@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 {999, title = {DLG4-related synaptopathy: a new rare brain disorder.}, journal = {Genet Med}, volume = {23}, year = {2021}, month = {2021 05}, pages = {888-899}, abstract = {

PURPOSE: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants.

METHODS: The clinical and genetic information were~collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing.

RESULTS: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not~be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies.

CONCLUSION: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.

}, keywords = {Autism Spectrum Disorder, Brain, Brain Diseases, Disks Large Homolog 4 Protein, Humans, Intellectual Disability, Neurodevelopmental Disorders, Phenotype}, issn = {1530-0366}, doi = {10.1038/s41436-020-01075-9}, author = {Rodr{\'\i}guez-Palmero, Agust{\'\i} and Boerrigter, Melissa Maria and G{\'o}mez-Andr{\'e}s, David and Aldinger, Kimberly A and Marcos-Alcalde, {\'I}{\~n}igo and Popp, Bernt and Everman, David B and Lovgren, Alysia Kern and Arpin, Stephanie and Bahrambeigi, Vahid and Beunders, Gea and Bisgaard, Anne-Marie and Bjerregaard, V A and Bruel, Ange-Line and Challman, Thomas D and Cogn{\'e}, Benjamin and Coubes, Christine and de Man, Stella A and Denomm{\'e}-Pichon, Anne-Sophie and Dye, Thomas J and Elmslie, Frances and Feuk, Lars and Garcia-Minaur, Sixto and Gertler, Tracy and Giorgio, Elisa and Gruchy, Nicolas and Haack, Tobias B and Haldeman-Englert, Chad R and Haukanes, Bj{\o}rn Ivar and Hoyer, Juliane and Hurst, Anna C E and Isidor, Bertrand and Soller, Maria Johansson and Kushary, Sulagna and Kvarnung, Malin and Landau, Yuval E and Leppig, Kathleen A and Lindstrand, Anna and Kleinendorst, Lotte and MacKenzie, Alex and Mandrile, Giorgia and Mendelsohn, Bryce A and Moghadasi, Setareh and Morton, Jenny E and Moutton, S{\'e}bastien and M{\"u}ller, Amelie J and O{\textquoteright}Leary, Melanie and Pacio-Miguez, Marta and Palomares-Bralo, Maria and Parikh, Sumit and Pfundt, Rolph and Pode-Shakked, Ben and Rauch, Anita and Repnikova, Elena and Revah-Politi, Anya and Ross, Meredith J and Ruivenkamp, Claudia A L and Sarrazin, Elisabeth and Savatt, Juliann M and Schluter, Agatha and Sch{\"o}newolf-Greulich, Bitten and Shad, Zohra and Shaw-Smith, Charles and Shieh, Joseph T and Shohat, Motti and Spranger, Stephanie and Thiese, Heidi and Mau-Them, Frederic Tran and van Bon, Bregje and van de Burgt, Ineke and van de Laar, Ingrid M B H and van Drie, Esm{\'e}e and van Haelst, Mieke M and van Ravenswaaij-Arts, Conny M and Verdura, Edgard and Vitobello, Antonio and Waldm{\"u}ller, Stephan and Whiting, Sharon and Zweier, Christiane and Prada, Carlos E and de Vries, Bert B A and Dobyns, William B and Reiter, Simone F and G{\'o}mez-Puertas, Paulino and Pujol, Aurora and T{\"u}mer, Zeynep} } @article {1000, title = {A DNA repair disorder caused by de novo monoallelic DDB1 variants is associated with a neurodevelopmental syndrome.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 04 01}, pages = {749-756}, abstract = {

The DNA damage-binding protein 1 (DDB1) is part of the CUL4-DDB1 ubiquitin E3 ligase complex (CRL4), which is essential for DNA repair, chromatin remodeling, DNA replication, and signal transduction. Loss-of-function variants in genes encoding the complex components CUL4 and PHIP have been reported to cause syndromic intellectual disability with hypotonia and obesity, but no phenotype has been reported in association with DDB1 variants. Here, we report eight unrelated individuals, identified through Matchmaker Exchange, with de novo monoallelic variants in DDB1, including one recurrent variant in four individuals. The affected individuals have a consistent phenotype of hypotonia, mild to moderate intellectual disability, and similar facies, including horizontal or slightly bowed eyebrows, deep-set eyes, full cheeks, a short nose, and large, fleshy and forward-facing earlobes, demonstrated in the composite face generated from the cohort. Digital anomalies, including brachydactyly and syndactyly, were common. Three older individuals have obesity. We show that cells derived from affected individuals have altered DDB1 function resulting in abnormal DNA damage signatures and histone methylation following UV-induced DNA damage. Overall, our study adds to the growing family of neurodevelopmental phenotypes mediated by disruption of the CRL4 ubiquitin ligase pathway and begins to delineate the phenotypic and molecular effects of DDB1 misregulation.

}, keywords = {Adolescent, Alleles, Child, Child, Preschool, DNA Repair, DNA-Binding Proteins, Female, Humans, Male, Mutation, Neurodevelopmental Disorders, Phenotype, Syndrome}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.03.007}, author = {White, Susan M and Bhoj, Elizabeth and Nellaker, Christoffer and Lachmeijer, Augusta M A and Marshall, Aren E and Boycott, Kym M and Li, Dong and Smith, Wendy and Hartley, Taila and McBride, Arran and Ernst, Michelle E and May, Alison S and Wieczorek, Dagmar and Abou Jamra, Rami and Koch-Hogrebe, Margarete and {\~O}unap, Katrin and Pajusalu, Sander and van Gassen, K L I and Sadedin, Simon and Ellingwood, Sara and Tan, Tiong Yang and Christodoulou, John and Barea, Jaime and Lockhart, Paul J and Nezarati, Marjan M and Kernohan, Kristin D} } @article {1001, title = {Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder.}, journal = {Nat Commun}, volume = {12}, year = {2021}, month = {2021 05 07}, pages = {2558}, abstract = {

