[en] Purpose
Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned.
Methods
Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted.
Results
We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency).
Conclusion
The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock.
Research center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Disciplines :
Human health sciences: Multidisciplinary, general & others Genetics & genetic processes
Author, co-author :
Denommé-Pichon, Anne-Sophie
Matalonga, Leslie
de Boer, Elke
Jackson, Adam
Benetti, Elisa
Banka, Siddharth
Bruel, Ange-Line
Ciolfi, Andrea
Clayton-Smith, Jill
Dallapiccola, Bruno
Duffourd, Yannis
Ellwanger, Kornelia
Fallerini, Chiara
Gilissen, Christian
Graessner, Holm
Haack, Tobias B.
Havlovicova, Marketa
Hoischen, Alexander
Jean-Marçais, Nolwenn
Kleefstra, Tjitske
López-Martín, Estrella
Macek, Milan
Mencarelli, Maria Antonietta
Moutton, Sébastien
Pfundt, Rolph
Pizzi, Simone
Posada, Manuel
Radio, Francesca Clementina
Renieri, Alessandra
Rooryck, Caroline
Ryba, Lukas
Safraou, Hana
Schwarz, Martin
Tartaglia, Marco
Thauvin-Robinet, Christel
Thevenon, Julien
Tran Mau-Them, Frédéric
Trimouille, Aurélien
Votypka, Pavel
de Vries, Bert B. A.
Willemsen, Marjolein H.
Zurek, Birte
Verloes, Alain
Philippe, Christophe
Abbott, Kristin M.
Faivre, Laurence
Kerstjens, Mieke
Martín, Estrella López
Macek Jr., Milan
Maystadt, Isabelle
Morleo, Manuela
Nigro, Vicenzo
Pinelli, Michele
Radio, Francesca C.
Riess, Olaf
Agathe, Jean-Madeleine De Sainte
Santen, Gijs W. E.
Thauvin, Christel
Torella, Annalaura
Vissers, Lisenka
Vitobello, Antonio
Zguro, Kristina
Boer, Elke De
Cohen, Enzo
Danis, Daniel
Gao, Fei
Horvath, Rita
Johari, Mridul
Johanson, Lennart
Li, Shuang
Morsy, Heba
Nelson, Isabelle
Paramonov, Ida
te Paske, Iris B. A. W.
Robinson, Peter
Savarese, Marco
Steyaert, Wouter
Töpf, Ana
van der Velde, Joeri K.
Vandrovcova, Jana
Ossowski, Stephan
Demidov, German
Sturm, Marc
Schulze-Hentrich, Julia M.
Schüle, Rebecca
Xu, Jishu
Kessler, Christoph
Wayand, Melanie
Synofzik, Matthis
Wilke, Carlo
Traschütz, Andreas
Schöls, Ludger
Hengel, Holger
Lerche, Holger
Kegele, Josua
Heutink, Peter
Brunner, Han
Scheffer, Hans
Hoogerbrugge, Nicoline
`t Hoen, Peter A. C.
Vissers, Lisenka E. L. M.
Sablauskas, Karolis
de Voer, Richarda M.
Kamsteeg, Erik-Jan
van de Warrenburg, Bart
van Os, Nienke
Paske, Iris Te
Janssen, Erik
Steehouwer, Marloes
Yaldiz, Burcu
Brookes, Anthony J.
Veal, Colin
Gibson, Spencer
Maddi, Vatsalya
Mehtarizadeh, Mehdi
Riaz, Umar
Warren, Greg
Dizjikan, Farid Yavari
Shorter, Thomas
Straub, Volker
Bettolo, Chiara Marini
Manera, Jordi Diaz
Hambleton, Sophie
Engelhardt, Karin
Alexander, Elizabeth
Peyron, Christine
Pélissier, Aurore
Beltran, Sergi
Gut, Ivo Glynne
Laurie, Steven
Piscia, Davide
Papakonstantinou, Anastasios
Bullich, Gemma
Corvo, Alberto
Fernandez-Callejo, Marcos
Hernández, Carles
Picó, Daniel
Lochmüller, Hanns
Gumus, Gulcin
Bros-Facer, Virginie
Rath, Ana
Hanauer, Marc
Lagorce, David
Hongnat, Oscar
Chahdil, Maroua
Lebreton, Emeline
Stevanin, Giovanni
Durr, Alexandra
Davoine, Claire-Sophie
Guillot-Noel, Léna
Heinzmann, Anna
Coarelli, Giulia
Bonne, Gisèle
Evangelista, Teresinha
Allamand, Valérie
Ben Yaou, Rabah
Metay, Corinne
Eymard, Bruno
Atalaia, Antonio
Stojkovic, Tanya
Turnovec, Marek
Thomasová, Dana
Kremliková, Radka Pourová
Franková, Vera
Havlovicová, Markéta
Li\vsková, Petra
Dole\vzalová, Pavla
Parkinson, Helen
Keane, Thomas
Freeberg, Mallory
Thomas, Coline
Spalding, Dylan
Robert, Glenn
Costa, Alessia
Patch, Christine
Hanna, Mike
Houlden, Henry
Reilly, Mary
Efthymiou, Stephanie
Cali, Elisa
Magrinelli, Francesca
Sisodiya, Sanjay M.
