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A deep intronic variant in DNM1 in a patient with developmental and epileptic encephalopathy creates a splice acceptor site and affects only transcript variants including exon 10a

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Abstract

DNM1 developmental and epileptic encephalopathy (DEE) is characterized by severe to profound intellectual disability, hypotonia, movement disorder, and refractory epilepsy, typically presenting with infantile spasms. Most of the affected individuals had de novo missense variants in DNM1. DNM1 undergoes alternative splicing that results in expression of six different transcript variants. One alternatively spliced region affects the tandemly arranged exons 10a and 10b, producing isoforms DNM1A and DNM1B, respectively. Pathogenic variants in the DNM1 coding region affect all transcript variants. Recently, a de novo DNM1 NM_001288739.1:c.1197-8G > A variant located in intron 9 has been reported in several unrelated individuals with DEE that causes in-frame insertion of two amino acids and leads to disease through a dominant-negative mechanism. We report on a patient with DEE and a de novo DNM1 variant NM_001288739.2:c.1197-46C > G in intron 9, upstream of exon 10a. By RT-PCR and Sanger sequencing using fibroblast-derived cDNA of the patient, we identified aberrantly spliced DNM1 mRNAs with exon 9 spliced to the last 45 nucleotides of intron 9 followed by exon 10a (NM_001288739.2:r.1196_1197ins[1197-1_1197-45]). The encoded DNM1A mutant is predicted to contain 15 novel amino acids between Ile398 and Arg399 [NP_001275668.1:p.(Ile398_Arg399ins15)] and likely functions in a dominant-negative manner, similar to other DNM1 mutants. Our data confirm the importance of the DNM1 isoform A for normal human brain function that is underscored by previously reported predominant expression of DMN1A transcripts in pediatric brain, functional differences of the mouse Dnm1a and Dnm1b isoforms, and the Dnm1 fitful mouse, an epilepsy mouse model.

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References

  1. Ferguson SM, Brasnjo G, Hayashi M, Wolfel M, Collesi C, Giovedi S, Raimondi A, Gong LW, Ariel P, Paradise S, O’Toole E, Flavell R, Cremona O, Miesenbock G, Ryan TA, De Camilli P (2007) A selective activity-dependent requirement for dynamin 1 in synaptic vesicle endocytosis. Science 316(5824):570–574. https://doi.org/10.1126/science.1140621

    Article  CAS  PubMed  Google Scholar 

  2. Robinson PJ, Sontag JM, Liu JP, Fykse EM, Slaughter C, McMahon H, Sudhof TC (1993) Dynamin GTPase regulated by protein kinase C phosphorylation in nerve terminals. Nature 365(6442):163–166. https://doi.org/10.1038/365163a0

    Article  CAS  PubMed  Google Scholar 

  3. van der Bliek AM, Meyerowitz EM (1991) Dynamin-like protein encoded by the Drosophila shibire gene associated with vesicular traffic. Nature 351(6325):411–414. https://doi.org/10.1038/351411a0

    Article  PubMed  Google Scholar 

  4. Nakata T, Iwamoto A, Noda Y, Takemura R, Yoshikura H, Hirokawa N (1991) Predominant and developmentally regulated expression of dynamin in neurons. Neuron 7(3):461–469. https://doi.org/10.1016/0896-6273(91)90298-e

    Article  CAS  PubMed  Google Scholar 

  5. Scaife R, Margolis RL (1990) Biochemical and immunochemical analysis of rat brain dynamin interaction with microtubules and organelles in vivo and in vitro. J Cell Biol 111(6 Pt 2):3023–3033. https://doi.org/10.1083/jcb.111.6.3023

    Article  CAS  PubMed  Google Scholar 

  6. RM Boumil VA Letts MC Roberts C Lenz CL Mahaffey ZW Zhang T Moser WN Frankel 2010 A missense mutation in a highly conserved alternate exon of dynamin 1 causes epilepsy in fitful mice PLoS Genet 6 8. https://doi.org/10.1371/journal.pgen.1001046

  7. Cao H, Garcia F, McNiven MA (1998) Differential distribution of dynamin isoforms in mammalian cells. Mol Biol Cell 9(9):2595–2609. https://doi.org/10.1091/mbc.9.9.2595

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sontag JM, Fykse EM, Ushkaryov Y, Liu JP, Robinson PJ, Sudhof TC (1994) Differential expression and regulation of multiple dynamins. J Biol Chem 269(6):4547–4554

