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Sarenur Gokben, Huseyin Onay, Sanem Yilmaz, Tahir Atik, Gul Serdaroglu, Hande Tekin, Ferda Ozkinay
We investigated the genetic background of early-onset epileptic encephalopathy (EE) using targeted next generation sequencing analysis. Thirty sporadic or familial cases associated with early-onset EE were included. An early-onset EE gene panel including sixteen genes (ARX, CDKL5, CNTNAP2, FOLR1, FOXG1, LAMC3, MBD5, MECP2, NTNG1, PCDH19, PNKP, SCN1A, SCN1B, SCN2A, STXBP1, KCNQ2) was constituted. Nine definite and three potential causal mutations in 30 cases (40 %) were identified. All mutations presented heterozygously except one...
October 12, 2016: Acta Neurologica Belgica
Ryan N Doan, Byoung-Il Bae, Beatriz Cubelos, Cindy Chang, Amer A Hossain, Samira Al-Saad, Nahit M Mukaddes, Ozgur Oner, Muna Al-Saffar, Soher Balkhy, Generoso G Gascon, Marta Nieto, Christopher A Walsh
Comparative analyses have identified genomic regions potentially involved in human evolution but do not directly assess function. Human accelerated regions (HARs) represent conserved genomic loci with elevated divergence in humans. If some HARs regulate human-specific social and behavioral traits, then mutations would likely impact cognitive and social disorders. Strikingly, rare biallelic point mutations-identified by whole-genome and targeted "HAR-ome" sequencing-showed a significant excess in individuals with ASD whose parents share common ancestry compared to familial controls, suggesting a contribution in 5% of consanguineous ASD cases...
October 6, 2016: Cell
Stella Lilles, Inga Talvik, Klari Noormets, Ulvi Vaher, Katrin Õunap, Tiia Reimand, Valentin Sander, Pilvi Ilves, Tiina Talvik
Cyclin-dependent kinase-like 5 (CDKL5) gene mutations have mainly been found in females with early infantile epileptic encephalopathy (EIEE), severe intellectual disability, and Rett-like features. To date, only 22 boys have been reported, presenting with far more severe phenotypic features. We report the first cases of CDKL5 gene-related EIEE in Estonia diagnosed using panels of epilepsy-associated genes and describe the phenotype-genotype correlations in three male and one female patient. One of the mutations, identified in a male patient, was a novel de novo hemizygous frameshift mutation (NM_003159...
September 6, 2016: Neuropediatrics
Mario Lucariello, Enrique Vidal, Silvia Vidal, Mauricio Saez, Laura Roa, Dori Huertas, Mercè Pineda, Esther Dalfó, Joaquin Dopazo, Paola Jurado, Judith Armstrong, Manel Esteller
Classical Rett syndrome (RTT) is a neurodevelopmental disorder where most of cases carry MECP2 mutations. Atypical RTT variants involve mutations in CDKL5 and FOXG1. However, a subset of RTT patients remains that do not carry any mutation in the described genes. Whole exome sequencing was carried out in a cohort of 21 female probands with clinical features overlapping with those of RTT, but without mutations in the customarily studied genes. Candidates were functionally validated by assessing the appearance of a neurological phenotype in Caenorhabditis elegans upon disruption of the corresponding ortholog gene...
December 2016: Human Genetics
Stephanie Fehr, Jenny Downs, Gladys Ho, Nick de Klerk, David Forbes, John Christodoulou, Simon Williams, Helen Leonard
Functional abilities in the CDKL5 disorder have been described as severely impaired, yet some individuals are able to run and use phrases for speech. Our study investigated gross motor, hand function, and expressive communication abilities in individuals with the CDKL5 disorder. Data for 108 females and 16 males registered with the International CDKL5 disorder database and with a pathogenic CDKL5 mutation were analyzed. Relationships between functional abilities, age, genotype, and gender were analyzed using regression models...
November 2016: American Journal of Medical Genetics. Part A
Stefania Trazzi, Claudia Fuchs, Rocchina Viggiano, Marianna De Franceschi, Emanuele Valli, Paulina Jedynak, Finn K Hansen, Giovanni Perini, Roberto Rimondini, Thomas Kurz, Renata Bartesaghi, Elisabetta Ciani
Cyclin-dependent kinase-like 5 (CDKL5) is a Ser/Thr protein kinase predominantly expressed in the brain. Mutations of the CDKL5 gene lead to CDKL5 disorder, a neurodevelopmental pathology that shares several features with Rett Syndrome and is characterized by severe intellectual disability. The phosphorylation targets of CDKL5 are largely unknown, which hampers the discovery of therapeutic strategies for improving the neurological phenotype due to CDKL5 mutations. Here, we show that the histone deacetylase 4 (HDAC4) is a direct phosphorylation target of CDKL5 and that CDKL5-dependent phosphorylation promotes HDAC4 cytoplasmic retention...
