@article {998, title = {CSNK2B: A broad spectrum of neurodevelopmental disability and epilepsy severity.}, journal = {Epilepsia}, year = {2021}, month = {2021 May 26}, abstract = {

CSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and epilepsy. Information about developmental outcomes has been limited by the young age and short follow-up for many of the previously reported cases, and further delineation of the spectrum of associated phenotypes is needed. We present 25 new patients with variants in CSNK2B and refine the associated NDD and epilepsy phenotypes. CSNK2B variants were identified by research or clinical exome sequencing, and investigators from different centers were connected via GeneMatcher. Most individuals had developmental delay and generalized epilepsy with onset in the first 2 years. However, we found a broad spectrum of phenotypic severity, ranging from early normal development with pharmacoresponsive seizures to profound intellectual disability with intractable epilepsy and recurrent refractory status epilepticus. These findings suggest that CSNK2B should be considered in the diagnostic evaluation of patients with a broad range of NDD with treatable or intractable seizures.

}, issn = {1528-1167}, doi = {10.1111/epi.16931}, author = {Ernst, Michelle E and Baugh, Evan H and Thomas, Amanda and Bier, Louise and Lippa, Natalie and Stong, Nicholas and Mulhern, Maureen S and Kushary, Sulagna and Akman, Cigdem I and Heinzen, Erin L and Yeh, Raymond and Bi, Weimin and Hanchard, Neil A and Burrage, Lindsay C and Leduc, Magalie S and Chong, Josephine S C and Bend, Renee and Lyons, Michael J and Lee, Jennifer A and Suwannarat, Pim and Brilstra, Eva and Simon, Marleen and Koopmans, Marije and van Binsbergen, Ellen and Groepper, Daniel and Fleischer, Julie and Nava, Caroline and Keren, Boris and Mignot, Cyril and Mathieu, Sophie and Mancini, Grazia M S and Madan-Khetarpal, Suneeta and Infante, Elena M and Bluvstein, Judith and Seeley, Andrea and Bachman, Kristine and Klee, Eric W and Schultz-Rogers, Laura E and Hasadsri, Linda and Barnett, Sarah and Ellingson, Marissa S and Ferber, Matthew J and Narayanan, Vinodh and Ramsey, Keri and Rauch, Anita and Joset, Pascal and Steindl, Katharina and Sheehan, Theodore and Poduri, Annapurna and Vasquez, Alejandra and Ruivenkamp, Claudia and White, Susan M and Pais, Lynn and Monaghan, Kristin G and Goldstein, David B and Sands, Tristan T and Aggarwal, Vimla} } @article {918, title = {De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy.}, journal = {Genet Med}, volume = {23}, year = {2021}, month = {2021 04}, pages = {653-660}, abstract = {

PURPOSE: This study aims to provide a comprehensive description of the phenotypic and genotypic spectrum of SNAP25 developmental and epileptic encephalopathy (SNAP25-DEE) by reviewing newly identified and previously reported individuals.

METHODS: Individuals harboring heterozygous missense or loss-of-function variants in SNAP25 were assembled through collaboration with international colleagues, matchmaking platforms, and literature review. For each individual, detailed phenotyping, classification, and structural modeling of the identified variant were performed.

RESULTS: The cohort comprises 23 individuals with pathogenic or likely pathogenic de novo variants in SNAP25. Intellectual disability and early-onset epilepsy were identified as the core symptoms of SNAP25-DEE, with recurrent findings of movement disorders, cerebral visual impairment, and brain atrophy. Structural modeling for all variants predicted possible functional defects concerning SNAP25 or impaired interaction with other components of the SNARE complex.

CONCLUSION: We provide a comprehensive description of SNAP25-DEE with intellectual disability and early-onset epilepsy mostly occurring before the age of two years. These core symptoms and additional recurrent phenotypes show an overlap to genes encoding other components or associated proteins of the SNARE complex such as STX1B, STXBP1, or VAMP2. Thus, these findings advance the concept of a group of neurodevelopmental disorders that may be termed "SNAREopathies."

