ARX – Non-syndromic X-linked Intellectual Disability

The aristaless-related homeobox gene ARX encodes a paired-type homeodomain transcription factor essential for forebrain interneuron development. Hemizygous loss-of-function and polyalanine expansion mutations in ARX underlie a spectrum of X-linked disorders, including non-syndromic X-linked intellectual disability (Non-syndromic X-linked intellectual disability, NS-XLID).

1 Assess Clinical Validity

ARX meets a Moderate ClinGen gene–disease validity for NS-XLID based on at least nine unrelated male probands in nine families with pathogenic variants, segregation in affected male relatives, and concordant functional data.

2 Genetic Evidence

NS-XLID is inherited in an X-linked recessive manner. In a cohort of 65 Iranian families, one family was found to harbor the recurrent 24 bp duplication, c.428_451dup (p.Gly143_Ala150dup) (PMID:22642246). In a broader screen of 613 individuals with intellectual disability, eight additional families were identified with ARX mutations (1.31%) across polyalanine expansions and homeodomain variants (PMID:21496008). Two affected male cousins with a null variant, c.81C>G (p.Tyr27Ter), demonstrate segregation in a single pedigree (PMID:19738637).

3 Variant Spectrum

Pathogenic alleles include polyalanine tract expansions (dup24, dup27, dup33), nonsense and frameshift truncations, and homeodomain missense changes. The recurrent c.428_451dup (p.Gly143_Ala150dup) accounts for ~40% of ARX-related cases. Missense mutations cluster in the paired-type homeodomain, correlating with phenotype severity.

4 Functional / Experimental Evidence

ARX operates as a Groucho/TLE-dependent transcriptional repressor. The c.98T>C (p.Leu33Pro) mutation abolishes TLE1 binding and relaxes repression, while polyalanine expansions enhance repression proportional to tract length (PMID:17331656). Homeodomain missense variants disrupt DNA binding and reduce repression of endogenous targets LMO1 and SHOX2 (PMID:22194193).

5 Animal Model

A knock-in mouse model carrying the human c.428_451dup24 allele exhibits hyperactivity, increased stereotypies, fine motor impairments, interneuron migration defects, and excitatory/inhibitory imbalance in the amygdala, mirroring NS-XLID phenotypes (PMID:29659809).

6 Integration and Conclusion

Combined genetic segregation, recurrent pathogenic variants, robust in vitro functional assays, and an informative mouse model support a Moderate gene–disease association between ARX and NS-XLID. Routine ARX molecular testing is recommended in male patients with familial non-syndromic intellectual disability. Key Take-home: ARX mutations are a clinically actionable cause of NS-XLID with established genetic and functional evidence informing diagnosis.

References

• Archives of Iranian medicine • 2012 • Mutational screening of ARX gene in Iranian families with X-linked intellectual disability. PMID:22642246
• Clinical genetics • 2011 • Screening and cell-based assessment of mutations in the Aristaless-related homeobox (ARX) gene. PMID:21496008
• Neuroscience • 2007 • Aristaless-related homeobox gene, the gene responsible for West syndrome and related disorders, is a Groucho/transducin-like enhancer of split dependent transcriptional repressor. PMID:17331656
• Human molecular genetics • 2012 • ARX homeodomain mutations abolish DNA binding and lead to a loss of transcriptional repression. PMID:22194193
• Human molecular genetics • 2018 • A new mouse model of ARX dup24 recapitulates the patients' behavioral and fine motor alterations. PMID:29659809

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