Variants in HOXA1 were first reported in humans with autosomal recessive syndromic intellectual disability as early as 2003 (Holve et al., PMID:12833395). Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least 4 variants (e.g. nonsense and frameshift) have been reported in humans. Variants in this gene have been reported in at least 16 probands in 3 publications (12833395, 16155570, 18412118). Variants in this gene segregated with disease in 8 additional family members. All affected individuals identified thus far are Saudi Arabian, Turkish, or Native American, and the authors asserted that the variants associated were likely founder variants. The mechanism for disease is homozygous loss of function. Of note, this gene has also been implicated in brain malformation. This will be assessed separately. This gene-disease association is supported by expression studies and animal models. In summary, HOXA1 is definitively associated with autosomal recessive syndromic intellectual disability. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 6/19/19 (SOP Version 6).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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