Human Gene Module / Chromosome 16 / IRX5

IRX5iroquois homeobox 5

SFARI Gene Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
2 / 3
Rare Variants / Common Variants
3 / 0
Aliases
-
Associated Syndromes
16q12.1-q21 deletion syndrome
Chromosome Band
16q12.2
Associated Disorders
-
Relevance to Autism

Whole genome and/or whole exome sequencing of 435 individuals in 116 ASD families in Viggiano et al., 2024 identified a de novo nonsense variant in the IRX5 gene in a male ASD proband who also presented with atypical language and borderline IQ. A de novo frameshift variant and a de novo in-frame deletion variant in this gene has previously been reported in a female SPARK proband and a male MSSNG proband, respectively, in Zhou et al., 2022. Apuzzo et al., 2020 reported that IRX5 was located with the minimal region of overlap in 16q12.1-q21 deletion syndrome, an extremely rare microdeletion syndrome characterized by dysmorphic features, short stature, microcephaly, eye abnormalities, epilepsy, development delay, intellectual disability, and autism spectrum disorder.

Molecular Function

This gene encodes a member of the iroquois homeobox gene family, which are involved in several embryonic developmental processes. Knockout mice lacking this gene show that it is required for retinal cone bipolar cell differentiation, and that it negatively regulates potassium channel gene expression in the heart to ensure coordinated cardiac repolarization. Hamamy syndrome (OMIM 611174) is an autosomal recessive disorder characterized by severe hypertelorism with midface prominence, myopia, intellectual disability, and bone fragility caused by homozygous mutations in the IRX5 gene, while cone dystrophy with early-onset tritanopic color vision defect (OMIM 619649) is a contiguous gene duplication syndrome on chromosome 16q12 involving the IRX5 gene.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to IRX5 (3 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support - Diletta Apuzzo et al. (2020) No -
2 Support - Zhou X et al. (2022) Yes -
3 Primary - Marta Viggiano et al. (2024) Yes ID
Rare Variants   (3)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.28C>T p.Gln10Ter stop_gained De novo - Simplex 38519481 Marta Viggiano et al. (2024)
c.232_234del p.Ala78del inframe_deletion De novo - Simplex 35982159 Zhou X et al. (2022)
c.1010dup p.Leu337PhefsTer119 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
Common Variants  

No common variants reported.

SFARI Gene score
3S

Suggestive Evidence, Syndromic

Score Delta: Score remained at 3S

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

7/1/2024
icon
3S

Increased from to 3S

Krishnan Probability Score

Score 0.49184523481413

Ranking 5001/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
Sanders TADA Score

Score 0.93778739618531

Ranking 13642/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score -0.58788464177296

Ranking 19829/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
Submit New Gene

Report an Error