Genome sequencing reanalysis increases the diagnostic yield in dystonia

We investigated the contribution of genomic data reanalysis to the diagnostic yield of dystonia patients who remained undiagnosed after prior genome sequencing. Probands with heterogeneous dystonia phenotypes who underwent initial genome sequencing (GS) analysis in 2019 were included in the reanalys...

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Published in:Parkinsonism & related disorders 2024-07, Vol.124, p.107010, Article 107010
Main Authors: Fellner, Avi, Wali, Gurusidheshwar M., Mahant, Neil, Grosz, Bianca R., Ellis, Melina, Narayanan, Ramesh K., Ng, Karl, Davis, Ryan L., Tchan, Michel C., Kotschet, Katya, Yeow, Dennis, Rudaks, Laura I., Siow, Sue-Faye, Wali, Gautam, Yiannikas, Con, Hobbs, Matthew, Copty, Joseph, Geaghan, Michael, Darveniza, Paul, Liang, Christina, Williams, Laura J., Chang, Florence C.F., Morales-Briceño, Hugo, Tisch, Stephen, Hayes, Michael, Whyte, Scott, Kummerfeld, Sarah, Kennerson, Marina L., Cowley, Mark J., Fung, Victor S.C., Sue, Carolyn M., Kumar, Kishore R.
Format: Article
Language:English
Subjects:
Diagnostic yield
Dystonia
Genome sequencing
Reanalysis
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Summary:We investigated the contribution of genomic data reanalysis to the diagnostic yield of dystonia patients who remained undiagnosed after prior genome sequencing. Probands with heterogeneous dystonia phenotypes who underwent initial genome sequencing (GS) analysis in 2019 were included in the reanalysis, which was performed through gene-specific discovery collaborations and systematic genomic data reanalysis. Initial GS analysis in 2019 (n = 111) identified a molecular diagnosis in 11.7 % (13/111) of cases. Reanalysis between 2020 and 2023 increased the diagnostic yield by 7.2 % (8/111); 3.6 % (4/111) through focused gene-specific clinical correlation collaborative efforts [VPS16 (two probands), AOPEP and POLG], and 3.6 % (4/111) by systematic reanalysis completed in 2023 [NUS1 (two probands) and DDX3X variants, and a microdeletion encompassing VPS16]. Seven of these patients had a high phenotype-based dystonia score ≥3. Notable unverified findings in four additional cases included suspicious variants of uncertain significance in FBXL4 and EIF2AK2, and potential phenotypic expansion associated with SLC2A1 and TREX1 variants. GS data reanalysis increased the diagnostic yield from 11.7 % to 18.9 %, with potential extension up to 22.5 %. While optimal timing for diagnostic reanalysis remains to be determined, this study demonstrates that periodic re-interrogation of dystonia GS datasets can provide additional genetic diagnoses, which may have significant implications for patients and their families. •Genome sequencing reanalysis increased the diagnostic yield from 11.7 % to 18.9 %.•Phenotype-based dystonia score ≥3 was associated with a higher diagnostic yield.•Periodic genomic data reanalysis can provide additional diagnoses in dystonia.
ISSN:1353-8020
1873-5126
1873-5126
DOI:10.1016/j.parkreldis.2024.107010