GEMIN5, an RNA-binding protein is essential for assembly of the survival motor neuron (SMN) protein complex and facilitates the formation of small nuclear ribonucleoproteins (snRNPs), the building blocks of spliceosomes. Here, we have identified 30 affected individuals from 22 unrelated families presenting with developmental delay, hypotonia, and cerebellar ataxia harboring biallelic variants in the GEMIN5 gene. Mutations in GEMIN5 perturb the subcellular distribution, stability, and expression of GEMIN5 protein and its interacting partners in patient iPSC-derived neurons, suggesting a potential loss-of-function mechanism. GEMIN5 mutations result in disruption of snRNP complex assembly formation in patient iPSC neurons. Furthermore, knock down of rigor mortis, the fly homolog of human GEMIN5, leads to developmental defects, motor dysfunction, and a reduced lifespan. Interestingly, we observed that GEMIN5 variants disrupt a distinct set of transcripts and pathways as compared to SMA patient neurons, suggesting different molecular pathomechanisms. These findings collectively provide evidence that pathogenic variants in GEMIN5 perturb physiological functions and result in a neurodevelopmental delay and ataxia syndrome.

}, keywords = {Alleles, Amino Acid Sequence, Animals, Child, Preschool, Developmental Disabilities, Drosophila, Female, Gene Expression Regulation, Developmental, Gene Knockdown Techniques, Gene Ontology, HEK293 Cells, Humans, Induced Pluripotent Stem Cells, Loss of Function Mutation, Male, Muscle Hypotonia, Myoclonic Cerebellar Dyssynergia, Neurodevelopmental Disorders, Neurons, Pedigree, Polymorphism, Single Nucleotide, Ribonucleoproteins, Small Nuclear, Rigor Mortis, RNA-Seq, SMN Complex Proteins}, issn = {2041-1723}, doi = {10.1038/s41467-021-22627-w}, author = {Kour, Sukhleen and Rajan, Deepa S and Fortuna, Tyler R and Anderson, Eric N and Ward, Caroline and Lee, Youngha and Lee, Sangmoon and Shin, Yong Beom and Chae, Jong-Hee and Choi, Murim and Siquier, Karine and Cantagrel, Vincent and Amiel, Jeanne and Stolerman, Elliot S and Barnett, Sarah S and Cousin, Margot A and Castro, Diana and McDonald, Kimberly and Kirmse, Brian and Nemeth, Andrea H and Rajasundaram, Dhivyaa and Innes, A Micheil and Lynch, Danielle and Frosk, Patrick and Collins, Abigail and Gibbons, Melissa and Yang, Michele and Desguerre, Isabelle and Boddaert, Nathalie and Gitiaux, Cyril and Rydning, Siri Lynne and Selmer, Kaja K and Urreizti, Roser and Garcia-Oguiza, Alberto and Osorio, Andr{\'e}s Nascimento and Verdura, Edgard and Pujol, Aurora and McCurry, Hannah R and Landers, John E and Agnihotri, Sameer and Andriescu, E Corina and Moody, Shade B and Phornphutkul, Chanika and Sacoto, Maria J Guillen and Begtrup, Amber and Houlden, Henry and Kirschner, Janbernd and Schorling, David and Rudnik-Sch{\"o}neborn, Sabine and Strom, Tim M and Leiz, Steffen and Juliette, Kali and Richardson, Randal and Yang, Ying and Zhang, Yuehua and Wang, Minghui and Wang, Jia and Wang, Xiaodong and Platzer, Konrad and Donkervoort, Sandra and B{\"o}nnemann, Carsten G and Wagner, Matias and Issa, Mahmoud Y and Elbendary, Hasnaa M and Stanley, Valentina and Maroofian, Reza and Gleeson, Joseph G and Zaki, MAH S and Senderek, Jan and Pandey, Udai Bhan} } @article {1008, title = {SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 03 04}, pages = {502-516}, abstract = {

Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.