Rohrer, Jonathan
Muntoni, Francesco
Zaharieva, Irina
Sarkozy, Anna
Timmerman, Vincent
Baets, Jonathan
de Vries, Geert
De Winter, Jonathan
Beijer, Danique
de Jonghe, Peter
Van de Vondel, Liedewei
De Ridder, Willem
Weckhuysen, Sarah
Nigro, Vincenzo
Mutarelli, Margherita
Varavallo, Alessandra
Banfi, Sandro
Musacchia, Francesco
Piluso, Giulio
Ferlini, Alessandra
Selvatici, Rita
Gualandi, Francesca
Bigoni, Stefania
Rossi, Rachele
Neri, Marcella
Aretz, Stefan
Spier, Isabel
Sommer, Anna Katharina
Peters, Sophia
Oliveira, Carla
Pelaez, Jose Garcia
Matos, Ana Rita
José, Celina São
Ferreira, Marta
Gullo, Irene
Fernandes, Susana
Garrido, Luzia
Ferreira, Pedro
Carneiro, Fátima
Swertz, Morris A.
Johansson, Lennart
van der Vries, Gerben
Neerincx, Pieter B.
Ruvolo, David
Kerstjens Frederikse, Wilhemina S.
Zonneveld-Huijssoon, Eveline
Roelofs-Prins, Dieuwke
van Gijn, Marielle
Köhler, Sebastian
Metcalfe, Alison
Drunat, Séverine
Heron, Delphine
Mignot, Cyril
Keren, Boris
Lacombe, Didier
Trimouille, Aurelien
Capella, Gabriel
Valle, Laura
Holinski-Feder, Elke
Laner, Andreas
Steinke-Lange, Verena
Cilio, Maria-Roberta
Carpancea, Evelina
Depondt, Chantal
Lederer, Damien
Sznajer, Yves
Duerinckx, Sarah
Mary, Sandrine
Macaya, Alfons
Cazurro-Gutiérrez, Ana
Pérez-Dueñas, Belén
Munell, Francina
Jarava, Clara Franco
Masó, Laura Batlle
Marcé-Grau, Anna
Colobran, Roger
Hackman, Peter
Udd, Bjarne
Hemelsoet, Dimitri
Dermaut, Bart
Schuermans, Nika
Poppe, Bruce
Verdin, Hannah
Osorio, Andrés Nascimento
Depienne, Christel
Roos, Andreas
Cordts, Isabell
Deschauer, Marcus
Striano, Pasquale
Zara, Federico
Riva, Antonella
Iacomino, Michele
Uva, Paolo
Scala, Marcello
Scudieri, Paolo
Claeys, Kristl
Boztug, Kaan
Haimel, Matthias
W.E, Gijs
Ruivenkamp, Claudia A. L.
Natera de Benito, Daniel
Thompson, Rachel
Polavarapu, Kiran
Grimbacher, Bodo
Zaganas, Ioannis
Kokosali, Evgenia
Lambros, Mathioudakis
Evangeliou, Athanasios
Spilioti, Martha
Kapaki, Elisabeth
Bourbouli, Mara
Balicza, Peter
Molnar, Maria Judit
De la Paz, Manuel Posada
Sánchez, Eva Bermejo
Delgado, Beatriz Martínez
Alonso García de la Rosa, F. Javier
Schröck, Evelin
Rump, Andreas
Mei, Davide
Vetro, Annalisa
Balestrini, Simona
Guerrini, Renzo
Chinnery, Patrick F.
Ratnaike, Thiloka
Schon, Katherine
Maver, Ales
Peterlin, Borut
Münchau, Alexander
Lohmann, Katja
Herzog, Rebecca
Pauly, Martje
MAY, Patrick ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core
Dong, X., Liu, B., Yang, L., et al. Clinical exome sequencing as the first-tier test for diagnosing developmental disorders covering both CNV and SNV: a Chinese cohort. J Med Genet 57:8 (2020), 558–566, 10.1136/jmedgenet-2019-106377.
