ALDH7A1

Inheritance Pattern: AR

Disease ID:MONDO:0020741

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0020741

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0020741

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0020741

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0009945

Submitter: ClinGen

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.

Inheritance Pattern: AR

Disease ID:MONDO:0009945

Submitter: Illumina

The ALDH7A1 gene is located on chromosome 5 at 5q23.2 and encodes the aldehyde dehydrogenase 7 family member A1 protein. This enzyme plays a key role in lysine metabolism and may indirectly regulate inhibitory neurotransmission in the brain by affecting pyridoxal 5’-phosphate-dependent synthesis. The ALDH7A1 gene was first reported in relation to autosomal recessive pyridoxine-dependent epilepsy in 2006 (16491085: Mills et al. 2006). Evidence supporting this gene-disease relationship includes case level data and experimental data. From a selection of the literature, at least eight variants, including missense, splicing, stop-gained, and one synonymous with a splicing effect, have been reported in either a homozygous or compound heterozygous state in seven individuals with pyridoxine dependent epilepsy (16491085 Mills et al. 2006; 17721876: Salomons et al. 2007). Considerably more case-level evidence is available in the literature (30043187: Coughlin et al. 2018), but the maximum score for genetic evidence (12 pts) has been reached. The mechanism of disease is homozygous loss of function; missense variants demonstrate an absent or reduced recombinant enzyme activity (22784480: Coulter-Mackie et al. 2012). A zebrafish Aldh7A1 knock out model recapitulates the biochemical deficiency, seizure phenotype, and mechanism of disease, as well as amelioration of disease features with pyridoxine treatment (29061647: Pena et al. 2017). In summary, the ALDH7A1 gene is definitively associated with autosomal recessive pyridoxine dependent epilepsy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

Inheritance Pattern: AR

Disease ID:MONDO:0009945

Submitter: Orphanet