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Retinal disorders

Gene: IRX5

Red List (low evidence)

IRX5 (iroquois homeobox 5)
EnsemblGeneIds (GRCh38): ENSG00000176842
EnsemblGeneIds (GRCh37): ENSG00000176842
OMIM: 606195, Gene2Phenotype
IRX5 is in 6 panels

3 reviews

Eleanor Williams (Genomics England Curator)

I don't know

Ideally, a region representing the IRX5/IRX6 duplication should be added to PanelApp with a monallelic mode of inheritance. There is a lack of single nucleotide variants reported in this gene with relevance to retinal disorders and and therefore adding this gene as green risks reporting irrelevant SNVs alongside carrier status for Hamamy syndrome (biallelic)
Created: 28 Sep 2021, 12:50 p.m. | Last Modified: 28 Sep 2021, 12:50 p.m.
Panel Version: 2.216
Associated with Hamamy syndrome #611174 (AR) in OMIM. Hamamy syndrome is characterised by craniofacial dysmorphism, hearing loss, skeletal anomalies, microcytic hypochromic anemia and congenital heart defects. Severe myopia has also been reported. Homozygous missense variants in IRX5 were reported in 2 families with this condition (PMID: 22581230;17230486)

Duplication of gene
-------------------
PMID: 33891002 - Kohl et al 2021 - report 3 unrelated families with duplications of a region covering the genes IRX5 and IRX6 completely, and the proximal exons of MMP2 and cone dystrophy. They propose that overexpression of IRX5 and IRX6 may be the cause of the disease, and this is supported by expression analysis in patient-derived fibroblasts and zebrafish experiments.

Initial family is a large 5 generation German family with 14 members with autosomal dominant cone dystrophy in which a 600kb duplicated region covering IRX5/IRX6 and part of MMP2 was identified. 2 additional families of Chinese and Dutch descent with copy number gains of ~700 and ~850 kb, covering the same region were then identified. The smallest region of overlap is 608kb. In addition another family of German decent is reported with adCD and the same duplication as the first German family. It is not known if they are distantly related. Segregation analysis on available members of all families showed the duplication in affected members and not in unaffected.

They find that IRX5, IRX6 and MMP2 are expressed in human adult retina. Several lincRNA within the locus are also expressed. In patient derived fibroblasts IRX5 and IRX6 showed increased expression levels. Over expression of IRX5 and IRX6 results in impaired visual performance in zebrafish larvae.

Loss of gene/small variants
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PMID: 28041643 - Carss et al 2017 - screened a cohort of 722 individuals with inherited retinal disease using WES/WGS. 1 case reported with a biallelic deletion in IRX5 reported which leads to a frameshift ENST00000394636.4; c.1362_1366delTAAAG, p.Lys455ProfsTer19 in a patient with retinitis pigmentosa.

PMID: 32045705 - Apuzzo et al 2020 - report 2 cases of loss of a region in 16q12.1q21 which encompasses IRX5 and IRX6 and many other genes, which together with 3 other previous reports of deletions in this region help define a syndrome with features that include dysmorphic features, short stature, microcephaly, global developmental delay/intellectual disability, autism spectrum disorder (ASD) and ocular abnormalities (nystagmus and strabismus).
Created: 7 Jul 2021, 12:54 p.m. | Last Modified: 28 Sep 2021, 12:52 p.m.
Panel Version: 2.216

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
cone dystrophy, MONDO:0000455; retinitis pigmentosa, MONDO:0019200

Publications

Mode of pathogenicity
Other

Gavin Arno (UCL Institute of Ophthalmology/Moorfields Eye Hospital)

I don't know

in carss et al 2017 as one of the biallelic LOF genes - not really enough to include. But this may be a real one
Created: 30 Aug 2019, 2:12 p.m. | Last Modified: 30 Aug 2019, 2:12 p.m.
Panel Version: 1.159

Louise Daugherty (Genomics England Curator)

Red List (low evidence)

Candidate IRD-associated gene from publication PMID:28041643. Gene containing _2 predicted protein-truncating alleles (High impact), including SVs that are likely to be biallelic. Genomic coordinates refer to genome build GRCh37.
Created: 17 Jan 2017, 5:13 p.m.

Phenotypes
Retinitis pigmentosa

Publications

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • NHS GMS
  • Literature
Phenotypes
  • cone dystrophy, MONDO:0000455
  • retinitis pigmentosa, MONDO:0019200
Tags
cnv Q3_21_rating Q3_21_expert_review
OMIM
606195
Clinvar variants
Variants in IRX5
Penetrance
Complete
Publications
Mode of Pathogenicity
Other
Panels with this gene

History Filter Activity

28 Sep 2021, Gel status: 1

Added Tag

Eleanor Williams (Genomics England Curator)

Tag Q3_21_expert_review tag was added to gene: IRX5.

7 Jul 2021, Gel status: 1

Set Phenotypes

Eleanor Williams (Genomics England Curator)

Phenotypes for gene: IRX5 were changed from cone dystrophy, MONDO:0000455 to cone dystrophy, MONDO:0000455; retinitis pigmentosa, MONDO:0019200

7 Jul 2021, Gel status: 1

Added Tag, Added Tag

Eleanor Williams (Genomics England Curator)

Tag cnv tag was added to gene: IRX5. Tag Q3_21_rating tag was added to gene: IRX5.

7 Jul 2021, Gel status: 1

Set Phenotypes

Eleanor Williams (Genomics England Curator)

Phenotypes for gene: IRX5 were changed from Retinitis pigmentosa to cone dystrophy, MONDO:0000455

7 Jul 2021, Gel status: 1

Set publications

Eleanor Williams (Genomics England Curator)

Publications for gene: IRX5 were set to 28041643

7 Jul 2021, Gel status: 1

Set mode of pathogenicity

Eleanor Williams (Genomics England Curator)

Mode of pathogenicity for gene: IRX5 was changed from to Other

7 Jul 2021, Gel status: 1

Set mode of inheritance

Eleanor Williams (Genomics England Curator)

Mode of inheritance for gene: IRX5 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

3 Apr 2019, Gel status: 1

Added New Source

Ivone Leong (Genomics England Curator)

Source NHS GMS was added to IRX5.

17 Jan 2017, Gel status: 0

Added New Source

Louise Daugherty (Genomics England Curator)

IRX5 was added to Posterior segment abnormalitiespanel. Sources: Literature

17 Jan 2017, Gel status: 0

Created

Louise Daugherty (Genomics England Curator)

IRX5 was created by LouiseD