Identification of candidate genetic susceptibility variants in the carnitine (Cn) transporter and carnitine biosynthesis gene families in Autism Spectrum Disorder: A novel precision medicine target

Background: That brain Cn deficiency might lead to ASD has been suggested by reports of severe Cn deficiency in ASD and by evidence that TMLHE deficiency is a risk factor for ASD supporting a mixed, common gene variant-environment hypothesis; male predominance may relate to X-linked SLC6A14 whose inactivation could limit transport of Cn across the blood-brain barrier. It has been proposed that 10-20% of nonsyndromic ASD involving extreme male bias may develop due to early brain Cn deficiency that may be amenable to early reversal and prevention. Objective: To identify predicted loss-of function variants and copy number variations in the Cn transporter (SLC22A4, SLC22A5, SLC6A14) and Cn biosynthesis (TMLHE, BBOX1) genes that are enriched in individuals with ASD. Methods: We surveyed for variants in our target genes that were enriched in ASD cases in the Autism Speaks MSSNG and Simons Simplex Cohort genomes (n= 7,642) compared to typically developed, healthy controls (n=7,000). Results: We identified 20 deletions ranging from 6.4 kb to 189 kb in TMLHE, which are heterozygous in 7 females (one a triplication; 3 paternally inherited) and hemizygous in males (all maternally inherited) and one deletion of 10kb in SLC22A5 in a male (paternal inheritance). There were 17 rare heterozygous, inherited loss-of-function mutations impacting the SLC22A4, SLC22A5, and BBOX1 genes. Conclusions: Early identification of children with ASD and dysregulation of Cn homeostasis with implementation of L-Cn tx should improve the clinical phenotype via the roles of Cn in cerebral bioenergetics, cholinergic neurotransmission, and neuroprotection affecting early brain development.