    Article  CAS  PubMed  Google Scholar 

  9. Urrutia R, Henley JR, Cook T, McNiven MA (1997) The dynamins: redundant or distinct functions for an expanding family of related GTPases? Proc Natl Acad Sci USA 94(2):377–384. https://doi.org/10.1073/pnas.94.2.377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Antonny B, Burd C, De Camilli P, Chen E, Daumke O, Faelber K, Ford M, Frolov VA, Frost A, Hinshaw JE, Kirchhausen T, Kozlov MM, Lenz M, Low HH, McMahon H, Merrifield C, Pollard TD, Robinson PJ, Roux A, Schmid S (2016) Membrane fission by dynamin: what we know and what we need to know. EMBO J 35(21):2270–84. https://doi.org/10.15252/embj.201694613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ferguson SM, De Camilli P (2012) Dynamin, a membrane-remodelling GTPase. Nat Rev Mol Cell Biol 13(2):75–88. https://doi.org/10.1038/nrm3266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Euro E-RESC, Phenome E, Genome P, Epi KC (2014) De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am J Hum Genet 95(4):360–370. https://doi.org/10.1016/j.ajhg.2014.08.013

    Article  CAS  Google Scholar 

  13. John A, Ng-Cordell E, Hanna N, Brkic D, Baker K (2021) The neurodevelopmental spectrum of synaptic vesicle cycling disorders. J Neurochem 157(2):208–228. https://doi.org/10.1111/jnc.15135

    Article  CAS  PubMed  Google Scholar 

  14. Fernandez-Marmiesse A, Roca I, Diaz-Flores F, Cantarin V, Perez-Poyato MS, Fontalba A, Laranjeira F, Quintans S, Moldovan O, Felgueroso B, Rodriguez-Pedreira M, Simon R, Camacho A, Quijada P, Ibanez-Mico S, Domingno MR, Benito C, Calvo R, Perez-Cejas A, Carrasco ML, Ramos F, Couce ML, Ruiz-Falco ML, Gutierrez-Solana L, Martinez-Atienza M (2019) Rare variants in 48 genes account for 42% of cases of epilepsy with or without neurodevelopmental delay in 246 pediatric patients. Front Neurosci 13:1135. https://doi.org/10.3389/fnins.2019.01135

    Article  PubMed  PubMed Central  Google Scholar 

  15. Investigators GPP, Smedley D, Smith KR, Martin A, Thomas EA, McDonagh EM, Cipriani V, Ellingford JM, Arno G, Tucci A, Vandrovcova J, Chan G, Williams HJ, Ratnaike T, Wei W, Stirrups K, Ibanez K, Moutsianas L, Wielscher M, Need A, Barnes MR, Vestito L, Buchanan J, Wordsworth S, Ashford S, Rehmstrom K, Li E, Fuller G, Twiss P, Spasic-Boskovic O, Halsall S, Floto RA, Poole K, Wagner A, Mehta SG, Gurnell M, Burrows N, James R, Penkett C, Dewhurst E, Graf S, Mapeta R, Kasanicki M, Haworth A, Savage H, Babcock M, Reese MG, Bale M, Baple E, Boustred C, Brittain H, de Burca A, Bleda M, Devereau A, Halai D, Haraldsdottir E, Hyder Z, Kasperaviciute D, Patch C, Polychronopoulos D, Matchan A, Sultana R, Ryten M, Tavares ALT, Tregidgo C, Turnbull C, Welland M, Wood S, Snow C, Williams E, Leigh S, Foulger RE, Daugherty LC, Niblock O, Leong IUS, Wright CF, Davies J, Crichton C, Welch J, Woods K, Abulhoul L, Aurora P, Bockenhauer D, Broomfield A, Cleary MA, Lam T, Dattani M, Footitt E, Ganesan V, Grunewald S, Compeyrot-Lacassagne S, Muntoni F, Pilkington C, Quinlivan R, Thapar N, Wallis C, Wedderburn LR, Worth A, Bueser T, Compton C, Deshpande C, Fassihi H, Haque E, Izatt L, Josifova D, Mohammed S, Robert L, Rose S, Ruddy D, Sarkany R, Say G, Shaw AC, Wolejko A, Habib B, Burns G, Hunter S, Grocock RJ, Humphray SJ, Robinson PN, Haendel M, Simpson MA, Banka S, Clayton-Smith J, Douzgou S, Hall G, Thomas HB, O’Keefe RT, Michaelides M, Moore AT, Malka S, Pontikos N, Browning AC, Straub V, Gorman GS, Horvath R, Quinton R, Schaefer AM, Yu-Wai-Man P, Turnbull DM, McFarland R, Taylor RW, O’Connor E, Yip J, Newland K, Morris HR, Polke J, Wood NW, Campbell C, Camps C, Gibson K, Koelling N, Lester T, Nemeth AH, Palles C, Patel S, Roy NBA, Sen A, Taylor J, Cacheiro P, Jacobsen JO, Seaby EG, Davison V, Chitty L, Douglas A, Naresh K, McMullan D, Ellard S, Temple IK, Mumford AD, Wilson G, Beales P, Bitner-Glindzicz M, Black G, Bradley JR, Brennan P, Burn J, Chinnery PF, Elliott P, Flinter F, Houlden H, Irving M, Newman W, Rahman S, Sayer JA, Taylor JC, Webster AR, Wilkie AOM, Ouwehand WH, Raymond FL, Chisholm J, Hill S, Bentley D, Scott RH, Fowler T, Rendon A, Caulfield M (2021) 100,000 genomes pilot on rare-disease diagnosis in health care - preliminary report. N Engl J Med 385(20):1868–1880. https://doi.org/10.1056/NEJMoa2035790