}, keywords = {Adolescent, Autism Spectrum Disorder, Child, Child, Preschool, Chromosome Deletion, Chromosome Disorders, Chromosomes, Human, Pair 1, Chromosomes, Human, X, DNA Methylation, DNA-Binding Proteins, Epigenesis, Genetic, Female, Haploinsufficiency, Humans, Intellectual Disability, Male, Neurodevelopmental Disorders, Phenotype, RNA-Binding Proteins, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.01.015}, author = {Radio, Francesca Clementina and Pang, Kaifang and Ciolfi, Andrea and Levy, Michael A and Hernandez-Garcia, Andres and Pedace, Lucia and Pantaleoni, Francesca and Liu, Zhandong and de Boer, Elke and Jackson, Adam and Bruselles, Alessandro and McConkey, Haley and Stellacci, Emilia and Lo Cicero, Stefania and Motta, Marialetizia and Carrozzo, Rosalba and Dentici, Maria Lisa and McWalter, Kirsty and Desai, Megha and Monaghan, Kristin G and Telegrafi, Aida and Philippe, Christophe and Vitobello, Antonio and Au, Margaret and Grand, Katheryn and Sanchez-Lara, Pedro A and Baez, Joanne and Lindstrom, Kristin and Kulch, Peggy and Sebastian, Jessica and Madan-Khetarpal, Suneeta and Roadhouse, Chelsea and MacKenzie, Jennifer J and Monteleone, Berrin and Saunders, Carol J and Jean Cuevas, July K and Cross, Laura and Zhou, Dihong and Hartley, Taila and Sawyer, Sarah L and Monteiro, Fabiola Paoli and Secches, Tania Vertemati and Kok, Fernando and Schultz-Rogers, Laura E and Macke, Erica L and Morava, Eva and Klee, Eric W and Kemppainen, Jennifer and Iascone, Maria and Selicorni, Angelo and Tenconi, Romano and Amor, David J and Pais, Lynn and Gallacher, Lyndon and Turnpenny, Peter D and Stals, Karen and Ellard, Sian and Cabet, Sara and Lesca, Gaetan and Pascal, Joset and Steindl, Katharina and Ravid, Sarit and Weiss, Karin and Castle, Alison M R and Carter, Melissa T and Kalsner, Louisa and de Vries, Bert B A and van Bon, Bregje W and Wevers, Marijke R and Pfundt, Rolph and Stegmann, Alexander P A and Kerr, Bronwyn and Kingston, Helen M and Chandler, Kate E and Sheehan, Willow and Elias, Abdallah F and Shinde, Deepali N and Towne, Meghan C and Robin, Nathaniel H and Goodloe, Dana and Vanderver, Adeline and Sherbini, Omar and Bluske, Krista and Hagelstrom, R Tanner and Zanus, Caterina and Faletra, Flavio and Musante, Luciana and Kurtz-Nelson, Evangeline C and Earl, Rachel K and Anderlid, Britt-Marie and Morin, Gilles and van Slegtenhorst, Marjon and Diderich, Karin E M and Brooks, Alice S and Gribnau, Joost and Boers, Ruben G and Finestra, Teresa Robert and Carter, Lauren B and Rauch, Anita and Gasparini, Paolo and Boycott, Kym M and Barakat, Tahsin Stefan and GrAHm, John M and Faivre, Laurence and Banka, Siddharth and Wang, Tianyun and Eichler, Evan E and Priolo, Manuela and Dallapiccola, Bruno and Vissers, Lisenka E L M and Sadikovic, Bekim and Scott, Daryl A and Holder, Jimmy Lloyd and Tartaglia, Marco} } @article {974, title = {Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia.}, journal = {Genet Med}, volume = {23}, year = {2021}, month = {2021 05}, pages = {881-887}, abstract = {

PURPOSE: Neurodevelopmental disorders (NDDs) encompass a spectrum of genetically heterogeneous disorders with features that commonly include developmental delay, intellectual disability, and autism spectrum disorders. We sought to delineate the molecular and phenotypic spectrum of a novel neurodevelopmental disorder caused by variants in the GNAI1 gene.

METHODS: Through large cohort trio-based exome sequencing and international data-sharing, we identified 24 unrelated individuals with NDD phenotypes and a variant in GNAI1, which encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. We collected detailed genotype and phenotype information for each affected individual.

RESULTS: We identified 16 unique variants in GNAI1 in 24 affected individuals; 23 occurred de novo and 1 was inherited from a mosaic parent. Most affected individuals have a severe neurodevelopmental disorder. Core features include global developmental delay, intellectual disability, hypotonia, and epilepsy.

CONCLUSION: This collaboration establishes GNAI1 variants as a cause of NDDs. GNAI1-related NDD is most often characterized by severe to profound delays, hypotonia, epilepsy that ranges from self-limiting to intractable, behavior problems, and variable mild dysmorphic features.

}, keywords = {Child, Developmental Disabilities, Humans, Intellectual Disability, Muscle Hypotonia, Neurodevelopmental Disorders, Seizures, Whole Exome Sequencing}, issn = {1530-0366}, doi = {10.1038/s41436-020-01076-8}, author = {Muir, Alison M and Gardner, Jennifer F and van Jaarsveld, Richard H and de Lange, Iris M and van der Smagt, Jasper J and Wilson, Golder N and Dubbs, Holly and Goldberg, Ethan M and Zitano, Lia and Bupp, Caleb and Martinez, Jose and Srour, Myriam and Accogli, Andrea and Alhakeem, Afnan and Meltzer, Meira and Gropman, Andrea and Brewer, Carole and Caswell, Richard C and Montgomery, Tara and McKenna, Caoimhe and McKee, Shane and Powell, Corinna and Vasudevan, Pradeep C and Brady, Angela F and Joss, Shelagh and Tysoe, Carolyn and Noh, Grace and Tarnopolsky, Mark and Brady, Lauren and Zafar, Muhammad and Schrier Vergano, Samantha A and Murray, Brianna and Sawyer, Lindsey and Hainline, Bryan E and Sapp, Katherine and DeMarzo, Danielle and Huismann, Darcy J and Wentzensen, Ingrid M and Schnur, Rhonda E and Monaghan, Kristin G and Juusola, Jane and Rhodes, Lindsay and Dobyns, William B and Lecoquierre, Francois and Goldenberg, Alice and Polster, Tilman and Axer-Schaefer, Susanne and Platzer, Konrad and Kl{\"o}ckner, Chiara and Hoffman, Trevor L and MacArthur, Daniel G and O{\textquoteright}Leary, Melanie C and VanNoy, Grace E and England, Eleina and Varghese, Vinod C and Mefford, Heather C} } @article {758, title = {Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy.}, journal = {Ann Clin Transl Neurol}, volume = {7}, year = {2020}, month = {2020 05}, pages = {610-627}, abstract = {

OBJECTIVE: Defects in ion channels and neurotransmitter receptors are implicated in developmental and epileptic encephalopathy (DEE). Metabotropic glutamate receptor 7 (mGluR7), encoded by GRM7, is a presynaptic G-protein-coupled glutamate receptor critical for synaptic transmission. We previously proposed GRM7 as a candidate disease gene in two families with neurodevelopmental disorders (NDDs). One additional family has been published since. Here, we describe three additional families with GRM7 biallelic variants and deeply characterize the associated clinical neurological and electrophysiological phenotype and molecular data in 11 affected individuals from six unrelated families.

METHODS: Exome sequencing and family-based rare variant analyses on a cohort of 220 consanguineous families with NDDs revealed three families with GRM7 biallelic variants; three additional families were identified through literature search and collaboration with a clinical molecular laboratory.

