March 30, 2021; 96 (13) Article
Diagnostic Yield of Whole Genome Sequencing After Nondiagnostic Exome Sequencing or Gene Panel in Developmental and Epileptic Encephalopathies
View ORCID ProfileElizabeth Emma Palmer, Rani Sachdev, Rebecca Macintosh, Uirá Souto Melo, Stefan Mundlos, View ORCID ProfileSarah Righetti, Tejaswi Kandula, Andre E. Minoche, Clare Puttick, Velimir Gayevskiy, Luke Hesson, Senel Idrisoglu, View ORCID ProfileCheryl Shoubridge, View ORCID ProfileMonica Hong Ngoc Thai, View ORCID ProfileRyan L. Davis, View ORCID ProfileAlexander P. Drew, Hugo Sampaio, Peter Ian Andrews, View ORCID ProfileJohn Lawson, Michael Cardamone, David Mowat, Alison Colley, Sarah Kummerfeld, View ORCID ProfileMarcel E. Dinger, View ORCID ProfileMark J. Cowley, Tony Roscioli, View ORCID ProfileAnn Bye, Edwin Kirk
First published February 10, 2021, DOI: https://doi.org/10.1212/WNL.0000000000011655
Elizabeth Emma Palmer
From the School of Women's and Children's Health (E.E.P., R.S., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., M.J.C., A.B., E.K.), The School of Biotechnology and Biomolecular Sciences (M.E.D.), Childrens Cancer Institute (M.J.C.), and NeuRA (T.R.), University of New South Wales; Sydney Childrens Hospital Randwick (E.E.P., R.S., R.M., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., A.B., E.K.), Sydney Childrens Hospital Network; GOLD Service (E.E.P.), Hunter Genetics; Kinghorn Centre for Clinical Genomics (E.E.P., A.E.M., C.P., V.G., L.H., S.I., R.L.D., A.P.D., S.K., M.J.C.), Garvan Institute of Medical Research, Sydney, Australia; RG Development & Disease (U.S.M., S.M.), Max Planck Institute for Molecular Genetics; Institute for Medical Genetics and Human Genetics (U.S.M., S.M.), Charité-Universitätsmedizin, Berlin, Germany; Faculty of Medicine, Prince of Wales Clinical School (L.H.), and Faculty of Medicine, St Vincents Clinical School (S.K.), UNSW Sydney, Randwick; Adelaide Medical School (C.S., M.H.N.T.), University of Adelaide; Kolling Institute (R.L.D.), University of Sydney; SWSLHD Liverpool Hospital (A.C.), Liverpool; and New South Wales Health Pathology Randwick Genomics Laboratory (T.R., E.K.), Australia.
Rani Sachdev
From the School of Women's and Children's Health (E.E.P., R.S., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., M.J.C., A.B., E.K.), The School of Biotechnology and Biomolecular Sciences (M.E.D.), Childrens Cancer Institute (M.J.C.), and NeuRA (T.R.), University of New South Wales; Sydney Childrens Hospital Randwick (E.E.P., R.S., R.M., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., A.B., E.K.), Sydney Childrens Hospital Network; GOLD Service (E.E.P.), Hunter Genetics; Kinghorn Centre for Clinical Genomics (E.E.P., A.E.M., C.P., V.G., L.H., S.I., R.L.D., A.P.D., S.K., M.J.C.), Garvan Institute of Medical Research, Sydney, Australia; RG Development & Disease (U.S.M., S.M.), Max Planck Institute for Molecular Genetics; Institute for Medical Genetics and Human Genetics (U.S.M., S.M.), Charité-Universitätsmedizin, Berlin, Germany; Faculty of Medicine, Prince of Wales Clinical School (L.H.), and Faculty of Medicine, St Vincents Clinical School (S.K.), UNSW Sydney, Randwick; Adelaide Medical School (C.S., M.H.N.T.), University of Adelaide; Kolling Institute (R.L.D.), University of Sydney; SWSLHD Liverpool Hospital (A.C.), Liverpool; and New South Wales Health Pathology Randwick Genomics Laboratory (T.R., E.K.), Australia.
Rebecca Macintosh
From the School of Women's and Children's Health (E.E.P., R.S., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., M.J.C., A.B., E.K.), The School of Biotechnology and Biomolecular Sciences (M.E.D.), Childrens Cancer Institute (M.J.C.), and NeuRA (T.R.), University of New South Wales; Sydney Childrens Hospital Randwick (E.E.P., R.S., R.M., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., A.B., E.K.), Sydney Childrens Hospital Network; GOLD Service (E.E.P.), Hunter Genetics; Kinghorn Centre for Clinical Genomics (E.E.P., A.E.M., C.P., V.G., L.H., S.I., R.L.D., A.P.D., S.K., M.J.C.), Garvan Institute of Medical Research, Sydney, Australia; RG Development & Disease (U.S.M., S.M.), Max Planck Institute for Molecular Genetics; Institute for Medical Genetics and Human Genetics (U.S.M., S.M.), Charité-Universitätsmedizin, Berlin, Germany; Faculty of Medicine, Prince of Wales Clinical School (L.H.), and Faculty of Medicine, St Vincents Clinical School (S.K.), UNSW Sydney, Randwick; Adelaide Medical School (C.S., M.H.N.T.), University of Adelaide; Kolling Institute (R.L.D.), University of Sydney; SWSLHD Liverpool Hospital (A.C.), Liverpool; and New South Wales Health Pathology Randwick Genomics Laboratory (T.R., E.K.), Australia.