}, keywords = {Brain Diseases, Child, Preschool, Epilepsy, Humans, Intellectual Disability, Neurodevelopmental Disorders, Phenotype, Synaptosomal-Associated Protein 25}, issn = {1530-0366}, doi = {10.1038/s41436-020-01020-w}, author = {Kl{\"o}ckner, Chiara and Sticht, Heinrich and Zacher, Pia and Popp, Bernt and Babcock, Holly E and Bakker, Dewi P and Barwick, Katy and Bonfert, Michaela V and B{\"o}nnemann, Carsten G and Brilstra, Eva H and Chung, Wendy K and Clarke, Angus J and Devine, Patrick and Donkervoort, Sandra and Fraser, Jamie L and Friedman, Jennifer and Gates, Alyssa and Ghoumid, Jamal and Hobson, Emma and Horvath, Gabriella and Keller-Ramey, Jennifer and Keren, Boris and Kurian, Manju A and Lee, Virgina and Leppig, Kathleen A and Lundgren, Johan and McDonald, Marie T and McLaughlin, Heather M and McTague, Amy and Mefford, Heather C and Mignot, Cyril and Mikati, Mohamad A and Nava, Caroline and Raymond, F Lucy and Sampson, Julian R and Sanchis-Juan, Alba and Shashi, Vandana and Shieh, Joseph T C and Shinawi, Marwan and Slavotinek, Anne and St{\"o}dberg, Tommy and Stong, Nicholas and Sullivan, Jennifer A and Taylor, Ashley C and Toler, Tomi L and van den Boogaard, Marie-Jos{\'e} and van der Crabben, Saskia N and van Gassen, Koen L I and van Jaarsveld, Richard H and Van Ziffle, Jessica and Wadley, Alexandrea F and Wagner, Matias and Wigby, Kristen and Wortmann, Saskia B and Zarate, Yuri A and M{\o}ller, Rikke S and Lemke, Johannes R and Platzer, Konrad} } @article {1010, title = {De novo variants in TCF7L2 are associated with a syndromic neurodevelopmental disorder.}, journal = {Am J Med Genet A}, year = {2021}, month = {2021 May 18}, abstract = {

TCF7L2 encodes transcription factor 7-like 2 (OMIM 602228), a key mediator of the evolutionary conserved canonical Wnt signaling pathway. Although several large-scale sequencing studies have implicated TCF7L2 in intellectual disability and autism, both the genetic mechanism and clinical phenotype have remained incompletely characterized. We present here a comprehensive genetic and phenotypic description of 11 individuals who have been identified to carry de novo variants in TCF7L2, both truncating and missense. Missense variation is clustered in or near a high mobility group box domain, involving this region in these variants{\textquoteright} pathogenicity. All affected individuals present with developmental delays in childhood, but most ultimately achieved normal intelligence or had only mild intellectual disability. Myopia was present in approximately half of the individuals, and some individuals also possessed dysmorphic craniofacial features, orthopedic abnormalities, or neuropsychiatric comorbidities including autism and attention-deficit/hyperactivity disorder (ADHD). We thus present an initial clinical and genotypic spectrum associated with variation in TCF7L2, which will be important in informing both medical management and future research.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.62254}, author = {Dias, Caroline and Pfundt, Rolph and Kleefstra, Tjitske and Shuurs-Hoeijmakers, Janneke and Boon, Elles M J and van Hagen, Johanna M and Zwijnenburg, Petra and Weiss, Marjan M and Keren, Boris and Mignot, Cyril and Isapof, Arnaud and Weiss, Karin and Hershkovitz, Tova and Iascone, Maria and Maitz, Silvia and Feichtinger, Ren{\'e} G and Kotzot, Dieter and Mayr, Johannes A and Ben-Omran, Tawfeg and Mahmoud, Laila and Pais, Lynn S and Walsh, Christopher A and Shashi, Vandana and Sullivan, Jennifer A and Stong, Nicholas and Lecoquierre, Francois and Guerrot, Anne-Marie and Charollais, Aude and Rodan, Lance H} } @article {769, title = {Delineation of a Human Mendelian Disorder of the DNA Demethylation Machinery: TET3 Deficiency.}, journal = {Am J Hum Genet}, volume = {106}, year = {2020}, month = {2020 02 06}, pages = {234-245}, abstract = {

Germline pathogenic variants in chromatin-modifying enzymes are a common cause of pediatric developmental disorders. These enzymes catalyze reactions that regulate epigenetic inheritance via histone post-translational modifications and DNA methylation. Cytosine methylation (5-methylcytosine [5mC]) of DNA is the quintessential epigenetic mark, yet no human Mendelian disorder of DNA demethylation has yet been delineated. Here, we describe in detail a Mendelian disorder caused by the disruption of DNA demethylation. TET3 is a methylcytosine dioxygenase that initiates DNA demethylation during early zygote formation, embryogenesis, and neuronal differentiation and is intolerant to haploinsufficiency in mice and humans. We identify and characterize 11 cases of human TET3 deficiency in eight families with the common phenotypic features of intellectual disability and/or global developmental delay; hypotonia; autistic traits; movement disorders; growth abnormalities; and facial dysmorphism. Mono-allelic frameshift and nonsense variants in TET3 occur throughout the coding region. Mono-allelic and bi-allelic missense variants localize to conserved residues; all but one such variant occur within the catalytic domain, and most display hypomorphic function in an assay of catalytic activity. TET3 deficiency and other Mendelian disorders of the epigenetic machinery show substantial phenotypic overlap, including features of intellectual disability and abnormal growth, underscoring shared disease mechanisms.