Wright, C.F., Fitzgerald, T.W., Jones, W.D., et al. Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data. Lancet 385:9975 (2015), 1305–1314, 10.1016/S0140-6736(14)61705-0.
Choi, M., Scholl, U.I., Ji, W., et al. Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc Natl Acad Sci U S A 106:45 (2009), 19096–19101, 10.1073/pnas.0910672106.
Wenger, A.M., Guturu, H., Bernstein, J.A., Bejerano, G., Systematic reanalysis of clinical exome data yields additional diagnoses: implications for providers. Genet Med 19:2 (2017), 209–214, 10.1038/gim.2016.88.
Al-Nabhani, M., Al-Rashdi, S., Al-Murshedi, F., et al. Reanalysis of exome sequencing data of intellectual disability samples: yields and benefits. Clin Genet 94:6 (2018), 495–501, 10.1111/cge.13438.
Nambot, S., Thevenon, J., Kuentz, P., et al. Clinical whole-exome sequencing for the diagnosis of rare disorders with congenital anomalies and/or intellectual disability: substantial interest of prospective annual reanalysis. Genet Med 20:6 (2018), 645–654, 10.1038/gim.2017.162.
Ewans, L.J., Schofield, D., Shrestha, R., et al. Whole-exome sequencing reanalysis at 12 months boosts diagnosis and is cost-effective when applied early in Mendelian disorders. Genet Med 20:12 (2018), 1564–1574, 10.1038/gim.2018.39.
Genetics Initiative, Epilepsy, The Epilepsy Genetics Initiative: systematic reanalysis of diagnostic exomes increases yield. Epilepsia 60:5 (2019), 797–806, 10.1111/epi.14698.
Al-Murshedi, F., Meftah, D., Scott, P., Underdiagnoses resulting from variant misinterpretation: time for systematic reanalysis of whole exome data?. Eur J Med Genet 62:1 (2019), 39–43, 10.1016/j.ejmg.2018.04.016.
Li, J., Gao, K., Yan, H., et al. Reanalysis of whole exome sequencing data in patients with epilepsy and intellectual disability/mental retardation. Gene 700 (2019), 168–175, 10.1016/j.gene.2019.03.037.
Liu, P., Meng, L., Normand, E.A., et al. Reanalysis of clinical exome sequencing data. N Engl J Med 380:25 (2019), 2478–2480, 10.1056/NEJMc1812033.
Schmitz-Abe, K., Li, Q., Rosen, S.M., et al. Unique bioinformatic approach and comprehensive reanalysis improve diagnostic yield of clinical exomes. Eur J Hum Genet 27:9 (2019), 1398–1405, 10.1038/s41431-019-0401-x.
Jalkh, N., Corbani, S., Haidar, Z., et al. The added value of WES reanalysis in the field of genetic diagnosis: lessons learned from 200 exomes in the Lebanese population. BMC Med Genomics, 12(1), 2019, 11, 10.1186/s12920-019-0474-y.
Salfati, E.L., Spencer, E.G., Topol, S.E., et al. Re-analysis of whole-exome sequencing data uncovers novel diagnostic variants and improves molecular diagnostic yields for sudden death and idiopathic diseases. Genome Med, 11(1), 2019, 83, 10.1186/s13073-019-0702-2.
Tan, N.B., Stapleton, R., Stark, Z., et al. Evaluating systematic reanalysis of clinical genomic data in rare disease from single center experience and literature review. Mol Genet Genomic Med, 8(11), 2020, e1508, 10.1002/mgg3.1508.
James, K.N., Clark, M.M., Camp, B., et al. Partially automated whole-genome sequencing reanalysis of previously undiagnosed pediatric patients can efficiently yield new diagnoses. NPJ Genom Med, 5(1), 2020, 33, 10.1038/s41525-020-00140-1.
Matalonga, L., Hernández-Ferrer, C., Piscia, D., et al. Solving patients with rare diseases through programmatic reanalysis of genome-phenome data. Eur J Hum Genet 29:9 (2021), 1337–1347, 10.1038/s41431-021-00852-7.
Ji, J., Leung, M.L., Baker, S., Deignan, J.L., Santani, A., Clinical exome reanalysis: current practice and beyond. Mol Diagn Ther 25:5 (2021), 529–536, 10.1007/s40291-021-00541-7.
Wright, C.F., McRae, J.F., Clayton, S., et al. Making new genetic diagnoses with old data: iterative reanalysis and reporting from genome-wide data in 1,133 families with developmental disorders. Genet Med 20:10 (2018), 1216–1223, 10.1038/gim.2017.246.