RESULTS: We compared the observed clinical features and variants of 11 affected individuals from the six unrelated families. Identified novel deleterious variants included two homozygous missense variants (c.2671G>A:p.Glu891Lys and c.1973G>A:p.Arg685Gln) and one homozygous stop-gain variant (c.1975C>T:p.Arg659Ter). Developmental delay, neonatal- or infantile-onset epilepsy, and microcephaly were universal. Three individuals had hypothalamic-pituitary-axis dysfunction without pituitary structural abnormality. Neuroimaging showed cerebral atrophy and hypomyelination in a majority of cases. Two siblings demonstrated progressive loss of myelination by 2~years in both and an acquired microcephaly pattern in one. Five individuals died in early or late childhood.

CONCLUSION: Detailed clinical characterization of 11 individuals from six unrelated families demonstrates that rare biallelic GRM7 pathogenic variants can cause DEEs, microcephaly, hypomyelination, and cerebral atrophy.

}, keywords = {Adolescent, Alleles, Atrophy, Child, Child, Preschool, Cohort Studies, Consanguinity, Epilepsy, Female, Humans, Infant, Male, Microcephaly, Neurodevelopmental Disorders, Pedigree, Phenotype, Receptors, Metabotropic Glutamate, Whole Exome Sequencing}, issn = {2328-9503}, doi = {10.1002/acn3.51003}, author = {Marafi, Dana and Mitani, Tadahiro and Isikay, Sedat and Hertecant, Jozef and Almannai, Mohammed and Manickam, Kandamurugu and Abou Jamra, Rami and El-Hattab, Ayman W and Rajah, Jaishen and Fatih, Jawid M and Du, Haowei and Karaca, Ender and Bayram, Yavuz and Punetha, Jaya and Rosenfeld, Jill A and Jhangiani, Shalini N and Boerwinkle, Eric and Akdemir, Zeynep C and Erdin, Serkan and Hunter, Jill V and Gibbs, Richard A and Pehlivan, Davut and Posey, Jennifer E and Lupski, James R} } @article {711, title = {De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder.}, journal = {Genet Med}, volume = {22}, year = {2020}, month = {2020 03}, pages = {538-546}, abstract = {

PURPOSE: Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous neurodevelopmental disorders. We sought to delineate the clinical, molecular, and neuroimaging spectrum of a novel neurodevelopmental disorder caused by variants in the zinc finger protein 292 gene (ZNF292).

METHODS: We ascertained a cohort of 28 families with ID due to putatively pathogenic ZNF292 variants that were identified via targeted and exome sequencing. Available data were analyzed to characterize the canonical phenotype and examine genotype-phenotype relationships.

RESULTS: Probands presented with ID as well as a spectrum of neurodevelopmental features including ASD, among others. All ZNF292 variants were de novo, except in one family with dominant inheritance. ZNF292 encodes a highly conserved zinc finger protein that acts as a transcription factor and is highly expressed in the developing human brain supporting its critical role in neurodevelopment.

CONCLUSION: De novo and dominantly inherited variants in ZNF292 are associated with a range of neurodevelopmental features including ID and ASD. The clinical spectrum is broad, and most individuals present with mild to moderate ID with or without other syndromic features. Our results suggest that variants in ZNF292 are likely a recurrent cause of a neurodevelopmental disorder manifesting as ID with or without ASD.

}, keywords = {Adolescent, Autism Spectrum Disorder, Carrier Proteins, Child, Child, Preschool, Female, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing, Humans, Male, Nerve Tissue Proteins, Neurodevelopmental Disorders, Neuroimaging, Whole Exome Sequencing}, issn = {1530-0366}, doi = {10.1038/s41436-019-0693-9}, author = {Mirzaa, Ghayda M and Chong, Jessica X and Piton, Am{\'e}lie and Popp, Bernt and Foss, Kimberly and Guo, Hui and Harripaul, Ricardo and Xia, Kun and Scheck, Joshua and Aldinger, Kimberly A and Sajan, Samin A and Tang, Sha and Bonneau, Dominique and Beck, Anita and White, Janson and Mahida, Sonal and Harris, Jacqueline and Smith-Hicks, Constance and Hoyer, Juliane and Zweier, Christiane and Reis, Andr{\'e} and Thiel, Christian T and Jamra, Rami Abou and Zeid, Natasha and Yang, Amy and Farach, Laura S and Walsh, Laurence and Payne, Katelyn and Rohena, Luis and Velinov, Milen and Ziegler, Alban and Schaefer, Elise and Gatinois, Vincent and Genevi{\`e}ve, David and Simon, Marleen E H and Kohler, Jennefer and Rotenberg, Joshua and Wheeler, Patricia and Larson, Austin and Ernst, Michelle E and Akman, Cigdem I and Westman, Rachel and Blanchet, Patricia and Schillaci, Lori-Anne and Vincent-Delorme, Catherine and Gripp, Karen W and Mattioli, Francesca and Guyader, Gwena{\"e}l Le and Gerard, B{\'e}n{\'e}dicte and Mathieu-Dramard, Mich{\`e}le and Morin, Gilles and Sasanfar, Roksana and Ayub, Muhammad and Vasli, Nasim and Yang, Sandra and Person, Rick and Monaghan, Kristin G and Nickerson, Deborah A and van Binsbergen, Ellen and Enns, Gregory M and Dries, Annika M and Rowe, Leah J and Tsai, Anne C H and Svihovec, Shayna and Friedman, Jennifer and Agha, Zehra and Qamar, Raheel and Rodan, Lance H and Martinez-Agosto, Julian and Ockeloen, Charlotte W and Vincent, Marie and Sunderland, William James and Bernstein, Jonathan A and Eichler, Evan E and Vincent, John B and Bamshad, Michael J} } @article {738, title = {Deficiencies in vesicular transport mediated by TRAPPC4 are associated with severe syndromic intellectual disability.}, journal = {Brain}, volume = {143}, year = {2020}, month = {2020 01 01}, pages = {112-130}, abstract = {