Uirá Souto Melo
From the School of Women's and Children's Health (E.E.P., R.S., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., M.J.C., A.B., E.K.), The School of Biotechnology and Biomolecular Sciences (M.E.D.), Childrens Cancer Institute (M.J.C.), and NeuRA (T.R.), University of New South Wales; Sydney Childrens Hospital Randwick (E.E.P., R.S., R.M., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., A.B., E.K.), Sydney Childrens Hospital Network; GOLD Service (E.E.P.), Hunter Genetics; Kinghorn Centre for Clinical Genomics (E.E.P., A.E.M., C.P., V.G., L.H., S.I., R.L.D., A.P.D., S.K., M.J.C.), Garvan Institute of Medical Research, Sydney, Australia; RG Development & Disease (U.S.M., S.M.), Max Planck Institute for Molecular Genetics; Institute for Medical Genetics and Human Genetics (U.S.M., S.M.), Charité-Universitätsmedizin, Berlin, Germany; Faculty of Medicine, Prince of Wales Clinical School (L.H.), and Faculty of Medicine, St Vincents Clinical School (S.K.), UNSW Sydney, Randwick; Adelaide Medical School (C.S., M.H.N.T.), University of Adelaide; Kolling Institute (R.L.D.), University of Sydney; SWSLHD Liverpool Hospital (A.C.), Liverpool; and New South Wales Health Pathology Randwick Genomics Laboratory (T.R., E.K.), Australia.
Stefan Mundlos
From the School of Women's and Children's Health (E.E.P., R.S., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., M.J.C., A.B., E.K.), The School of Biotechnology and Biomolecular Sciences (M.E.D.), Childrens Cancer Institute (M.J.C.), and NeuRA (T.R.), University of New South Wales; Sydney Childrens Hospital Randwick (E.E.P., R.S., R.M., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., A.B., E.K.), Sydney Childrens Hospital Network; GOLD Service (E.E.P.), Hunter Genetics; Kinghorn Centre for Clinical Genomics (E.E.P., A.E.M., C.P., V.G., L.H., S.I., R.L.D., A.P.D., S.K., M.J.C.), Garvan Institute of Medical Research, Sydney, Australia; RG Development & Disease (U.S.M., S.M.), Max Planck Institute for Molecular Genetics; Institute for Medical Genetics and Human Genetics (U.S.M., S.M.), Charité-Universitätsmedizin, Berlin, Germany; Faculty of Medicine, Prince of Wales Clinical School (L.H.), and Faculty of Medicine, St Vincents Clinical School (S.K.), UNSW Sydney, Randwick; Adelaide Medical School (C.S., M.H.N.T.), University of Adelaide; Kolling Institute (R.L.D.), University of Sydney; SWSLHD Liverpool Hospital (A.C.), Liverpool; and New South Wales Health Pathology Randwick Genomics Laboratory (T.R., E.K.), Australia.
Sarah Righetti
From the School of Women's and Children's Health (E.E.P., R.S., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., M.J.C., A.B., E.K.), The School of Biotechnology and Biomolecular Sciences (M.E.D.), Childrens Cancer Institute (M.J.C.), and NeuRA (T.R.), University of New South Wales; Sydney Childrens Hospital Randwick (E.E.P., R.S., R.M., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., A.B., E.K.), Sydney Childrens Hospital Network; GOLD Service (E.E.P.), Hunter Genetics; Kinghorn Centre for Clinical Genomics (E.E.P., A.E.M., C.P., V.G., L.H., S.I., R.L.D., A.P.D., S.K., M.J.C.), Garvan Institute of Medical Research, Sydney, Australia; RG Development & Disease (U.S.M., S.M.), Max Planck Institute for Molecular Genetics; Institute for Medical Genetics and Human Genetics (U.S.M., S.M.), Charité-Universitätsmedizin, Berlin, Germany; Faculty of Medicine, Prince of Wales Clinical School (L.H.), and Faculty of Medicine, St Vincents Clinical School (S.K.), UNSW Sydney, Randwick; Adelaide Medical School (C.S., M.H.N.T.), University of Adelaide; Kolling Institute (R.L.D.), University of Sydney; SWSLHD Liverpool Hospital (A.C.), Liverpool; and New South Wales Health Pathology Randwick Genomics Laboratory (T.R., E.K.), Australia.
Tejaswi Kandula
From the School of Women's and Children's Health (E.E.P., R.S., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., M.J.C., A.B., E.K.), The School of Biotechnology and Biomolecular Sciences (M.E.D.), Childrens Cancer Institute (M.J.C.), and NeuRA (T.R.), University of New South Wales; Sydney Childrens Hospital Randwick (E.E.P., R.S., R.M., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., A.B., E.K.), Sydney Childrens Hospital Network; GOLD Service (E.E.P.), Hunter Genetics; Kinghorn Centre for Clinical Genomics (E.E.P., A.E.M., C.P., V.G., L.H., S.I., R.L.D., A.P.D., S.K., M.J.C.), Garvan Institute of Medical Research, Sydney, Australia; RG Development & Disease (U.S.M., S.M.), Max Planck Institute for Molecular Genetics; Institute for Medical Genetics and Human Genetics (U.S.M., S.M.), Charité-Universitätsmedizin, Berlin, Germany; Faculty of Medicine, Prince of Wales Clinical School (L.H.), and Faculty of Medicine, St Vincents Clinical School (S.K.), UNSW Sydney, Randwick; Adelaide Medical School (C.S., M.H.N.T.), University of Adelaide; Kolling Institute (R.L.D.), University of Sydney; SWSLHD Liverpool Hospital (A.C.), Liverpool; and New South Wales Health Pathology Randwick Genomics Laboratory (T.R., E.K.), Australia.
