Submission Details

Variants in ABAT were first reported in association with an infantile epilepsy phenotype in 1984 by Jaeken et al. (PMID:6148708). This publication described a two-year-old patient with frequent convulsions, severe psychomotor retardation, hypotonia, and hyperreflexia. Cerebrospinal fluid amino acid analysis revealed a GABA transaminase deficiency. A sibling with similar features died in infancy. Subsequent reports from 1984 to the present day continue to support an association between ABAT and a rare genetic epilepsy condition. In total, nine subjects have been described. In all subjects, this condition was inherited in an autosomal recessive pattern (four homozygous from consanguinous parents; five heterozygous from non-consanguinous parents).

Summary of Case Level Data: In 1999, Medina-Kauwe et al. (PMID:10407778) reported a subject with a very similar phenotype to Jaeken et al., including seizures immediately after birth. Unfortunately, genetic information was limited (only noting a deletion in the 3’ end of ABAT), and so a minimal score of 0.1 was provided (i.e. unclear if a second variant was present in trans or not, fitting the autosomal recessive phenotype). Tsuji et al. (2010, PMID:20052547), Besse et al. (2015, PMID:27903293) and Nagappa et al. (2017, PMID:27596361) reported compound heterozygous variants in ABAT, inherited from non-consanguineous parents. Publications from Besse et al. (2015, PMID:25738457), Louro et al. (2016, PMID:27376954), Koenig et al. (2017, PMID:28411234) and Oshi et al. (2021, PMID:33768830) reported probands with homozygous missense variants. The cases from Koenig and Oshi were confirmed to be inherited from consanguineous parents. In all nine cases reported thus far, there is a clear ABAT phenotype, consisting of recurrent seizures that begin during infancy, uncontrolled limb movements, hyperreflexia, hypotonia, and accelerated linear growth with failure to thrive. Most do not survive past the first two years.

Cases were scored in line with the ClinGen SOP Ver. 8 guidelines for autosomal recessive variants, after consultation with its Epilepsy Expert Panel on April 19, 2022. Some adjustments were made, taking into account inheritance, genotyping methods used, and strength of the overall evidence.

Experimental Evidence: At this time, experimental evidence for this rare ABAT epilepsy phenotype is lacking. With time and additional case reports, experimental studies/functional analysis will clarify the impact of ABAT variants on cellular function and overall human disease seizure phenotype.

In summary, at present there is moderate case-level evidence to support a definitive classification for this gene-disease relationship. It must be noted that this is not due to insufficient strength of individual cases, but rather, an insufficient number of cases overall to reach definitive status under ClinGen scoring guidelines. As more reports and studies become available, it is likely confidence in this gene-disease association will only increase. A subsequent re-curation should be conducted in the future to incorporate any future cases into this existing curation, along with an updated score.