July 27, 2016: Human Molecular Genetics
Yan Wang, Wei Peng, Hong-Yan Guo, Hui Li, Jie Tian, Yu-Jing Shi, Xiao Yang, Yao Yang, Wan-Qiao Zhang, Xin Liu, Guan-Nan Liu, Tao Deng, Yi-Min Sun, Wan-Li Xing, Jing Cheng, Zhi-Chun Feng
Neonatal hypotonia is extremely challenging to diagnose because numerous disorders present similar clinical manifestations. Two panels for diagnosing neonatal hypotonia were developed, which enriches 35 genes corresponding to 61 neonatal hypotonia-related disorders. A cohort of 214 neonates with hypotonia was recruited from 2012 to 2014 in China for this study. Of these subjects, twenty-eight neonates with hypotonia were eliminated according to exclusion criteria and 97 were confirmed using traditional detection methods...
2016: Scientific Reports
Pawel Gawlinski, Renata Posmyk, Tomasz Gambin, Danuta Sielicka, Monika Chorazy, Beata Nowakowska, Shalini N Jhangiani, Donna M Muzny, Monika Bekiesinska-Figatowska, Jerzy Bal, Eric Boerwinkle, Richard A Gibbs, James R Lupski, Wojciech Wiszniewski
BACKGROUND: Progressive encephalopathy with edema, hypsarrhythmia and optic atrophy (PEHO) syndrome is a distinct neurodevelopmental disorder. Patients without optic nerve atrophy and brain imaging abnormalities but fulfilling other PEHO criteria are often described as a PEHO-like syndrome. The molecular bases of both clinically defined conditions remain unknown in spite of the widespread application of genome analyses in both clinic and research. METHODS: We enrolled two patients with a prior diagnosis of PEHO and two individuals with PEHO-like syndrome...
July 2016: Pediatric Neurology
Ralph D Hector, Owen Dando, Nicoletta Landsberger, Charlotte Kilstrup-Nielsen, Peter C Kind, Mark E S Bailey, Stuart R Cobb
Mutations in the X-linked Cyclin-Dependent Kinase-Like 5 gene (CDKL5) cause early onset infantile spasms and subsequent severe developmental delay in affected children. Deleterious mutations have been reported to occur throughout the CDKL5 coding region. Several studies point to a complex CDKL5 gene structure in terms of exon usage and transcript expression. Improvements in molecular diagnosis and more extensive research into the neurobiology of CDKL5 and pathophysiology of CDKL5 disorders necessitate an updated analysis of the gene...
2016: PloS One
Ewa Pronicka, Dorota Piekutowska-Abramczuk, Elżbieta Ciara, Joanna Trubicka, Dariusz Rokicki, Agnieszka Karkucińska-Więckowska, Magdalena Pajdowska, Elżbieta Jurkiewicz, Paulina Halat, Joanna Kosińska, Agnieszka Pollak, Małgorzata Rydzanicz, Piotr Stawinski, Maciej Pronicki, Małgorzata Krajewska-Walasek, Rafał Płoski
BACKGROUND: Whole-exome sequencing (WES) has led to an exponential increase in identification of causative variants in mitochondrial disorders (MD). METHODS: We performed WES in 113 MD suspected patients from Polish paediatric reference centre, in whom routine testing failed to identify a molecular defect. WES was performed using TruSeqExome enrichment, followed by variant prioritization, validation by Sanger sequencing, and segregation with the disease phenotype in the family...
2016: Journal of Translational Medicine
Antonius Christianto, Syouichi Katayama, Isamu Kameshita, Tetsuya Inazu
Rett syndrome (RTT) is a severe X-linked dominant inheritance disorder with a wide spectrum of clinical manifestations. Mutations in Methyl CpG binding protein 2 (MECP2), Cyclin dependent kinase-like 5 (CDKL5) and Forkhead box G1 (FOXG1) have been associated with classic and/or variant RTT. This study was conducted to identify the responsible gene(s) in atypical RTT patient, and to examine the effect of the mutation on protein function. DNA sequence analysis showed a novel heterozygous mutation in CDKL5 identified as c...
August 1, 2016: Clinica Chimica Acta; International Journal of Clinical Chemistry
Jin Sook Lee, Yongjin Yoo, Byung Chan Lim, Ki Joong Kim, Junghan Song, Murim Choi, Jong-Hee Chae
There have been a few reports of GM3 synthase deficiency since the disease of the ganglioside biosynthetic pathway was first reported in 2004. It is characterized by infantile-onset epilepsy with severe intellectual disability, blindness, cutaneous dyspigmentation, and choreoathetosis. Here we report the cases of two Korean female siblings with ST3GAL5 variants, who presented with a Rett-like phenotype. They had delayed speech, hand stereotypies with a loss of purposeful hand movements, and choreoathetosis, but no clinical seizures...
August 2016: American Journal of Medical Genetics. Part A
D Záhoráková, M Langová, K Brožová, J Laštůvková, Z Kalina, L Rennerová, P Martásek
The X-linked CDKL5 gene, which encodes cyclin-dependent kinase-like 5 protein, has been implicated in early-onset encephalopathy and atypical Rett syndrome with early-onset seizures. The CDKL5 protein is a kinase required for neuronal development and morphogenesis, but its precise functions are still largely unexplored. Individuals with CDKL5 mutations present with severe global developmental delay, intractable epilepsy, and Rett-like features. A clear genotype-phenotype correlation has not been established due to an insufficient number of reported cases...
