The NIH’s All of Us Research Program and NHGRI’s Genomic Analysis Visualization and Informatics Lab Space (AnVIL) are collaborating to build an imputation service, backed by the largest imputation panel in the world. The panel is derived from whole genome data of over 515,000 participants, including more than 250,000 from non-European ancestries.  Attendees will hear about the development of the service, learn to submit data to the service for imputation, and perform a down stream analysis calculating a polygenic risk score on data imputed with the service. 

Participants will be provided with a test vcf to submit to the service, and will be instructed in the use of a dedicated command line tool for interacting with the service.  PRS calculation will be performed using PLINK.

Learning Objectives:

• Illustrate the utility of imputation in genomic analysis 

• Apply the AoU/AnVIL imputation service to genomic data 

• Evaluate the accuracy of imputed datasets 

• Plan future analyses that can be enhanced using imputation 

With the advent of new technologies and deepening understanding of the nature of genomic aberrations and/or pathogenic variants, there is an increasing need for an international nomenclature to report complex genomic findings. The International System for Cytogenomic Nomenclature (ISCN) enables individuals to describe and communicate effectively normal and abnormal results found in their research or diagnostic studies. Globally, ISCN is used to describe numerical and structural variation, haplotypes, gene fusion and repeat expansion results at a genome level effectively and without ambiguity to clinicians, public databases and in publications. It provides a standard approach to describe any genomic rearrangement identified by karyotyping, FISH, microarray, genome mapping, DNA sequencing  and various region-specific assays. ISCN also incorporates, as applicable, whether the abnormality is inherited or de novo, the proportion of the sample with the aberration and the variant allele frequency (VAF).

ISCN 2024 represents one of the most significant reviews with the generic rules being codified, plus the inclusion of genome mapping, targeted karyotyping, targeted arrays, imprinted and fusion gene nomenclature.

This interactive workshop will present the recently released ISCN 2024, some complex examples, the educational platforms available through Genomic Quality Assessment (GenQA) to provide training and competency tools for laboratories and clinicians alike as well as an interactive question and answer session plus an audience quiz. This workshop is suitable for all staff working in genomics, especially those working in the field of cytogenomics. A basic knowledge of ISCN is required for this workshop.

Learning Objectives

1. Understand the rules and the practical application of cytogenomic ISCN nomenclature
2. The ability to differentiate when to apply ISCN or HGVS nomenclature
3. To be able to formulate and use the ISCN 2024 nomenclature in their own laboratories, clinical practices and in publications
4. To be able to apply ISCN for real complex examples

There will not be a recording of this workshop available on-demand.

Illumina Digital CoLab - Constellation: The Next Generation of Whole Genome Sequencing (WGS), hosted by the Emerging Laboratory Technologies SIG

Ali Crawford is a Sr. Director at Illumina. In this CoLab, Ali Crawford, PhD will present on Constellation mapped reads, a novel on flow cell whole genome assay. The Constellation mapped reads workflow moves typical DNA library prep directly onto the flow cell, where DNA is tagmented and sequenced in nanowells on the flow cell surface. Using information from neighboring nanowells, many additional insights can be derived with Constellation as compared to traditional short read whole genome sequencing. This workflow can be utilized for any researcher who is interested in additional insights from Illumina whole genome sequencing including haplotype information, improved callability in high homologous regions, and improved structural variant calling and visualization. This presentation will cover how these genomes compare to other sequencing technologies and ways to interpret these new outputs.

Overview of Presentation

• Overview of the Constellation technology
• Review of data outputs and benchmarks to other technology
• Specific examples of Constellation specific insights and how to interpret them

Almost all individuals will carry a genetic marker that affects their drug response and warrants therapy adjustments. Pauline Lanting, PharmD, will discuss the feasibility of a low-cost, pre-emptive pharmacogenetic passport that could be readily implemented in clinical settings to ensure patients receive optimal drug therapy based on their genetic makeup.

Overview of Presentation:

• Taking advantage of existing genetic data generated in two biobanks, we developed and validated Asterix, a low-cost, clinical-grade PGx passport pipeline for 12 PGx genes.
• We performed and clinically validated genetic variant calling and statistical phasing and imputation. In addition, we developed and validated a CYP2D6 copy-number-variant-calling tool, forgoing the need to use separate PCR-based copy-number detection.
• We returned 1,227 PGx passports to biobank participants via a layperson-friendly app, improving knowledge of PGx among citizens.
• Our study demonstrates the feasibility of a low-cost, clinical-grade PGx passport pipeline that could be readily implemented in clinical settings to enhance personalized healthcare, ensuring that patients receive the most effective and safe drug therapy based on their unique genetic makeup.

A discussion of, "De novo variants in FRYL are associated with developmental delay, intellectual disability, and dysmorphic features" with Xueyang Pan, PhD and hosts, Martin Breuss, PhD and Noha Sharafeldin, MBBCh, MSc, PhD.

A discussion of, "Contribution and therapeutic implications of retroelement insertions in ataxia telangiectasia" with Boxun Zhao and hosts, Martin Breuss, PhD and Noha Sharafeldin, MBBCh, MSc, PhD.

A discussion of, "MagicalRsq-X: A cross-cohort transferable genotype imputation quality metric" with Quan Sun and host, Noha Sharafeldin, MBBCh, MSc, PhD.

Episodes for the Trainee Excellence podcast are bundled here.

Music courtesy of Scott Holmes Music, available here. 

License language here.

Adam Bates will discuss results from leveraging the All of Us Research Program to study previously identified pathogenic germline variants and their relationship to cancer occurrence. This work highlights the importance of using diverse study populations to make cancer research more broadly applicable. 

Overview of Presentation

• We took over 500 pathogenic germline variants that had been discovered in TCGA and identified individuals in the All of Us Research Program that had these variants. 

• Presence of these variants was generally associated with increased cancer occurrence in some groups of genetic similarity, but not others. 

• Variants in specific genes showed strong associations with cancer phenotypes, especially in EUR-like individuals. For example, unsurprisingly, we saw strong associations between variants in BRCA2 and breast/ovarian cancer. 

• Importantly, pathogenic germline variants were not distributed evenly across the genetic similarity groups, showing significant enrichment in EUR-like individuals. 

• While our statistical power was somewhat limited in the All of Us version 6 dataset, we are excited about the improved power that will come in future All of Us releases. 

Mahmoud Koko, MBBS, Dr rer nat, will discuss findings from a meta-analysis of two large autism cohorts investigating the extent to which damaging coding variants influence a person's chances of having an autism diagnosis, and whether this influence varies by sex. 

Overview of Presentation:

• There are notable sex differences in autism prevalence. This work asks whether autosomal rare variants contribute to this disparity.
• We found that the effects of rare damaging variants on the chances of having an autism diagnosis were similar between sexes. 
• These variants, however, were not sufficient on their own to reach the diagnostic threshold for autism.
• When disrupted, autism-linked genes were more likely to predispose to neurodevelopmental disorders in general than autism specifically.