The conserved transport protein particle (TRAPP) complexes regulate key trafficking events and are required for autophagy. TRAPPC4, like its yeast Trs23 orthologue, is a core component of the TRAPP complexes and one of the essential subunits for guanine nucleotide exchange factor activity for Rab1 GTPase. Pathogenic variants in specific TRAPP subunits are associated with neurological disorders. We undertook exome sequencing in three unrelated families of Caucasian, Turkish and French-Canadian ethnicities with seven affected children that showed features of early-onset seizures, developmental delay, microcephaly, sensorineural deafness, spastic quadriparesis and progressive cortical and cerebellar atrophy in an effort to determine the genetic aetiology underlying neurodevelopmental disorders. All seven affected subjects shared the same identical rare, homozygous, potentially pathogenic variant in a non-canonical, well-conserved splice site within TRAPPC4 (hg19:chr11:g.118890966A>G; TRAPPC4: NM_016146.5; c.454+3A>G). Single nucleotide polymorphism array analysis revealed there was no haplotype shared between the tested Turkish and Caucasian families suggestive of a variant hotspot region rather than a founder effect. In silico analysis predicted the variant to cause aberrant splicing. Consistent with this, experimental evidence showed both a reduction in full-length transcript levels and an increase in levels of a shorter transcript missing exon 3, suggestive of an incompletely penetrant splice defect. TRAPPC4 protein levels were significantly reduced whilst levels of other TRAPP complex subunits remained unaffected. Native polyacrylamide gel electrophoresis and size exclusion chromatography demonstrated a defect in TRAPP complex assembly and/or stability. Intracellular trafficking through the Golgi using the marker protein VSVG-GFP-ts045 demonstrated significantly delayed entry into and exit from the Golgi in fibroblasts derived from one of the affected subjects. Lentiviral expression of wild-type TRAPPC4 in these fibroblasts restored trafficking, suggesting that the trafficking defect was due to reduced TRAPPC4 levels. Consistent with the recent association of the TRAPP complex with autophagy, we found that the fibroblasts had a basal autophagy defect and a delay in autophagic flux, possibly due to unsealed autophagosomes. These results were validated using a yeast trs23 temperature sensitive variant that exhibits constitutive and stress-induced autophagic defects at permissive temperature and a secretory defect at restrictive temperature. In summary we provide strong evidence for pathogenicity of this variant in a member of the core TRAPP subunit, TRAPPC4 that associates with vesicular trafficking and autophagy defects. This is the first report of a TRAPPC4 variant, and our findings add to the growing number of TRAPP-associated neurological disorders.

}, keywords = {Atrophy, Autophagy, Cerebellum, Cerebral Cortex, Child, Child, Preschool, Craniofacial Abnormalities, Deafness, Developmental Disabilities, Epilepsy, Female, Fibroblasts, Hearing Loss, Sensorineural, Humans, Infant, Infant, Newborn, Intellectual Disability, Male, Microcephaly, Microscopy, Fluorescence, Muscle Spasticity, Nerve Tissue Proteins, Neurodevelopmental Disorders, Pedigree, Quadriplegia, RNA Splice Sites, Syndrome, Vesicular Transport Proteins}, issn = {1460-2156}, doi = {10.1093/brain/awz374}, author = {Van Bergen, Nicole J and Guo, Yiran and Al-Deri, Noraldin and Lipatova, Zhanna and Stanga, Daniela and Zhao, Sarah and Murtazina, Rakhilya and Gyurkovska, Valeriya and Pehlivan, Davut and Mitani, Tadahiro and Gezdirici, Alper and Antony, Jayne and Collins, Felicity and Willis, Mary J H and Coban Akdemir, Zeynep H and Liu, Pengfei and Punetha, Jaya and Hunter, Jill V and Jhangiani, Shalini N and Fatih, Jawid M and Rosenfeld, Jill A and Posey, Jennifer E and Gibbs, Richard A and Karaca, Ender and Massey, Sean and Ranasinghe, Thisara G and Sleiman, Patrick and Troedson, Chris and Lupski, James R and Sacher, Michael and Segev, Nava and Hakonarson, Hakon and Christodoulou, John} } @article {574, title = {Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 02 12}, pages = {707}, abstract = {

Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. To date, biallelic mutations in 31 ARS genes are known to cause recessive, early-onset severe multi-organ diseases. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. Here, we report seven patients from five unrelated families with five different biallelic missense variants in VARS. Subjects present with a range of global developmental delay, epileptic encephalopathy and primary or progressive microcephaly. Longitudinal assessment demonstrates progressive cortical atrophy and white matter volume loss. Variants map to the VARS tRNA binding domain and adjacent to the anticodon domain, and disrupt highly conserved residues. Patient primary cells show intact VARS protein but reduced enzymatic activity, suggesting partial loss of function. The implication of VARS in pediatric neurodegeneration broadens the spectrum of human diseases due to mutations in tRNA synthetase genes.

