Diagnostic capabilities of nanopore long-read sequencing in muscular dystrophy

Christine C. Bruels; Hannah R. Littel; Audrey L. Daugherty; Seth Stafki; Elicia A. Estrella; Emily S. McGaughy; Don Truong; Jonathan P. Badalamenti; Lynn Pais; Vijay S. Ganesh; Anne O'Donnell-Luria; Heather J. Stalker; Yang Wang; Christin Collins; Andrea Behlmann; Richard J.L.F. Lemmers; Silvère M. van der Maarel; Regina Laine; Partha S. Ghosh; Basil T. Darras; Carla D. Zingariello; Christina A. Pacak; Louis M. Kunkel; Peter B Kang

doi:10.1002/acn3.51612

Diagnostic capabilities of nanopore long-read sequencing in muscular dystrophy

Christine C. Bruels, Hannah R. Littel, Audrey L. Daugherty, Seth Stafki, Elicia A. Estrella, Emily S. McGaughy, Don Truong, Jonathan P. Badalamenti, Lynn Pais, Vijay S. Ganesh, Anne O'Donnell-Luria, Heather J. Stalker, Yang Wang, Christin Collins, Andrea Behlmann, Richard J.L.F. Lemmers, Silvère M. van der Maarel, Regina Laine, Partha S. Ghosh, Basil T. DarrasCarla D. Zingariello, Christina A. Pacak, Louis M. Kunkel, Peter B Kang

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

19 Scopus citations

Abstract

Many individuals with muscular dystrophies remain genetically undiagnosed despite clinical diagnostic testing, including exome sequencing. Some may harbor previously undetected structural variants (SVs) or cryptic splice sites. We enrolled 10 unrelated families: nine had muscular dystrophy but lacked complete genetic diagnoses and one had an asymptomatic DMD duplication. Nanopore genomic long-read sequencing identified previously undetected pathogenic variants in four individuals: an SV in DMD, an SV in LAMA2, and two single nucleotide variants in DMD that alter splicing. The DMD duplication in the asymptomatic individual was in tandem. Nanopore sequencing may help streamline genetic diagnostic approaches for muscular dystrophy.

Original language	English (US)
Pages (from-to)	1302-1309
Number of pages	8
Journal	Annals of Clinical and Translational Neurology
Volume	9
Issue number	8
DOIs	https://doi.org/10.1002/acn3.51612
State	Published - Aug 2022

Bibliographical note

Funding Information:
We thank the patients and their families who contributed to the samples used in this study and helped to make this research possible. This project was funded in part by the NIH U01HG011755 (A. O’. D. L. and L. P.), T32HG010464 (V. S. G.), R01AR064300 (L. M. K.), the Bernard F. and Alva B. Gimbel Foundation (L. M. K.), and NIH R01NS080929 (P. B. K.). Short-read sequencing and analysis support were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG), funded by the National Human Genome Research Institute (NHGRI) grant numbers UM1HG008900 and R01HG009141. The authors thank the Minnesota Supercomputing Institute (MSI) at the University of Minnesota (http://www.msi.umn.edu) and Research Computing at the University of Florida (UFRC). The authors are grateful to Abby Schmitt, Dinesha Walek, and Kenneth Beckman at the University of Minnesota Genomics Center (UMGC) for providing platforms for Sanger sequencing and long-read nanopore sequencing.

Funding Information:
We thank the patients and their families who contributed to the samples used in this study and helped to make this research possible. This project was funded in part by the NIH U01HG011755 (A. O’. D. L. and L. P.), T32HG010464 (V. S. G.), R01AR064300 (L. M. K.), the Bernard F. and Alva B. Gimbel Foundation (L. M. K.), and NIH R01NS080929 (P. B. K.). Short‐read sequencing and analysis support were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG), funded by the National Human Genome Research Institute (NHGRI) grant numbers UM1HG008900 and R01HG009141. The authors thank the Minnesota Supercomputing Institute (MSI) at the University of Minnesota ( http://www.msi.umn.edu ) and Research Computing at the University of Florida (UFRC). The authors are grateful to Abby Schmitt, Dinesha Walek, and Kenneth Beckman at the University of Minnesota Genomics Center (UMGC) for providing platforms for Sanger sequencing and long‐read nanopore sequencing.

Funding Information:
This project was funded in part by the NIH U01HG011755 (A. O’. L. and L. P.), T32HG010464 (V. S. G.), R01AR064300 (L. M. K.), the Bernard F. and Alva B. Gimbel Foundation (L. M. K.), and NIH R01NS080929 (P. B. K.). Short‐read sequencing and analysis support were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG), funded by the National Human Genome Research Institute (NHGRI) grant numbers UM1HG008900 and R01HG009141.

