Abstract
Unlike some other childhood neurodevelopmental disorders, no diagnostic biochemical marker has been identified in all individuals with an autism spectrum disorder (ASD). This deficit likely results from genetic heterogeneity among the population. Therefore, we evaluated a subset of individuals with ASDs, specifically, individuals with or without macrocephaly in the presence or absence of PTEN mutations. We sought to determine if amino or organic acid markers could be used to identify individuals with ASDs with or without macrocephaly in the presence or absence of PTEN mutations, and to establish the degree of macrocephaly in individuals with ASDs and PTEN mutation. Urine, blood and occipital–frontal circumference (OFC) measurements were collected from 69 individuals meeting DSM-IV-TR criteria. Urine and plasma samples were subjected to amino and organic acid analyses. PTEN was Sanger-sequenced from germline genomic DNA. Germline PTEN mutations were identified in 27% (6/22) of the macrocephalic ASD population. All six PTEN mutation-positive individuals were macrocephalic with average OFC+4.35 standard deviations (SDs) above the mean. No common biochemical abnormalities were identified in macrocephalic ASD individuals with or without PTEN mutations. In contrast, among the collective ASD population, elevation of urine aspartic acid (87%; 54/62), plasma taurine (69%; 46/67) and reduction of plasma cystine (72%; 46/64) were observed. PTEN sequencing should be carried out for all individuals with ASDs and macrocephaly with OFC ≥2SDs above the mean. A proportion of individuals with ASDs may have an underlying disorder in sulfur amino acid metabolism.
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Acknowledgements
We wish to acknowledge the contributions of the Genomic Medicine Biorepository, Genomic Medicine Institute, Cleveland Clinic for preparation of genomic DNA, and processing of blood and urine samples, the Eng lab and the Genomics Core Facility, Genomic Medicine Institute, Cleveland Clinic, for PCR-based Sanger sequencing and MLPA analyses. This work was funded in part, by the Pediatrics Institute Strategic Investment Funds, Cleveland Clinic (to TWF) and Breast Cancer Research Foundation (to CE). CE is the Sondra J and Stephen R Hardis Endowed Chair of Cancer Genomic Medicine at the Cleveland Clinic, and holds an American Cancer Society Clinical Research Professorship, generously funded, in part, by the FM Kirby Foundation.
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Dr Frazier has received federal funding or research support from, acted as a consultant to, received travel support from, and/or received a speaker’s honorarium from the Simons Foundation, Forest Laboratories, Ecoeos, IntegraGen, Shire Development, Bristol-Myers Squibb, National Institutes of Health, and the Brain and Behavior Research Foundation. Ms. Embacher has received funding from IntegraGen. Dr Eng is co-PI of a sponsored research agreement from IntegraGen and is an unpaid member of the external advisory boards of Ecoeos.com, GenomOncology and Complete Genomics, Inc. The remaining authors declare no conflict of interest.
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Hobert, J., Embacher, R., Mester, J. et al. Biochemical screening and PTEN mutation analysis in individuals with autism spectrum disorders and macrocephaly. Eur J Hum Genet 22, 273–276 (2014). https://doi.org/10.1038/ejhg.2013.114
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DOI: https://doi.org/10.1038/ejhg.2013.114
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