    Article  Google Scholar 

  16. Nakashima M, Kouga T, Lourenco CM, Shiina M, Goto T, Tsurusaki Y, Miyatake S, Miyake N, Saitsu H, Ogata K, Osaka H, Matsumoto N (2016) De novo DNM1 mutations in two cases of epileptic encephalopathy. Epilepsia 57(1):e18-23. https://doi.org/10.1111/epi.13257

    Article  CAS  PubMed  Google Scholar 

  17. von Spiczak S, Helbig KL, Shinde DN, Huether R, Pendziwiat M, Lourenco C, Nunes ME, Sarco DP, Kaplan RA, Dlugos DJ, Kirsch H, Slavotinek A, Cilio MR, Cervenka MC, Cohen JS, McClellan R, Fatemi A, Yuen A, Sagawa Y, Littlejohn R, McLean SD, Hernandez-Hernandez L, Maher B, Moller RS, Palmer E, Lawson JA, Campbell CA, Joshi CN, Kolbe DL, Hollingsworth G, Neubauer BA, Muhle H, Stephani U, Scheffer IE, Pena SDJ, Sisodiya SM, Helbig I, Epi KC, Euro E-RESNWG (2017) DNM1 encephalopathy: a new disease of vesicle fission. Neurology 89(4):385–394. https://doi.org/10.1212/WNL.0000000000004152

    Article  CAS  Google Scholar 

  18. Li H, Fang F, Xu M, Liu Z, Zhou J, Wang X, Wang X, Han T (2019) Clinical assessments and EEG analyses of encephalopathies associated with dynamin-1 mutation. Front Pharmacol 10:1454. https://doi.org/10.3389/fphar.2019.01454

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lin L, Zhang Y, Pan H, Wang J, Qi Y, Ma Y (2020) Clinical and genetic characteristics and prenatal diagnosis of patients presented GDD/ID with rare monogenic causes. Orphanet J Rare Dis 15(1):317. https://doi.org/10.1186/s13023-020-01599-y