}, keywords = {Adult, Amino Acid Sequence, Autistic Disorder, Child, Child, Preschool, Developmental Disabilities, Dioxygenases, DNA Demethylation, Embryonic Development, Female, Gene Expression Regulation, Developmental, Growth Disorders, Humans, Infant, Male, Middle Aged, Movement Disorders, Pedigree, Protein Conformation, Sequence Homology, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.12.007}, author = {Beck, David B and Petracovici, Ana and He, Chongsheng and Moore, Hannah W and Louie, Raymond J and Ansar, Muhammad and Douzgou, Sofia and Sithambaram, Sivagamy and Cottrell, Trudie and Santos-Cortez, Regie Lyn P and Prijoles, Eloise J and Bend, Renee and Keren, Boris and Mignot, Cyril and Nougues, Marie-Christine and {\~O}unap, Katrin and Reimand, Tiia and Pajusalu, Sander and Zahid, Muhammad and Saqib, Muhammad Arif Nadeem and Buratti, Julien and Seaby, Eleanor G and McWalter, Kirsty and Telegrafi, Aida and Baldridge, Dustin and Shinawi, Marwan and Leal, Suzanne M and Schaefer, G Bradley and Stevenson, Roger E and Banka, Siddharth and Bonasio, Roberto and Fahrner, Jill A} } @article {500, title = {Genetic variants in components of the NALCN-UNC80-UNC79 ion channel complex cause a broad clinical phenotype (NALCN channelopathies).}, journal = {Hum Genet}, volume = {137}, year = {2018}, month = {2018 Sep}, pages = {753-768}, abstract = {

NALCN is a conserved cation channel, which conducts a permanent sodium leak current and regulates resting membrane potential and neuronal excitability. It is part of a large ion channel complex, the "NALCN channelosome", consisting of multiple proteins including UNC80 and UNC79. The predominant neuronal expression pattern and its function suggest an important role in neuronal function and disease. So far, biallelic NALCN and UNC80 variants have been described in a small number of individuals leading to infantile hypotonia, psychomotor retardation, and characteristic facies 1 (IHPRF1, OMIM 615419) and 2 (IHPRF2, OMIM 616801), respectively. Heterozygous de novo NALCN missense variants in the S5/S6 pore-forming segments lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD, OMIM 616266) with some clinical overlap. In this study, we present detailed clinical information of 16 novel individuals with biallelic NALCN variants, 1 individual with a heterozygous de novo NALCN missense variant and an interesting clinical phenotype without contractures, and 12 individuals with biallelic UNC80 variants. We report for the first time a missense NALCN variant~located in the predicted S6 pore-forming unit inherited in an autosomal-recessive manner leading to mild IHPRF1. We show evidence of clinical variability, especially among IHPRF1-affected individuals, and discuss differences between the IHPRF1- and IHPRF2 phenotypes. In summary, we provide a comprehensive overview of IHPRF1 and IHPRF2 phenotypes based on the largest cohort of individuals reported so far and provide additional insights into the clinical phenotypes of these neurodevelopmental diseases to help improve counseling of affected families.

