by Catherine Ziats, MD
Researcher, Author
Below is a summary of our research article entitled ‘Functional genomics analysis of Phelan-McDermid syndrome 22q13 region during human neurodevelopment’ published in PLoS ONE March 2019. You may read the full article here.
Phelan-McDermid syndrome (PMS) is a neurogenetic condition that frequently results from terminal deletions of chromosome 22. Loss of SHANK3 explains many of the problems associated with deletions, however, the clinical presentation is variable.
Evidence from other studies (deletion size, probability of loss-of-function intolerance and interstitial deletions) suggest that problems may arise from multiple genes of 22q13. More work is needed to characterize the impact of these genes, especially their impact on human brain development. We set out to improve our understanding the distinct contributions of SHANK3, and the other genes of 22q13, to brain development.
To better understand PMS genes, we analyzed gene expression of 65 PMS genes that cover up to 7.7 Mb of chromosome 22. We analyzed RNA from post-mortem brain tissue of neurologically normal donors whose ages spanned pre-conception through adulthood. This type of analysis tells us which genes are being used during brain development, where in the brain they are being used, and which ones are being used the most. Because PMS results in neurodevelopmental problems, we reasoned that this information will help highlight which genes might contribute most to the condition.
Our results show that most PMS genes are active in the brain at some point during development, especially in the early post-natal period. The early post-natal period is a time when the neurons have already been formed, but the connections (“wiring”) between neurons are being established and refined. While most areas of the brain had similar patterns of gene expression, the timing of cerebellum development appears unique. The cerebellum is important for smooth and accurate movement, and may also be important for cognitive tasks. Our new finding agrees with growing evidence that the cerebellum is important for understanding neurodevelopmental disorders. We also found four genes that stood out above the rest. These four genes may play a particularly important role in PMS.
Overall, our study suggests that in addition to SHANK3 there are many genes from the chromosome 22 PMS region that are expressed dynamically in the human brain during neurodevelopment. Four of these genes (ATXN10, MLC1, SULT4A1 and MAPK8IP2) are found at especially high levels during development. Further exploration of these genes may lead to greater insight into the variable nature of PMS.