    Article  PubMed  PubMed Central  Google Scholar 

  20. Takata A, Nakashima M, Saitsu H, Mizuguchi T, Mitsuhashi S, Takahashi Y, Okamoto N, Osaka H, Nakamura K, Tohyama J, Haginoya K, Takeshita S, Kuki I, Okanishi T, Goto T, Sasaki M, Sakai Y, Miyake N, Miyatake S, Tsuchida N, Iwama K, Minase G, Sekiguchi F, Fujita A, Imagawa E, Koshimizu E, Uchiyama Y, Hamanaka K, Ohba C, Itai T, Aoi H, Saida K, Sakaguchi T, Den K, Takahashi R, Ikeda H, Yamaguchi T, Tsukamoto K, Yoshitomi S, Oboshi T, Imai K, Kimizu T, Kobayashi Y, Kubota M, Kashii H, Baba S, Iai M, Kira R, Hara M, Ohta M, Miyata Y, Miyata R, Takanashi JI, Matsui J, Yokochi K, Shimono M, Amamoto M, Takayama R, Hirabayashi S, Aiba K, Matsumoto H, Nabatame S, Shiihara T, Kato M, Matsumoto N (2019) Comprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic encephalopathy. Nat Commun 10(1):2506. https://doi.org/10.1038/s41467-019-10482-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bowling KM, Thompson ML, Amaral MD, Finnila CR, Hiatt SM, Engel KL, Cochran JN, Brothers KB, East KM, Gray DE, Kelley WV, Lamb NE, Lose EJ, Rich CA, Simmons S, Whittle JS, Weaver BT, Nesmith AS, Myers RM, Barsh GS, Bebin EM, Cooper GM (2017) Genomic diagnosis for children with intellectual disability and/or developmental delay. Genome Med 9(1):43. https://doi.org/10.1186/s13073-017-0433-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhu X, Padmanabhan R, Copeland B, Bridgers J, Ren Z, Kamalakaran S, O’Driscoll-Collins A, Berkovic SF, Scheffer IE, Poduri A, Mei D, Guerrini R, Lowenstein DH, Allen AS, Heinzen EL, Goldstein DB (2017) A case-control collapsing analysis identifies epilepsy genes implicated in trio sequencing studies focused on de novo mutations. PLoS Genet 13(11):e1007104. https://doi.org/10.1371/journal.pgen.1007104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Deng XL, Yin F, Zhang CL, Ma YP, He F, Wu LW, Peng J (2016) Dynamin-1-related infantile spasms: a case report and review of literature. Zhonghua Er Ke Za Zhi 54(11):856–859. https://doi.org/10.3760/cma.j.issn.0578-1310.2016.11.014

    Article  CAS  PubMed  Google Scholar 

  24. Fung CW, Kwong AK, Wong VC (2017) Gene panel analysis for nonsyndromic cryptogenic neonatal/infantile epileptic encephalopathy. Epilepsia Open 2(2):236–243. https://doi.org/10.1002/epi4.12055

    Article  PubMed  PubMed Central  Google Scholar 

  25. Yao R, Zhou Y, Tang J, Li N, Yu T, He Y, Wang C, Wang J, Wang J (2021) Genetic diagnosis spectrum and multigenic burden of exome-level rare variants in a childhood epilepsy cohort. Front Genet 12:782419. https://doi.org/10.3389/fgene.2021.782419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Allen NM, Conroy J, Shahwan A, Lynch B, Correa RG, Pena SD, McCreary D, Magalhaes TR, Ennis S, Lynch SA, King MD (2016) Unexplained early onset epileptic encephalopathy: exome screening and phenotype expansion. Epilepsia 57(1):e12–e17. https://doi.org/10.1111/epi.13250

    Article  CAS  PubMed  Google Scholar 

  27. Epi KC, Phenome E, Genome P, Allen AS, Berkovic SF, Cossette P, Delanty N, Dlugos D, Eichler EE, Epstein MP, Glauser T, Goldstein DB, Han Y, Heinzen EL, Hitomi Y, Howell KB, Johnson MR, Kuzniecky R, Lowenstein DH, Lu YF, Madou MR, Marson AG, Mefford HC, Esmaeeli Nieh S, O’Brien TJ, Ottman R, Petrovski S, Poduri A, Ruzzo EK, Scheffer IE, Sherr EH, Yuskaitis CJ, Abou-Khalil B, Alldredge BK, Bautista JF, Berkovic SF, Boro A, Cascino GD, Consalvo D, Crumrine P, Devinsky O, Dlugos D, Epstein MP, Fiol M, Fountain NB, French J, Friedman D, Geller EB, Glauser T, Glynn S, Haut SR, Hayward J, Helmers SL, Joshi S, Kanner A, Kirsch HE, Knowlton RC, Kossoff EH, Kuperman R, Kuzniecky R, Lowenstein DH, McGuire SM, Motika PV, Novotny EJ, Ottman R, Paolicchi JM, Parent JM, Park K, Poduri A, Scheffer IE, Shellhaas RA, Sherr EH, Shih JJ, Singh R, Sirven J, Smith MC, Sullivan J, Lin Thio L, Venkat A, Vining EP, Von Allmen GK, Weisenberg JL, Widdess-Walsh P, Winawer MR (2013) De novo mutations in epileptic encephalopathies. Nature 501(7466):217–221. https://doi.org/10.1038/nature12439

