Intracytoplasmic Sperm Injection and Autism Risk: an Epigenetic Connection?

A JAMA paper by Sandin et al looked at neurodevelopmental differences in IVF and non-IVF children, and considered differences between IVF methods. There were slight trends, but no significant differences, associating autism and retardation in all IVF-produced children (RRs 1.14 and 1.18). The big news was the RR increase in intracytoplasmic sperm injection (ICSI, where sperm DNA is injected into eggs): for autism and retardation the RR was 4.6 and 2.35, both statistically significant. The obvious confounder here would be age but they controlled for it.

A few speculative ideas about what could explain these findings:

- epigenetic changes resulting from ICSI relative to normal sperm penetration and genome delivery. This could be due to changes introduced by the handling of the sperm and genetic material or because of lack of a physiologic egg penetration event resulting in aberrant methylation
- co-occurring diseases influencing both sperm mobility/penetrance and neuronal migration. There are known syndromes where defects cause loss-of-function in both sperm and lung cilia. Bypassing defective DNA delivery by sperm in individuals who are heterozygous recessive, have a de novo mutation or are mosaic would allow these to appear in the offspring.
- mechanical damage caused to chromosomes by the injection process
- damage to the membrane from the injection process influencing neurodevelopment in ways we don't yet understand


If the first bullet at least partly explains the problem, we now have an unfortunate set of natural experiments to investigate the speculated relationship between epigenetics and neuropsychiatric illness. GWAS studies on these diseases have produced frustrating few replicable results. We now know that non-coding regions of the genome do produce RNAs that are more likely to come from disease-associated SNPs outside open reading frames, and specifically in some cases are associated with neuropsychiatric disease, possibly we can start to connect the dots.


References:

Sven Sandin, Karl-Gösta Nygren, Anastasia Iliadou, Christina M. Hultman, Abraham Reichenberg. Autism and Mental Retardation Among Offspring Born After In Vitro Fertilization. JAMA. 2013;310(1):75-84.

Matthew J. Hangauer, Ian W. Vaughn, Michael T. McManus. Pervasive Transcription of the Human Genome Produces Thousands of Previously Unidentified Long Intergenic Noncoding RNAs. PLoS Genetics, 2013; 9 (6).

Alexander D. Ramos, Aaron Diaz, Abhinav Nellore, Ryan N. Delgado, Ki-Youb Park, Gabriel Gonzales-Roybal1, Michael C. Oldham, Jun S. Song, Daniel A. Lim. Integration of Genome-wide Approaches Identifies lncRNAs of Adult Neural Stem Cells and Their Progeny In Vivo. Cell Stem Cell, Volume 12, Issue 5, 2 May 2013, Pages 616–628.