}, keywords = {Alleles, Anticodon, Child, Child, Preschool, Disease Progression, Epilepsy, Female, Genetic Predisposition to Disease, Humans, Longitudinal Studies, Loss of Function Mutation, Male, Microcephaly, Models, Molecular, Mutation, Neurodevelopmental Disorders, Pedigree, Protein Biosynthesis, Protein Interaction Domains and Motifs, RNA, Transfer, Valine-tRNA Ligase, Whole Exome Sequencing, Whole Genome Sequencing}, issn = {2041-1723}, doi = {10.1038/s41467-018-07067-3}, author = {Friedman, Jennifer and Smith, Desiree E and Issa, Mahmoud Y and Stanley, Valentina and Wang, Rengang and Mendes, Marisa I and Wright, Meredith S and Wigby, Kristen and Hildreth, Amber and Crawford, John R and Koehler, Alanna E and Chowdhury, Shimul and Nahas, Shareef and Zhai, Liting and Xu, Zhiwen and Lo, Wing-Sze and James, Kiely N and Musaev, Damir and Accogli, Andrea and Guerrero, Kether and Tran, Luan T and Omar, Tarek E I and Ben-Omran, Tawfeg and Dimmock, David and Kingsmore, Stephen F and Salomons, Gajja S and Zaki, Maha S and Bernard, Genevi{\`e}ve and Gleeson, Joseph G} } @article {573, title = {Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 02 12}, pages = {708}, abstract = {

Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often complex neurological disease traits. Here we report an allelic series consisting of seven novel and two previously reported biallelic variants in valyl-tRNA synthetase (VARS) in ten patients with a developmental encephalopathy with microcephaly, often associated with early-onset epilepsy. In silico, in vitro, and yeast complementation assays demonstrate that the underlying pathomechanism of these mutations is most likely a loss of protein function. Zebrafish modeling accurately recapitulated some of the key neurological disease traits. These results provide both genetic and biological insights into neurodevelopmental disease and pave the way for further in-depth research on ARS related recessive disorders and precision therapies.

}, keywords = {Alleles, Animals, Brain Diseases, Cell Line, Disease Models, Animal, Epilepsy, Female, Fibroblasts, Gene Knockout Techniques, Genetic Predisposition to Disease, Humans, Loss of Function Mutation, Male, Microcephaly, Models, Molecular, Neurodevelopmental Disorders, Pedigree, Prosencephalon, Valine-tRNA Ligase, Zebrafish}, issn = {2041-1723}, doi = {10.1038/s41467-018-07953-w}, author = {Siekierska, Aleksandra and Stamberger, Hannah and Deconinck, Tine and Oprescu, Stephanie N and Partoens, Mich{\`e}le and Zhang, Yifan and Sourbron, Jo and Adriaenssens, Elias and Mullen, Patrick and Wiencek, Patrick and Hardies, Katia and Lee, Jeong-Soo and Giong, Hoi-Khoanh and Distelmaier, Felix and Elpeleg, Orly and Helbig, Katherine L and Hersh, Joseph and Isikay, Sedat and Jordan, Elizabeth and Karaca, Ender and Kecskes, Angela and Lupski, James R and Kovacs-Nagy, Reka and May, Patrick and Narayanan, Vinodh and Pendziwiat, Manuela and Ramsey, Keri and Rangasamy, Sampathkumar and Shinde, Deepali N and Spiegel, Ronen and Timmerman, Vincent and von Spiczak, Sarah and Helbig, Ingo and Weckhuysen, Sarah and Francklyn, Christopher and Antonellis, Anthony and de Witte, Peter and De Jonghe, Peter} } @article {575, title = {De Novo SOX4 Variants Cause a Neurodevelopmental Disease Associated with Mild Dysmorphism.}, journal = {Am J Hum Genet}, volume = {104}, year = {2019}, month = {2019 02 07}, pages = {246-259}, abstract = {

SOX4, together with SOX11 and SOX12, forms group C of SRY-related (SOX) transcription factors. They play key roles, often in redundancy, in multiple developmental pathways, including neurogenesis and skeletogenesis. De novo SOX11 heterozygous mutations have been shown to cause intellectual disability, growth deficiency, and dysmorphic features compatible with mild Coffin-Siris syndrome. Using trio-based exome sequencing, we here identify de novo SOX4 heterozygous missense variants in four children who share developmental delay, intellectual disability, and mild facial and digital morphological abnormalities. SOX4 is highly expressed in areas of active neurogenesis in human fetuses, and sox4 knockdown in Xenopus embryos diminishes brain and whole-body size. The SOX4 variants cluster in the highly conserved, SOX family-specific HMG domain, but each alters a different residue. In silico tools predict that each variant affects a distinct structural feature of this DNA-binding domain, and functional assays demonstrate that these SOX4 proteins carrying these variants are unable to bind DNA in~vitro and transactivate SOX reporter genes in cultured cells. These variants are not found in the gnomAD database of individuals with presumably normal development, but 12 other SOX4 HMG-domain missense variants~are recorded and all demonstrate partial to full activity in the reporter assay. Taken together, these findings point to specific SOX4 HMG-domain missense variants as the cause of a characteristic human neurodevelopmental disorder associated with mild facial and digital dysmorphism.

}, keywords = {Abnormalities, Multiple, Amino Acid Sequence, Animals, Child, Child, Preschool, Coffin-Lowry Syndrome, Cohort Studies, Conserved Sequence, DNA, Female, Heterozygote, HMG-Box Domains, Humans, Male, Mutation, Missense, Neurodevelopmental Disorders, SOXC Transcription Factors, Transcriptional Activation, Xenopus}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.12.014}, author = {Zawerton, Ash and Yao, Baojin and Yeager, J Paige and Pippucci, Tommaso and Haseeb, Abdul and Smith, Joshua D and Wischmann, Lisa and K{\"u}hl, Susanne J and Dean, John C S and Pilz, Daniela T and Holder, Susan E and McNeill, Alisdair and Graziano, Claudio and Lefebvre, V{\'e}ronique} } @article {494, title = {A homozygous founder mutation in associates with a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features.}, journal = {J Med Genet}, volume = {55}, year = {2018}, month = {2018 01}, pages = {48-54}, abstract = {

BACKGROUND: Transport protein particle (TRAPP) is a multisubunit complex that regulates membrane trafficking through the Golgi apparatus. The clinical phenotype associated with mutations in various TRAPP subunits has allowed elucidation of their functions in specific tissues. The role of some subunits in human disease, however, has not been fully established, and their functions remain uncertain.

OBJECTIVE: We aimed to expand the range of neurodevelopmental disorders associated with mutations in TRAPP subunits by exome sequencing of consanguineous families.