    Article  CAS  Google Scholar 

  28. Ko A, Youn SE, Kim SH, Lee JS, Kim S, Choi JR, Kim HD, Lee ST, Kang HC (2018) Targeted gene panel and genotype-phenotype correlation in children with developmental and epileptic encephalopathy. Epilepsy Res 141:48–55. https://doi.org/10.1016/j.eplepsyres.2018.02.003

    Article  CAS  PubMed  Google Scholar 

  29. Snoeijen-Schouwenaars FM, van Ool JS, Verhoeven JS, van Mierlo P, Braakman HMH, Smeets EE, Nicolai J, Schoots J, Teunissen MWA, Rouhl RPW, Tan IY, Yntema HG, Brunner HG, Pfundt R, Stegmann AP, Kamsteeg EJ, Schelhaas HJ, Willemsen MH (2019) Diagnostic exome sequencing in 100 consecutive patients with both epilepsy and intellectual disability. Epilepsia 60(1):155–164. https://doi.org/10.1111/epi.14618

    Article  PubMed  Google Scholar 

  30. Yuskaitis CJ, Ruzhnikov MRZ, Howell KB, Allen IE, Kapur K, Dlugos DJ, Scheffer IE, Poduri A, Sherr EH (2018) Infantile spasms of unknown cause: predictors of outcome and genotype-phenotype correlation. Pediatr Neurol 87:48–56. https://doi.org/10.1016/j.pediatrneurol.2018.04.012

    Article  PubMed  PubMed Central  Google Scholar 

  31. Dhindsa RS, Bradrick SS, Yao X, Heinzen EL, Petrovski S, Krueger BJ, Johnson MR, Frankel WN, Petrou S, Boumil RM, Goldstein DB (2015) Epileptic encephalopathy-causing mutations in DNM1 impair synaptic vesicle endocytosis. Neurol Genet 1(1):e4. https://doi.org/10.1212/01.NXG.0000464295.65736.da

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Epi KC (2016) De novo mutations in SLC1A2 and CACNA1A are important causes of epileptic encephalopathies. Am J Hum Genet 99(2):287–298. https://doi.org/10.1016/j.ajhg.2016.06.003

    Article  CAS  Google Scholar 

  33. Lazzara A, Asghar S, Zacharia T, Byler D (2018) DNM1 mutation in a child associated with progressive bilateral mesial temporal sclerosis. Clin Case Rep 6(11):2037–2039. https://doi.org/10.1002/ccr3.1793

    Article  PubMed  PubMed Central  Google Scholar 

  34. Naess K, Bruhn H, Stranneheim H, Freyer C, Wibom R, Mourier A, Engvall M, Nennesmo I, Lesko N, Wredenberg A, Wedell A, von Dobeln U (2021) Clinical presentation, genetic etiology, and coenzyme Q10 levels in 55 children with combined enzyme deficiencies of the mitochondrial respiratory chain J Pediatr 228:240–51 e2. https://doi.org/10.1016/j.jpeds.2020.08.025

