Abstract
Developmental and epileptic encephalopathies (DEEs) are genetically heterogenous conditions, often characterized by early onset, EEG interictal epileptiform abnormalities, polymorphous and drug-resistant seizures, and neurodevelopmental impairments. In this study, we investigated the genetic defects in two siblings who presented with severe DEE, microcephaly, spastic tetraplegia, diffuse brain hypomyelination, cerebellar atrophy, short stature, and kyphoscoliosis. Whole exome next-generation sequencing (WES) identified in both siblings a homozygous non-sense variant in the ACTL6B gene (NM_016188:c.820C>T;p.Gln274*) coding for a subunit of the neuron-specific chromatin remodeling complex nBAF. To further support these findings, a targeted ACTL6B sequencing assay was performed on a cohort of 85 unrelated DEE individuals, leading to the identification of a homozygous missense variant (NM_016188:c.1045G>A;p.Gly349Ser) in a patient. This variant did not segregate in the unaffected siblings in this family and was classified as deleterious by several prediction softwares. Interestingly, in both families, homozygous patients shared a rather homogeneous phenotype. Very few patients with ACTL6B gene variants have been sporadically reported in WES cohort studies of patients with neurodevelopmental disorders and/or congenital brain malformations. However, the limited number of patients with incomplete clinical information yet reported in the literature did not allow to establish a strong gene–disease association. Here, we provide additional genetic and clinical data on three new cases that support the pathogenic role of ACTL6B gene mutation in a syndromic form of DEE.
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Berg AT, Chakravorty S, Koh S, Grinspan ZM, Shellhaas RA, Saneto RP, Wirrell EC, Coryell J, Chu CJ, Mytinger JR, Gaillard WD, Valencia I, Knupp KG, Loddenkemper T, Sullivan JE, Poduri A, Millichap JJ, Keator C, Wusthoff C, Ryan N, Dobyns WB, Hegde M (2018) Why West? Comparisons of clinical, genetic and molecular features of infants with and without spasms. PLoS One 13:e0193599. https://doi.org/10.1371/journal.pone.0193599
Bögershausen N, Wollnik B (2018) Mutational landscapes and phenotypic spectrum of SWI/SNF-related intellectual disability disorders. Front Mol Neurosci 11:252. https://doi.org/10.3389/fnmol.2018.00252
Carvill GL, Heavin SB, Yendle SC, McMahon JM, O’Roak BJ, Cook J, Khan A, Dorschner MO, Weaver M, Calvert S, Malone S, Wallace G, Stanley T, Bye AM, Bleasel A, Howell KB, Kivity S, Mackay MT, Rodriguez-Casero V, Webster R, Korczyn A, Afawi Z, Zelnick N, Lerman-Sagie T, Lev D, Moller RS, Gill D, Andrade DM, Freeman JL, Sadleir LG, Shendure J, Berkovic SF, Scheffer IE, Mefford HC (2013) Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet 45:825–830. https://doi.org/10.1038/ng.2646
Chesi A, Staahl BT, Jovicic A, Couthouis J, Fasolino M, Raphael AR, Yamazaki T, Elias L, Polak M, Kelly C, Williams KL, Fifita JA, Maragakis NJ, Nicholson GA, King OD, Reed R, Crabtree GR, Blair IP, Glass JD, Gitler AD (2013) Exome sequencing to identify de novo mutations in sporadic ALS trios. Nat Neurosci 16:851–855. https://doi.org/10.1038/nn.3412
Goodwin LR, Picketts DJ (2018) The role of ISWI chromatin remodeling complexes in brain development and neurodevelopmental disorders. Mol Cell Neurosci 87:55–64. https://doi.org/10.1016/j.mcn.2017.10.008
Hannula-Jouppi K, Muurinen M, Lipsanen-Nyman M, Reinius LE, Ezer S, Greco D, Kere J (2014) Differentially methylated regions in maternal and paternal uniparental disomy for chromosome 7. Epigenetics 9:351–65. https://doi.org/10.4161/epi.27160