2016: Folia Biologica (Praha)
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
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...
May 12, 2016: Genetics in Medicine: Official Journal of the American College of Medical Genetics
S Sivilia, C Mangano, S Beggiato, A Giuliani, R Torricella, V A Baldassarro, M Fernandez, L Lorenzini, L Giardino, A C Borelli, L Ferraro, L Calzà
Mutations in the X-linked cyclin-dependent kinase-like 5 gene (CDKL5) are associated to severe neurodevelopmental alterations including motor symptoms. In order to elucidate the neurobiological substrate of motor symptoms in CDKL5 syndrome, we investigated the motor function, GABA and glutamate pathways in the cerebellum of CDKL5 knockout female mice. Behavioural data indicate that CDKL5-KO mice displayed impaired motor coordination on the Rotarod test, and altered steps, as measured by the gait analysis using the CatWalk test...
June 2016: Genes, Brain, and Behavior
Meghana Mangatt, Kingsley Wong, Barbara Anderson, Amy Epstein, Stuart Hodgetts, Helen Leonard, Jenny Downs
BACKGROUND: Initially described as an early onset seizure variant of Rett syndrome, the CDKL5 disorder is now considered as an independent entity. However, little is currently known about the full spectrum of comorbidities that affect these patients and available literature is limited to small case series. This study aimed to use a large international sample to examine the prevalence in this disorder of comorbidities of epilepsy, gastrointestinal problems including feeding difficulties, sleep and respiratory problems and scoliosis and their relationships with age and genotype...
2016: Orphanet Journal of Rare Diseases
L Allou, S Julia, D Amsallem, S El Chehadeh, L Lambert, J Thevenon, Y Duffourd, A Saunier, P Bouquet, S Pere, A Moustaïne, L Ruaud, V Roth, P Jonveaux, C Philippe
Several genes have been implicated in Rett syndrome in its typical and variant forms. We applied next-generation sequencing to evaluate for mutations in known or new candidate genes in patients with variant forms of Rett or Rett-like phenotypes of unknown molecular aetiology. In the first step, we used NGS with a custom panel including MECP2, CDKL5, FOXG1, MEF2C and IQSEC2. In addition to a FOXG1 mutation in a patient with all core features of the congenital variant of RTT, we identified a missense (p.Ser240Thr) in CDKL5 in a patient who appeared to be seizure free...
April 7, 2016: Clinical Genetics
Carl Ernst
Several lines of evidence suggest that proliferation and differentiation in neural stem cells (NSCs) are a major convergence point of neurodevelopmental disorders (NDDs). Most genes with truncating mutations are implicated in NSC proliferation and differentiation (e.g., MBD5, CDKL5, and MECP2). Similarly, reciprocal deletion/duplication copy-number variants (CNVs), such as 1q21.1 and 16p11.2, are inversely correlated with head size. In addition, pathways such as MAPK, mTOR, and RAS, which are important in cancer, a disease of uncontrolled cell proliferation, are implicated in NDDs...
May 2016: Trends in Neurosciences
E M Boggio, L Pancrazi, M Gennaro, C Lo Rizzo, F Mari, I Meloni, F Ariani, A Panighini, E Novelli, M Biagioni, E Strettoi, J Hayek, A Rufa, T Pizzorusso, A Renieri, M Costa
The Forkead Box G1 (FOXG1 in humans, Foxg1 in mice) gene encodes for a DNA-binding transcription factor, essential for the development of the telencephalon in mammalian forebrain. Mutations in FOXG1 have been reported to be involved in the onset of Rett Syndrome, for which sequence alterations of MECP2 and CDKL5 are known. While visual alterations are not classical hallmarks of Rett syndrome, an increasing body of evidence shows visual impairment in patients and in MeCP2 and CDKL5 animal models. Herein we focused on the functional role of FOXG1 in the visual system of animal models (Foxg1(+/Cre) mice) and of a cohort of subjects carrying FOXG1 mutations or deletions...
June 2, 2016: Neuroscience
Natalie Trump, Amy McTague, Helen Brittain, Apostolos Papandreou, Esther Meyer, Adeline Ngoh, Rodger Palmer, Deborah Morrogh, Christopher Boustred, Jane A Hurst, Lucy Jenkins, Manju A Kurian, Richard H Scott
BACKGROUND: We sought to investigate the diagnostic yield and mutation spectrum in previously reported genes for early-onset epilepsy and disorders of severe developmental delay. METHODS: In 400 patients with these disorders with no known underlying aetiology and no major structural brain anomaly, we analysed 46 genes using a combination of targeted sequencing on an Illumina MiSeq platform and targeted, exon-level microarray copy number analysis. RESULTS: We identified causative mutations in 71/400 patients (18%)...
May 2016: Journal of Medical Genetics
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