  35. Palmer EE, Schofield D, Shrestha R, Kandula T, Macintosh R, Lawson JA, Andrews I, Sampaio H, Johnson AM, Farrar MA, Cardamone M, Mowat D, Elakis G, Lo W, Zhu Y, Ying K, Morris P, Tao J, Dias KR, Buckley M, Dinger ME, Cowley MJ, Roscioli T, Kirk EP, Bye A, Sachdev RK (2018) Integrating exome sequencing into a diagnostic pathway for epileptic encephalopathy: evidence of clinical utility and cost effectiveness. Mol Genet Genomic Med 6(2):186–199. https://doi.org/10.1002/mgg3.355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hamdan FF, Myers CT, Cossette P, Lemay P, Spiegelman D, Laporte AD, Nassif C, Diallo O, Monlong J, Cadieux-Dion M, Dobrzeniecka S, Meloche C, Retterer K, Cho MT, Rosenfeld JA, Bi W, Massicotte C, Miguet M, Brunga L, Regan BM, Mo K, Tam C, Schneider A, Hollingsworth G, Deciphering Developmental Disorders S, FitzPatrick DR, Donaldson A, Canham N, Blair E, Kerr B, Fry AE, Thomas RH, Shelagh J, Hurst JA, Brittain H, Blyth M, Lebel RR, Gerkes EH, Davis-Keppen L, Stein Q, Chung WK, Dorison SJ, Benke PJ, Fassi E, Corsten-Janssen N, Kamsteeg EJ, Mau-Them FT, Bruel AL, Verloes A, Ounap K, Wojcik MH, Albert DVF, Venkateswaran S, Ware T, Jones D, Liu YC, Mohammad SS, Bizargity P, Bacino CA, Leuzzi V, Martinelli S, Dallapiccola B, Tartaglia M, Blumkin L, Wierenga KJ, Purcarin G, O’Byrne JJ, Stockler S, Lehman A, Keren B, Nougues MC, Mignot C, Auvin S, Nava C, Hiatt SM, Bebin M, Shao Y, Scaglia F, Lalani SR, Frye RE, Jarjour IT, Jacques S, Boucher RM, Riou E, Srour M, Carmant L, Lortie A, Major P, Diadori P, Dubeau F, D’Anjou G, Bourque G, Berkovic SF, Sadleir LG, Campeau PM, Kibar Z, Lafreniere RG, Girard SL, Mercimek-Mahmutoglu S, Boelman C, Rouleau GA, Scheffer IE, Mefford HC, Andrade DM, Rossignol E, Minassian BA, Michaud JL (2017) High rate of recurrent de novo mutations in developmental and epileptic encephalopathies. Am J Hum Genet 101(5):664–685. https://doi.org/10.1016/j.ajhg.2017.09.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Helbig KL, Farwell Hagman KD, Shinde DN, Mroske C, Powis Z, Li S, Tang S, Helbig I (2016) Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy. Genet Med 18(9):898–905. https://doi.org/10.1038/gim.2015.186

    Article  CAS  PubMed  Google Scholar 

  38. Joshi C, Kolbe DL, Mansilla MA, Mason SO, Smith RJ, Campbell CA (2016) Reducing the cost of the diagnostic odyssey in early onset epileptic encephalopathies. Biomed Res Int 2016:6421039. https://doi.org/10.1155/2016/6421039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Moller RS, Larsen LH, Johannesen KM, Talvik I, Talvik T, Vaher U, Miranda MJ, Farooq M, Nielsen JE, Svendsen LL, Kjelgaard DB, Linnet KM, Hao Q, Uldall P, Frangu M, Tommerup N, Baig SM, Abdullah U, Born AP, Gellert P, Nikanorova M, Olofsson K, Jepsen B, Marjanovic D, Al-Zehhawi LI, Penalva SJ, Krag-Olsen B, Brusgaard K, Hjalgrim H, Rubboli G, Pal DK, Dahl HA (2016) Gene panel testing in epileptic encephalopathies and familial epilepsies. Mol Syndromol 7(4):210–219. https://doi.org/10.1159/000448369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Rim JH, Kim SH, Hwang IS, Kwon SS, Kim J, Kim HW, Cho MJ, Ko A, Youn SE, Kim J, Lee YM, Chung HJ, Lee JS, Kim HD, Choi JR, Lee ST, Kang HC (2018) Efficient strategy for the molecular diagnosis of intractable early-onset epilepsy using targeted gene sequencing. BMC Med Genomics 11(1):6. https://doi.org/10.1186/s12920-018-0320-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kolnikova M, Skopkova M, Ilencikova D, Foltan T, Payerova J, Danis D, Klimes I, Stanik J, Gasperikova D (2018) DNM1 encephalopathy - atypical phenotype with hypomyelination due to a novel de novo variant in the DNM1 gene. Seizure 56:31–33. https://doi.org/10.1016/j.seizure.2018.01.020

    Article  PubMed  Google Scholar 

  42. Posey JE, Harel T, Liu P, Rosenfeld JA, James RA, Coban Akdemir ZH, Walkiewicz M, Bi W, Xiao R, Ding Y, Xia F, Beaudet AL, Muzny DM, Gibbs RA, Boerwinkle E, Eng CM, Sutton VR, Shaw CA, Plon SE, Yang Y, Lupski JR (2017) Resolution of disease phenotypes resulting from multilocus genomic variation. N Engl J Med 376(1):21–31. https://doi.org/10.1056/NEJMoa1516767

    Article  CAS  PubMed  Google Scholar 

  43. French CE, Dolling H, Megy K, Sanchis-Juan A, Kumar A, Delon I, Wakeling M, Mallin L, Agrawal S, Austin T, Walston F, Park SM, Parker A, Piyasena C, Bradbury K, Next Generation Children's Project C, Ellard S, Rowitch DH, Raymond FL (2022) Refinements and considerations for trio whole-genome sequence analysis when investigating Mendelian diseases presenting in early childhood HGG Adv 3 3 100113. https://doi.org/10.1016/j.xhgg.2022.100113