Deignan, J.L., Chung, W.K., Kearney, H.M., et al. Points to consider in the reevaluation and reanalysis of genomic test results: a statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med 21:6 (2019), 1267–1270, 10.1038/s41436-019-0478-1.
Zurek, B., Ellwanger, K., Vissers, L.E.L.M., et al. Solve-RD: systematic pan-European data sharing and collaborative analysis to solve rare diseases. Eur J Hum Genet 29:9 (2021), 1325–1331, 10.1038/s41431-021-00859-0.
Landrum, M.J., Lee, J.M., Benson, M., et al. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res 46:D1 (2018), D1062–D1067, 10.1093/nar/gkx1153.
de Ligt, J., Willemsen, M.H., van Bon, B.W., et al. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med 367:20 (2012), 1921–1929, 10.1056/NEJMoa1206524.
Thevenon, J., Duffourd, Y., Masurel-Paulet, A., et al. Diagnostic odyssey in severe neurodevelopmental disorders: toward clinical whole-exome sequencing as a first-line diagnostic test. Clin Genet 89:6 (2016), 700–707, 10.1111/cge.12732.
Laurie, S., Fernandez-Callejo, M., Marco-Sola, S., et al. From wet-lab to variations: concordance and speed of bioinformatics pipelines for whole genome and whole exome sequencing. Hum Mutat 37:12 (2016), 1263–1271, 10.1002/humu.23114.
Richards, S., Aziz, N., Bale, S., et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:5 (2015), 405–424, 10.1038/gim.2015.30.
Cogné, B., Ehresmann, S., Beauregard-Lacroix, E., et al. Missense variants in the histone acetyltransferase complex component Gene TRRAP Cause autism and syndromic intellectual disability. Am J Hum Genet 104:3 (2019), 530–541, 10.1016/j.ajhg.2019.01.010.
Senaratne, T.N., Quintero-Rivera, F., NFIA-related disorder. Adam, M.P., Everman, D.B., Mirzaa, G.M., et al. (eds.) GeneReviews [Internet], 1993-2023, University of Washington, Seattle Accessed September 06, 2021 http://www.ncbi.nlm.nih.gov/books/NBK542336/.
Koenig M, Tranchant C, Anheim M. Autosomal recessive cerebellar ataxia 3 due to homozygote c.132dupA mutation within the ANO10 gene–reply. JAMA Neurol. 2015;72(2):239-240. Published correction appears in JAMA Neurol. 2015;72(4):481. https://doi.org/10.1001/jamaneurol.2014.3921.
Hamdan, F.F., Daoud, H., Piton, A., et al. De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism. Biol Psychiatry 69:9 (2011), 898–901, 10.1016/j.biopsych.2010.11.015.
de Boer, E., Yaldiz, B., Denommé-Pichon, A.S., et al. Genome-wide variant calling in reanalysis of exome sequencing data uncovered a pathogenic TUBB3 variant. Eur J Med Genet, 65(1), 2022, 104402, 10.1016/j.ejmg.2021.104402.
Breuss, M., Heng, J.I., Poirier, K., et al. Mutations in the β-tubulin gene TUBB5 cause microcephaly with structural brain abnormalities. Cell Rep 2:6 (2012), 1554–1562, 10.1016/j.celrep.2012.11.017.
Giunta, C., Rohrbach, M., Fauth, C., Baumann, M., FKBP14 kyphoscoliotic Ehlers-Danlos syndrome. Adam, M.P., Everman, D.B., Mirzaa, G.M., et al. (eds.) GeneReviews [Internet], 1993-2023, University of Washington, Seattle Accessed September 08, 2021 [online]. http://www.ncbi.nlm.nih.gov/books/NBK541503/ Seattle, (WA): University of Washington, Seattle.
Wright, C.F., Eberhardt, R.Y., Constantinou, P., et al. Evaluating variants classified as pathogenic in ClinVar in the DDD Study. Genet Med 23:3 (2021), 571–575, 10.1038/s41436-020-01021-9.
Li, H., Improving SNP discovery by base alignment quality. Bioinformatics 27:8 (2011), 1157–1158, 10.1093/bioinformatics/btr076.
Tian, S., Yan, H., Kalmbach, M., Slager, S.L., Impact of post-alignment processing in variant discovery from whole exome data. BMC Bioinformatics, 17(1), 2016, 403, 10.1186/s12859-016-1279-z.
Yauy, K., Lecoquierre, F., Baert-Desurmont, S., et al. ‘Genome Alert!: a standardized procedure for genomic variant reinterpretation and automated genotype-phenotype reassessment in clinical routine. Genet Med 24:6 (2022), 1316–1327, 10.1016/j.gim.2022.02.008.