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.

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