}, keywords = {Adolescent, Adult, Carrier Proteins, Channelopathies, Child, Child, Preschool, Developmental Disabilities, Female, Genetic Markers, Genetic Variation, Humans, Infant, Infant, Newborn, Male, Membrane Proteins, Phenotype, Sodium Channels, Young Adult}, issn = {1432-1203}, doi = {10.1007/s00439-018-1929-5}, author = {Bramswig, Nuria C and Bertoli-Avella, Aida M and Albrecht, Beate and Al Aqeel, Aida I and Alhashem, Amal and Al-Sannaa, Nouriya and Bah, Maissa and Br{\"o}hl, Katharina and Depienne, Christel and Dorison, Nathalie and Doummar, Diane and Ehmke, Nadja and Elbendary, Hasnaa M and Gorokhova, Svetlana and H{\'e}ron, Delphine and Horn, Denise and James, Kiely and Keren, Boris and Kuechler, Alma and Ismail, Samira and Issa, Mahmoud Y and Marey, Isabelle and Mayer, Mich{\`e}le and McEvoy-Venneri, Jennifer and Megarbane, Andre and Mignot, Cyril and Mohamed, Sarar and Nava, Caroline and Philip, Nicole and Ravix, Cecile and Rolfs, Arndt and Sadek, Abdelrahim Abdrabou and Segebrecht, Lara and Stanley, Valentina and Trautman, Camille and Valence, Stephanie and Villard, Laurent and Wieland, Thomas and Engels, Hartmut and Strom, Tim M and Zaki, Maha S and Gleeson, Joseph G and L{\"u}decke, Hermann-Josef and Bauer, Peter and Wieczorek, Dagmar} } @article {560, title = {Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.}, journal = {EMBO J}, volume = {37}, year = {2018}, month = {2018 Dec 03}, abstract = {

A set of glutamylases and deglutamylases controls levels of tubulin polyglutamylation, a prominent post-translational modification of neuronal microtubules. Defective tubulin polyglutamylation was first linked to neurodegeneration in the () mouse, which lacks deglutamylase CCP1, displays massive cerebellar atrophy, and accumulates abnormally glutamylated tubulin in degenerating neurons. We found biallelic rare and damaging variants in the gene encoding CCP1 in 13 individuals with infantile-onset neurodegeneration and confirmed the absence of functional CCP1 along with dysregulated tubulin polyglutamylation. The human disease mainly affected the cerebellum, spinal motor neurons, and peripheral nerves. We also demonstrate previously unrecognized peripheral nerve and spinal motor neuron degeneration in mice, which thus recapitulated key features of the human disease. Our findings link human neurodegeneration to tubulin polyglutamylation, entailing this post-translational modification as a potential target for drug development for neurodegenerative disorders.

}, issn = {1460-2075}, doi = {10.15252/embj.2018100540}, author = {Shashi, Vandana and Magiera, Maria M and Klein, Dennis and Zaki, Maha and Schoch, Kelly and Rudnik-Sch{\"o}neborn, Sabine and Norman, Andrew and Lopes Abath Neto, Osorio and Dusl, Marina and Yuan, Xidi and Bartesaghi, Luca and De Marco, Patrizia and Alfares, Ahmed A and Marom, Ronit and Arold, Stefan T and Guzm{\'a}n-Vega, Francisco J and Pena, Loren Dm and Smith, Edward C and Steinlin, Maja and Babiker, Mohamed Oe and Mohassel, Payam and Foley, A Reghan and Donkervoort, Sandra and Kaur, Rupleen and Ghosh, Partha S and Stanley, Valentina and Musaev, Damir and Nava, Caroline and Mignot, Cyril and Keren, Boris and Scala, Marcello and Tassano, Elisa and Picco, Paolo and Doneda, Paola and Fiorillo, Chiara and Issa, Mahmoud Y and Alassiri, Ali and Alahmad, Ahmed and Gerard, Amanda and Liu, Pengfei and Yang, Yaping and Ertl-Wagner, Birgit and Kranz, Peter G and Wentzensen, Ingrid M and Stucka, Rolf and Stong, Nicholas and Allen, Andrew S and Goldstein, David B and Schoser, Benedikt and R{\"o}sler, Kai M and Alfadhel, Majid and Capra, Valeria and Chrast, Roman and Strom, Tim M and Kamsteeg, Erik-Jan and B{\"o}nnemann, Carsten G and Gleeson, Joseph G and Martini, Rudolf and Janke, Carsten and Senderek, Jan} } @article {388, title = {Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood.}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Aug 03}, pages = {267-273}, abstract = {

Ribosomal RNA (rRNA) is transcribed from rDNA by RNA polymerase I (Pol I) to produce the 45S precursor of the 28S, 5.8S, and 18S rRNA components of the ribosome. Two transcription factors have been defined for Pol I in mammals, the selectivity factor SL1, and the upstream binding transcription factor (UBF), which interacts with the upstream control element to facilitate the assembly of the transcription initiation complex including SL1 and Pol I. In seven unrelated affected individuals, all suffering from developmental regression starting at 2.5-7 years, we identified a heterozygous variant, c.628G>A in UBTF, encoding p.Glu210Lys in UBF, which occurred de novo in~all cases. While the levels of UBF, Ser388 phosphorylated UBF, and other Pol I-related components (POLR1E, TAF1A, and TAF1C) remained unchanged in cells of an affected individual, the variant conferred gain of function to UBF, manifesting by markedly increased UBF binding to the rDNA promoter and to the 5{\textquoteright}- external transcribed spacer. This was associated with significantly increased 18S expression, and enlarged nucleoli which were reduced in number per cell. The data link neurodegeneration in childhood with altered rDNA chromatin status and rRNA metabolism.

