IRX1

Chr 5

iroquois homeobox 1

Also known as: IRX-5, IRXA1

NCBI Gene: 79192 ENSG00000170549 UniProt: P78414 OMIM: 606197

This gene encodes an Iroquois homeobox transcription factor that regulates embryonic pattern formation. Mutations cause autosomal dominant developmental delay, intellectual disability, and multiple congenital anomalies affecting craniofacial features, limbs, and other organ systems. The gene shows low constraint against loss-of-function variants, consistent with the dominant inheritance pattern observed in affected families.

OMIM ResearchSummary from RefSeq

This gene encodes a member of the Iroquois homeobox protein family. Homeobox genes in this family are involved in pattern formation in the embryo. The gene product has been identified as a tumor suppressor in gastric (PMID: 21602894, 20440264) and head and neck cancers (PMID: 18559491). A pseudogene of this gene is located on chromosome 13. [provided by RefSeq, Dec 2011]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.07

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.07LOEUF

pLI 0.000

Z-score 1.40

OE 0.57 (0.32–1.07)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.59Z-score

OE missense 1.11 (1.00–1.23)

266 obs / 240.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.57 (0.32–1.07)

0≤0.351.4

Missense OE?1.11 (1.00–1.23)

0≤0.61.4

Synonymous OE?1.43

0≤1.21.6

LoF obs/exp: 7 / 12.3Missense obs/exp: 266 / 240.2Syn Z: -3.62

Background carrier burden — how many people carry a rare variant somewhere in IRX1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 100

823 rare PASS variants

Rare truncating (LoF)

1 in 5,900

46 rare PASS variants

Rare synonymous (reference)

1 in 94

387 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for IRX1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 140	1 in 5,000
South Asian	~43k	1 in 75	1 in 3,100
Remaining (unassigned)	~30k	1 in 80	≈ 1 in 7,500
European (Finnish)	~27k	1 in 180	1 in 2,500
Admixed American	~22k	1 in 73	≈ 1 in 5,200
African / African American	~21k	1 in 90	≈ 1 in 21,000
East Asian	~20k	1 in 55	≈ 1 in 9,900
Ashkenazi Jewish	~13k	1 in 210	≈ 1 in 11,000
Middle Eastern	~2,884	1 in 88	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 3 of 4 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 4.? see exons ↓