Advanced Maternal Age and Autism Spectrum Disorders (ASDs): The Role of Covert Mosaicism, Uniparental Disomy, and DNA Methylation in the Etiology of ASDs

Thursday, May 17, 2012
Sheraton Hall (Sheraton Centre Toronto)
11:00 AM
E. R. Berko1, F. Beren2, M. Suzuki3, S. Molholm4, J. J. Foxe4, R. W. Marion5 and J. M. Greally3, (1)Dept of Genetics, Albert Einstein College of Medicine, Bronx, NY, (2)Stern College for Women of Yeshiva University, New York, NY, (3)Dept of Genetics and Center for Epigenomics, Albert Einstein College of Medicine, Bronx, NY, (4)Dept of Pediatrics & Neuroscience, Albert Einstein College of Medicine, Bronx, NY, (5)Dept of Pediatrics, Albert Einstein College of Medicine, Bronx, NY
Background: Recent reports have demonstrated the correlation between increasing rates of autism prevalence and advanced parental age, suggesting that mechanisms involved in pathology of the aging germline may contribute to the etiology of Autism Spectrum Disorders (ASDs). While the effects of paternal age, namely higher rates of mutation and copy number variation in offspring, have indeed been linked to ASDs, no study has determined the potential role of maternal age.  We propose that maternal non-disjunction and resulting aneuploidy, as well as tissue specific epigenetic changes, could cause ASDs and remain undetected.  Since most aneuploidies are lethal embryonically, surviving offspring often undergo a “rescue” event that restores normal chromosome number.  Depending on when an aneuploidy rescue occurs and which chromosome is lost, offspring exhibit either covert mosaic aneuploidy in sub-populations of cells or heterodisomic uniparental disomy (UPD).  These defects are unlikely to be detected by current genetic approaches that utilize cultured blood, a tissue that demonstrates low or absent levels of aneuploidy in mosaic individuals.  While baseline rates of covert mosaicism in the general population are unknown, recent studies have demonstrated that up to 50% of IVF-generated embryos possess a chromosomal aneuploidy in some cells.  Additionally, epigenetic modifications can become dysregulated during aging, and may therefore induce subtle epigenetic differences that could contribute to ASDs.


  1. To determine if the prevalence of UPD and mosaicism in children with ASDs born to mothers 35 and older is higher than control, typically developing children born to mothers in the same age range.
  2. To study the epigenetic differences in CG methylation in children with ASDs born to older mothers versus control, typically developing children born to mothers 35 and older.

Methods: For this study, we have assembled a unique, culturally diverse patient cohort of typically developing children and children with ASDs born to mothers 35 and older.  We collected DNA from the subjects’ buccal epithelium, a tissue of the same embryonic ectodermal lineage as neurons; a recent study of mosaic trisomy proved buccal epithelium to be a better predictor of brain chromosomal status than blood.  To detect mosaic trisomy and UPD we are employing SNP arrays, and have optimized a computational approach to accurately discover these events.  We are concurrently analyzing the same buccal epithelial samples using methylation arrays to study potential DNA methylation differences in these populations, as buccal cells may serve as better indicators of brain tissue methylation status.

Results: We are currently completing the molecular assays on our entire patient cohort and are expecting completed results in the next 2-3 months.

Conclusions: The discovery of higher rates of mosaicism, UPD, or epigenetic dysregulation in our ASD cohort will significantly enhance our understanding of the etiology of ASDs, especially in the population of older mothers.  The results may also help better direct therapeutic interventions in affected children with an ASD attributed to one of these genetic or epigenetic events.

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