Comprehensive reanalysis for CNVs in ES data from unsolved rare disease cases results in new diagnoses

German Demidov; Burcu Yaldiz; José Garcia-Pelaez; Elke de Boer; Nika Schuermans; Liedewei Van de Vondel; Ida Paramonov; Lennart F. Johansson; Francesco Musacchia; Elisa Benetti; Gemma Bullich; Karolis Sablauskas; Sergi Beltran; Christian Gilissen; Alexander Hoischen; Stephan Ossowski; Richarda de Voer; Katja Lohmann; Carla Oliveira; Ana Topf; Lisenka E.L.M. Vissers; Steven Laurie

doi:10.1038/s41525-024-00436-6

Comprehensive reanalysis for CNVs in ES data from unsolved rare disease cases results in new diagnoses

German Demidov^*, Burcu Yaldiz, José Garcia-Pelaez, Elke de Boer, Nika Schuermans, Liedewei Van de Vondel, Ida Paramonov, Lennart F. Johansson, Francesco Musacchia, Elisa Benetti, Gemma Bullich, Karolis Sablauskas, Sergi Beltran, Christian Gilissen, Alexander Hoischen, Stephan Ossowski, Richarda de Voer, Katja Lohmann, Carla Oliveira, Ana TopfLisenka E.L.M. Vissers, , Steven Laurie^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

We report the results of a comprehensive copy number variant (CNV) reanalysis of 9171 exome sequencing datasets from 5757 families affected by a rare disease (RD). The data reanalysed was extremely heterogeneous, having been generated using 28 different enrichment kits by 42 different research groups across Europe partnering in the Solve-RD project. Each research group had previously undertaken their own analysis of the data but failed to identify disease-causing variants. We applied three CNV calling algorithms to maximise sensitivity, and rare CNVs overlapping genes of interest, provided by four partner European Reference Networks, were taken forward for interpretation by clinical experts. This reanalysis has resulted in a molecular diagnosis being provided to 51 families in this sample, with ClinCNV performing the best of the three algorithms. We also identified partially explanatory pathogenic CNVs in a further 34 individuals. This work illustrates the value of reanalysing ES cold cases for CNVs.

Original language	English
Article number	49
Journal	npj Genomic Medicine
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41525-024-00436-6
Publication status	Published - 26 Oct 2024

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Demidov, G., Yaldiz, B., Garcia-Pelaez, J., de Boer, E., Schuermans, N., Van de Vondel, L., Paramonov, I., Johansson, L. F., Musacchia, F., Benetti, E., Bullich, G., Sablauskas, K., Beltran, S., Gilissen, C., Hoischen, A., Ossowski, S., de Voer, R., Lohmann, K., Oliveira, C., ... Laurie, S. (2024). Comprehensive reanalysis for CNVs in ES data from unsolved rare disease cases results in new diagnoses. npj Genomic Medicine, 9(1), Article 49. https://doi.org/10.1038/s41525-024-00436-6

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title = "Comprehensive reanalysis for CNVs in ES data from unsolved rare disease cases results in new diagnoses",

abstract = "We report the results of a comprehensive copy number variant (CNV) reanalysis of 9171 exome sequencing datasets from 5757 families affected by a rare disease (RD). The data reanalysed was extremely heterogeneous, having been generated using 28 different enrichment kits by 42 different research groups across Europe partnering in the Solve-RD project. Each research group had previously undertaken their own analysis of the data but failed to identify disease-causing variants. We applied three CNV calling algorithms to maximise sensitivity, and rare CNVs overlapping genes of interest, provided by four partner European Reference Networks, were taken forward for interpretation by clinical experts. This reanalysis has resulted in a molecular diagnosis being provided to 51 families in this sample, with ClinCNV performing the best of the three algorithms. We also identified partially explanatory pathogenic CNVs in a further 34 individuals. This work illustrates the value of reanalysing ES cold cases for CNVs.",

author = "German Demidov and Burcu Yaldiz and Jos{\'e} Garcia-Pelaez and {de Boer}, Elke and Nika Schuermans and {Van de Vondel}, Liedewei and Ida Paramonov and Johansson, {Lennart F.} and Francesco Musacchia and Elisa Benetti and Gemma Bullich and Karolis Sablauskas and Sergi Beltran and Christian Gilissen and Alexander Hoischen and Stephan Ossowski and {de Voer}, Richarda and Katja Lohmann and Carla Oliveira and Ana Topf and Vissers, {Lisenka E.L.M.} and Kristina Zguro and Federico Zara and Ioannis Zaganas and Y{\'e}pez, {Vicente A.} and Brunhilde Wirth and David Webb and Hannah Verdin and {Van Nieuwenhove}, Erika and {van Montfrans}, Joris and {van Heurck}, Roxane and {van der Veken}, Lars and Laura Valle and Paolo Uva and Bjarne Udd and Aurelien Trimouille and Rachel Thompson and Marco Tartaglia and Yves Sznajer and Pasquale Striano and Verena Steinke-Lange and Martha Spilioti and Paolo Scudieri and Evelin Schr{\"o}ck and Katherine Schon and Marcello Scala and Helen Leavis and Manon Huibers and {van Gijn}, Marielle and {de Vries}, Geert and Steven Laurie",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