Publisher Copyright:
© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

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Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

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Bruels, C. C., Littel, H. R., Daugherty, A. L., Stafki, S., Estrella, E. A., McGaughy, E. S., Truong, D., Badalamenti, J. P., Pais, L., Ganesh, V. S., O'Donnell-Luria, A., Stalker, H. J., Wang, Y., Collins, C., Behlmann, A., Lemmers, R. J. L. F., van der Maarel, S. M., Laine, R., Ghosh, P. S., ... Kang, P. B. (2022). Diagnostic capabilities of nanopore long-read sequencing in muscular dystrophy. Annals of Clinical and Translational Neurology, 9(8), 1302-1309. https://doi.org/10.1002/acn3.51612

Bruels, CC , Littel, HR , Daugherty, AL, Stafki, S, Estrella, EA, McGaughy, ES, Truong, D, Badalamenti, JP, Pais, L, Ganesh, VS, O'Donnell-Luria, A, Stalker, HJ, Wang, Y, Collins, C, Behlmann, A, Lemmers, RJLF, van der Maarel, SM, Laine, R, Ghosh, PS, Darras, BT, Zingariello, CD, Pacak, CA, Kunkel, LM & Kang, PB 2022, 'Diagnostic capabilities of nanopore long-read sequencing in muscular dystrophy', Annals of Clinical and Translational Neurology, vol. 9, no. 8, pp. 1302-1309. https://doi.org/10.1002/acn3.51612

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title = "Diagnostic capabilities of nanopore long-read sequencing in muscular dystrophy",

abstract = "Many individuals with muscular dystrophies remain genetically undiagnosed despite clinical diagnostic testing, including exome sequencing. Some may harbor previously undetected structural variants (SVs) or cryptic splice sites. We enrolled 10 unrelated families: nine had muscular dystrophy but lacked complete genetic diagnoses and one had an asymptomatic DMD duplication. Nanopore genomic long-read sequencing identified previously undetected pathogenic variants in four individuals: an SV in DMD, an SV in LAMA2, and two single nucleotide variants in DMD that alter splicing. The DMD duplication in the asymptomatic individual was in tandem. Nanopore sequencing may help streamline genetic diagnostic approaches for muscular dystrophy.",

author = "Bruels, {Christine C.} and Littel, {Hannah R.} and Daugherty, {Audrey L.} and Seth Stafki and Estrella, {Elicia A.} and McGaughy, {Emily S.} and Don Truong and Badalamenti, {Jonathan P.} and Lynn Pais and Ganesh, {Vijay S.} and Anne O'Donnell-Luria and Stalker, {Heather J.} and Yang Wang and Christin Collins and Andrea Behlmann and Lemmers, {Richard J.L.F.} and {van der Maarel}, {Silv{\`e}re M.} and Regina Laine and Ghosh, {Partha S.} and Darras, {Basil T.} and Zingariello, {Carla D.} and Pacak, {Christina A.} and Kunkel, {Louis M.} and Kang, {Peter B}",

note = "Funding Information: We thank the patients and their families who contributed to the samples used in this study and helped to make this research possible. This project was funded in part by the NIH U01HG011755 (A. O{\textquoteright}. D. L. and L. P.), T32HG010464 (V. S. G.), R01AR064300 (L. M. K.), the Bernard F. and Alva B. Gimbel Foundation (L. M. K.), and NIH R01NS080929 (P. B. K.). Short-read sequencing and analysis support were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG), funded by the National Human Genome Research Institute (NHGRI) grant numbers UM1HG008900 and R01HG009141. The authors thank the Minnesota Supercomputing Institute (MSI) at the University of Minnesota (http://www.msi.umn.edu) and Research Computing at the University of Florida (UFRC). The authors are grateful to Abby Schmitt, Dinesha Walek, and Kenneth Beckman at the University of Minnesota Genomics Center (UMGC) for providing platforms for Sanger sequencing and long-read nanopore sequencing. Funding Information: We thank the patients and their families who contributed to the samples used in this study and helped to make this research possible. This project was funded in part by the NIH U01HG011755 (A. O{\textquoteright}. D. L. and L. P.), T32HG010464 (V. S. G.), R01AR064300 (L. M. K.), the Bernard F. and Alva B. Gimbel Foundation (L. M. K.), and NIH R01NS080929 (P. B. K.). Short‐read sequencing and analysis support were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG), funded by the National Human Genome Research Institute (NHGRI) grant numbers UM1HG008900 and R01HG009141. The authors thank the Minnesota Supercomputing Institute (MSI) at the University of Minnesota ( http://www.msi.umn.edu ) and Research Computing at the University of Florida (UFRC). The authors are grateful to Abby Schmitt, Dinesha Walek, and Kenneth Beckman at the University of Minnesota Genomics Center (UMGC) for providing platforms for Sanger sequencing and long‐read nanopore sequencing. Funding Information: This project was funded in part by the NIH U01HG011755 (A. O{\textquoteright}. L. and L. P.), T32HG010464 (V. S. G.), R01AR064300 (L. M. K.), the Bernard F. and Alva B. Gimbel Foundation (L. M. K.), and NIH R01NS080929 (P. B. K.). Short‐read sequencing and analysis support were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG), funded by the National Human Genome Research Institute (NHGRI) grant numbers UM1HG008900 and R01HG009141. Publisher Copyright: {\textcopyright} 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.",

