Evaluating systematic reanalysis of clinical genomic data in rare disease from single center experience and literature review

Tan, Natalie B; Stapleton, Rachel; Stark, Zornitza; Delatycki, Martin B.; Yeung, Alison; Hunter, Matthew F.; Amor, David J.; Brown, Natasha J; Stutterd, Chloe; McGillivray, George; Yap, Patrick; Regan, Matthew; Chong, Belinda; Fernandez, Miriam Fanjul; Marum, Justine E; Phelan, Dean; Pais, Lynn; White, Susan; Lunke, Sebastian; Tan, Tiong Yang

doi:10.1002/mgg3.1508

Cited by 62 publications

(70 citation statements)

References 58 publications

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“…In the event of a VUS, consultation with clinical genetics is helpful, as further detailed phenotyping or functional studies may be required to clarify whether the change in the specific gene fits with the clinical presentation reported in the literature. In explaining a negative or rather an uninformative result, it is important to highlight to families that regular re‐analysis of data can provide an additional diagnostic yield of 10–15%, due to the ongoing discovery of new gene‐phenotype relationships 23,44 . This is recommended every 18 months, 44 has been assigned a Medicare item number (Item 73360), and is available twice after the initial test.…”

Section: Discussion With a Clinical Geneticistmentioning

confidence: 99%

Paediatric genomic testing: Navigating medicare rebatable genomic testing

Sachdev

Field

Baynam

et al. 2021

J Paediatrics Child Health

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Genomic testing for a genetic diagnosis is becoming standard of care for many children, especially those with a syndromal intellectual disability. While previously this type of specialised testing was performed mainly by clinical genetics teams, it is increasingly being ‘mainstreamed’ into standard paediatric care. With the introduction of a new Medicare rebate for genomic testing in May 2020, this type of testing is now available for paediatricians to order, in consultation with clinical genetics. Children must be aged less than 10 years with facial dysmorphism and multiple congenital abnormalities or have global developmental delay or moderate to severe intellectual disability. This rebate should increase the likelihood of a genetic diagnosis, with accompanying benefits for patient management, reproductive planning and diagnostic certainty. Similar to the introduction of chromosomal microarray into mainstream paediatrics, this genomic testing will increase the number of genetic diagnoses, however, will also yield more variants of uncertain significance, incidental findings, and negative results. This paper aims to guide paediatricians through the process of genomic testing, and represents the combined expertise of educators, clinical geneticists, paediatricians and genomic pathologists around Australia. Its purpose is to help paediatricians navigate choosing the right genomic test, consenting patients and understanding the possible outcomes of testing.

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Section: Discussion With a Clinical Geneticistmentioning

confidence: 99%

Paediatric genomic testing: Navigating medicare rebatable genomic testing

Sachdev

Field

Baynam

et al. 2021

J Paediatrics Child Health

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“…For the last category, it is expected that exome reanalysis would increase diagnostic yield. Based on previously published studies, exome reanalysis results in an increase in diagnostic yield of approximately 12%, with reported increases ranging from 5 to 26% [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Although the reported interval between initial analysis and reanalysis varies from 6 months to 7 years among reanalysis studies, the majority of reanalyses were performed at 1-to 2-year intervals [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19].…”

Section: Benefits Of Exome Reanalysismentioning

confidence: 99%

“…Based on previously published studies, exome reanalysis results in an increase in diagnostic yield of approximately 12%, with reported increases ranging from 5 to 26% [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Although the reported interval between initial analysis and reanalysis varies from 6 months to 7 years among reanalysis studies, the majority of reanalyses were performed at 1-to 2-year intervals [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Larger studies may be helpful for defining a standard practice for the timing of reanalysis, taking into consideration the evolving rate of novel gene-disease and variant-disease discovery versus cost and labor required for reanalysis.…”

Section: Benefits Of Exome Reanalysismentioning

confidence: 99%

“…Ultimately, such efforts may result in changes to the clinical management of the patients and families. Several previous studies have demonstrated the clinical validity of exome reanalysis to increase the diagnostic yield [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19], and the American College of Medical Genetics and Genomics (ACMG) recently published a series of points to consider regarding the reevaluation and reanalysis of genomic test results at various levels [20]. While challenges remain, it is important for both ordering physicians and clinical laboratories to recognize the need for exome reanalysis as a routine clinical practice, given the evolving nature of the genomic field.…”