Andre E. Minoche
From the School of Women's and Children's Health (E.E.P., R.S., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., M.J.C., A.B., E.K.), The School of Biotechnology and Biomolecular Sciences (M.E.D.), Childrens Cancer Institute (M.J.C.), and NeuRA (T.R.), University of New South Wales; Sydney Childrens Hospital Randwick (E.E.P., R.S., R.M., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., A.B., E.K.), Sydney Childrens Hospital Network; GOLD Service (E.E.P.), Hunter Genetics; Kinghorn Centre for Clinical Genomics (E.E.P., A.E.M., C.P., V.G., L.H., S.I., R.L.D., A.P.D., S.K., M.J.C.), Garvan Institute of Medical Research, Sydney, Australia; RG Development & Disease (U.S.M., S.M.), Max Planck Institute for Molecular Genetics; Institute for Medical Genetics and Human Genetics (U.S.M., S.M.), Charité-Universitätsmedizin, Berlin, Germany; Faculty of Medicine, Prince of Wales Clinical School (L.H.), and Faculty of Medicine, St Vincents Clinical School (S.K.), UNSW Sydney, Randwick; Adelaide Medical School (C.S., M.H.N.T.), University of Adelaide; Kolling Institute (R.L.D.), University of Sydney; SWSLHD Liverpool Hospital (A.C.), Liverpool; and New South Wales Health Pathology Randwick Genomics Laboratory (T.R., E.K.), Australia.
Clare Puttick
From the School of Women's and Children's Health (E.E.P., R.S., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., M.J.C., A.B., E.K.), The School of Biotechnology and Biomolecular Sciences (M.E.D.), Childrens Cancer Institute (M.J.C.), and NeuRA (T.R.), University of New South Wales; Sydney Childrens Hospital Randwick (E.E.P., R.S., R.M., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., A.B., E.K.), Sydney Childrens Hospital Network; GOLD Service (E.E.P.), Hunter Genetics; Kinghorn Centre for Clinical Genomics (E.E.P., A.E.M., C.P., V.G., L.H., S.I., R.L.D., A.P.D., S.K., M.J.C.), Garvan Institute of Medical Research, Sydney, Australia; RG Development & Disease (U.S.M., S.M.), Max Planck Institute for Molecular Genetics; Institute for Medical Genetics and Human Genetics (U.S.M., S.M.), Charité-Universitätsmedizin, Berlin, Germany; Faculty of Medicine, Prince of Wales Clinical School (L.H.), and Faculty of Medicine, St Vincents Clinical School (S.K.), UNSW Sydney, Randwick; Adelaide Medical School (C.S., M.H.N.T.), University of Adelaide; Kolling Institute (R.L.D.), University of Sydney; SWSLHD Liverpool Hospital (A.C.), Liverpool; and New South Wales Health Pathology Randwick Genomics Laboratory (T.R., E.K.), Australia.
Velimir Gayevskiy
From the School of Women's and Children's Health (E.E.P., R.S., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., M.J.C., A.B., E.K.), The School of Biotechnology and Biomolecular Sciences (M.E.D.), Childrens Cancer Institute (M.J.C.), and NeuRA (T.R.), University of New South Wales; Sydney Childrens Hospital Randwick (E.E.P., R.S., R.M., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., A.B., E.K.), Sydney Childrens Hospital Network; GOLD Service (E.E.P.), Hunter Genetics; Kinghorn Centre for Clinical Genomics (E.E.P., A.E.M., C.P., V.G., L.H., S.I., R.L.D., A.P.D., S.K., M.J.C.), Garvan Institute of Medical Research, Sydney, Australia; RG Development & Disease (U.S.M., S.M.), Max Planck Institute for Molecular Genetics; Institute for Medical Genetics and Human Genetics (U.S.M., S.M.), Charité-Universitätsmedizin, Berlin, Germany; Faculty of Medicine, Prince of Wales Clinical School (L.H.), and Faculty of Medicine, St Vincents Clinical School (S.K.), UNSW Sydney, Randwick; Adelaide Medical School (C.S., M.H.N.T.), University of Adelaide; Kolling Institute (R.L.D.), University of Sydney; SWSLHD Liverpool Hospital (A.C.), Liverpool; and New South Wales Health Pathology Randwick Genomics Laboratory (T.R., E.K.), Australia.
Luke Hesson
From the School of Women's and Children's Health (E.E.P., R.S., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., M.J.C., A.B., E.K.), The School of Biotechnology and Biomolecular Sciences (M.E.D.), Childrens Cancer Institute (M.J.C.), and NeuRA (T.R.), University of New South Wales; Sydney Childrens Hospital Randwick (E.E.P., R.S., R.M., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., A.B., E.K.), Sydney Childrens Hospital Network; GOLD Service (E.E.P.), Hunter Genetics; Kinghorn Centre for Clinical Genomics (E.E.P., A.E.M., C.P., V.G., L.H., S.I., R.L.D., A.P.D., S.K., M.J.C.), Garvan Institute of Medical Research, Sydney, Australia; RG Development & Disease (U.S.M., S.M.), Max Planck Institute for Molecular Genetics; Institute for Medical Genetics and Human Genetics (U.S.M., S.M.), Charité-Universitätsmedizin, Berlin, Germany; Faculty of Medicine, Prince of Wales Clinical School (L.H.), and Faculty of Medicine, St Vincents Clinical School (S.K.), UNSW Sydney, Randwick; Adelaide Medical School (C.S., M.H.N.T.), University of Adelaide; Kolling Institute (R.L.D.), University of Sydney; SWSLHD Liverpool Hospital (A.C.), Liverpool; and New South Wales Health Pathology Randwick Genomics Laboratory (T.R., E.K.), Australia.
