Dr. Jonathan Pevsner discusses the impact of Bionano on his autism genomics research. Autism is a neurodevelopmental disorder that affects millions of children and adults worldwide. There is ample evidence that structural variations, including large chromosomal rearrangements and copy number variants, are major contributors to the disorder.
Dr. Pevsner is a research scientist at the Kennedy Krieger Institute, an internationally recognized institution dedicated to improving the lives of children with neurodevelopmental disorders. He holds a primary faculty appointment as professor at the Johns Hopkins School of Medicine. His lab studies genomic changes that occur in autism spectrum disorder (ASD). They perform whole genome sequence studies, particularly of the genomes of children with very severe behavioral disorders such as those with self-injurious behavior.
Q: Can you discuss the importance of driving greater understanding of autism genomics?
A: Autism spectrum disorder is extremely common, and according to the Centers for Disease Control and Prevention (CDC) it is now thought to affect 1 in 68 children. We also know that ASD is highly heritable (with some estimates as high as 90%). And yet we only understand the genetic basis of ASD in perhaps 25% of all cases. In contrast to rare, monogenic disorders ASD is very heterogeneous at the levels of both genotype and phenotype. Mutations in any of as many as several hundred different genes confer increased risk for ASD.
Q: What role do structural variations play in autism?
A: Beginning with cytogenetics studies in the 1970s and continuing through the eras of SNP arrays and sequencing, it has been established that many structural variants are implicated in ASD. Large chromosomal abnormalities may be responsible for about 10% of all cases, although some estimates are substantially higher. There are several hotspots for copy number variants, including deletions or duplications on chromosome 16p11.2 and duplication of 22q11.2. I think that 10% is a low estimate because many cryptic structural variations are likely to contribute to ASD. Our ability to “see” structural variation has been relatively limited, so we don’t yet know the true proportion of structural variations that have causal roles.
Q: How has Bionano impacted your understanding of structural variations in autism?
A: We are studying the case of a girl who has autism spectrum disorder, global developmental delay, and severe self-injurious behavior. She has a three-way translocation involving chromosomes 3, 10, and 14. We obtained whole genome sequence data at standard (30x) depth of coverage using short-read sequencing technology, and this was useful to begin mapping the breakpoints. But this technology was not sufficient to gain a complete understanding of the nature of the translocations in the mother (who is a carrier harboring balanced translocations) and the affected child.
Using Bionano genome mapping we have been able to identify the translocations at high resolution and resolve extremely complex structural variation. Our goal is to further understand which genes are disrupted by the translocations to explore whether any therapeutic intervention is possible based on a new understanding of the genomic basis of the child’s condition.
Q: Do you consider Bionano essential to genomic research?
A: I do. We study a clinical population at the Kennedy Krieger Institute where children have autism and other developmental disorders. In recent years we migrated from SNP arrays to whole exome sequencing to whole genome sequencing approaches. Even with WGS we obtain data on only about 90% of the genome because a substantial portion is too repetitive to align to a reference genome. Many reads do not map to the reference at all. And de novo assembly of genomes is severely limited using short-read technology. Bionano technology allows us to see deeper into the genome to search for the variation that explains disease, exploring places that are inaccessible to WGS. The fact that Bionano mapping relies on de novo assembly is an important benefit. For me personally, meeting the patients and their families, we know who we want to help and to do so we want to see as deeply into these genomes as possible.
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