METHODS: Linkage and homozygosity mapping and candidate gene analysis were used to identify homozygous mutations in families. Patient fibroblasts were used to study splicing defect and zebrafish to model the disease.

RESULTS: We identified six individuals from three unrelated families with a founder homozygous splice mutation in , encoding a core subunit of the complex TRAPP I. Patients manifested a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features, and showed splicing defect. Zebrafish morphants replicated the human phenotype, displaying decreased head size and neuronal hyperexcitability, leading to a lower seizure threshold.

CONCLUSION: This study provides clinical and functional evidence of the role of in brain development and function.

}, keywords = {Animals, Autistic Disorder, Epilepsy, Founder Effect, Genetic Association Studies, Homozygote, Humans, Microcephaly, Mutation, Neurodevelopmental Disorders, Phenotype, Vesicular Transport Proteins, Zebrafish}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2017-104627}, author = {Marin-Valencia, Isaac and Novarino, Gaia and Johansen, Anide and Rosti, Basak and Issa, Mahmoud Y and Musaev, Damir and Bhat, Gifty and Scott, Eric and Silhavy, Jennifer L and Stanley, Valentina and Rosti, Rasim O and Gleeson, Jeremy W and Imam, Farhad B and Zaki, Maha S and Gleeson, Joseph G} } @article {498, title = {Novel candidate genes and variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability.}, journal = {Hum Genet}, volume = {137}, year = {2018}, month = {2018 Sep}, pages = {735-752}, abstract = {

Identification of Mendelian genes for neurodevelopmental disorders using exome sequencing to study autosomal recessive (AR) consanguineous pedigrees has been highly successful. To identify causal variants for syndromic and non-syndromic intellectual disability (ID), exome sequencing was performed using DNA samples from 22 consanguineous Pakistani families with ARID, of which 21 have additional phenotypes including microcephaly. To aid in variant identification, homozygosity mapping and linkage analysis were performed. DNA samples from affected family member(s) from every pedigree underwent exome sequencing. Identified rare damaging exome variants were tested for co-segregation with ID using Sanger sequencing. For seven ARID families, variants were identified in genes not previously associated with ID, including: EI24, FXR1 and TET3 for which knockout mouse models have brain defects; and CACNG7 and TRAPPC10 where cell studies suggest roles in important neural pathways. For two families, the novel ARID genes CARNMT1 and GARNL3 lie within previously reported ID microdeletion regions. We also observed homozygous variants in two ID candidate genes, GRAMD1B and TBRG1, for which each has been previously reported in a single family. An additional 14 families have homozygous variants in established ID genes, of which 11 variants are novel. All ARID genes have increased expression in specific structures of the developing and adult human brain and 91\% of the genes are differentially expressed in utero or during early childhood. The identification of novel ARID candidate genes and variants adds to the knowledge base that is required to further understand human brain function and development.

}, keywords = {Adult, Consanguinity, Family, Female, Genes, Recessive, Genetic Markers, Humans, Intellectual Disability, Male, Middle Aged, Mutation, Neurodevelopmental Disorders, Pedigree}, issn = {1432-1203}, doi = {10.1007/s00439-018-1928-6}, author = {Santos-Cortez, Regie Lyn P and Khan, Valeed and Khan, Falak Sher and Mughal, Zaib-Un-Nisa and Chakchouk, Imen and Lee, Kwanghyuk and Rasheed, Memoona and Hamza, Rifat and Acharya, Anushree and Ullah, Ehsan and Saqib, Muhammad Arif Nadeem and Abbe, Izoduwa and Ali, Ghazanfar and Hassan, Muhammad Jawad and Khan, Saadullah and Azeem, Zahid and Ullah, Irfan and Bamshad, Michael J and Nickerson, Deborah A and Schrauwen, Isabelle and Ahmad, Wasim and Ansar, Muhammad and Leal, Suzanne M} } @article {335, title = {De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder.}, journal = {Am J Hum Genet}, volume = {100}, year = {2017}, month = {2017 Feb 02}, pages = {352-363}, abstract = {

Degradation of proteins by the ubiquitin-proteasome system (UPS) is an essential biological process in the development of eukaryotic organisms. Dysregulation of this mechanism leads to numerous human neurodegenerative or neurodevelopmental disorders. Through a multi-center collaboration, we identified six de novo genomic deletions and four de novo point mutations involving PSMD12, encoding the non-ATPase subunit PSMD12 (aka RPN5) of the 19S regulator of 26S proteasome complex, in unrelated individuals with intellectual disability, congenital malformations, ophthalmologic anomalies, feeding difficulties, deafness, and subtle dysmorphic facial features. We observed reduced PSMD12 levels and an accumulation of ubiquitinated proteins without any impairment of proteasome catalytic activity. Our PSMD12 loss-of-function zebrafish CRISPR/Cas9 model exhibited microcephaly, decreased convolution of the renal tubules, and abnormal craniofacial morphology. Our data support the biological importance of PSMD12 as a scaffolding subunit in proteasome function during development and neurogenesis in particular; they enable the definition of a neurodevelopmental disorder due to PSMD12 variants, expanding the phenotypic spectrum of UPS-dependent disorders.