Senel Idrisoglu
From the School of Women's and Children's Health (E.E.P., R.S., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., M.J.C., A.B., E.K.), The School of Biotechnology and Biomolecular Sciences (M.E.D.), Childrens Cancer Institute (M.J.C.), and NeuRA (T.R.), University of New South Wales; Sydney Childrens Hospital Randwick (E.E.P., R.S., R.M., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., A.B., E.K.), Sydney Childrens Hospital Network; GOLD Service (E.E.P.), Hunter Genetics; Kinghorn Centre for Clinical Genomics (E.E.P., A.E.M., C.P., V.G., L.H., S.I., R.L.D., A.P.D., S.K., M.J.C.), Garvan Institute of Medical Research, Sydney, Australia; RG Development & Disease (U.S.M., S.M.), Max Planck Institute for Molecular Genetics; Institute for Medical Genetics and Human Genetics (U.S.M., S.M.), Charité-Universitätsmedizin, Berlin, Germany; Faculty of Medicine, Prince of Wales Clinical School (L.H.), and Faculty of Medicine, St Vincents Clinical School (S.K.), UNSW Sydney, Randwick; Adelaide Medical School (C.S., M.H.N.T.), University of Adelaide; Kolling Institute (R.L.D.), University of Sydney; SWSLHD Liverpool Hospital (A.C.), Liverpool; and New South Wales Health Pathology Randwick Genomics Laboratory (T.R., E.K.), Australia.
Cheryl Shoubridge
From the School of Women's and Children's Health (E.E.P., R.S., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., M.J.C., A.B., E.K.), The School of Biotechnology and Biomolecular Sciences (M.E.D.), Childrens Cancer Institute (M.J.C.), and NeuRA (T.R.), University of New South Wales; Sydney Childrens Hospital Randwick (E.E.P., R.S., R.M., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., A.B., E.K.), Sydney Childrens Hospital Network; GOLD Service (E.E.P.), Hunter Genetics; Kinghorn Centre for Clinical Genomics (E.E.P., A.E.M., C.P., V.G., L.H., S.I., R.L.D., A.P.D., S.K., M.J.C.), Garvan Institute of Medical Research, Sydney, Australia; RG Development & Disease (U.S.M., S.M.), Max Planck Institute for Molecular Genetics; Institute for Medical Genetics and Human Genetics (U.S.M., S.M.), Charité-Universitätsmedizin, Berlin, Germany; Faculty of Medicine, Prince of Wales Clinical School (L.H.), and Faculty of Medicine, St Vincents Clinical School (S.K.), UNSW Sydney, Randwick; Adelaide Medical School (C.S., M.H.N.T.), University of Adelaide; Kolling Institute (R.L.D.), University of Sydney; SWSLHD Liverpool Hospital (A.C.), Liverpool; and New South Wales Health Pathology Randwick Genomics Laboratory (T.R., E.K.), Australia.
Monica Hong Ngoc Thai
From the School of Women's and Children's Health (E.E.P., R.S., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., M.J.C., A.B., E.K.), The School of Biotechnology and Biomolecular Sciences (M.E.D.), Childrens Cancer Institute (M.J.C.), and NeuRA (T.R.), University of New South Wales; Sydney Childrens Hospital Randwick (E.E.P., R.S., R.M., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., A.B., E.K.), Sydney Childrens Hospital Network; GOLD Service (E.E.P.), Hunter Genetics; Kinghorn Centre for Clinical Genomics (E.E.P., A.E.M., C.P., V.G., L.H., S.I., R.L.D., A.P.D., S.K., M.J.C.), Garvan Institute of Medical Research, Sydney, Australia; RG Development & Disease (U.S.M., S.M.), Max Planck Institute for Molecular Genetics; Institute for Medical Genetics and Human Genetics (U.S.M., S.M.), Charité-Universitätsmedizin, Berlin, Germany; Faculty of Medicine, Prince of Wales Clinical School (L.H.), and Faculty of Medicine, St Vincents Clinical School (S.K.), UNSW Sydney, Randwick; Adelaide Medical School (C.S., M.H.N.T.), University of Adelaide; Kolling Institute (R.L.D.), University of Sydney; SWSLHD Liverpool Hospital (A.C.), Liverpool; and New South Wales Health Pathology Randwick Genomics Laboratory (T.R., E.K.), Australia.
Ryan L. Davis
From the School of Women's and Children's Health (E.E.P., R.S., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., M.J.C., A.B., E.K.), The School of Biotechnology and Biomolecular Sciences (M.E.D.), Childrens Cancer Institute (M.J.C.), and NeuRA (T.R.), University of New South Wales; Sydney Childrens Hospital Randwick (E.E.P., R.S., R.M., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., A.B., E.K.), Sydney Childrens Hospital Network; GOLD Service (E.E.P.), Hunter Genetics; Kinghorn Centre for Clinical Genomics (E.E.P., A.E.M., C.P., V.G., L.H., S.I., R.L.D., A.P.D., S.K., M.J.C.), Garvan Institute of Medical Research, Sydney, Australia; RG Development & Disease (U.S.M., S.M.), Max Planck Institute for Molecular Genetics; Institute for Medical Genetics and Human Genetics (U.S.M., S.M.), Charité-Universitätsmedizin, Berlin, Germany; Faculty of Medicine, Prince of Wales Clinical School (L.H.), and Faculty of Medicine, St Vincents Clinical School (S.K.), UNSW Sydney, Randwick; Adelaide Medical School (C.S., M.H.N.T.), University of Adelaide; Kolling Institute (R.L.D.), University of Sydney; SWSLHD Liverpool Hospital (A.C.), Liverpool; and New South Wales Health Pathology Randwick Genomics Laboratory (T.R., E.K.), Australia.
