Open Access Highly Accessed Research article

Heterozygous FA2H mutations in autism spectrum disorders

Isabelle Scheid123, Anna Maruani123, Guillaume Huguet12, Claire S Leblond12, Gudrun Nygren4, Henrik Anckarsäter5, Anita Beggiato1236, Maria Rastam5, Fréderique Amsellem37, I Carina Gillberg4, Monique Elmaleh8, Marion Leboyer67, Christopher Gillberg49, Catalina Betancur101112, Mary Coleman13, Hiroko Hama14, Edwin H Cook15, Thomas Bourgeron1162 and Richard Delorme123*

Author Affiliations

1 Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France

2 CNRS URA2182, Paris, France

3 APHP, Robert Debré Hospital, Child and Adolescent Psychiatry, Paris, France

4 Gillberg Neuropsychiatry Centre, Gothenburg University, Göteborg, Sweden

5 Department of Clinical Sciences, Lund University, Lund, Sweden

6 Fondation FondaMental, French National Science Foundation, Creteil, France

7 INSERM U955, Psychiatry Genetics, Créteil, France

8 APHP, Robert Debré Hospital Paediatric Imaging, Paris, France

9 Institute of Child Health, University College London, London, UK

10 INSERM U952, Paris, France

11 CNRS UMR7224, Paris, France

12 UPMC Univ Paris 06, Paris, France

13 Foundation for Autism Research, Sarasota, Florida 34235-7117, USA

14 Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA

15 Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Illinois, USA

16 University Denis Diderot Paris 7, 75013 Paris, France

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BMC Medical Genetics 2013, 14:124  doi:10.1186/1471-2350-14-124

Published: 3 December 2013



Widespread abnormalities in white matter development are frequently reported in cases of autism spectrum disorders (ASD) and could be involved in the disconnectivity suggested in these disorders. Homozygous mutations in the gene coding for fatty-acid 2-hydroxylase (FA2H), an enzyme involved in myelin synthesis, are associated with complex leukodystrophies, but little is known about the functional impact of heterozygous FA2H mutations. We hypothesized that rare deleterious heterozygous mutations of FA2H might constitute risk factors for ASD.


We searched deleterious mutations affecting FA2H, by genotyping 1256 independent patients with ASD genotyped using Genome Wide SNP arrays, and also by sequencing in independent set of 186 subjects with ASD and 353 controls. We then explored the impact of the identified mutations by measuring FA2H enzymatic activity and expression, in transfected COS7 cells.


One heterozygous deletion within 16q22.3-q23.1 including FA2H was observed in two siblings who share symptoms of autism and severe cognitive impairment, axial T2-FLAIR weighted MRI posterior periventricular white matter lesions. Also, two rare non-synonymous mutations (R113W and R113Q) were reported. Although predictive models suggested that R113W should be a deleterious, we did not find that FA2H activity was affected by expression of the R113W mutation in cultured COS cells.


While our results do not support a major role for FA2H coding variants in ASD, a screening of other genes related to myelin synthesis would allow us to better understand the role of non-neuronal elements in ASD susceptibility.

Autism; Brain; Gene; Myelin