  44. Parthasarathy S, Ruggiero SM, Gelot A, Soardi FC, Ribeiro BFR, Pires DEV, Ascher DB, Schmitt A, Rambaud C, Represa A, Xie HM, Lusk L, Wilmarth O, McDonnell PP, Juarez OA, Grace AN, Buratti J, Mignot C, Gras D, Nava C, Pierce SR, Keren B, Kennedy BC, Pena SDJ, Helbig I, Cuddapah VA (2022) A recurrent de novo splice site variant involving DNM1 exon 10a causes developmental and epileptic encephalopathy through a dominant-negative mechanism. Am J Hum Genet 109(12):2253–2269. https://doi.org/10.1016/j.ajhg.2022.11.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Truty R, Patil N, Sankar R, Sullivan J, Millichap J, Carvill G, Entezam A, Esplin ED, Fuller A, Hogue M, Johnson B, Khouzam A, Kobayashi Y, Lewis R, Nykamp K, Riethmaier D, Westbrook J, Zeman M, Nussbaum RL, Aradhya S (2019) Possible precision medicine implications from genetic testing using combined detection of sequence and intragenic copy number variants in a large cohort with childhood epilepsy. Epilepsia Open 4(3):397–408. https://doi.org/10.1002/epi4.12348

    Article  PubMed  PubMed Central  Google Scholar 

  46. Brereton E, Fassi E, Araujo GC, Dodd J, Telegrafi A, Pathak SJ, Shinawi M (2018) Mutations in the PH Domain of DNM1 are associated with a nonepileptic phenotype characterized by developmental delay and neurobehavioral abnormalities. Mol Genet Genomic Med 6(2):294–300. https://doi.org/10.1002/mgg3.362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Choi E, Dale B, RamachandranNair R, Ejaz R (2021) Pathogenic DNM1 gene variant presenting with unusually nonsevere neurodevelopmental phenotype a case report. Neurol Genet 7(5):e618. https://doi.org/10.1212/NXG.0000000000000618

    Article  PubMed  PubMed Central  Google Scholar 

  48. van der Ven AT, Johannsen J, Kortum F, Wagner M, Tsiakas K, Bierhals T, Lessel D, Herget T, Kloth K, Lisfeld J, Scholz T, Obi N, Wortmann S, Prokisch H, Kubisch C, Denecke J, Santer R, Hempel M (2021) Prevalence and clinical prediction of mitochondrial disorders in a large neuropediatric cohort. Clin Genet 100(6):766–770. https://doi.org/10.1111/cge.14061

    Article  CAS  PubMed  Google Scholar 

  49. Devanna P, van de Vorst M, Pfundt R, Gilissen C, Vernes SC (2018) Genome-wide investigation of an ID cohort reveals de novo 3’UTR variants affecting gene expression. Hum Genet 137(9):717–721. https://doi.org/10.1007/s00439-018-1925-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Sahly AN, Krochmalnek E, St-Onge J, Srour M, Myers KA (2020) Severe DNM1 encephalopathy with dysmyelination due to recurrent splice site pathogenic variant. Hum Genet 139(12):1575–1578. https://doi.org/10.1007/s00439-020-02224-5

    Article  CAS  PubMed  Google Scholar 

  51. Chappie JS, Acharya S, Leonard M, Schmid SL, Dyda F (2010) G domain dimerization controls dynamin’s assembly-stimulated GTPase activity. Nature 465(7297):435–440. https://doi.org/10.1038/nature09032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Damke H, Binns DD, Ueda H, Schmid SL, Baba T (2001) Dynamin GTPase domain mutants block endocytic vesicle formation at morphologically distinct stages. Mol Biol Cell 12(9):2578–2589. https://doi.org/10.1091/mbc.12.9.2578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Ford MG, Jenni S, Nunnari J (2011) The crystal structure of dynamin. Nature 477(7366):561–566. https://doi.org/10.1038/nature10441

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Marks B, Stowell MH, Vallis Y, Mills IG, Gibson A, Hopkins CR, McMahon HT (2001) GTPase activity of dynamin and resulting conformation change are essential for endocytosis. Nature 410(6825):231–235. https://doi.org/10.1038/35065645

