Enrichment of mutations in chromatin regulators in people with Rett syndrome lacking mutations in MECP2

Samin A Sajan, Shalini N Jhangiani, Donna M Muzny, Richard A Gibbs, James R Lupski, Daniel G Glaze, Walter E Kaufmann, Steven A Skinner, Fran Annese, Michael J Friez, Jane Lane, Alan K Percy, Jeffrey L Neul, Samin A Sajan, Shalini N Jhangiani, Donna M Muzny, Richard A Gibbs, James R Lupski, Daniel G Glaze, Walter E Kaufmann, Steven A Skinner, Fran Annese, Michael J Friez, Jane Lane, Alan K Percy, Jeffrey L Neul

Abstract

Purpose: Rett syndrome (RTT) is a neurodevelopmental disorder caused primarily by de novo mutations in MECP2 and sometimes in CDKL5 and FOXG1. However, some RTT patients lack mutations in these genes.

Methods: Twenty-two RTT patients without apparent MECP2, CDKL5, and FOXG1 mutations were subjected to both whole-exome sequencing and single-nucleotide polymorphism array-based copy-number variant (CNV) analyses.

Results: Three patients had MECP2 mutations initially missed by clinical testing. Of the remaining 19, 17 (89.5%) had 29 other likely pathogenic intragenic mutations and/or CNVs (10 patients had 2 or more). Interestingly, 13 patients had mutations in a gene/region previously reported in other neurodevelopmental disorders (NDDs), thereby providing a potential diagnostic yield of 68.4%. These mutations were significantly enriched in chromatin regulators (corrected P = 0.0068) and moderately enriched in postsynaptic cell membrane molecules (corrected P = 0.076), implicating glutamate receptor signaling.

Conclusion: The genetic etiology of RTT without MECP2, CDKL5, and FOXG1 mutations is heterogeneous, overlaps with other NDDs, and complicated by a high mutation burden. Dysregulation of chromatin structure and abnormal excitatory synaptic signaling may form two common pathological bases of RTT.Genet Med 19 1, 13-19.

Figures

Figure 1
Figure 1
An interaction network of genes with likely pathogenic mutations contributing to RTT in our cases. Black circles are input genes and gray circles are genes highly related to the input genes chosen by the network-building algorithm to maximize connectivity. The network was generated by using an input list of 46 genes with likely pathogenic mutations listed in Table 2 as well as the 3 known RTT genes MECP2, CDKL5, and FOXG1. Of the 46 genes, 23 were found to interact amongst each other either directly or indirectly through at least one of three ways: physical interactions (orange lines), co-localization of protein products (light blue lines), and participating in the same step of a given pathway (light green lines). Asterisks indicate genes related to input genes that have been reported to either carry de novo mutations in at least one patient with other NDDs (TBL1XR1, MTMR2, AKR1C4) or whose expression has been reported to be significantly altered in a MECP2 mutant model system (DAB1, ITGA2, LAMA5), or both (GLIS2, LAMC3, SMARCE1). Network weighting was assigned based on query genes so as to maximize connectivity among input genes, and at most 20 related genes and 10 related attributes were allowed to be incorporated in the network.

