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Evidence from multiple genetic studies indicates that alterations in TMLHE (HGNC:18308), which encodes the first enzyme in carnitine biosynthesis, are associated with an increased risk for autism (MONDO_0005260). Several independent studies have identified copy number variants and sequence alterations in TMLHE among male probands diagnosed with autism, highlighting an association that is particularly evident in multiplex families. In one study, an exon 2 deletion was detected in a male proband with autism and additional affected male siblings, supporting a role for TMLHE deficiency in the disorder (PMID:22566635).
Genetic evidence for TMLHE involvement includes both copy number deletions and point mutations. Notably, a reported variant, c.730G>C (p.Asp244His), has been identified in affected individuals and is accompanied by other loss‑of‑function alleles such as a nonsense change (c.229C>T, p.Arg77Ter) and a missense alteration (c.1107G>T, p.Glu369Asp) (PMID:23092983). These findings are supported by segregation data in families, where multiple affected male relatives share the deleterious allele, thereby strengthening the genetic association with autism.
Functional studies provide a complementary perspective by demonstrating that TMLHE variants lead to reduced enzymatic activity and disrupted carnitine biosynthesis. In vitro assays and cellular models have shown that mutations in the TMLHE gene impair proper mitochondrial targeting and enzymatic function, which mechanistically supports the link between altered carnitine metabolism and neurodevelopmental defects observed in autism (PMID:15754339). Additionally, expression studies have elucidated the impact of alternative splicing and promoter regulation on TMLHE transcript levels, further emphasizing the complexity of its functional biology.
The cumulative evidence from case reports, familial segregation, and in-depth functional assays has led to a ClinGen gene‑disease association score in the moderate range for TMLHE and autism. This classification is based on the presence of sequence-level and copy number alterations in independent probands (with at least 11 probands reported overall (PMID:22566635; PMID:23092983)) and the robust experimental data showing loss‑of‑function effects in cellular systems.
Although the penetrance of TMLHE variants appears to be low (estimated at 2–4%), the convergence of genetic and functional evidence supports its role as a risk factor for nondysmorphic autism. The observed segregation among affected siblings in multiplex families underscores the relevance of familial studies in establishing genetic risk. Moreover, while additional factors likely contribute to the overall etiopathogenesis of autism, the specific disruption in carnitine metabolism attributable to TMLHE variants offers a targeted mechanism that may be explored for diagnostic and therapeutic strategies.
In summary, the genetic and functional data provide a coherent narrative linking TMLHE deficiency to autism, justifying its consideration in diagnostic evaluations and offering a foundation for future research. Key take‑home message: The integration of genetic alterations and functional assay results in TMLHE supports its role as a moderate‐risk factor for autism, underscoring its potential clinical utility in risk assessment and tailored management strategies.
Gene–Disease AssociationModerateMultiple independent studies report TMLHE deletions and sequence mutations in affected male probands with supportive family segregation data (PMID:22566635, PMID:23092983). Genetic EvidenceModerateThe identification of pathogenic copy number variants and point mutations, such as c.730G>C (p.Asp244His), in multiple probands and affected relatives provides moderate genetic support. Functional EvidenceModerateIn vitro and cellular studies have consistently demonstrated that TMLHE pathogenic variants impair enzymatic activity and disrupt carnitine biosynthesis, concordant with neurodevelopmental phenotypes (PMID:15754339). |