    Article  CAS  PubMed  Google Scholar 

  55. Pucadyil TJ, Schmid SL (2008) Real-time visualization of dynamin-catalyzed membrane fission and vesicle release. Cell 135(7):1263–1275. https://doi.org/10.1016/j.cell.2008.11.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Vallis Y, Wigge P, Marks B, Evans PR, McMahon HT (1999) Importance of the pleckstrin homology domain of dynamin in clathrin-mediated endocytosis. Curr Biol 9(5):257–260. https://doi.org/10.1016/s0960-9822(99)80114-6

    Article  CAS  PubMed  Google Scholar 

  57. van der Bliek AM, Redelmeier TE, Damke H, Tisdale EJ, Meyerowitz EM, Schmid SL (1993) Mutations in human dynamin block an intermediate stage in coated vesicle formation. J Cell Biol 122(3):553–563. https://doi.org/10.1083/jcb.122.3.553

    Article  PubMed  Google Scholar 

  58. Chen S, Zhou Y, Chen Y, Gu J (2018) fastp: an ultra-fast all-in-one FASTQ preprocessor. Bioinformatics 34(17):i884–i890. https://doi.org/10.1093/bioinformatics/bty560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Li H, Durbin R (2010) Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics 26(5):589–595. https://doi.org/10.1093/bioinformatics/btp698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kim S, Scheffler K, Halpern AL, Bekritsky MA, Noh E, Kallberg M, Chen X, Kim Y, Beyter D, Krusche P, Saunders CT (2018) Strelka2: fast and accurate calling of germline and somatic variants. Nat Methods 15(8):591–594. https://doi.org/10.1038/s41592-018-0051-x

    Article  CAS  PubMed  Google Scholar 

  61. McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, Garimella K, Altshuler D, Gabriel S, Daly M, DePristo MA (2010) The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20(9):1297–1303. https://doi.org/10.1101/gr.107524.110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. McLaren W, Gil L, Hunt SE, Riat HS, Ritchie GR, Thormann A, Flicek P, Cunningham F (2016) The ensembl variant effect predictor. Genome Biol 17(1):122. https://doi.org/10.1186/s13059-016-0974-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. AlTassan R, AlQudairy H, Alromayan R, Alfalah A, AlHarbi OA, Gonzalez-Alvarez AC, Arold ST, Kaya N (2022) Clinical radiological and genetic characterization of a patient with a novel homoallelic loss-of-function variant in DNM1 Genes (Basel) 13 12 https://doi.org/10.3390/genes13122252

  64. Yigit G, Sheffer R, Daana M, Li Y, Kaygusuz E, Mor-Shakad H, Altmuller J, Nurnberg P, Douiev L, Kaulfuss S, Burfeind P, Wollnik B, Brockmann K (2022) Loss-of-function variants in DNM1 cause a specific form of developmental and epileptic encephalopathy only in biallelic state. J Med Genet 59(6):549–553. https://doi.org/10.1136/jmedgenet-2021-107769

    Article  CAS  PubMed  Google Scholar 

  65. Ramachandran R, Surka M, Chappie JS, Fowler DM, Foss TR, Song BD, Schmid SL (2007) The dynamin middle domain is critical for tetramerization and higher-order self-assembly. EMBO J 26(2):559–566. https://doi.org/10.1038/sj.emboj.7601491

    Article  CAS  PubMed  Google Scholar 

  66. Asinof S, Mahaffey C, Beyer B, Frankel WN, Boumil R (2016) Dynamin 1 isoform roles in a mouse model of severe childhood epileptic encephalopathy. Neurobiol Dis 95:1–11. https://doi.org/10.1016/j.nbd.2016.06.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the patient’s family for participation in this study. We further thank Henrike Wilshusen and Elena Hamdorf for skilful technical assistance.

Funding

This study was supported by a grant from the Deutsche Forschungsgemeinschaft (KU 1240/13–1 to K.K.).

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Authors and Affiliations

  1. Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany

    Frederike L. Harms, Jasmin Lisfeld & Kerstin Kutsche

  2. Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Deike Weiss

  3. Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Malik Alawi

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Harms, F.L., Weiss, D., Lisfeld, J. et al. A deep intronic variant in DNM1 in a patient with developmental and epileptic encephalopathy creates a splice acceptor site and affects only transcript variants including exon 10a. Neurogenetics 24, 171–180 (2023). https://doi.org/10.1007/s10048-023-00716-w

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