2009 Faculty Researchers

Judith Miles, MD, PhD

Delineation of the Genetic Basis and Heterogeneity of Autism

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Department

Thompson Center for Autism & Neurodevelopmental Disorders; Div. Medical Genetics, Dept. Child Health

Office Location

Thompson Center, Research and Training Pavilion, 400 Keene, (right next to Columbia Regional Hospital)

Phone #:

Office: (573) 882-8933
Fax: (573) 884-1151

Website:

thompsoncenter.missouri.edu

Summary

Understanding complex behavioral disorders is an exciting area of modern genetic research. Autism spectrum disorders affect 1/150 children and are highly genetic (heritability index over 90%). However, the genetics is complex and obfuscated by clinical heterogeneity, incomplete penetrance and difficulty quantitating behavioral phenotypes. We are working to delineate the clinical and genetic heterogeneity within the autism behavioral diagnosis and use this information to improve diagnosis, to find specific genetic and epigenetic causes and to direct treatment choices which will improve outcomes. One project has determined that the primary step in the delineation of autism subgroups is to determine whether an individual has essential or complex neurodevelopmental autism. About 30% of individuals with autism have the complex phenotype, which is diagnosed on the basis of a pattern of physical dysmorphology, indicating an alteration in early morphogenesis. The remainder has essential autism that is not associated with a clear insult to morphogenesis and occurs with a higher male to female ratio and higher sib recurrence risk. We are studying variable autism phenotypes, biological endophenotypes, and ultimately the abnormal genes themselves in these groups. Data on over 700 autism patients and their families seen at the Autism Center are available for study through a relational database, which includes data on pregnancies, health, autistic symptoms, diet, family history, physical, neurologic and dysmorphology exams, and all test results (EEGs, MRIs, chromosomes, metabolic studies). We are currently working on projects to describe complex phenotypes with dysmorphology and a specific facial structure, determine the relationship of brain morphology to autism phenotypes, the role of macrocephaly, pupillary response endophenotype, and how girls are protected from developing autism. The specific summer project will involve a detailed study of one aspect of autism research and will be directed to preparing an abstract for the annual International Society for Autism Research meeting. Work will include examination of autistic children and their families, literature review of aspects of autism, data collection and analysis of data.

Examples of summer projects include, but not limited to:

1. Analysis of the differences in recurrence risks for siblings of children with various subset of autism. We know that recurrence risks are lower if the ASD child has complex autism and that risks over all are less for girls.
2. Males are affected with autism 4 -7 times females and affected females are generally less severely affected. Many avenues of study can be applied to trying to sort out why, including assessment of growth patterns, onset of puberty, and investigation of hormonal differences.
3. A subset of children with autism regress in teenage years. Recent studies describe a catatonia-like syndrome and we have identified other medical problems including the development of celiac disease causing late regression. This project would determine in our population the prevalence of regression and develop a differential of causes that should be addressed with these patients.
4. Investigate the clinical relevance of a new autism endophenotype, the Pupillary Light Reflex.
5. Investigate the relationship between various autism phenotype and specifically prove that IQ and dysmorphology are separate indicators of subgroup designation.