The application of rapid exome sequencing (rES) has emerged as a crucial advance in diagnostic landscape, especially for critically ill patients presenting with rare diseases. This editorial reflects findings from a comprehensive study involving 575 patients that highlighted the transformative impact of rES on clinical decision-making and patient outcomes .
In recent years, rES has become the preferred genetic testing modality for critically ill patients, including neonates and young infants, in urgent clinical situations. Its ability to provide timely diagnoses can significantly guide management decisions and improve clinical care pathways. The study, conducted over 4 years (2016–2019) provides valuable insights into the operational effectiveness and clinical utility of rES. The study reported a notable increase in rES referrals, escalating from two in the first quarter of 2016 to ten per week by late 2019. This increase reflects growing recognition of rES as a critical tool in diagnosing complex genetic disorders. The median turnaround time for results improved from 17 days to 11 days, this highlighted advances in sequencing technology and laboratory efficiencies.
The overall diagnostic yield was 30.4%, with variations observed across different clinical entities. For instance, craniofacial anomalies showed a high diagnostic yield of 58.3%, whereas conditions like severe combined immune deficiency yielded no diagnoses at all. These findings suggest that rES, although not universally effective for all conditions, is vital for many patients and offers information that can change clinical management even in the absence of a definitive diagnosis.
The importance of rES extends beyond providing definitive genetic diagnoses. Even if genetic causes remain elusive, information gleaned from rES may influence clinical decisions such as direction of treatment or the need for further investigation. This dual effect in both making diagnoses and informing clinical strategies highlights the multifaceted role of rES in patient care.
Implementation of rES should be accompanied by careful ethical considerations, particularly regarding informed consent and genetic counselling. In high-stake situations, it is very important to ensure that patients and families understand the implications of genetic tests. Clinicians must navigate the complexity of informing uncertain or negative findings while remaining sensitive to the emotional impact on families.
As rES continues to evolve, its integration into routine clinical practice for older patients should be prioritized. The potential for RES to guide treatment decisions in cancer care and other adult-onset conditions is significant and requires further investigation. Ongoing research should focus on optimizing diagnostic strategies and understanding the broader implications of genetic findings in diverse cohorts.
Lessons learned from the use of rapid exome sequencing in critically ill patients underline its fundamental role in modern medicine era. The ability to quickly identify genetic causes of rare diseases not only increases diagnostic accuracy but also improves clinical outcomes. As these technologies continue to be developed and their applications expanded, the hope is to further close the gap between genetics and clinical practice, ultimately benefiting patients across the healthcare.
Wojcik MH, Lemire G, Berger E, Zaki MS, Wissmann M, Win W, White SM, Weisburd B, Wieczorek D, Waddell LB, Verboon JM, VanNoy GE, Töpf A, Tan TY, Syrbe S, Strehlow V, Straub V, Stenton SL, Snow H, Singer-Berk M, Silver J, Shril S, Seaby EG, Schneider R, Sankaran VG, Sanchis-Juan A, Russell KA, Reinson K, Ravenscroft G, Radtke M, Popp D, Polster T, Platzer K, Pierce EA, Place EM, Pajusalu S, Pais L, Õunap K, Osei-Owusu I, Opperman H, Okur V, Oja KT, O'Leary M, O'Heir E, Morel CF, Merkenschlager A, Marchant RG, Mangilog BE, Madden JA, MacArthur D, Lovgren A, Lerner-Ellis JP, Lin J, Laing N, Hildebrandt F, Hentschel J, Groopman E, Goodrich J, Gleeson JG, Ghaoui R, Genetti CA, Gburek-Augustat J, Gazda HT, Ganesh VS, Ganapathi M, Gallacher L, Fu JM, Evangelista E, England E, Donkervoort S, DiTroia S, Cooper ST, Chung WK, Christodoulou J, Chao KR, Cato LD, Bujakowska KM, Bryen SJ, Brand H, Bönnemann CG, Beggs AH, Baxter SM, Bartolomaeus T, Agrawal PB, Talkowski M, Austin-Tse C, Abou Jamra R, Rehm HL, O'Donnell-Luria A. Genome Sequencing for Diagnosing Rare Diseases. N Engl J Med. 2024 Jun 6;390(21):1985-1997. doi: 10.1056/NEJMoa2314761. PMID: 38838312; PMCID: PMC11350637.
Abstract
Background: Genetic variants that cause rare disorders may remain elusive even after expansive testing, such as exome sequencing. The diagnostic yield of genome sequencing, particularly after a negative evaluation, remains poorly defined.
Methods: We sequenced and analyzed the genomes of families with diverse phenotypes who were suspected to have a rare monogenic disease and for whom genetic testing had not revealed a diagnosis, as well as the genomes of a replication cohort at an independent clinical center.
