Elizabeth Emma Palmer1, Rani Sachdev2, Rebecca Macintosh2, Uirá Souto Melo2, Stefan Mundlos2, Sarah Righetti2, Tejaswi Kandula2, Andre E Minoche2, Clare Puttick2, Velimir Gayevskiy2, Luke Hesson2, Senel Idrisoglu2, Cheryl Shoubridge2, Monica Hong Ngoc Thai2, Ryan L Davis2, Alexander P Drew2, Hugo Sampaio2, Peter Ian Andrews2, John Lawson2, Michael Cardamone2, David Mowat2, Alison Colley2, Sarah Kummerfeld2, Marcel E Dinger2, Mark J Cowley2, Tony Roscioli2, Ann Bye2, Edwin Kirk2. 1. 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. elizabeth.palmer@health.nsw.gov.au. 2. 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.
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.
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.
Authors: Dana Marafi; Jawid M Fatih; Rauan Kaiyrzhanov; Matteo P Ferla; Charul Gijavanekar; Aljazi Al-Maraghi; Ning Liu; Emily Sites; Hessa S Alsaif; Mohammad Al-Owain; Mohamed Zakkariah; Ehab El-Anany; Ulviyya Guliyeva; Sughra Guliyeva; Colette Gaba; Ateeq Haseeb; Amal M Alhashem; Enam Danish; Vasiliki Karageorgou; Christian Beetz; Alaa A Subhi; Sureni V Mullegama; Erin Torti; Monisha Sebastin; Margo Sheck Breilyn; Susan Duberstein; Mohamed S Abdel-Hamid; Tadahiro Mitani; Haowei Du; Jill A Rosenfeld; Shalini N Jhangiani; Zeynep Coban Akdemir; Richard A Gibbs; Jenny C Taylor; Khalid A Fakhro; Jill V Hunter; Davut Pehlivan; Maha S Zaki; Joseph G Gleeson; Reza Maroofian; Henry Houlden; Jennifer E Posey; V Reid Sutton; Fowzan S Alkuraya; Sarah H Elsea; James R Lupski Journal: Brain Date: 2022-04-29 Impact factor: 15.255
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Authors: Lata Vadlamudi; Carmen Maree Bennett; Melanie Tom; Ghusoon Abdulrasool; Kristian Brion; Ben Lundie; Hnin Aung; Chiyan Lau; Jonathan Rodgers; Kate Riney; Louisa Gordon Journal: J Clin Med Date: 2022-07-21 Impact factor: 4.964
Authors: Sara Álvaro-Sánchez; Irene Abreu-Rodríguez; Anna Abulí; Clara Serra-Juhe; Maria Del Carmen Garrido-Navas Journal: Diagnostics (Basel) Date: 2021-12-09
Authors: Luciana Musante; Paola Costa; Caterina Zanus; Flavio Faletra; Flora M Murru; Anna M Bianco; Martina La Bianca; Giulia Ragusa; Emmanouil Athanasakis; Adamo P d'Adamo; Marco Carrozzi; Paolo Gasparini Journal: Genes (Basel) Date: 2022-03-12 Impact factor: 4.096