Submission Details

The X-linked TMLHE gene encodes trimethyllysine dioxygenase, the first enzyme in the carnitine biosynthesis pathway. Celestino-Soper et al. (2011, PMID: 21865298) identified a deletion of exon 2 of TMLHE resulting in enzyme deficiency in a male with autism spectrum disorder (ASD). Subsequently, Celestino-Soper et al. (2012, PMID: 22566635) reported a total of 16 male ASD probands, 6 affected male siblings, and 24 healthy adult males with deletions of exon 2, indicating that this is a relatively common variant. The frequency of TMLHE deficiency in probands from simplex autism families (9 in 2,904 or 1 in 323) was not increased compared to control males (24 in 8,787 or 1 in 366). In agreement with these findings, TMLHE is not constrained for truncating variants (pLI = 0 in gnomAD v2.1.1). Therefore, these deletions were not scored. Three sequence variants resulting in TMLHE deficiency (nonsense, frameshift, and missense) have been reported in males with ASD (PMID: 23092983, 25943046). These variants were also not scored given the lack of evidence regarding their implication in ASD.

No experimental evidence was applicable to the relationship between TMLHE and autism. Reduced Tmlhe expression caused diminished neural stem cell pools in the mouse embryonic neocortex and carnitine supplementation rescued this phenotype (PMID: 26832401). In the absence of human genetic evidence linking TMLHE to autism, this experimental evidence was not scored. In summary, the genetic evidence reported thus far does not provide convincing evidence to support a role for TMLHE in ASD, so this gene-disease relationship was classified as disputed. This classification was approved by the ClinGen Intellectual Disability/Autism GCEP on the meeting date March 2, 2021 (SOP Version 8).