}, keywords = {Adolescent, Adult, Atrophy, Brain, Brain Diseases, Cell Nucleolus, Child, Chromatin, DNA-Binding Proteins, Female, Humans, Male, Neurodegenerative Diseases, Pol1 Transcription Initiation Complex Proteins, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, RNA, Ribosomal, 18S, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.07.002}, author = {Edvardson, Simon and Nicolae, Claudia M and Agrawal, Pankaj B and Mignot, Cyril and Payne, Katelyn and Prasad, Asuri Narayan and Prasad, Chitra and Sadler, Laurie and Nava, Caroline and Mullen, Thomas E and Begtrup, Amber and Baskin, Berivan and Powis, Z{\"o}e and Shaag, Avraham and Keren, Boris and Moldovan, George-Lucian and Elpeleg, Orly} } @article {453, title = {High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Nov 02}, pages = {664-685}, abstract = {

Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32\%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy.

}, keywords = {Brain Diseases, Child, Child, Preschool, Epilepsy, Female, Genome, Human, Genome-Wide Association Study, Humans, Intellectual Disability, Male, Mutation, Recurrence, Seizures}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.09.008}, author = {Hamdan, Fadi F and Myers, Candace T and Cossette, Patrick and Lemay, Philippe and Spiegelman, Dan and Laporte, Alexandre Dionne and Nassif, Christina and Diallo, Ousmane and Monlong, Jean and Cadieux-Dion, Maxime and Dobrzeniecka, Sylvia and Meloche, Caroline and Retterer, Kyle and Cho, Megan T and Rosenfeld, Jill A and Bi, Weimin and Massicotte, Christine and Miguet, Marguerite and Brunga, Ledia and Regan, Brigid M and Mo, Kelly and Tam, Cory and Schneider, Amy and Hollingsworth, Georgie and FitzPatrick, David R and Donaldson, Alan and Canham, Natalie and Blair, Edward and Kerr, Bronwyn and Fry, Andrew E and Thomas, Rhys H and Shelagh, Joss and Hurst, Jane A and Brittain, Helen and Blyth, Moira and Lebel, Robert Roger and Gerkes, Erica H and Davis-Keppen, Laura and Stein, Quinn and Chung, Wendy K and Dorison, Sara J and Benke, Paul J and Fassi, Emily and Corsten-Janssen, Nicole and Kamsteeg, Erik-Jan and Mau-Them, Frederic T and Bruel, Ange-Line and Verloes, Alain and {\~O}unap, Katrin and Wojcik, Monica H and Albert, Dara V F and Venkateswaran, Sunita and Ware, Tyson and Jones, Dean and Liu, Yu-Chi and Mohammad, Shekeeb S and Bizargity, Peyman and Bacino, Carlos A and Leuzzi, Vincenzo and Martinelli, Simone and Dallapiccola, Bruno and Tartaglia, Marco and Blumkin, Lubov and Wierenga, Klaas J and Purcarin, Gabriela and O{\textquoteright}Byrne, James J and Stockler, Sylvia and Lehman, Anna and Keren, Boris and Nougues, Marie-Christine and Mignot, Cyril and Auvin, St{\'e}phane and Nava, Caroline and Hiatt, Susan M and Bebin, Martina and Shao, Yunru and Scaglia, Fernando and Lalani, Seema R and Frye, Richard E and Jarjour, Imad T and Jacques, St{\'e}phanie and Boucher, Renee-Myriam and Riou, Emilie and Srour, Myriam and Carmant, Lionel and Lortie, Anne and Major, Philippe and Diadori, Paola and Dubeau, Fran{\c c}ois and D{\textquoteright}Anjou, Guy and Bourque, Guillaume and Berkovic, Samuel F and Sadleir, Lynette G and Campeau, Philippe M and Kibar, Zoha and Lafreni{\`e}re, Ronald G and Girard, Simon L and Mercimek-Mahmutoglu, Saadet and Boelman, Cyrus and Rouleau, Guy A and Scheffer, Ingrid E and Mefford, Heather C and Andrade, Danielle M and Rossignol, Elsa and Minassian, Berge A and Michaud, Jacques L} }