References

    1. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999;23(2):185–188.
    1. Laurvick CL, de Klerk N, Bower C, et al. Rett syndrome in Australia: a review of the epidemiology. J Pediatr. 2006;148(3):347–352.
    1. Neul JL, Kaufmann WE, Glaze DG, et al. Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol. 2010 Dec;68(6):944–950.
    1. Neul JL, Lane JB, Lee HS, et al. Developmental delay in Rett syndrome: data from the natural history study. J Neurodev Disord. 2014;6(1):20.
    1. Percy AK, Lane JB, Childers J, et al. Rett syndrome: North American database. J Child Neurol. 2007 Dec;22(12):1338–1341.
    1. Ariani F, Hayek G, Rondinella D, et al. FOXG1 is responsible for the congenital variant of Rett syndrome. Am J Hum Genet. 2008 Jul;83(1):89–93.
    1. Bahi-Buisson N, Nectoux J, Rosas-Vargas H, et al. Key clinical features to identify girls with CDKL5 mutations. Brain. 2008 Oct;131(Pt 10):2647–2661.
    1. Lombardi LM, Baker SA, Zoghbi HY. MECP2 disorders: from the clinic to mice and back. J Clin Invest. 2015 Aug 3;125(8):2914–2923.
    1. Guerrini R, Parrini E. Epilepsy in Rett syndrome, and CDKL5- and FOXG1-gene-related encephalopathies. Epilepsia. 2012 Dec;53(12):2067–2078.
    1. Lambert L, Bienvenu T, Allou L, et al. MEF2C mutations are a rare cause of Rett or severe Rett-like encephalopathies. Clin Genet. 2012 Nov;82(5):499–501.
    1. Ohba C, Nabatame S, Iijima Y, et al. De novo WDR45 mutation in a patient showing clinically Rett syndrome with childhood iron deposition in brain. J Hum Genet. 2014 May;59(5):292–295.
    1. Romaniello R, Saettini F, Panzeri E, Arrigoni F, Bassi MT, Borgatti R. A de-novo STXBP1 gene mutation in a patient showing the Rett syndrome phenotype. Neuroreport. 2015 Mar 25;26(5):254–257.
    1. Olson HE, Tambunan D, LaCoursiere C, et al. Mutations in epilepsy and intellectual disability genes in patients with features of Rett syndrome. Am J Med Genet A. 2015 Apr 25;
    1. Gilissen C, Hehir-Kwa JY, Thung DT, et al. Genome sequencing identifies major causes of severe intellectual disability. Nature. 2014 Jul 17;511(7509):344–347.
    1. Lupski JR, Gonzaga-Jauregui C, Yang Y, et al. Exome sequencing resolves apparent incidental findings and reveals further complexity of SH3TC2 variant alleles causing Charcot-Marie-Tooth neuropathy. Genome Med. 2013;5(6):57.
    1. Epi KC, Epilepsy Phenome/Genome P. Allen AS, et al. De novo mutations in epileptic encephalopathies. Nature. 2013 Sep 12;501(7466):217–221.
    1. Euro E-RESCEae-RESuab, Epilepsy Phenome/Genome P, Epi KC, Euro E-RESC, Epilepsy Phenome/Genome P, Epi KC. De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies. Am J Hum Genet. 2014 Oct 2;95(4):360–370.
    1. Iossifov I, O'Roak BJ, Sanders SJ, et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature. 2014 Nov 13;515(7526):216–221.
    1. O'Roak BJ, Deriziotis P, Lee C, et al. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat Genet. 2011 Jun;43(6):585–589.
    1. O'Roak BJ, Vives L, Girirajan S, et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature. 2012 May 10;485(7397):246–250.
    1. O'Roak BJ, Stessman HA, Boyle EA, et al. Recurrent de novo mutations implicate novel genes underlying simplex autism risk. Nat Commun. 2014;5:5595.
    1. Jiang YH, Yuen RK, Jin X, et al. Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing. Am J Hum Genet. 2013 Aug 8;93(2):249–263.
    1. Hamdan FF, Srour M, Capo-Chichi JM, et al. De novo mutations in moderate or severe intellectual disability. PLoS Genet. 2014 Oct;10(10):e1004772.
    1. Wright CF, Fitzgerald TW, Jones WD, et al. Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data. Lancet. 2014 Dec 16;
    1. Deciphering Developmental Disorders. Large-scale discovery of novel genetic causes of developmental disorders. Nature. 2015 Mar 12;519(7542):223–228.
    1. Saunders CJ, Minassian BE, Chow EW, Zhao W, Vincent JB. Novel exon 1 mutations in MECP2 implicate isoform MeCP2_e1 in classical Rett syndrome. Am J Med Genet A. 2009 May;149A(5):1019–1023.
    1. Rauch A, Wieczorek D, Graf E, et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet. 2012 Nov 10;380(9854):1674–1682.
    1. Lasalle JM. Autism genes keep turning up chromatin. OA Autism. 2013 Jun 19;1(2):14.
    1. Chao HT, Zoghbi HY, Rosenmund C. MeCP2 controls excitatory synaptic strength by regulating glutamatergic synapse number. Neuron. 2007 Oct 4;56(1):58–65.
    1. Zhang W, Peterson M, Beyer B, Frankel WN, Zhang ZW. Loss of MeCP2 from forebrain excitatory neurons leads to cortical hyperexcitation and seizures. J Neurosci. 2014 Feb 12;34(7):2754–2763.
    1. Rojas DC. The role of glutamate and its receptors in autism and the use of glutamate receptor antagonists in treatment. J Neural Transm. 2014 Aug;121(8):891–905.
    1. Gonzaga-Jauregui C, Harel T, Gambin T, et al. Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy. Cell Rep. 2015 Aug 18;12(7):1169–1183.
    1. Foti SB, Chou A, Moll AD, Roskams AJ. HDAC inhibitors dysregulate neural stem cell activity in the postnatal mouse brain. Int J Dev Neurosci. 2013;31(6):434–447.
    1. Carvill GL, McMahon JM, Schneider A, et al. Mutations in the GABA Transporter SLC6A1 Cause Epilepsy with Myoclonic-Atonic Seizures. Am J Hum Genet. 2015;96(5):808–815.
    1. Matejas V, Hinkes B, Alkandari F, et al. Mutations in the human laminin beta2 (LAMB2) gene and the associated phenotypic spectrum. Hum Mutat. 2010;31(9):992–1002.
    1. Sarkozy A, Carta C, Moretti S, et al. Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. Hum Mutat. 2009;30(4):695–702.
    1. Kashevarova AA, Nazarenko LP, Schultz-Pedersen S, et al. Single gene microdeletions and microduplication of 3p26.3 in three unrelated families: CNTN6 as a new candidate gene for intellectual disability. Mol Cytogenet. 2014;7(1):97.
    1. Coppinger J, McDonald-McGinn D, Zackai E, et al. Identification of familial and de novo microduplications of 22q11.21-q11.23 distal to the 22q11.21 microdeletion syndrome region. Hum Mol Genet. 2009;18(8):1377–1383.
    1. Esplin ED, Li B, Slavotinek A, et al. Nine patients with Xp22.31 microduplication, cognitive deficits, seizures, and talipes anomalies. Am J Med Genet A. 2014;164A(8):2097–2103.
    1. Srivastava S, Cohen J, Pevsner J, et al. A novel variant in GABRB2 associated with intellectual disability and epilepsy. Am J Med Genet A. 2014;164A(11):2914–2921.
    1. Sanders SJ, Murtha MT, Gupta AR, et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012;485(7397):237–41.

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