the normal development of the vertebral column (By similarity). {ECO:0000250}.;
Disease: DISEASE: Otofaciocervical syndrome 2 (OTFCS2) [MIM:615560]: A disorder characterized by facial dysmorphism, cup-shaped low-set ears, preauricular fistulas, hearing loss, branchial defects, skeletal anomalies including vertebral defects, low-set clavicles, winged scapulae, sloping shoulders, and mild intellectual disability. {ECO:0000269|PubMed:23851939}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.302

Intolerance Scores

LoFtool: 0.182
RVIS EVS: 0.35
RVIS percentile EVS: 74.37

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.896

Gene Damage Prediction

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