@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 {705, title = {Disruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 Oct 15}, pages = {4679}, abstract = {

Postsynaptic density (PSD) proteins have been implicated in the pathophysiology of neurodevelopmental and psychiatric disorders. Here, we present detailed clinical and genetic data for 20 patients with likely gene-disrupting mutations in TANC2-whose protein product interacts with multiple PSD proteins. Pediatric patients with disruptive mutations present with autism, intellectual disability, and delayed language and motor development. In addition to a variable degree of epilepsy and facial dysmorphism, we observe a pattern of more complex psychiatric dysfunction or behavioral problems in adult probands or carrier parents. Although this observation requires replication to establish statistical significance, it also suggests that mutations in this gene are associated with a variety of neuropsychiatric disorders consistent with its postsynaptic function. We find that TANC2 is expressed broadly in the human developing brain, especially in excitatory neurons and glial cells, but shows a more restricted pattern in Drosophila glial cells where its disruption affects behavioral outcomes.

}, issn = {2041-1723}, doi = {10.1038/s41467-019-12435-8}, author = {Guo, Hui and Bettella, Elisa and Marcogliese, Paul C and Zhao, Rongjuan and Andrews, Jonathan C and Nowakowski, Tomasz J and Gillentine, Madelyn A and Hoekzema, Kendra and Wang, Tianyun and Wu, Huidan and Jangam, Sharayu and Liu, Cenying and Ni, Hailun and Willemsen, Marjolein H and van Bon, Bregje W and Rinne, Tuula and Stevens, Servi J C and Kleefstra, Tjitske and Brunner, Han G and Yntema, Helger G and Long, Min and Zhao, Wenjing and Hu, Zhengmao and Colson, Cindy and Richard, Nicolas and Schwartz, Charles E and Romano, Corrado and Castiglia, Lucia and Bottitta, Maria and Dhar, Shweta U and Erwin, Deanna J and Emrick, Lisa and Keren, Boris and Afenjar, Alexandra and Zhu, Baosheng and Bai, Bing and Stankiewicz, Pawel and Herman, Kristin and Mercimek-Andrews, Saadet and Juusola, Jane and Wilfert, Amy B and Abou Jamra, Rami and B{\"u}ttner, Benjamin and Mefford, Heather C and Muir, Alison M and Scheffer, Ingrid E and Regan, Brigid M and Malone, Stephen and Gecz, Jozef and Cobben, Jan and Weiss, Marjan M and Waisfisz, Quinten and Bijlsma, Emilia K and Hoffer, Mariette J V and Ruivenkamp, Claudia A L and Sartori, Stefano and Xia, Fan and Rosenfeld, Jill A and Bernier, Raphael A and Wangler, Michael F and Yamamoto, Shinya and Xia, Kun and Stegmann, Alexander P A and Bellen, Hugo J and Murgia, Alessandra and Eichler, Evan E} } @article {520, title = {Biallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome.}, journal = {Am J Hum Genet}, volume = {103}, year = {2018}, month = {2018 09 06}, pages = {431-439}, abstract = {

ADP-ribosylation, the addition of poly-ADP ribose (PAR) onto proteins, is a response signal to cellular challenges, such as excitotoxicity or oxidative stress. This process is catalyzed by a group of enzymes referred to as poly(ADP-ribose) polymerases (PARPs). Because the accumulation of proteins with this modification results in cell death, its negative regulation restores cellular homeostasis: a process mediated by poly-ADP ribose glycohydrolases (PARGs) and ADP-ribosylhydrolase proteins (ARHs). Using linkage analysis and exome or genome sequencing, we identified recessive inactivating mutations in ADPRHL2 in six families. Affected individuals exhibited a pediatric-onset neurodegenerative disorder with progressive brain atrophy, developmental regression, and seizures in association with periods of stress, such as infections. Loss of the Drosophila paralog Parg showed lethality in response to oxidative challenge that was rescued by human ADPRHL2, suggesting functional conservation. Pharmacological inhibition of PARP also rescued the phenotype, suggesting the possibility of postnatal treatment for this genetic condition.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.07.010}, author = {Ghosh, Shereen G and Becker, Kerstin and Huang, He and Dixon-Salazar, Tracy and Chai, Guoliang and Salpietro, Vincenzo and Al-Gazali, Lihadh and Waisfisz, Quinten and Wang, Haicui and Vaux, Keith K and Stanley, Valentina and Manole, Andreea and Akpulat, Ugur and Weiss, Marjan M and Efthymiou, Stephanie and Hanna, Michael G and Minetti, Carlo and Striano, Pasquale and Pisciotta, Livia and De Grandis, Elisa and Altm{\"u}ller, Janine and N{\"u}rnberg, Peter and Thiele, Holger and Yis, Uluc and Okur, Tuncay Derya and Polat, Ayse Ipek and Amiri, Nafise and Doosti, Mohammad and Karimani, Ehsan Ghayoor and Toosi, Mehran B and Haddad, Gabriel and Karakaya, Mert and Wirth, Brunhilde and van Hagen, Johanna M and Wolf, Nicole I and Maroofian, Reza and Houlden, Henry and Cirak, Sebahattin and Gleeson, Joseph G} } @article {51, title = {Loss-of-Function Mutations in FRRS1L Lead to an Epileptic-Dyskinetic Encephalopathy.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 06 02}, pages = {1249-1255}, abstract = {

Glutamatergic neurotransmission governs excitatory signaling in the mammalian brain, and abnormalities of glutamate signaling have been shown to contribute to both epilepsy and hyperkinetic movement disorders. The etiology of many severe childhood movement disorders and epilepsies remains uncharacterized. We describe a neurological disorder with epilepsy and prominent choreoathetosis caused by biallelic pathogenic variants in FRRS1L, which encodes an AMPA receptor outer-core protein. Loss of FRRS1L function attenuates AMPA-mediated currents, implicating chronic abnormalities of glutamatergic neurotransmission in this monogenic neurological disease of childhood.

}, keywords = {alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid, Brain Diseases, Electrophysiology, Epilepsy, Female, Humans, Hyperkinesis, Infant, Male, Membrane Proteins, Mutation, Nerve Tissue Proteins, Pedigree, Synaptic Transmission}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.04.008}, author = {Madeo, Marianna and Stewart, Michelle and Sun, Yuyang and Sahir, Nadia and Wiethoff, Sarah and Chandrasekar, Indra and Yarrow, Anna and Rosenfeld, Jill A and Yang, Yaping and Cordeiro, Dawn and McCormick, Elizabeth M and Muraresku, Colleen C and Jepperson, Tyler N and McBeth, Lauren J and Seidahmed, Mohammed Zain and El Khashab, Heba Y and Hamad, Muddathir and Azzedine, Hamid and Clark, Karl and Corrochano, Silvia and Wells, Sara and Elting, Mariet W and Weiss, Marjan M and Burn, Sabrina and Myers, Angela and Landsverk, Megan and Crotwell, Patricia L and Waisfisz, Quinten and Wolf, Nicole I and Nolan, Patrick M and Padilla-Lopez, Sergio and Houlden, Henry and Lifton, Richard and Mane, Shrikant and Singh, Brij B and Falk, Marni J and Mercimek-Mahmutoglu, Saadet and Bilguvar, Kaya and Salih, Mustafa A and Acevedo-Arozena, Abraham and Kruer, Michael C} }