Ingrid Tein, Anne-Marie Lamhonwah, Mehdi Zarrei, Evdokia Anagnostou, Stephen Scherer

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. Keywords: carnitine transporter and biosynthesis genes, ASD Ingrid Tein The Hospital for Sick Children, University of Toronto Canada Anne-Marie Lamhonwah The Hospital for Sick Children, University of Toronto Canada Mehdi Zarrei The Hospital for Sick Children, University of Toronto Canada Evdokia Anagnostou Holland Bloorview Kids Rehabilitation Hospital, University of Toronto Canada Stephen Scherer The Hospital for Sick Children, University of Toronto Canada