Submission Details

ARX has been reported in association with multiple X-linked recessive neurodevelopmental disorders including: intellectual disability, epilepsy, and Partington syndrome (PMIDs: 29659809, 30945278, 26029707, 12177367, 32383243, 17641262). ARX has previously been evaluated for its relationship with early-onset infantile encephalopathy by the ClinGen Epilepsy Gene Curation Expert Panel, focusing on individuals with seizure onset prior to three months of age. That gene-disease relationship was determined to be definitive on 6/21/19. This curation, specifically evaluating evidence to support a role for ARX in X-linked complex neurodevelopmental disorder, focuses on individuals with intellectual disability with or without seizures occurring later than 3 months of age, as well as individuals diagnosed with Partington syndrome, which is characterized by focal dystonia in addition to neurodevelopmental presentations. Notably, ARX has also been associated with X-linked lissencephaly, hydranencephaly with abnormal genitalia and Proud syndrome, all of which are outside the scope of work for this group and therefore were not included. Case-level, segregation and experimental data support this gene-disease relationship. At least 32 variants (missense, nonsense, duplication, deletion, etc.) have been reported in patients (PMID:16650978). To date no definitive genotypic-phenotypic correlation has been established, however, truncating variants have been associated with more severe phenotypes such as lissencephaly and missense variants have been associated with milder phenotypes such as non-syndromic intellectual disability (PMID: 16650978). The 24 polyalanine expansion, c.428_451dup, has been identified in approximately 40% of all ARX-related cases; the patients often present with intellectual disability (PMID: 16650978). Of the probands scored in this curation, 8 had a global developmental delay, 4 had intellectual disability, and 3 had epilepsy with seizure onset ranging from infancy to 3 years. Two probands were diagnosed with Partington syndrome. Relevant experimental data includes two mouse models and expression studies (PMIDs: 29659809, 19605412, 12359145). In summary, ARX is definitively associated with X-linked complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 12/1/2020.