Genome sequencing with comprehensive variant calling identifies structural variants and repeat expansions in a large fraction of individuals with ataxia and/or neuromuscular disorders

被引：3

作者：

Ek, Marlene ^{[1
,2
]}

Nilsson, Daniel ^{[1
,2
,3
]}

Engvall, Martin ^{[1
,4
]}

Malmgren, Helena ^{[1
,2
]}

Thonberg, Hakan ^{[1
,2
]}

Pettersson, Maria ^{[1
,2
]}

Anderlid, Britt-Marie ^{[1
,2
]}

Hammarsjo, Anna ^{[1
,2
]}

Helgadottir, Hafdis T. ^{[1
,2
]}

Arnardottir, Snjolaug ^{[5
]}

Naess, Karin ^{[4
,6
]}

Nennesmo, Inger ^{[7
]}

Paucar, Martin ^{[1
,2
]}

Hjartarson, Helgi Thor ^{[8
]}

Press, Rayomand ^{[9
]}

Solders, Goran ^{[5
,9
]}

Sejersen, Thomas ^{[8
,10
]}

Lindstrand, Anna ^{[1
,2
]}

Kvarnung, Malin ^{[1
,2
]}

机构：

[1] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden

[2] Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden

[3] Karolinska Inst, Dept Mol Med & Surg, Sci Life Lab, Sci Pk, Solna, Sweden

[4] Karolinska Univ Hosp, Ctr Inherited Metab Dis, Stockholm, Sweden

[5] Karolinska Univ Hosp, Dept Neurol, Stockholm, Sweden

[6] Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden

[7] Karolinska Univ Hosp, Dept Oncol Pathol, Stockholm, Sweden

[8] Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Dept Neuropediat, Stockholm, Sweden

[9] Karolinska Univ Hosp, Dept Clin Neurophysiol, Stockholm, Sweden

[10] Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden

来源：

FRONTIERS IN NEUROLOGY | 2023年 / 14卷

关键词：

neuromuscular disorders; genome sequencing; single nucleotide variant; structural variant; repeat expansion; ataxia;

D O I：

10.3389/fneur.2023.1170005

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

IntroductionNeuromuscular disorders (NMDs) have a heterogeneous etiology. A genetic diagnosis is key to personalized healthcare and access to targeted treatment for the affected individuals. MethodsIn this study, 861 patients with NMDs were analyzed with genome sequencing and comprehensive variant calling including single nucleotide variants, small insertions/deletions (SNVs/INDELs), and structural variants (SVs) in a panel of 895 NMD genes, as well as short tandem repeat expansions (STRs) at 28 loci. In addition, for unsolved cases with an unspecific clinical presentation, the analysis of a panel with OMIM disease genes was added. ResultsIn the cohort, 27% (232/861) of the patients harbored pathogenic variants, of which STRs and SVs accounted for one-third of the patients (71/232). The variants were found in 107 different NMD genes. Furthermore, 18 pediatric patients harbored pathogenic variants in non-NMD genes. DiscussionOur results highlight that for children with unspecific hypotonia, a genome-wide analysis rather than a disease-based gene panel should be considered as a diagnostic approach. More importantly, our results clearly show that it is crucial to include STR- and SV-analyses in the diagnostics of patients with neuromuscular disorders.

引用

页数：13

共 16 条

[1] High rate of hypomorphic variants as the cause of inherited ataxia and related diseases: study of a cohort of 366 families [J].

Benkirane, Mehdi ;

Marelli, Cecilia ;

Guissart, Claire ;

Roubertie, Agathe ;

Ollagnon, Elizabeth ;

Choumert, Ariane ;

Fluchere, Frederique ;

Magne, Fabienne Ory ;

Halleb, Yosra ;

Renaud, Mathilde ;

Larrieu, Lise ;

Baux, David ;

Patat, Olivier ;

Bousquet, Idriss ;

Ravel, Jean-Marie ;

Cuntz-Shadfar, Danielle ;

Sarret, Catherine ;

Ayrignac, Xavier ;

Rolland, Anne ;

Morales, Raoul ;

Pointaux, Morgane ;

Lieutard-Haag, Cathy ;

Laurens, Brice ;

Tillikete, Caroline ;

Bernard, Emilien ;

Mallaret, Martial ;

Carra-Dalliere, Clarisse ;

