AHI1 was first reported in relation to autosomal recessive Joubert Syndrome in 2004 (Ferland et al., PMID: 15322546; Dixon-Salazar et al., PMID: 15467982). The clinical features reported are consistent with Joubert syndrome with intellectual disability and brain imaging findings of molar tooth sign and cerebellar vermian hypoplasia. Additional features associated with AHI1 include polymicrogyria and a higher incidence of ocular disease (e.g. retinitis pigmentosa) compared to other genes associated with Joubert Syndrome. Liver disease and polydactyly are uncommon in AHI1 associated conditions. Six variants (missense, in-frame indel, frameshift) reported in six unique probands in three publications (PMID: 25616960, 15322546, 16453322) are included in this curation. More evidence is available in the literature, but there is sufficient evidence to classify this gene-disease pair as definitive. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by experimental evidence from a zebrafish model (PMID: 25616960), a knockout mouse model (PMID: 21623382), and biochemical functional data (PMID: 23532844). In summary, AHI1 is definitively associated with autosomal recessive Joubert Syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification has been approved by the Brain Malformations GCEP on 10/26/2021.
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