Mendeliome
Gene: IRX5 Green List (high evidence)Green List (high evidence)
Third family with Hamamy syndrome and homozygous missense variant reported, p.Arg168His. Two cousins, >4 meioses, good segregation data.
4th family as part of large heterogenous cohort of consanguineous families also reported with homozygous frameshift (last exon), but limited phenotypic data.Created: 7 Mar 2022, 11:14 p.m. | Last Modified: 7 Mar 2022, 11:14 p.m.
Panel Version: 0.11189
Two families reported with Hamamy syndrome, some functional data.
Association with cone dystrophy relates to CNV data only, two genes included.Created: 9 Jul 2021, 4:48 a.m. | Last Modified: 9 Jul 2021, 4:48 a.m.
Panel Version: 0.8296
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Hamamy syndrome, MIM# 611174
Publications
Green List (high evidence)
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
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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 function/gene
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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, 1 p.m. | Last Modified: 8 Jul 2021, 1:41 p.m.
Panel Version: 0.8292
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
cone dystrophy, MONDO:0000455; retinitis pigmentosa, MONDO:0019200
Publications
Mode of pathogenicity
Other
Publications for gene: IRX5 were set to 27453922; 33891002; 28041643; 32045705; 22581230; 17230486
Mode of pathogenicity for gene: IRX5 was changed from to None
Gene: irx5 has been classified as Green List (High Evidence).
Gene: irx5 has been classified as Amber List (Moderate Evidence).
Tag SV/CNV tag was added to gene: IRX5.
Phenotypes for gene: IRX5 were changed from to Hamamy syndrome, MIM# 611174; cone dystrophy, MONDO:0000455
Publications for gene: IRX5 were set to
Mode of inheritance for gene: IRX5 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Gene: irx5 has been classified as Amber List (Moderate Evidence).
gene: IRX5 was added gene: IRX5 was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: IRX5 was set to Unknown
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at panelapp@genomicsengland.co.uk
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.