year = "2022",

month = aug,

doi = "10.1002/acn3.51612",

language = "English (US)",

volume = "9",

pages = "1302--1309",

journal = "Annals of Clinical and Translational Neurology",

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T1 - Diagnostic capabilities of nanopore long-read sequencing in muscular dystrophy

AU - Bruels, Christine C.

AU - Littel, Hannah R.

AU - Daugherty, Audrey L.

AU - Stafki, Seth

AU - Estrella, Elicia A.

AU - McGaughy, Emily S.

AU - Truong, Don

AU - Badalamenti, Jonathan P.

AU - Pais, Lynn

AU - Ganesh, Vijay S.

AU - O'Donnell-Luria, Anne

AU - Stalker, Heather J.

AU - Wang, Yang

AU - Collins, Christin

AU - Behlmann, Andrea

AU - Lemmers, Richard J.L.F.

AU - van der Maarel, Silvère M.

AU - Laine, Regina

AU - Ghosh, Partha S.

AU - Darras, Basil T.

AU - Zingariello, Carla D.

AU - Pacak, Christina A.

AU - Kunkel, Louis M.

AU - Kang, Peter B

N1 - Funding Information: We thank the patients and their families who contributed to the samples used in this study and helped to make this research possible. This project was funded in part by the NIH U01HG011755 (A. O’. D. L. and L. P.), T32HG010464 (V. S. G.), R01AR064300 (L. M. K.), the Bernard F. and Alva B. Gimbel Foundation (L. M. K.), and NIH R01NS080929 (P. B. K.). Short-read sequencing and analysis support were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG), funded by the National Human Genome Research Institute (NHGRI) grant numbers UM1HG008900 and R01HG009141. The authors thank the Minnesota Supercomputing Institute (MSI) at the University of Minnesota (http://www.msi.umn.edu) and Research Computing at the University of Florida (UFRC). The authors are grateful to Abby Schmitt, Dinesha Walek, and Kenneth Beckman at the University of Minnesota Genomics Center (UMGC) for providing platforms for Sanger sequencing and long-read nanopore sequencing. Funding Information: We thank the patients and their families who contributed to the samples used in this study and helped to make this research possible. This project was funded in part by the NIH U01HG011755 (A. O’. D. L. and L. P.), T32HG010464 (V. S. G.), R01AR064300 (L. M. K.), the Bernard F. and Alva B. Gimbel Foundation (L. M. K.), and NIH R01NS080929 (P. B. K.). Short‐read sequencing and analysis support were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG), funded by the National Human Genome Research Institute (NHGRI) grant numbers UM1HG008900 and R01HG009141. The authors thank the Minnesota Supercomputing Institute (MSI) at the University of Minnesota ( http://www.msi.umn.edu ) and Research Computing at the University of Florida (UFRC). The authors are grateful to Abby Schmitt, Dinesha Walek, and Kenneth Beckman at the University of Minnesota Genomics Center (UMGC) for providing platforms for Sanger sequencing and long‐read nanopore sequencing. Funding Information: This project was funded in part by the NIH U01HG011755 (A. O’. L. and L. P.), T32HG010464 (V. S. G.), R01AR064300 (L. M. K.), the Bernard F. and Alva B. Gimbel Foundation (L. M. K.), and NIH R01NS080929 (P. B. K.). Short‐read sequencing and analysis support were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG), funded by the National Human Genome Research Institute (NHGRI) grant numbers UM1HG008900 and R01HG009141. Publisher Copyright: © 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

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AB - Many individuals with muscular dystrophies remain genetically undiagnosed despite clinical diagnostic testing, including exome sequencing. Some may harbor previously undetected structural variants (SVs) or cryptic splice sites. We enrolled 10 unrelated families: nine had muscular dystrophy but lacked complete genetic diagnoses and one had an asymptomatic DMD duplication. Nanopore genomic long-read sequencing identified previously undetected pathogenic variants in four individuals: an SV in DMD, an SV in LAMA2, and two single nucleotide variants in DMD that alter splicing. The DMD duplication in the asymptomatic individual was in tandem. Nanopore sequencing may help streamline genetic diagnostic approaches for muscular dystrophy.

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Diagnostic capabilities of nanopore long-read sequencing in muscular dystrophy

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