Commentaries and scoping literature reviews that discuss rare disease, genomic medicine and general NGS considerations
Meta-analysis of the diagnostic and clinical utility of exome and genome sequencing in pediatric and adult patients with rare disease across diverse populations
Chung CCY, Hue SPY, Ng NYT et al. Genet Med. 2023;

The aim of this meta-analysis was to compare the diagnostic and clinical utility of exome sequencing (ES) versus genome sequencing (GS) in patients with rare disease including papers published from 2012 to 2021. A total of 161 studies from 31 countries/regions reporting on 50,412 probands were evaluated after initial review. Half of the studies included exclusively pediatric probands, 43% were mixed pediatric and adult probands and 3% were exclusively adult. The remaining were unknown. The pooled diagnostic yield did not find a significant difference between ES and GS (38% vs. 34%; P=.01); however, the yield was higher in pediatric probands compared to adult probands. Clinical utility was reported in 62 publications noting that the proportion of patients experiencing a change in management was significantly greater following GS than ES (61% vs. 48%; p=0.07). Differences in diagnostic yield between ES and GS were also assessed with respect to trio vs. proband-only testing, clinical indication, rapid vs. non-rapid testing and number of variants of uncertain significance. To date, this is the most comprehensive comparison of diagnostic and clinical utility between ES and GS. Despite similar diagnostic yields between the two modalities, clinical utility following GS is significantly greater than that of ES.

Systematic evidence-based review: outcomes from exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability.
Malinowski J, Miller DT, Demmer L, Gannon J, Pereira EM, Schroeder MC, Scheuner MT, Chun-Hui Tsai A, Hickey SE, Shen J on behalf of the ACMG Professional Practice and Guidelines Committee.

This review compiled primary literature from 2007 to 2019 to evaluate the utility of exome/ genome sequencing in patients with congenital anomalies, developmental delay or intellectual disability (CA/DD/ID). After review of 7178 publications, 167 met criteria for evaluation including 36 with >20 patients. For the studies with larger  sample sizes, utility was evaluated following ES and/or GS (ES= 27; GS = 7; ES/GS = 2) with a range in sample size from 22-278.  Ninety-five percent of studies reported a change in clinical management including changes in medication, procedures, specialist referrals, redirection of care and clinical trial opportunities.  More than half of patients experienced a reported clinical impact related to a ES/GS diagnosis and more than half of studies with >20 patients identified an impact on family planning or reproductive decision-making. There was a paucity of data describing improved morbidity and mortality; however, there was sufficient, indirect evidence of the clinical and personal utility of exome/genome sequencing in patients with CA/DD/ID. The committee concluded that there is a need for a more formal framework to evaluate outcomes for ES/GS. This review will be used to guide the development of an evidence-based guideline.

Ontario Health (Quality). Genome-Wide Sequencing for Unexplained Developmental Disabilities or Multiple Congenital Anomalies: A Health Technology Assessment.
Ont Health Technol Assess Ser. 2020 Mar 6;20(11):1-178. PMID: 32194879; PMCID: PMC7080457.
Estimating cumulative point prevalence of rare disease: analysis of the Orphanet database.
Nguengang Wakap S, Lambert DM, Orly A, Rodwell C, Gueydan C, Lanneau V, Murphy D, Le Cam Y, Rath A.. Europ J Hum Genet. 2019;

Nguengang Wakap et al. analyzed epidemiological data in the Orphanet database to determine a cumulative point prevalence of rare disease. Analysis included information in database as of October 1, 2018. Based on all cases in the database, the authors estimate that RD affects at least 3.5-5.9% of the global population and approximately 72% of RD are reported to have a genetic etiology. This publication limits its calculations to only unique clinical disorders, therefore, removing the possibility of duplicate counting and overestimation.

Genomic medicine for undiagnosed diseases
Wise AL, Manolio TA, Mesah GA, Peterson JF, Roden DM, Tamburro C, Williams MS, Green ED.. Lancet, 2019; 394: 533-40.
Case for genome sequencing in infants and children with rare, and undiagnosed genetic disease.
Bick D, Jones, M, Taylor SL, Taft RJ, Belmont J. J Med Genet 2019;0:1–9. doi:10.1136/jmedgenet-2019-106111.
The clinical utility of exome and genome sequencing across clinical indications: a systematic evidence review.
Schick S, Mighton C, Uleryk E, Pechlivanoglou P, Bombard Y. Hum Genet.2021 Oct;140(10):1403-1416.doi: 10.1007/s00439-021-02331-x. Epub 2021 Aug 8.

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