Tranchant, Christine ;

Meyer, Pierre ;

Damaj, Lena ;

Pasquier, Laurent ;

Acquaviva, Cecile ;

Chaussenot, Annabelle ;

Isidor, Bertrand ;

Nguyen, Karine ;

Camu, William ;

Eusebio, Alexandre ;

Carriere, Nicolas ;

Riquet, Audrey ;

Thouvenot, Eric ;

Gonzales, Victoria ;

Carme, Emilie ;

Attarian, Shahram ;

Odent, Sylvie ;

Castrioto, Anna ;

Ewenczyk, Claire ;

Charles, Perrine ;

Kremer, Laurent ;

Sissaoui, Samira ;

Bahi-buisson, Nadia .

GENETICS IN MEDICINE, 2021, 23 (11) :2160-2170

[2] The 2022 version of the gene table of neuromuscular disorders (nuclear genome) [J].

Cohen, Enzo ;

Bonne, Gisele ;

Rivier, Francois ;

Hamroun, Dalil .

NEUROMUSCULAR DISORDERS, 2021, 31 (12) :1313-1357

[3]

Dalil Hamroun GB., 2023, GENE TABLE NEUROMUSC

[4] Use of Whole-Exome Sequencing for Diagnosis of Limb-Girdle Muscular Dystrophy Outcomes and Lessons Learned [J].

Ghaoui, Roula ;

Cooper, Sandra T. ;

Lek, Monkol ;

Jones, Kristi ;

Corbett, Alastair ;

Reddel, StephenW. ;

Needham, Merrilee ;

Liang, Christina ;

Waddell, Leigh B. ;

Nicholson, Garth ;

O'Grady, Gina ;

Kaur, Simranpreet ;

Ong, Royston ;

Davis, Mark ;

Sue, Carolyn M. ;

Laing, Nigel G. ;

North, Kathryn N. ;

MacArthur, Daniel G. ;

Clarke, Nigel F. .

JAMA NEUROLOGY, 2015, 72 (12) :1424-1432

[5] Exome sequences versus sequential gene testing in the UK highly specialised Service for Limb Girdle Muscular Dystrophy [J].

Harris, Elizabeth ;

Topf, Ana ;

Barresi, Rita ;

Hudson, Judith ;

Powell, Helen ;

Tellez, James ;

Hicks, Debbie ;

Porter, Anna ;

Bertoli, Marta ;

Evangelista, Teresinha ;

Marini-Betollo, Chiara ;

Magnusson, Olafur ;

Lek, Monkol ;

MacArthur, Daniel ;

Bushby, Kate ;

Lochmueller, Hanns ;

Straub, Volker .

ORPHANET JOURNAL OF RARE DISEASES, 2017, 12

[6] Diagnostic utility of exome sequencing in the evaluation of neuromuscular disorders [J].

Haskell, Gloria T. ;

Adams, Michael C. ;

Fan, Zheng ;

Amin, Krunal ;

Badillo, Roberto J. Guzman ;

Zhou, Linran ;

Bizon, Christopher ;

Chahin, Nizar ;

Greenwood, Robert S. ;

Milko, Laura V. ;

Shiloh-Malawsky, Yael ;

Crooks, Kristy R. ;

Strande, Natasha ;

Tennison, Michael ;

Tilley, Christian R. ;

Brandt, Alicia ;

Wilhelmsen, Kirk C. ;

Weck, Karen ;

Evans, James P. ;

Berg, Jonathan S. .

NEUROLOGY-GENETICS, 2018, 4 (01)

[7] Whole genome sequencing for the diagnosis of neurological repeat expansion disorders in the UK: a retrospective diagnostic accuracy and prospective clinical validation study [J].

Ibanez, Kristina ;

Polke, James ;

Hagelstrom, R. Tanner ;

Dolzhenko, Egor ;

Pasko, Dorota ;

Thomas, Ellen Rachel Amy ;

Daugherty, Louise C. ;

Kasperaviciute, Dalia ;

Smith, Katherine R. ;

Deans, Zandra C. ;

Hill, Sue ;

Fowler, Tom ;

Scott, Richard H. ;

Hardy, John ;

Chinnery, Patrick F. ;

Houlden, Henry ;

Rendon, Augusto ;

Caulfield, Mark J. ;

Eberle, Michael A. ;

Taft, Ryan J. ;

Tucci, Arianna .

