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

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Tan, NB; Stapleton, R; Stark, Z; Delatycki, MB; Yeung, A; Hunter, MF; Amor, DJ; Brown, NJ; Stutterd, CA; McGillivray, G; ...Date
2020-09-23Source Title
Molecular Genetics and Genomic MedicinePublisher
WILEYUniversity of Melbourne Author/s
Amor, David; Delatycki, Martin; Tan, Tiong Yang; Lunke, Sebastian; Fanjul-Fernandez, Miriam; Stark, Zornitza; White, Susan; Yeung, Alison; Stutterd, Chloe; Brown, Natasha; ...Affiliation
Paediatrics (RCH)Melbourne School of Population and Global Health
Clinical Pathology
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Tan, N. B., Stapleton, R., Stark, Z., Delatycki, M. B., Yeung, A., Hunter, M. F., Amor, D. J., Brown, N. J., Stutterd, C. A., McGillivray, G., Yap, P., Regan, M., Chong, B., Fanjul Fernandez, M., Marum, J., Phelan, D., Pais, L. S., White, S. M., Lunke, S. & Tan, T. Y. (2020). Evaluating systematic reanalysis of clinical genomic data in rare disease from single center experience and literature review. MOLECULAR GENETICS & GENOMIC MEDICINE, 8 (11), https://doi.org/10.1002/mgg3.1508.Access Status
Open AccessAbstract
BACKGROUND: Our primary aim was to evaluate the systematic reanalysis of singleton exome sequencing (ES) data for unsolved cases referred for any indication. A secondary objective was to undertake a literature review of studies examining the reanalysis of genomic data from unsolved cases. METHODS: We examined data from 58 unsolved cases referred between June 2016 and March 2017. First reanalysis at 4-13 months after the initial report considered genes newly associated with disease since the original analysis; second reanalysis at 9-18 months considered all disease-associated genes. At 25-34 months we reviewed all cases and the strategies which solved them. RESULTS: Reanalysis of existing ES data alone at two timepoints did not yield new diagnoses. Over the same timeframe, 10 new diagnoses were obtained (17%) from additional strategies, such as microarray detection of copy number variation, repeat sequencing to improve coverage, and trio sequencing. Twenty-seven peer-reviewed articles were identified on the literature review, with a median new diagnosis rate via reanalysis of 15% and median reanalysis timeframe of 22 months. CONCLUSION: Our findings suggest that an interval of greater than 18 months from the original report may be optimal for reanalysis. We also recommend a multi-faceted strategy for cases remaining unsolved after singleton ES.
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