Alexander P. Drew
From the School of Women's and Children's Health (E.E.P., R.S., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., M.J.C., A.B., E.K.), The School of Biotechnology and Biomolecular Sciences (M.E.D.), Childrens Cancer Institute (M.J.C.), and NeuRA (T.R.), University of New South Wales; Sydney Childrens Hospital Randwick (E.E.P., R.S., R.M., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., A.B., E.K.), Sydney Childrens Hospital Network; GOLD Service (E.E.P.), Hunter Genetics; Kinghorn Centre for Clinical Genomics (E.E.P., A.E.M., C.P., V.G., L.H., S.I., R.L.D., A.P.D., S.K., M.J.C.), Garvan Institute of Medical Research, Sydney, Australia; RG Development & Disease (U.S.M., S.M.), Max Planck Institute for Molecular Genetics; Institute for Medical Genetics and Human Genetics (U.S.M., S.M.), Charité-Universitätsmedizin, Berlin, Germany; Faculty of Medicine, Prince of Wales Clinical School (L.H.), and Faculty of Medicine, St Vincents Clinical School (S.K.), UNSW Sydney, Randwick; Adelaide Medical School (C.S., M.H.N.T.), University of Adelaide; Kolling Institute (R.L.D.), University of Sydney; SWSLHD Liverpool Hospital (A.C.), Liverpool; and New South Wales Health Pathology Randwick Genomics Laboratory (T.R., E.K.), Australia.
Hugo Sampaio
From the School of Women's and Children's Health (E.E.P., R.S., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., M.J.C., A.B., E.K.), The School of Biotechnology and Biomolecular Sciences (M.E.D.), Childrens Cancer Institute (M.J.C.), and NeuRA (T.R.), University of New South Wales; Sydney Childrens Hospital Randwick (E.E.P., R.S., R.M., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., A.B., E.K.), Sydney Childrens Hospital Network; GOLD Service (E.E.P.), Hunter Genetics; Kinghorn Centre for Clinical Genomics (E.E.P., A.E.M., C.P., V.G., L.H., S.I., R.L.D., A.P.D., S.K., M.J.C.), Garvan Institute of Medical Research, Sydney, Australia; RG Development & Disease (U.S.M., S.M.), Max Planck Institute for Molecular Genetics; Institute for Medical Genetics and Human Genetics (U.S.M., S.M.), Charité-Universitätsmedizin, Berlin, Germany; Faculty of Medicine, Prince of Wales Clinical School (L.H.), and Faculty of Medicine, St Vincents Clinical School (S.K.), UNSW Sydney, Randwick; Adelaide Medical School (C.S., M.H.N.T.), University of Adelaide; Kolling Institute (R.L.D.), University of Sydney; SWSLHD Liverpool Hospital (A.C.), Liverpool; and New South Wales Health Pathology Randwick Genomics Laboratory (T.R., E.K.), Australia.
Peter Ian Andrews
From the School of Women's and Children's Health (E.E.P., R.S., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., M.J.C., A.B., E.K.), The School of Biotechnology and Biomolecular Sciences (M.E.D.), Childrens Cancer Institute (M.J.C.), and NeuRA (T.R.), University of New South Wales; Sydney Childrens Hospital Randwick (E.E.P., R.S., R.M., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., A.B., E.K.), Sydney Childrens Hospital Network; GOLD Service (E.E.P.), Hunter Genetics; Kinghorn Centre for Clinical Genomics (E.E.P., A.E.M., C.P., V.G., L.H., S.I., R.L.D., A.P.D., S.K., M.J.C.), Garvan Institute of Medical Research, Sydney, Australia; RG Development & Disease (U.S.M., S.M.), Max Planck Institute for Molecular Genetics; Institute for Medical Genetics and Human Genetics (U.S.M., S.M.), Charité-Universitätsmedizin, Berlin, Germany; Faculty of Medicine, Prince of Wales Clinical School (L.H.), and Faculty of Medicine, St Vincents Clinical School (S.K.), UNSW Sydney, Randwick; Adelaide Medical School (C.S., M.H.N.T.), University of Adelaide; Kolling Institute (R.L.D.), University of Sydney; SWSLHD Liverpool Hospital (A.C.), Liverpool; and New South Wales Health Pathology Randwick Genomics Laboratory (T.R., E.K.), Australia.
