Feasibility of Ultra-Rapid Exome Sequencing in Critically Ill Infants and Children With Suspected Monogenic Conditions in the Australian Public Health Care System

Lunke, Sebastian; Eggers, Stefanie; Wilson, Meredith; Patel, Chirag; Barnett, Christopher; Pinner, Jason; Sandaradura, Sarah A.; Buckley, Michael F.; Krzesinski, Emma I.; Silva, Michelle G. de; Brett, Gemma R; Boggs, Kirsten; Mowat, David; Kirk, Edwin P.; Adès, Lesley C.; Akesson, Lauren S; Amor, David J.; Ayres, Samantha; Baxendale, Anne; Borrie, Sarah; Bray, Alessandra; Brown, Natasha J; Chan, Cheng Yee; Chong, Belinda; Cliffe, Corrina; Delatycki, Martin B.; Edwards, Matthew; Elakis, George; Fahey, Michael; Fennell, Andrew; Fowles, Lindsay F.; Gallacher, Lyndon; Higgins, Megan; Howell, Katherine; Hunt, Lauren; Hunter, Matthew F.; Jones, Kristi; King, Sarah; Kumble, Smitha; Lang, Sarah; Moing, Maelle Le; Ma, Alan; Phelan, Dean; Quinn, Michael C.; Richards, Anna; Richmond, Christopher; Riseley, Jessica R.; Rodgers, Jonathan; Sachdev, Rani; Schlapbach, Luregn J.; Smith, Janine; Springer, Amanda; Tan, Natalie B; Tan, Tiong Yang; Temple, Suzanna L.; Theda, Christiane; Vasudevan, Anand; White, Susan; Yeung, Alison; Zhu, Ying; Martyn, Melissa; Best, Stephanie; Roscioli, Tony; Christodoulou, John; Stark, Zornitza

doi:10.1097/01.ogx.0000722040.32795.04

Cited by 12 publications

(12 citation statements)

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“…Variants have been seen with higher rates of hydrops fetalis and spontaneous, long-lasting remission like the mother in our case [8]. In one case, a male infant with intrauterine grown restriction, craniofacial anomalies, cardiac abnormalities, and respiratory insufficiency was consented for WES on day of life 54 and was found to have a mutation at p.105, similar to our case [9]. Many of these features overlapped with our infant, however, our patient also presented with limb anomalies and severe anemia at birth, pointing toward the heterogenous clinical presentation of DBA.…”

Section: Discussion/conclusionsupporting

confidence: 79%

“…As above, RPL15 variants are rare and are associated with a variety of clinical presentations. The mechanism behind RPL15 variants includes large deletions or truncating or missense mutations [6-9]. Variants have been seen with higher rates of hydrops fetalis and spontaneous, long-lasting remission like the mother in our case [8].…”

Section: Discussion/conclusionmentioning

confidence: 90%

“…Genetic testing, such as rWES, is beneficial for definitively diagnosing DBA [11]. Rapid WES is a way to expediate a diagnosis in critically ill infants with clinical signs of a disease where diagnosis would change care, as well as exclude secondary health problems contributing to the observed phenotype, both of which were crucial in our case [9, 12].…”

Section: Discussion/conclusionmentioning

confidence: 99%

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Diamond-Blackfan Anemia: A Case Report and Review of the Literature

et al. 2021

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We report a case of a male neonate delivered urgently via cesarean at thirty-five 5/7 weeks gestation for non-reassuring fetal monitoring who was found to have severe anemia at birth that could not be explained by acute blood loss. He was born to a 24-year-old mother, whose pregnancy was complicated by abnormal ultrasound findings, including a radial ray defect and fetal growth restriction. Trio rapid whole-exome sequencing (rWES) confirmed Diamond-Blackfan anemia in both the neonate and mother. This case highlights the importance of fetal surveillance and the clinical utility of rWES in the neonatal intensive care setting.

