Clinical Genetic Clues to the Origins and Outcomes of Autism Spectrum Disorders

Background: The Autism Spectrum Disorders (ASDs) are the most common childhood developmental disorder. Despite high prevalence (>1/150 births) and clear evidence that early interventions can improve the adverse developmental and behavioural sequelae, ASDs are often not recognized until children reach 3 years of age or older. The population of individuals with ASDs is extremely heterogeneous in regards to clinical present­ation, concurrent disorders, co-morbidities and developmental outcomes. In some (up to 40%) cases, ASD are recognized as a component of a specific medical, genetic or chromo­somal disorder, and/or occur in association with identifiable teratogenic embryopathies. In most others, no specific genetic or medical etiologic diagnosis is apparent. Affected children can have seizures, co-existing psychiatric disorders, intellectual disability, immune, gastrointestinal disturb­ances, and major or minor physical anomalies that often occur as clusters of signs and symptoms (i.e., show patterns), suggesting syndromic relationships to each other and to ASDs.
Objectives: By identifying early, reliable biomarkers and mechanisms of ASD susceptibility, etio­logy and co-morbid­ity, we aim to enable earlier individualized treatments for improved outcomes, individual function and full quality of life for affected individuals. Our research program targets largely unexplored clusters/syndromic physio­logic co-morbidities of ASDs and is designed to address the overall hypothesis that they serve as clues for under­standing critical health similarities and differences among individuals with ASD.
Methods: To narrow our focus to the most informative co-morbidities serving as embryological antecedents of ASD susceptibility and/or etiology, we applied a series of standardized clinical genetic tools that allow for the selection of specific genetic, medical and teratogenic conditions known to co-exist with ASDs amongst a randomly selected cohort of > 450 individuals with an ADOS-G and ADI-R confirmed ASD. All individuals received comprehensive clinical genetics consultation including review of family, medical, psychiatric and developmental history with thorough dysmorphology exam, including 3D craniofacial and selective EEG and neurostructural imaging. Clinical investigations included Fragile X, karyotype, subtelomeric, and targeted FISH testing of autism-associated loci at 2q37, 7q11, 15q11, 22q11, 22q13 in all subjects. Targeted biochemical studies screened for ASD-associated inborn errors of metabolism, including mitochondrial or other neuropathies coincident with ASD. Samples were also taken for the purpose of high resolution CGH-microarray analysis in separate studies.
Results: Data were analyzed to identify and compare essential (non-syndromic/nondysmorphic) or complex (syndromic/dysmorphic) ASD subgroups that clearly differed in etiology, co-morbidities, outcome and genetic measures. Comprehensive clinical genetic assess­ments revealed syndromic co-morbidities encompassing intellectual disability (ID), craniofacial, systemic, growth and neuroclinical  anomalies [seizures, hearing, vision, psychiatric] within ASD subgroups commonly predictive of ASD-associated genetic, chromosomal, genomic, syndromic and non-syndromic disorders.
Conclusions: By identifying several cases sharing the same phenotypic pattern of symptoms, co-morbidities and/or clinical genetic/syndromic contributors to ASDs, we can begin to generate HealthCare Watches to facilitate optimal anticipatory management and functional outcomes for individuals and families living with ASDs. Our findings aim to set the standard for Clinical Genetic and Child Health Services critical to recognizing and managing brain and body features/co-morbidities of autism to improve individualized therapies and management over the life course.