LANCET NEUROLOGY, 2022, 21 (03) :234-245

[8] Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenita [J].

Laquerriere, Annie ;

Jaber, Dana ;

Abiusi, Emanuela ;

Maluenda, Jerome ;

Mejlachowicz, Dan ;

Vivanti, Alexandre ;

Dieterich, Klaus ;

Stoeva, Radka ;

Quevarec, Loic ;

Nolent, Flora ;

Biancalana, Valerie ;

Latour, Philippe ;

Sternberg, Damien ;

Capri, Yline ;

Verloes, Alain ;

Bessieres, Bettina ;

Loeuillet, Laurence ;

Attie-Bitach, Tania ;

Martinovic, Jelena ;

Blesson, Sophie ;

Petit, Florence ;

Beneteau, Claire ;

Whalen, Sandra ;

Marguet, Florent ;

Bouligand, Jerome ;

Heron, Delphine ;

Viot, Geraldine ;

Amiel, Jeanne ;

Amram, Daniel ;

Bellesme, Celine ;

Bucourt, Martine ;

Faivre, Laurence ;

Jouk, Pierre-Simon ;

Khung, Suonavy ;

Sigaudy, Sabine ;

Delezoide, Anne-Lise ;

Goldenberg, Alice ;

Jacquemont, Marie-Line ;

Lambert, Laetitia ;

Layet, Valerie ;

Lyonnet, Stanislas ;

Munnich, Arnold ;

Van Maldergem, Lionel ;

Piard, Juliette ;

Guimiot, Fabien ;

Landrieu, Pierre ;

Letard, Pascaline ;

Pelluard, Fanny ;

Perrin, Laurence ;

Saint-Frison, Marie-Helene .

JOURNAL OF MEDICAL GENETICS, 2022, 59 (06) :559-567

[9] Genome sequencing is a sensitive first-line test to diagnose individuals with intellectual disability [J].

Lindstrand, Anna ;

Ek, Marlene ;

Kvarnung, Malin ;

Anderlid, Britt-Marie ;

Bjoerck, Erik ;

Carlsten, Jonas ;

Eisfeldt, Jesper ;

Grigelioniene, Giedre ;

Gustavsson, Peter ;

Hammarsjoe, Anna ;

Helgadottir, Hafdis T. ;

Hellstroem-Pigg, Maritta ;

Kuchinskaya, Ekaterina ;

Lagerstedt-Robinson, Kristina ;

Levin, Lars-Ake ;

Lieden, Agne ;

Lindeloef, Hillevi ;

Malmgren, Helena ;

Nilsson, Daniel ;

Svensson, Eva ;

Paucar, Martin ;

Sahlin, Ellika ;

Tesi, Bianca ;

Tham, Emma ;

Winberg, Johanna ;

Winerdal, Max ;

Wincent, Josephine ;

Soller, Maria Johansson ;

Pettersson, Maria ;

Nordgren, Ann .

GENETICS IN MEDICINE, 2022, 24 (11) :2296-2307

[10] From cytogenetics to cytogenomics: whole-genome sequencing as a first-line test comprehensively captures the diverse spectrum of disease-causing genetic variation underlying intellectual disability [J].

Lindstrand, Anna ;

Eisfeldt, Jesper ;

Pettersson, Maria ;

Carvalho, Claudia M. B. ;

Kvarnung, Malin ;

Grigelioniene, Giedre ;

Anderlid, Britt-Marie ;

Bjerin, Olof ;

Gustavsson, Peter ;

Hammarsjo, Anna ;

Georgii-Hemming, Patrik ;

Iwarsson, Erik ;

Johansson-Soller, Maria ;

Lagerstedt-Robinson, Kristina ;

Lieden, Agne ;

Magnusson, Mans ;

Martin, Marcel ;

Malmgren, Helena ;

Nordenskjold, Magnus ;

Norling, Ameli ;

Sahlin, Ellika ;

Stranneheim, Henrik ;

Tham, Emma ;

Wincent, Josephine ;

Ygberg, Sofia ;

Wedell, Anna ;

Wirta, Valtteri ;

Nordgren, Ann ;

Lundin, Johanna ;

Nilsson, Daniel .

GENOME MEDICINE, 2019, 11 (01)

← 1 2 →