Section: Introductionmentioning

confidence: 99%

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Clinical Exome Reanalysis: Current Practice and Beyond

Leung

Baker

et al. 2021

Mol Diagn Ther

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Novel gene-disease discoveries, rapid advancements in technology, and improved bioinformatics tools all have the potential to yield additional molecular diagnoses through the reanalysis of exome sequencing data. Collaborations between clinical laboratories, ordering physicians, and researchers are also driving factors that can contribute to these new insights. Automation in ongoing natural history collection, evolving phenotype updates, advancements in processing next-generation sequencing data, and up-to-date variant-gene-disease databases are increasingly needed for systematic exome reanalysis. Here, we review some of the advantages and challenges for clinician-initiated and laboratory-initiated exome reanalysis, and we propose a model for the future that could potentially maximize the clinical utility of exome reanalysis by integrating information from electronic medical records and knowledge databases into routine clinical workflows. Key PointsExome reanalysis should be a routine clinical practice, as it may yield additional diagnoses, primarily due to novel gene-disease discoveries, updated clinical features, and improved bioinformatics tools.Challenges exist for both physician-initiated and laboratory-initiated exome reanalysis, and collaboration between clinical laboratories and clinicians is critical for its success.Better incorporation of automated workflows will greatly benefit the long term sustainability of exome reanalysis.

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“…This work showed that by using biomedical networks and systems medicine approaches our understanding of rare diseases can be improved based on phenotype co-occurrence patterns. It also showed the power of the re-analysis of existing data from public databases to obtain new knowledge, something that is recommended in the research community whenever possible (Kovalevskaya et al, 2016;Tan et al, 2020). In this work, the automated workflow PhenoClusters is used to investigate phenotype co-occurrence across NMDs and produce functionally coherent clusters of phenotypes with similar underlying biological functions.…”

Section: Introductionmentioning

confidence: 99%

Decoding Neuromuscular Disorders Using Phenotypic Clusters Obtained From Co-Occurrence Networks

Díaz-Santiago

Claros

Yahyaoui

et al. 2021

Front. Mol. Biosci.

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Neuromuscular disorders (NMDs) represent an important subset of rare diseases associated with elevated morbidity and mortality whose diagnosis can take years. Here we present a novel approach using systems biology to produce functionally-coherent phenotype clusters that provide insight into the cellular functions and phenotypic patterns underlying NMDs, using the Human Phenotype Ontology as a common framework. Gene and phenotype information was obtained for 424 NMDs in OMIM and 126 NMDs in Orphanet, and 335 and 216 phenotypes were identified as typical for NMDs, respectively. ‘Elevated serum creatine kinase’ was the most specific to NMDs, in agreement with the clinical test of elevated serum creatinine kinase that is conducted on NMD patients. The approach to obtain co-occurring NMD phenotypes was validated based on co-mention in PubMed abstracts. A total of 231 (OMIM) and 150 (Orphanet) clusters of highly connected co-occurrent NMD phenotypes were obtained. In parallel, a tripartite network based on phenotypes, diseases and genes was used to associate NMD phenotypes with functions, an approach also validated by literature co-mention, with KEGG pathways showing proportionally higher overlap than Gene Ontology and Reactome. Phenotype-function pairs were crossed with the co-occurrent NMD phenotype clusters to obtain 40 (OMIM) and 72 (Orphanet) functionally coherent phenotype clusters. As expected, many of these overlapped with known diseases and confirmed existing knowledge. Other clusters revealed interesting new findings, indicating informative phenotypes for differential diagnosis, providing deeper knowledge of NMDs, and pointing towards specific cell dysfunction caused by pleiotropic genes. This work is an example of reproducible research that i) can help better understand NMDs and support their diagnosis by providing a new tool that exploits existing information to obtain novel clusters of functionally-related phenotypes, and ii) takes us another step towards personalised medicine for NMDs.

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Evaluating systematic reanalysis of clinical genomic data in rare disease from single center experience and literature review

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 62 publications

References 58 publications

Paediatric genomic testing: Navigating medicare rebatable genomic testing

Paediatric genomic testing: Navigating medicare rebatable genomic testing

Clinical Exome Reanalysis: Current Practice and Beyond

Decoding Neuromuscular Disorders Using Phenotypic Clusters Obtained From Co-Occurrence Networks

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