He N, Lin ZJ, Wang J, Wei F, Meng H, Liu XR, Chen Q, Su T, Shi YW, Yi YH, Liao WP (2018) Evaluating the pathogenic potential of genes with de novo variants in epileptic encephalopathies. Genet Med. https://doi.org/10.1038/s41436-018-0011-y
Karaca E, Harel T, Pehlivan D, Jhangiani SN, Gambin T, Coban Akdemir Z, Gonzaga-Jauregui C, Erdin S, Bayram Y, Campbell IM, Hunter JV, Atik MM, Van Esch H, Yuan B, Wiszniewski W, Isikay S, Yesil G, Yuregir OO, Tug Bozdogan S, Aslan H, Aydin H, Tos T, Aksoy A, De Vivo DC, Jain P, Geckinli BB, Sezer O, Gul D, Durmaz B, Cogulu O, Ozkinay F, Topcu V, Candan S, Cebi AH, Ikbal M, Yilmaz Gulec E, Gezdirici A, Koparir E, Ekici F, Coskun S, Cicek S, Karaer K, Koparir A, Duz MB, Kirat E, Fenercioglu E, Ulucan H, Seven M, Guran T, Elcioglu N, Yildirim MS, Aktas D, Alikasifoglu M, Ture M, Yakut T, Overton JD, Yuksel A, Ozen M, Muzny DM, Adams DR, Boerwinkle E, Chung WK, Gibbs RA, Lupski JR (2015) Genes that affect brain structure and function identified by rare variant analyses of mendelian neurologic disease. Neuron 88:499–513. https://doi.org/10.1016/j.neuron.2015.09.048
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
Krupp DR, Barnard RA, Duffourd Y, Evans SA, Mulqueen RM, Bernier R, Riviere JB, Fombonne E, O’Roak BJ (2017) Exonic mosaic mutations contribute risk for autism spectrum disorder. Am J Hum Genet 101:369–390. https://doi.org/10.1016/j.ajhg.2017.07.016
Lelieveld SH, Wiel L, Venselaar H, Pfundt R, Vriend G, Veltman JA, Brunner HG, Vissers L, Gilissen C (2017) Spatial clustering of de novo missense mutations identifies candidate neurodevelopmental disorder-associated genes. Am J Hum Genet 101:478–484. https://doi.org/10.1016/j.ajhg.2017.08.004
Li H (2012) Exploring single-sample SNP and INDEL calling with whole-genome de novo assembly. Bioinformatics 28:1838–1844. https://doi.org/10.1093/bioinformatics/bts280
Lopez AJ, Wood MA (2015) Role of nucleosome remodeling in neurodevelopmental and intellectual disability disorders. Front Behav Neurosci 9:100. https://doi.org/10.3389/fnbeh.2015.00100
Maddirevula S, Alzahrani F, Al-Owain M, Al Muhaizea MA, Kayyali HR, AlHashem A, Rahbeeni Z, Al-Otaibi M, Alzaidan HI, Balobaid A, El Khashab HY, Bubshait DK, Faden M, Yamani SA, Dabbagh O, Al-Mureikhi M, Jasser AA, Alsaif HS, Alluhaydan I, Seidahmed MZ, Alabbasi BH, Almogarri I, Kurdi W, Akleh H, Qari A, Al Tala SM, Alhomaidi S, Kentab AY, Salih MA, Chedrawi A, Alameer S, Tabarki B, Shamseldin HE, Patel N, Ibrahim N, Abdulwahab F, Samira M, Goljan E, Abouelhoda M, Meyer BF, Hashem M, Shaheen R, AlShahwan S, Alfadhel M, Ben-Omran T, Al-Qattan MM, Monies D, Alkuraya FS (2018) Autozygome and high throughput confirmation of disease genes candidacy. Genet Med. https://doi.org/10.1038/s41436-018-0138-x
Magi A, Tattini L, Palombo F, Benelli M, Gialluisi A, Giusti B, Abbate R, Seri M, Gensini GF, Romeo G, Pippucci T (2014) H3M2: detection of runs of homozygosity from whole-exome sequencing data. Bioinformatics 30:2852–2859. https://doi.org/10.1093/bioinformatics/btu401
Marom R, Jain M, Burrage LC, Song IW, Graham BH, Brown CW, Stevens SJC, Stegmann APA, Gunter AT, Kaplan JD, Gavrilova RH, Shinawi M, Rosenfeld JA, Bae Y, Tran AA, Chen Y, Lu JT, Gibbs RA, Eng C, Yang Y, Rousseau J, de Vries BBA, Campeau PM, Lee B (2017) Heterozygous variants in ACTL6A, encoding a component of the BAF complex, are associated with intellectual disability. Hum Mutat 38:1365–1371. https://doi.org/10.1002/humu.23282
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 20:1297–1303. https://doi.org/10.1101/gr.107524.110
Myers KA, Johnstone DL, Dyment DA (2019) Epilepsy genetics: current knowledge, applications, and future directions. Clin Genet 95:95–111. https://doi.org/10.1111/cge.13414
