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In this video Dr. Stephan Sanders Presents: SYNGAP1 in the Developing Human Cortex.
Dr. Sanders speaks to us with experience in a number of different roles related to patients with developmental disabilities and autism spectrum disorder. He was first a pediatrician in his home country, the United Kingdom. In 2007, he and his wife moved to the United States where he signed on for a postdoctoral research position at Yale in Dr. Matthew State’s lab and completed his PhD work. He is currently an Assistant Professor at UCSF in the Department of Psychiatry.
Dr. Sanders’ work in genetics has been instrumental in developing our understanding of how de novo mutations are associated with autism spectrum disorder. Working with the Simons Simplex Collection, exome sequencing was used to develop early methods for identifying genes linked to autism. Further down the line, Sanders lab has prioritized characterizing and studying in depth genes which are strongly associated with ASD. Notably, his lab’s work on SCNA2 has combined genetic data with knowledge about the protein’s structure to understand both the gain and loss of function mutations and the differing phenotypes that they produce.
Sanders has continued to contribute to elucidating genetic links to autism by combining multiple cohorts including copy number variant data and exome data. In 2015 he published a paper identifying 71 risk loci for autism and SYNGAP1 was included as a risk gene. His lab is broadening our understanding further by developing and applying new statistical methods to analyze non-coding regions of the genome to illuminate the pathways in gene regulation which may contribute to autism.
His pioneering work in genetics has benefitted many patient communities and we are appreciative for him sharing with us today about that as well as some of his specific knowledge on SYNGAP1.
Chapters:
00:00 Welcome and introduction to the work of Dr Stephan Sanders
02:50 Overview of talk
03:35 Exome sequencing identifies de novo mutations in protein coding genes
05:26 In cases, these mutations accumulate in genes that contribute to risk of a disorder
06:16 Analysis of 35,584 samples identifies 102 genes associated with ASD
09:13 ASD genes fall into two major functional groups: gene expression regulation and neuronal communication
10:06 Many neuronal communication genes associated with ASD are specific to the brain
11:07 SYNGAP1 is expressed throughout the body, including. brain and the pituitary gland
16:06 ASD genes are highly enriched in the brain, especially the developing human cortex
18:14 SYNGAP1 has an unusual expression trajectory across development; it falls during childhood
21:55 Increasing expression or function should improve symptoms in SYNGAP1 loss-of-function mutations
26:51 CRISPRa can activate the remaining allele to restore function in haploinsufficient disorders
31:00 SYNGAP1 has long and short isoforms; few patient mutations are seen in the axons at the start or end
36:01 SYNGAP1 isoforms have opposing effects on synaptic strength; which effect needs to be increased?
43:18 Summary
47:19 Questions & Answers
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