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Section: Discussion/conclusionsupporting

confidence: 79%

Section: Discussion/conclusionmentioning

confidence: 90%

Section: Discussion/conclusionmentioning

confidence: 99%

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Diamond-Blackfan Anemia: A Case Report and Review of the Literature

et al. 2021

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“…Rapid or ultra-rapid genomic sequencing is increasingly offered in the first instance for pediatric patients with suspected monogenic conditions, meaning fewer parents may experience a protracted diagnostic odyssey [ 13 , 14 , 40 ]. Parental experience of the ultra-rapid process may differ from that of traditional diagnostic journeys [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

Receiving Genomic Sequencing Results through the Victorian Undiagnosed Disease Program: Exploring Parental Experiences

Martinussen

Chalk

Elliott

et al. 2022

JPM

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Rare diseases cumulatively affect a significant number of people, and for many, a diagnosis remains elusive. The Victorian Undiagnosed Disease Program (UDP-Vic) utilizes deep phenotyping, advanced genomic sequencing and functional studies to diagnose children with rare diseases for which previous clinical testing has been non-diagnostic. Whereas the diagnostic outcomes of undiagnosed disease programs have been well-described, here, we explore how parents experience participation in the UDP-Vic and the impact of receiving both diagnostic and non-diagnostic genomic sequencing results for their children. Semi-structured interviews ranging in length from 25 to 105 min were conducted with 21 parents of children in the program. Ten participants were parents of children who received a diagnosis through the program, and eleven were parents of children who remain undiagnosed. Although the experiences of families varied, five shared themes emerged from the data: (1) searching for a diagnosis, (2) varied impact of receiving a result, (3) feelings of relief and disappointment, (4) seeking connection and (5) moving towards acceptance. The findings demonstrate the shared experience of parents of children with rare disease both before and after a genomic sequencing result. The results have implications for genetic counselors and clinicians offering genomic sequencing and supporting families of children with rare diseases.

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“…Because of the broad spectrum of differential diagnoses in a (premature) infant with severe disease of unknown etiology, attending physicians are challenged by the appropriate clinical application of WES. Widely accepted guidelines or workflows for the clinical utility of WES are lacking [21, 22, 29]. We aimed to evaluate whether specific clinical presentations were more likely to be associated with a molecular genetic diagnosis, but we did not identify strong prediction parameters (online suppl.…”

Section: Discussionmentioning

confidence: 99%

Whole-Exome Sequencing in Critically Ill Neonates and Infants: Diagnostic Yield and Predictability of Monogenic Diagnosis

Scholz¹,

Blohm²,

Kortüm³

et al. 2021

Neonatology

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Introduction: Monogenic diseases play an important role in critically ill neonates and infants treated in the intensive care unit. This study aimed to determine the diagnostic yield of whole-exome sequencing (WES) for monogenic diseases and identify phenotypes more likely associated with a genetic etiology. Methods: From March 2017 to 2020, a comprehensive diagnostic workup including WES in a single academic center was performed in 61 unrelated, critically ill neonates and infants with an unknown underlying disease within the first year of life. We conducted 59 trio-WES, 1 duo-WES, and 1 single-WES analyses. Symptoms were classified according to the Human Phenotype Ontology. Results: The overall molecular genetic diagnostic rate within our cohort was 46% (28/61) and 50% (15/30) in the subgroup of preterm neonates. Identifying the genetic cause of disease facilitates individualized management in the majority of patients. A positive or negative predictive power of specific clinical features for a genetic diagnosis could not be observed. Conclusion: WES is a powerful noninvasive diagnostic tool in critically ill neonates and infants with a high diagnostic rate. We recommend initiating WES as early as possible due to the impact on management and family counseling. Recommendations regarding the clinical utility of WES in critically ill neonates and infants should not be based on the phenotype alone. Here, we present a clinical workflow for the application of WES for critically ill neonates and infants in an interdisciplinary setting.

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Feasibility of Ultra-Rapid Exome Sequencing in Critically Ill Infants and Children With Suspected Monogenic Conditions in the Australian Public Health Care System

Cited by 12 publications

References 0 publications

Diamond-Blackfan Anemia: A Case Report and Review of the Literature

Diamond-Blackfan Anemia: A Case Report and Review of the Literature

Receiving Genomic Sequencing Results through the Victorian Undiagnosed Disease Program: Exploring Parental Experiences

Whole-Exome Sequencing in Critically Ill Neonates and Infants: Diagnostic Yield and Predictability of Monogenic Diagnosis

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