John Lawson
From the School of Women's and Children's Health (E.E.P., R.S., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., M.J.C., A.B., E.K.), The School of Biotechnology and Biomolecular Sciences (M.E.D.), Childrens Cancer Institute (M.J.C.), and NeuRA (T.R.), University of New South Wales; Sydney Childrens Hospital Randwick (E.E.P., R.S., R.M., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., A.B., E.K.), Sydney Childrens Hospital Network; GOLD Service (E.E.P.), Hunter Genetics; Kinghorn Centre for Clinical Genomics (E.E.P., A.E.M., C.P., V.G., L.H., S.I., R.L.D., A.P.D., S.K., M.J.C.), Garvan Institute of Medical Research, Sydney, Australia; RG Development & Disease (U.S.M., S.M.), Max Planck Institute for Molecular Genetics; Institute for Medical Genetics and Human Genetics (U.S.M., S.M.), Charité-Universitätsmedizin, Berlin, Germany; Faculty of Medicine, Prince of Wales Clinical School (L.H.), and Faculty of Medicine, St Vincents Clinical School (S.K.), UNSW Sydney, Randwick; Adelaide Medical School (C.S., M.H.N.T.), University of Adelaide; Kolling Institute (R.L.D.), University of Sydney; SWSLHD Liverpool Hospital (A.C.), Liverpool; and New South Wales Health Pathology Randwick Genomics Laboratory (T.R., E.K.), Australia.
Michael Cardamone
From the School of Women's and Children's Health (E.E.P., R.S., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., M.J.C., A.B., E.K.), The School of Biotechnology and Biomolecular Sciences (M.E.D.), Childrens Cancer Institute (M.J.C.), and NeuRA (T.R.), University of New South Wales; Sydney Childrens Hospital Randwick (E.E.P., R.S., R.M., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., A.B., E.K.), Sydney Childrens Hospital Network; GOLD Service (E.E.P.), Hunter Genetics; Kinghorn Centre for Clinical Genomics (E.E.P., A.E.M., C.P., V.G., L.H., S.I., R.L.D., A.P.D., S.K., M.J.C.), Garvan Institute of Medical Research, Sydney, Australia; RG Development & Disease (U.S.M., S.M.), Max Planck Institute for Molecular Genetics; Institute for Medical Genetics and Human Genetics (U.S.M., S.M.), Charité-Universitätsmedizin, Berlin, Germany; Faculty of Medicine, Prince of Wales Clinical School (L.H.), and Faculty of Medicine, St Vincents Clinical School (S.K.), UNSW Sydney, Randwick; Adelaide Medical School (C.S., M.H.N.T.), University of Adelaide; Kolling Institute (R.L.D.), University of Sydney; SWSLHD Liverpool Hospital (A.C.), Liverpool; and New South Wales Health Pathology Randwick Genomics Laboratory (T.R., E.K.), Australia.
David Mowat
From the School of Women's and Children's Health (E.E.P., R.S., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., M.J.C., A.B., E.K.), The School of Biotechnology and Biomolecular Sciences (M.E.D.), Childrens Cancer Institute (M.J.C.), and NeuRA (T.R.), University of New South Wales; Sydney Childrens Hospital Randwick (E.E.P., R.S., R.M., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., A.B., E.K.), Sydney Childrens Hospital Network; GOLD Service (E.E.P.), Hunter Genetics; Kinghorn Centre for Clinical Genomics (E.E.P., A.E.M., C.P., V.G., L.H., S.I., R.L.D., A.P.D., S.K., M.J.C.), Garvan Institute of Medical Research, Sydney, Australia; RG Development & Disease (U.S.M., S.M.), Max Planck Institute for Molecular Genetics; Institute for Medical Genetics and Human Genetics (U.S.M., S.M.), Charité-Universitätsmedizin, Berlin, Germany; Faculty of Medicine, Prince of Wales Clinical School (L.H.), and Faculty of Medicine, St Vincents Clinical School (S.K.), UNSW Sydney, Randwick; Adelaide Medical School (C.S., M.H.N.T.), University of Adelaide; Kolling Institute (R.L.D.), University of Sydney; SWSLHD Liverpool Hospital (A.C.), Liverpool; and New South Wales Health Pathology Randwick Genomics Laboratory (T.R., E.K.), Australia.
Alison Colley
From the School of Women's and Children's Health (E.E.P., R.S., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., M.J.C., A.B., E.K.), The School of Biotechnology and Biomolecular Sciences (M.E.D.), Childrens Cancer Institute (M.J.C.), and NeuRA (T.R.), University of New South Wales; Sydney Childrens Hospital Randwick (E.E.P., R.S., R.M., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., A.B., E.K.), Sydney Childrens Hospital Network; GOLD Service (E.E.P.), Hunter Genetics; Kinghorn Centre for Clinical Genomics (E.E.P., A.E.M., C.P., V.G., L.H., S.I., R.L.D., A.P.D., S.K., M.J.C.), Garvan Institute of Medical Research, Sydney, Australia; RG Development & Disease (U.S.M., S.M.), Max Planck Institute for Molecular Genetics; Institute for Medical Genetics and Human Genetics (U.S.M., S.M.), Charité-Universitätsmedizin, Berlin, Germany; Faculty of Medicine, Prince of Wales Clinical School (L.H.), and Faculty of Medicine, St Vincents Clinical School (S.K.), UNSW Sydney, Randwick; Adelaide Medical School (C.S., M.H.N.T.), University of Adelaide; Kolling Institute (R.L.D.), University of Sydney; SWSLHD Liverpool Hospital (A.C.), Liverpool; and New South Wales Health Pathology Randwick Genomics Laboratory (T.R., E.K.), Australia.
