The relationship between ALDH7A1 and pyridoxine-dependent epilepsy (PDE) was evaluated using the ClinGen Clinical Validity Framework as of June 28th, 2019. Patients with this same condition have also been reported as having folinic acid responsive seizures (Gallagher et al, 2009, PMID 19142996). ALDH7A1 encodes alpha-aminoadipic acid semialdehyde dehydrogenase, also known as antiquitin, which converts alpha-aminoadipic acid semialdehyde (AASA) to alpha-aminoadipic acid, a critical step in lysine catabolism. Variants in ALDH7A1 causing PDE were first reported by Mills et al, 2006 (PMID 16491085). Since then, over eighty PDE-associated variants have been reported in ALDH7A1 (see Pena et al, 2017, PMID 30058881, for review). Data from 10 patients with 9 unique variants (missense, nonsense, frameshift, and splicing) from 2 publications were curated (Mills et al, 2006, PMID 16491085; Salomons et al, 2007, PMID 17721876). Additional cases are available in the literature but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is supported by the biochemical function of alpha-aminoadipic acid semialdehyde dehydrogenase (antiquitin), which is consistent with the biochemical and clinical features of the disease (Mills et al, 2006, PMID 16491085), expression in brain (Jansen et al, 2014; PMID 24122892), functional studies of missense variants (Coulter-Mackie et al, 2012, PMID 22784480), and the phenotype observed in two CRISPR-generated aldh7a1 zebrafish models (Pena et al, 2017; PMID 29061647; Zabinyakov et al, 2017, PMID 29053735). Additional experimental data supporting the gene-disease relationship is available but the maximum score for experimental evidence (6 points) has been reached. Data curated by Illumina is included in this curation. In summary, ALDH7A1 is definitively associated with autosomal recessive PDE. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on July 26, 2019.
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