As traditional barriers to the use of genome sequencing decrease, it is likely that the application of this testing will exceed the available capacity of geneticists and genetic counselors to disclose results. Various methods for extending the capacity of genetics providers have been explored, including training of non-genetics providers in genomic results disclosures. In SouthSeq, part of the Clinical Sequencing Evidence-Generating Research Consortium, genome sequencing is used as a first-line diagnostic tool for critically-ill infants with suspected genetic disorders; results are returned by either genetic counselors or trained non-genetics providers.

Exome and genome sequencing (ES/GS) have proven to be effective tools for the diagnosis of rare disorders, including neurodevelopmental disorders (NDDs), and multiple congenital anomalies (MCA), many of which are due to highly penetrant, often de novo, variation. However, while discovery power and diagnostic yield of genomic testing have consistently improved over time, most cases of NDD/MCAs cannot be attributed to currently detectable genetic variation. We have recently applied long-reads produced using the Pacific Biosciences circular consensus sequence (CCS) technology to unsolved cases.

The Alabama Genomic Health Initiative (AGHI) is a state-supported, IRB-approved research study, that began in 2017 to explore the utility and impact of population-based screening for rare Mendelian disorders, and has helped to serve as a model and platform for other participant-facing programs. Over the last year a new model has been developed that is focused on health care providers, with a primary goal to bring and apply genomic knowledge in a primary care setting.

Genome sequencing (GS) may shorten the diagnostic odyssey and guide clinical management in infants with suspected genetic disorders. GS detects a variety of genetic variant types (SNVs, indels, CNVs, aneuploidy) and permits phenotype-independent variant assessment, which is important in infants whose clinical presentation may not be well-defined until later in life. In SouthSeq, part of the Clinical Sequencing Evidence-Generating Research Consortium, we evaluated GS as a first-line diagnostic tool for infants with suspected but undiagnosed genetic disorders.

Long-read sequencing is a promising technology for performing genome sequencing while maintaining contiguity. Early studies suggest that variant calling from long-read data may be as accurate as that seen in clinical short-read sequencing data. While these long-read platforms are relatively expensive, they reportedly capture the same events as short-read sequencing (eg, single-nucleotide variants, insertions, deletions), while being demonstrably better at capturing larger or more complicated events (eg, structural variants, copy number variants, and repeat expansions).

Neurodevelopmental disorders (NDDs), which often result from rare highly penetrant genetic variants, present substantial medical, emotional, and financial hardships for affected children and their families. However, despite considerable progress in genomic research and technology, rates of discovery of causal variation among NDD probands remain less than 50%. One possible explanation for this observation is that there exist functional elements within human genomes that harbor causal variation but are missed as a result of incomplete genomic annotation.

Yearly, 450 000 pregnant Canadians are eligible for voluntary prenatal screening for trisomy 21. Different screening strategies select approximately 4% of women for invasive fetal chromosome testing. Non-invasive prenatal testing (NIPT) using maternal blood cell-free DNA could reduce those invasive procedures but is expensive. This study evaluated the cost-effectiveness of NIPT strategies compared with conventional strategies.This study used a decision analytic model to estimate the cost-effectiveness of 13 prenatal screening strategies for fetal aneuploidies: six frequently used strategies, universal NIPT, and six strategies incorporating NIPT as a second-tier test. The study considered a virtual cohort of pregnant women of similar size and age as women in Quebec. Model data were obtained from published sources and government databases. The study predicted the number of chromosomal anomalies detected (trisomies 21, 13, and 18), invasive procedures and euploid fetal losses, direct costs, and incremental cost-effectiveness ratios.Of the 13 strategies compared, eight identified fewer cases at a higher cost than at least one of the remaining five strategies. Integrated serum screening with conditional NIPT had the lowest cost, and the cost per case detected was $63 139, with a 90% reduction of invasive procedures. The number of cases identified was improved with four other screening strategies, but with increasing of incremental costs per case (from $61 623 to $1 553 615). Results remained robust, except when NIPT costs and risk cut-offs varied.NIPT as a second-tier test for high-risk women is likely to be cost-effective as compared with screening algorithms not involving NIPT.Chaque année, 450 000 femmes enceintes au Canada sont admissibles au dépistage prénatal volontaire de la trisomie 21. Dans le cadre de différentes stratégies de dépistage, environ 4 % se voient offrir un dépistage invasif des chromosomes fœtaux. Le recours à un test prénatal non invasif (TPNI) utilisant l’ADN acellulaire prélevé du sang maternel permettrait de réduire ces interventions invasives, mais le coût est très élevé. Notre étude s’est penchée sur le rapport coût-efficacité du TPNI par rapport aux stratégies habituelles.Dans le cadre de cette étude, un modèle d’analyse décisionnelle a été utilisé pour estimer le rapport coût-efficacité de 13 stratégies de dépistage prénatal des aneuploïdies fœtales : six stratégies courantes, le TPNI universel et six stratégies utilisant le TPNI comme deuxième test. L’étude portait sur une cohorte virtuelle de femmes enceintes de poids et d’âges semblables à ceux des femmes du Québec, et sur des données de modélisation tirées de sources publiées et de bases de données gouvernementales. Le but était de prédire le nombre d’anomalies chromosomiques détectées (trisomies 21, 13 et 18), d’interventions invasives et de décès de fœtus euploïdes, de même que les coûts directs et les rapports coût-efficacité incrémentiels.Parmi les 13 stratégies à l’étude, 8 ont mené à la détection de moins de cas, à un coût plus élevé, qu’au moins une des 5 autres stratégies. Le dépistage sérique intégré avec TPNI secondaire était la stratégie la moins coûteuse : le coût par cas détecté était de 63 139 $, et la réduction des interventions invasives était de 90 %. Quatre autres stratégies ont permis une détection améliorée, mais le coût incrémentiel par cas détecté était plus élevé (de 61 623 $ à 1 553 615 $). Les résultats sont demeurés fiables, sauf lorsque les coûts et les seuils de risque associés au TPNI variaient.L’utilisation du TPNI comme test secondaire chez les femmes à risque élevé pourrait présenter un meilleur rapport coût-efficacité que les algorithmes de dépistage ne comprenant pas ce test.