Sarah Kummerfeld
From the School of Women's and Children's Health (E.E.P., R.S., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., M.J.C., A.B., E.K.), The School of Biotechnology and Biomolecular Sciences (M.E.D.), Childrens Cancer Institute (M.J.C.), and NeuRA (T.R.), University of New South Wales; Sydney Childrens Hospital Randwick (E.E.P., R.S., R.M., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., A.B., E.K.), Sydney Childrens Hospital Network; GOLD Service (E.E.P.), Hunter Genetics; Kinghorn Centre for Clinical Genomics (E.E.P., A.E.M., C.P., V.G., L.H., S.I., R.L.D., A.P.D., S.K., M.J.C.), Garvan Institute of Medical Research, Sydney, Australia; RG Development & Disease (U.S.M., S.M.), Max Planck Institute for Molecular Genetics; Institute for Medical Genetics and Human Genetics (U.S.M., S.M.), Charité-Universitätsmedizin, Berlin, Germany; Faculty of Medicine, Prince of Wales Clinical School (L.H.), and Faculty of Medicine, St Vincents Clinical School (S.K.), UNSW Sydney, Randwick; Adelaide Medical School (C.S., M.H.N.T.), University of Adelaide; Kolling Institute (R.L.D.), University of Sydney; SWSLHD Liverpool Hospital (A.C.), Liverpool; and New South Wales Health Pathology Randwick Genomics Laboratory (T.R., E.K.), Australia.
Marcel E. Dinger
From the School of Women's and Children's Health (E.E.P., R.S., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., M.J.C., A.B., E.K.), The School of Biotechnology and Biomolecular Sciences (M.E.D.), Childrens Cancer Institute (M.J.C.), and NeuRA (T.R.), University of New South Wales; Sydney Childrens Hospital Randwick (E.E.P., R.S., R.M., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., A.B., E.K.), Sydney Childrens Hospital Network; GOLD Service (E.E.P.), Hunter Genetics; Kinghorn Centre for Clinical Genomics (E.E.P., A.E.M., C.P., V.G., L.H., S.I., R.L.D., A.P.D., S.K., M.J.C.), Garvan Institute of Medical Research, Sydney, Australia; RG Development & Disease (U.S.M., S.M.), Max Planck Institute for Molecular Genetics; Institute for Medical Genetics and Human Genetics (U.S.M., S.M.), Charité-Universitätsmedizin, Berlin, Germany; Faculty of Medicine, Prince of Wales Clinical School (L.H.), and Faculty of Medicine, St Vincents Clinical School (S.K.), UNSW Sydney, Randwick; Adelaide Medical School (C.S., M.H.N.T.), University of Adelaide; Kolling Institute (R.L.D.), University of Sydney; SWSLHD Liverpool Hospital (A.C.), Liverpool; and New South Wales Health Pathology Randwick Genomics Laboratory (T.R., E.K.), Australia.
Mark J. Cowley
From the School of Women's and Children's Health (E.E.P., R.S., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., M.J.C., A.B., E.K.), The School of Biotechnology and Biomolecular Sciences (M.E.D.), Childrens Cancer Institute (M.J.C.), and NeuRA (T.R.), University of New South Wales; Sydney Childrens Hospital Randwick (E.E.P., R.S., R.M., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., A.B., E.K.), Sydney Childrens Hospital Network; GOLD Service (E.E.P.), Hunter Genetics; Kinghorn Centre for Clinical Genomics (E.E.P., A.E.M., C.P., V.G., L.H., S.I., R.L.D., A.P.D., S.K., M.J.C.), Garvan Institute of Medical Research, Sydney, Australia; RG Development & Disease (U.S.M., S.M.), Max Planck Institute for Molecular Genetics; Institute for Medical Genetics and Human Genetics (U.S.M., S.M.), Charité-Universitätsmedizin, Berlin, Germany; Faculty of Medicine, Prince of Wales Clinical School (L.H.), and Faculty of Medicine, St Vincents Clinical School (S.K.), UNSW Sydney, Randwick; Adelaide Medical School (C.S., M.H.N.T.), University of Adelaide; Kolling Institute (R.L.D.), University of Sydney; SWSLHD Liverpool Hospital (A.C.), Liverpool; and New South Wales Health Pathology Randwick Genomics Laboratory (T.R., E.K.), Australia.
Tony Roscioli
From the School of Women's and Children's Health (E.E.P., R.S., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., M.J.C., A.B., E.K.), The School of Biotechnology and Biomolecular Sciences (M.E.D.), Childrens Cancer Institute (M.J.C.), and NeuRA (T.R.), University of New South Wales; Sydney Childrens Hospital Randwick (E.E.P., R.S., R.M., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., A.B., E.K.), Sydney Childrens Hospital Network; GOLD Service (E.E.P.), Hunter Genetics; Kinghorn Centre for Clinical Genomics (E.E.P., A.E.M., C.P., V.G., L.H., S.I., R.L.D., A.P.D., S.K., M.J.C.), Garvan Institute of Medical Research, Sydney, Australia; RG Development & Disease (U.S.M., S.M.), Max Planck Institute for Molecular Genetics; Institute for Medical Genetics and Human Genetics (U.S.M., S.M.), Charité-Universitätsmedizin, Berlin, Germany; Faculty of Medicine, Prince of Wales Clinical School (L.H.), and Faculty of Medicine, St Vincents Clinical School (S.K.), UNSW Sydney, Randwick; Adelaide Medical School (C.S., M.H.N.T.), University of Adelaide; Kolling Institute (R.L.D.), University of Sydney; SWSLHD Liverpool Hospital (A.C.), Liverpool; and New South Wales Health Pathology Randwick Genomics Laboratory (T.R., E.K.), Australia.