Olave I, Wang W, Xue Y, Kuo A, Crabtree GR (2002) Identification of a polymorphic, neuron-specific chromatin remodeling complex. Genes Dev 16:2509–2517. https://doi.org/10.1101/gad.992102
Sajan SA, Jhangiani SN, Muzny DM, Gibbs RA, Lupski JR, Glaze DG, Kaufmann WE, Skinner SA, Annese F, Friez MJ, Lane J, Percy AK, Neul JL (2017) Enrichment of mutations in chromatin regulators in people with Rett syndrome lacking mutations in MECP2. Genet Med 19:13–19. https://doi.org/10.1038/gim.2016.42
Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L, Hirsch E, Jain S, Mathern GW, Moshe SL, Nordli DR, Perucca E, Tomson T, Wiebe S, Zhang YH, Zuberi SM (2017) ILAE classification of the epilepsies: position paper of the ILAE commission for classification and terminology. Epilepsia 58:512–521. https://doi.org/10.1111/epi.13709
Sokpor G, Xie Y, Rosenbusch J, Tuoc T (2017) Chromatin remodeling BAF (SWI/SNF) complexes in neural development and disorders. Front Mol Neurosci 10:243. https://doi.org/10.3389/fnmol.2017.00243
Staahl BT, Crabtree GR (2013) Creating a neural specific chromatin landscape by npBAF and nBAF complexes. Curr Opin Neurobiol 23:903–913. https://doi.org/10.1016/j.conb.2013.09.003
Van der Auwera GA, Carneiro MO, Hartl C, Poplin R, Del Angel G, Levy-Moonshine A, Jordan T, Shakir K, Roazen D, Thibault J, Banks E, Garimella KV, Altshuler D, Gabriel S, DePristo MA (2013) From FastQ data to high confidence variant calls: the genome analysis toolkit best practices pipeline. Curr Protoc Bioinform 43(11 10):1–33. https://doi.org/10.1002/0471250953.bi1110s43
Vogel-Ciernia A, Matheos DP, Barrett RM, Kramar EA, Azzawi S, Chen Y, Magnan CN, Zeller M, Sylvain A, Haettig J, Jia Y, Tran A, Dang R, Post RJ, Chabrier M, Babayan AH, Wu JI, Crabtree GR, Baldi P, Baram TZ, Lynch G, Wood MA (2013) The neuron-specific chromatin regulatory subunit BAF53b is necessary for synaptic plasticity and memory. Nat Neurosci 16:552–561. https://doi.org/10.1038/nn.3359
Vogel-Ciernia A, Kramar EA, Matheos DP, Havekes R, Hemstedt TJ, Magnan CN, Sakata K, Tran A, Azzawi S, Lopez A, Dang R, Wang W, Trieu B, Tong J, Barrett RM, Post RJ, Baldi P, Abel T, Lynch G, Wood MA (2017) Mutation of neuron-specific chromatin remodeling subunit BAF53b: rescue of plasticity and memory by manipulating actin remodeling. Learn Mem 24:199–209. https://doi.org/10.1101/lm.044602.116
Wu JI, Lessard J, Olave IA, Qiu Z, Ghosh A, Graef IA, Crabtree GR (2007) Regulation of dendritic development by neuron-specific chromatin remodeling complexes. Neuron 56:94–108. https://doi.org/10.1016/j.neuron.2007.08.021
Yang H, Wang K (2015) Genomic variant annotation and prioritization with ANNOVAR and wANNOVAR. Nat Protoc 10:1556–1566. https://doi.org/10.1038/nprot.2015.105
Acknowledgements
We thank the probands and their families for the participation in this study. For technical support, we acknowledge the participation of Drs. Silvestra Amata, Angela Spalletta, Maurizio Sturnio, and Pietro Schinocca from the Laboratory of Medical Genetics, Oasi Research Institute—IRCCS, Troina (Italy). We also thank Dr. Anthony Charles for the English language editing. This work was funded by Grant RF-2011-02350693 from the Italian Ministry of Health to Marco Fichera.
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Fichera, M., Failla, P., Saccuzzo, L. et al. Mutations in ACTL6B, coding for a subunit of the neuron-specific chromatin remodeling complex nBAF, cause early onset severe developmental and epileptic encephalopathy with brain hypomyelination and cerebellar atrophy. Hum Genet 138, 187–198 (2019). https://doi.org/10.1007/s00439-019-01972-3
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DOI: https://doi.org/10.1007/s00439-019-01972-3