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day = "26",

doi = "10.1038/s41525-024-00436-6",

language = "English",

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Demidov, G, Yaldiz, B, Garcia-Pelaez, J, de Boer, E, Schuermans, N, Van de Vondel, L, Paramonov, I, Johansson, LF, Musacchia, F, Benetti, E, Bullich, G, Sablauskas, K, Beltran, S, Gilissen, C, Hoischen, A, Ossowski, S, de Voer, R, Lohmann, K, Oliveira, C, Topf, A, Vissers, LELM & Laurie, S 2024, 'Comprehensive reanalysis for CNVs in ES data from unsolved rare disease cases results in new diagnoses', npj Genomic Medicine, vol. 9, no. 1, 49. https://doi.org/10.1038/s41525-024-00436-6

TY - JOUR

T1 - Comprehensive reanalysis for CNVs in ES data from unsolved rare disease cases results in new diagnoses

AU - Demidov, German

AU - Yaldiz, Burcu

AU - Garcia-Pelaez, José

AU - de Boer, Elke

AU - Schuermans, Nika

AU - Van de Vondel, Liedewei

AU - Paramonov, Ida

AU - Johansson, Lennart F.

AU - Musacchia, Francesco

AU - Benetti, Elisa

AU - Bullich, Gemma

AU - Sablauskas, Karolis

AU - Beltran, Sergi

AU - Gilissen, Christian

AU - Hoischen, Alexander

AU - Ossowski, Stephan

AU - de Voer, Richarda

AU - Lohmann, Katja

AU - Oliveira, Carla

AU - Topf, Ana

AU - Vissers, Lisenka E.L.M.

AU - Zguro, Kristina

AU - Zara, Federico

AU - Zaganas, Ioannis

AU - Yépez, Vicente A.

AU - Wirth, Brunhilde

AU - Webb, David

AU - Verdin, Hannah

AU - Van Nieuwenhove, Erika

AU - van Montfrans, Joris

AU - van Heurck, Roxane

AU - van der Veken, Lars

AU - Valle, Laura

AU - Uva, Paolo

AU - Udd, Bjarne

AU - Trimouille, Aurelien

AU - Thompson, Rachel

AU - Tartaglia, Marco

AU - Sznajer, Yves

AU - Striano, Pasquale

AU - Steinke-Lange, Verena

AU - Spilioti, Martha

AU - Scudieri, Paolo

AU - Schröck, Evelin

AU - Schon, Katherine

AU - Scala, Marcello

AU - Leavis, Helen

AU - Huibers, Manon

AU - van Gijn, Marielle

AU - de Vries, Geert

AU - Laurie, Steven

PY - 2024/10/26

Y1 - 2024/10/26

N2 - We report the results of a comprehensive copy number variant (CNV) reanalysis of 9171 exome sequencing datasets from 5757 families affected by a rare disease (RD). The data reanalysed was extremely heterogeneous, having been generated using 28 different enrichment kits by 42 different research groups across Europe partnering in the Solve-RD project. Each research group had previously undertaken their own analysis of the data but failed to identify disease-causing variants. We applied three CNV calling algorithms to maximise sensitivity, and rare CNVs overlapping genes of interest, provided by four partner European Reference Networks, were taken forward for interpretation by clinical experts. This reanalysis has resulted in a molecular diagnosis being provided to 51 families in this sample, with ClinCNV performing the best of the three algorithms. We also identified partially explanatory pathogenic CNVs in a further 34 individuals. This work illustrates the value of reanalysing ES cold cases for CNVs.

AB - We report the results of a comprehensive copy number variant (CNV) reanalysis of 9171 exome sequencing datasets from 5757 families affected by a rare disease (RD). The data reanalysed was extremely heterogeneous, having been generated using 28 different enrichment kits by 42 different research groups across Europe partnering in the Solve-RD project. Each research group had previously undertaken their own analysis of the data but failed to identify disease-causing variants. We applied three CNV calling algorithms to maximise sensitivity, and rare CNVs overlapping genes of interest, provided by four partner European Reference Networks, were taken forward for interpretation by clinical experts. This reanalysis has resulted in a molecular diagnosis being provided to 51 families in this sample, with ClinCNV performing the best of the three algorithms. We also identified partially explanatory pathogenic CNVs in a further 34 individuals. This work illustrates the value of reanalysing ES cold cases for CNVs.

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U2 - 10.1038/s41525-024-00436-6

DO - 10.1038/s41525-024-00436-6

M3 - Article

AN - SCOPUS:85207830154

VL - 9

JO - npj Genomic Medicine

JF - npj Genomic Medicine

IS - 1

M1 - 49

ER -

Comprehensive reanalysis for CNVs in ES data from unsolved rare disease cases results in new diagnoses

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