Ann Bye
From the School of Women's and Children's Health (E.E.P., R.S., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., M.J.C., A.B., E.K.), The School of Biotechnology and Biomolecular Sciences (M.E.D.), Childrens Cancer Institute (M.J.C.), and NeuRA (T.R.), University of New South Wales; Sydney Childrens Hospital Randwick (E.E.P., R.S., R.M., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., A.B., E.K.), Sydney Childrens Hospital Network; GOLD Service (E.E.P.), Hunter Genetics; Kinghorn Centre for Clinical Genomics (E.E.P., A.E.M., C.P., V.G., L.H., S.I., R.L.D., A.P.D., S.K., M.J.C.), Garvan Institute of Medical Research, Sydney, Australia; RG Development & Disease (U.S.M., S.M.), Max Planck Institute for Molecular Genetics; Institute for Medical Genetics and Human Genetics (U.S.M., S.M.), Charité-Universitätsmedizin, Berlin, Germany; Faculty of Medicine, Prince of Wales Clinical School (L.H.), and Faculty of Medicine, St Vincents Clinical School (S.K.), UNSW Sydney, Randwick; Adelaide Medical School (C.S., M.H.N.T.), University of Adelaide; Kolling Institute (R.L.D.), University of Sydney; SWSLHD Liverpool Hospital (A.C.), Liverpool; and New South Wales Health Pathology Randwick Genomics Laboratory (T.R., E.K.), Australia.
Edwin Kirk
From the School of Women's and Children's Health (E.E.P., R.S., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., M.J.C., A.B., E.K.), The School of Biotechnology and Biomolecular Sciences (M.E.D.), Childrens Cancer Institute (M.J.C.), and NeuRA (T.R.), University of New South Wales; Sydney Childrens Hospital Randwick (E.E.P., R.S., R.M., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., A.B., E.K.), Sydney Childrens Hospital Network; GOLD Service (E.E.P.), Hunter Genetics; Kinghorn Centre for Clinical Genomics (E.E.P., A.E.M., C.P., V.G., L.H., S.I., R.L.D., A.P.D., S.K., M.J.C.), Garvan Institute of Medical Research, Sydney, Australia; RG Development & Disease (U.S.M., S.M.), Max Planck Institute for Molecular Genetics; Institute for Medical Genetics and Human Genetics (U.S.M., S.M.), Charité-Universitätsmedizin, Berlin, Germany; Faculty of Medicine, Prince of Wales Clinical School (L.H.), and Faculty of Medicine, St Vincents Clinical School (S.K.), UNSW Sydney, Randwick; Adelaide Medical School (C.S., M.H.N.T.), University of Adelaide; Kolling Institute (R.L.D.), University of Sydney; SWSLHD Liverpool Hospital (A.C.), Liverpool; and New South Wales Health Pathology Randwick Genomics Laboratory (T.R., E.K.), Australia.
Diagnostic Yield of Whole Genome Sequencing After Nondiagnostic Exome Sequencing or Gene Panel in Developmental and Epileptic Encephalopathies
Elizabeth Emma Palmer, Rani Sachdev, Rebecca Macintosh, Uirá Souto Melo, Stefan Mundlos, Sarah Righetti, Tejaswi Kandula, Andre E. Minoche, Clare Puttick, Velimir Gayevskiy, Luke Hesson, Senel Idrisoglu, Cheryl Shoubridge, Monica Hong Ngoc Thai, Ryan L. Davis, Alexander P. Drew, Hugo Sampaio, Peter Ian Andrews, John Lawson, Michael Cardamone, David Mowat, Alison Colley, Sarah Kummerfeld, Marcel E. Dinger, Mark J. Cowley, Tony Roscioli, Ann Bye, Edwin Kirk
Neurology Mar 2021, 96 (13) e1770-e1782; DOI: 10.1212/WNL.0000000000011655
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Abstract
Objective To assess the benefits and limitations of whole genome sequencing (WGS) compared to exome sequencing (ES) or multigene panel (MGP) in the molecular diagnosis of developmental and epileptic encephalopathies (DEE).
Methods We performed WGS of 30 comprehensively phenotyped DEE patient trios that were undiagnosed after first-tier testing, including chromosomal microarray and either research ES (n = 15) or diagnostic MGP (n = 15).
Results Eight diagnoses were made in the 15 individuals who received prior ES (53%): 3 individuals had complex structural variants; 5 had ES-detectable variants, which now had additional evidence for pathogenicity. Eleven diagnoses were made in the 15 MGP-negative individuals (68%); the majority (n = 10) involved genes not included in the panel, particularly in individuals with postneonatal onset of seizures and those with more complex presentations including movement disorders, dysmorphic features, or multiorgan involvement. A total of 42% of diagnoses were autosomal recessive or X-chromosome linked.
Conclusion WGS was able to improve diagnostic yield over ES primarily through the detection of complex structural variants (n = 3). The higher diagnostic yield was otherwise better attributed to the power of re-analysis rather than inherent advantages of the WGS platform. Additional research is required to assist in the assessment of pathogenicity of novel noncoding and complex structural variants and further improve diagnostic yield for patients with DEE and other neurogenetic disorders.
Glossary
- ACMG=
- American College of Medical Genetics;
- CMA=
- chromosomal microarray;
- DEE=
- developmental and epileptic encephalopathy;
- ES=
- exome sequencing;
- ILAE=
- International League Against Epilepsy;
- LCL=
- lymphoblastoid cell line;
- LRS=
- long-read sequencing;
- MGP=
- multigene panel;
- MPS=
- massively parallel sequencing;
- TAD=
- topologically associated domain;
- WGS=
- whole genome sequencing
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Infographic: links.lww.com/WNL/B349
Podcast: NPub.org/54tdpf
- Received September 8, 2020.
- Accepted in final form December 18, 2020.
- © 2021 American Academy of Neurology
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