Submission Details

The relationship between NAT8L and N-acetylaspartate deficiency (hypoacetylaspartia) was evaluated using the ClinGen Clinical Validity Framework as of October 7, 2020. NAT8L encodes N-acetyltransferase 8-like protein (also known as Aspartate N-acetyltransferase, NAA synthase), an enzyme highly expressed in neurons in the brain, which synthesizes N-acetylaspartate (NAA) from aspartate and acetylCoA. Of note, NAA is highly abundant in brain but its function is still not fully understood, despite extensive studies (Bogner-Strauss et al, 2017, PMID 28979238). The relationship between NAT8L and N-acetylaspartate deficiency is supported by case-level and experimental evidence. To date, only one individual with undetectable NAA in brain and variants in NAT8L has been reported (Wiame et al, 2009, PMID 19807691). This individual has the disease entity being curated for (i.e. N-acetylaspartate deficiency) and also severe neurological features including intellectual disability and seizures, and normal brain anatomy on MRI. Because only one case has been reported, it is not known if the NAA deficiency is responsible for the clinical features, or if the child could have another disorder as well. The child was adopted, with little information available on the parents, and the finding of a homozygous change in NAT8L in this patient raises the possibility of consanguinity. Experimental evidence supporting this gene-disease relationship includes the function of NAT8L (Wiame et al, 2009, PMID 19807691; Ariyannur et al, 2010, PMID 20385109) which is consistent with the biochemical findings in the single reported case; expression of NAT8L in neurons in the brain, where NAA is primarily found (Niwa et al, 2007, PMID 17626222); and reports of undetectable brain NAA in two different NAT8L knockout mouse models (Furukawa-Hibi et al, 2012, PMID 22940080; Maier et al, 2015, PMID 26511242). In summary, there is currently limited evidence to support the relationship between NAT8L and N-acetylaspartate deficiency. Although more evidence, specifically additional human cases, is needed to support the causal relationship, there is no convincing evidence that contradicts this gene-disease relationship.

This classification was originally approved by the Aminoacidopathy Gene Curation Expert Panel on October 23, 2020. This gene-disease relationship was re-evaluated on March 11, 2024. As a result of this re-evaluation, the classification did not change.