Date of Release: May 2, 2022
Expiration Date: April 30, 2024
Revised Expiration Date: August 31, 2025
Credits offered: CME, P.A.C.E.®,
Estimated time for completion: 4.5 hours
Course must be completed by the expiration date
Short-read genome and exome sequencing (GS/ES) have revealed the molecular basis of thousands of rare genetic diseases, however nearly 50% of individuals with a suspected genetic disorder remain undiagnosed after a complete clinical workup, which often includes GS/ES. There are several reasons for this low diagnostic rate, which include technical limitations and challenges with the analysis of short-read sequencing technology. Compared to GS/ES, which often result in 150 bp reads, long-read sequencing (LRS) of DNA or RNA generates reads anywhere from thousands of kb to several megabases, and can include additional regulatory information such as methylation. Long-read sequencing can better resolve disease-causing structural variants such as repeat expansions, insertions, deletions, and translocations and also identify variants in complex genomic regions such as segmental duplications. It has been shown that longer reads do allow more reliable alignment to the genome, leading to more comprehensive and accurate variant calling of both SNVs and larger structural variants (SVs), especially in complex regions of the genome. Current barriers to widespread implementation of long-read sequencing include cost, throughput, and error rates depending on the technology used.
In this session we will discuss how long-read sequencing can be used to identify clinically relevant variation in complex genomic regions. Presentations in this session will include discussion of the benefits and drawbacks of long read sequencing, and examples of causal variation that was missed by short-read GS/ES but was identified using long-read sequencing, including expansions of variation in simple repeat regions and more complex structural variants.
Presenters will also discuss how long-read sequencing could be used as a single test in the clinical space. We will discuss both whole-genome and targeted long-read sequencing of various cohorts. Overall, this session will demonstrate the clinical potential of long-read sequencing and how it may be used in the future to both increase the rate of diagnosis for rare genetic disorders and decrease the amount of time it takes to make a genetic diagnosis.
Target Audience:
Clinicians, including genetic counselors, clinical geneticists, and laboratory directors
Agenda
- Challenges and Genetic Counseling Considerations of Systematic Testing of Expansion Disorders- Emily Farrow, PhD, MGC
- Clinical application of long-read sequencing to neurodevelopmental disorders and congenital anomalies - Susan Hiatt, PhD
- Targeted long-read sequencing identifies missing disease-causing variation - Danny Miller MD, PhD
- Using Nanopore Sequencing to Interrogate the Genome, Epigenome, and Transcriptome - Winston Timp, PhD
- Unraveling the gene regulatory impact of genetic variants using single-molecule chromatin fiber sequencing- Andrew Stergachis MD, PhD
Allele Selective Antisense Therapies for Rare Neurological Diseases - Frank Bennett, PhD
Learning Objectives:
At the conclusion of this session, participants should be able to:
- Define the key technical differences between short-read and long-read sequencing (LRS).
- Describe different long read sequencing technologies.
- Summarize DNA input and quality requirements for both short and LRS and types of samples that may not be amenable to LRS.
- List variant types that may be more accurately called using LRS.
- Summarize different methods for targeted long-read sequencing.
- Identify clinical phenotypes cases that may benefit from further evaluation with long-read sequencing that includes methylation status.
- Summarize how detection of various DNA modifications may add value in addition to genomic sequence information.
- Describe the role of genomic, transcriptomic, and epigenomic phasing in studying rare diseases and the development of targeted ASO therapies.
- Discuss clinical implications of returning LRS results.
- Explain why you would consider using either technology.
- Explain the pros and cons of different LRS technologies.
- Describe types of DNA input samples that may not be amenable to LRS.
- Discuss the sensitivity of LRS vs short-read sequencing for all types of variants (SNVs, indels, SVs).
- Identify cases where targeted long-read sequencing could be used instead of whole-genome long-read sequencing.
- Describe the and challenges with counseling the complex changes that can be seen with LRS.