Results: We sequenced the genomes of 822 families (744 in the initial cohort and 78 in the replication cohort) and made a molecular diagnosis in 218 of 744 families (29.3%). Of the 218 families, 61 (28.0%) - 8.2% of families in the initial cohort - had variants that required genome sequencing for identification, including coding variants, intronic variants, small structural variants, copy-neutral inversions, complex rearrangements, and tandem repeat expansions. Most families in which a molecular diagnosis was made after previous nondiagnostic exome sequencing (63.5%) had variants that could be detected by reanalysis of the exome-sequence data (53.4%) or by additional analytic methods, such as copy-number variant calling, to exome-sequence data (10.8%). We obtained similar results in the replication cohort: in 33% of the families in which a molecular diagnosis was made, or 8% of the cohort, genome sequencing was required, which showed the applicability of these findings to both research and clinical environments.
Conclusions: The diagnostic yield of genome sequencing in a large, diverse research cohort and in a small clinical cohort of persons who had previously undergone genetic testing was approximately 8% and included several types of pathogenic variation that had not previously been detected by means of exome sequencing or other techniques. (Funded by the National Human Genome Research Institute and others.).
As rES continues to evolve, its integration into routine clinical practice for older patients should be prioritized. The potential for RES to guide treatment decisions in cancer care and other adult-onset conditions is significant and requires further investigation. Ongoing research should focus on optimizing diagnostic strategies and understanding the broader implications of genetic findings in diverse cohorts.
Lessons learned from the use of rapid exome sequencing in critically ill patients underline its fundamental role in modern medicine era. The ability to quickly identify genetic causes of rare diseases not only increases diagnostic accuracy but also improves clinical outcomes. As these technologies continue to be developed and their applications expanded, the hope is to further close the gap between genetics and clinical practice, ultimately benefiting patients across the healthcare.
Wojcik MH, Lemire G, Berger E, Zaki MS, Wissmann M, Win W, White SM, Weisburd B, Wieczorek D, Waddell LB, Verboon JM, VanNoy GE, Töpf A, Tan TY, Syrbe S, Strehlow V, Straub V, Stenton SL, Snow H, Singer-Berk M, Silver J, Shril S, Seaby EG, Schneider R, Sankaran VG, Sanchis-Juan A, Russell KA, Reinson K, Ravenscroft G, Radtke M, Popp D, Polster T, Platzer K, Pierce EA, Place EM, Pajusalu S, Pais L, Õunap K, Osei-Owusu I, Opperman H, Okur V, Oja KT, O'Leary M, O'Heir E, Morel CF, Merkenschlager A, Marchant RG, Mangilog BE, Madden JA, MacArthur D, Lovgren A, Lerner-Ellis JP, Lin J, Laing N, Hildebrandt F, Hentschel J, Groopman E, Goodrich J, Gleeson JG, Ghaoui R, Genetti CA, Gburek-Augustat J, Gazda HT, Ganesh VS, Ganapathi M, Gallacher L, Fu JM, Evangelista E, England E, Donkervoort S, DiTroia S, Cooper ST, Chung WK, Christodoulou J, Chao KR, Cato LD, Bujakowska KM, Bryen SJ, Brand H, Bönnemann CG, Beggs AH, Baxter SM, Bartolomaeus T, Agrawal PB, Talkowski M, Austin-Tse C, Abou Jamra R, Rehm HL, O'Donnell-Luria A. Genome Sequencing for Diagnosing Rare Diseases. N Engl J Med. 2024 Jun 6;390(21):1985-1997. doi: 10.1056/NEJMoa2314761. PMID: 38838312; PMCID: PMC11350637.
Abstract
Background: Genetic variants that cause rare disorders may remain elusive even after expansive testing, such as exome sequencing. The diagnostic yield of genome sequencing, particularly after a negative evaluation, remains poorly defined.
Methods: We sequenced and analyzed the genomes of families with diverse phenotypes who were suspected to have a rare monogenic disease and for whom genetic testing had not revealed a diagnosis, as well as the genomes of a replication cohort at an independent clinical center.
Results: We sequenced the genomes of 822 families (744 in the initial cohort and 78 in the replication cohort) and made a molecular diagnosis in 218 of 744 families (29.3%). Of the 218 families, 61 (28.0%) - 8.2% of families in the initial cohort - had variants that required genome sequencing for identification, including coding variants, intronic variants, small structural variants, copy-neutral inversions, complex rearrangements, and tandem repeat expansions. Most families in which a molecular diagnosis was made after previous nondiagnostic exome sequencing (63.5%) had variants that could be detected by reanalysis of the exome-sequence data (53.4%) or by additional analytic methods, such as copy-number variant calling, to exome-sequence data (10.8%). We obtained similar results in the replication cohort: in 33% of the families in which a molecular diagnosis was made, or 8% of the cohort, genome sequencing was required, which showed the applicability of these findings to both research and clinical environments.
Conclusions: The diagnostic yield of genome sequencing in a large, diverse research cohort and in a small clinical cohort of persons who had previously undergone genetic testing was approximately 8% and included several types of pathogenic variation that had not previously been detected by means of exome sequencing or other techniques. (Funded by the National Human Genome Research Institute and others.).
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