}, keywords = {Adolescent, Animals, Child, Child, Preschool, Disease Models, Animal, DNA Copy Number Variations, Down-Regulation, Female, Gene Deletion, Humans, Infant, Intellectual Disability, Male, Microcephaly, Neurodevelopmental Disorders, Polymorphism, Single Nucleotide, Proteasome Endopeptidase Complex, Zebrafish}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.01.003}, author = {K{\"u}ry, S{\'e}bastien and Besnard, Thomas and Ebstein, Fr{\'e}d{\'e}ric and Khan, Tahir N and Gambin, Tomasz and Douglas, Jessica and Bacino, Carlos A and Craigen, William J and Sanders, Stephan J and Lehmann, Andrea and Latypova, X{\'e}nia and Khan, Kamal and Pacault, Mathilde and Sacharow, Stephanie and Glaser, Kimberly and Bieth, Eric and Perrin-Sabourin, Laurence and Jacquemont, Marie-Line and Cho, Megan T and Roeder, Elizabeth and Denomm{\'e}-Pichon, Anne-Sophie and Monaghan, Kristin G and Yuan, Bo and Xia, Fan and Simon, Sylvain and Bonneau, Dominique and Parent, Philippe and Gilbert-Dussardier, Brigitte and Odent, Sylvie and Toutain, Annick and Pasquier, Laurent and Barbouth, Deborah and Shaw, Chad A and Patel, Ankita and Smith, Janice L and Bi, Weimin and Schmitt, S{\'e}bastien and Deb, Wallid and Nizon, Mathilde and Mercier, Sandra and Vincent, Marie and Rooryck, Caroline and Malan, Val{\'e}rie and Brice{\~n}o, Ignacio and G{\'o}mez, Alberto and Nugent, Kimberly M and Gibson, James B and Cogn{\'e}, Benjamin and Lupski, James R and Stessman, Holly A F and Eichler, Evan E and Retterer, Kyle and Yang, Yaping and Redon, Richard and Katsanis, Nicholas and Rosenfeld, Jill A and Kloetzel, Peter-Michael and Golzio, Christelle and B{\'e}zieau, St{\'e}phane and Stankiewicz, Pawe{\l} and Isidor, Bertrand} } @article {633, title = {De novo mutations in HNRNPU result in a neurodevelopmental syndrome.}, journal = {Am J Med Genet A}, volume = {173}, year = {2017}, month = {2017 Nov}, pages = {3003-3012}, abstract = {

Exome sequencing in the context of developmental disorders is a useful technique, but variants found need to be interpreted in the context of detailed phenotypic information. Whole gene deletions and loss-of-function-mutations in the HNRNPU gene have been associated with intellectual disability and seizures in some patients. However, a unifying syndromic phenotype has not been previously elucidated. Here, we report a total of seven patients (six patients identified through the Wellcome Trust Deciphering Developmental Disorders study, with one additional patient), who have heterozygous de novo mutations in HNRNPU. These were found via trio-based exome sequencing. All but one of the mutations is predicted to cause loss-of-function. These patients have dysmorphic features in common, including prominent eyebrows, long palpebral fissures, overhanging columella, and thin upper lip. All patients have developmental delay and intellectual disability (ID), ranging from moderate to severe. Seizures are common from early childhood. These initially occur in the context of febrile episodes. This series demonstrates common phenotypic features, including emerging dysmorphism, associated with heterozygous HNRNPU mutations. This allows us to define a novel neurodevelopmental syndrome, with a likely mechanism of haploinsufficiency.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Developmental Disabilities, Exome, Female, Genetic Predisposition to Disease, Haploinsufficiency, Heterogeneous-Nuclear Ribonucleoprotein U, Heterozygote, Humans, Infant, Intellectual Disability, Male, Mutation, Neurodevelopmental Disorders, Phenotype, Seizures, Young Adult}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38492}, author = {Yates, T Michael and Vasudevan, Pradeep C and Chandler, Kate E and Donnelly, Deirdre E and Stark, Zornitza and Sadedin, Simon and Willoughby, Josh and Balasubramanian, Meena} } @article {376, title = {Identification of novel candidate disease genes from de novo exonic copy number variants.}, journal = {Genome Med}, volume = {9}, year = {2017}, month = {2017 09 21}, pages = {83}, abstract = {

BACKGROUND: Exon-targeted microarrays can detect small (<1000~bp) intragenic copy number variants (CNVs), including those that affect only a single exon. This genome-wide high-sensitivity approach increases the molecular diagnosis for conditions with known disease-associated genes, enables better genotype-phenotype correlations, and facilitates variant allele detection allowing novel disease gene discovery.

METHODS: We retrospectively analyzed data from 63,127 patients referred for clinical chromosomal microarray analysis (CMA) at Baylor Genetics laboratories, including 46,755 individuals tested using exon-targeted arrays, from 2007 to 2017. Small CNVs harboring a single gene or two to five non-disease-associated genes were identified; the genes involved were evaluated for a potential disease association.

RESULTS: In this clinical population, among rare CNVs involving any single gene reported in 7200 patients (11\%), we identified 145 de novo autosomal CNVs (117 losses and 28 intragenic gains), 257 X-linked deletion CNVs in males, and 1049 inherited autosomal CNVs (878 losses and 171 intragenic gains); 111 known disease genes were potentially disrupted by de novo autosomal or X-linked (in males) single-gene CNVs. Ninety-one genes, either recently proposed as candidate disease genes or not yet associated with diseases, were disrupted by 147 single-gene CNVs, including 37 de novo deletions and ten de novo intragenic duplications on autosomes and 100 X-linked CNVs in males. Clinical features in individuals with de novo or X-linked CNVs encompassing at most five genes (224~bp to 1.6~Mb in size) were compared to those in individuals with larger-sized deletions (up to 5~Mb in size) in the internal CMA database or loss-of-function single nucleotide variants (SNVs) detected by clinical or research whole-exome sequencing (WES). This enabled the identification of recently published genes (BPTF, NONO, PSMD12, TANGO2, and TRIP12), novel candidate disease genes (ARGLU1 and STK3), and further confirmation of disease association for two recently proposed disease genes (MEIS2 and PTCHD1). Notably, exon-targeted CMA detected several pathogenic single-exon CNVs missed by clinical WES analyses.

CONCLUSIONS: Together, these data document the efficacy of exon-targeted CMA for detection of genic and exonic CNVs, complementing and extending WES in clinical diagnostics, and the potential for discovery of novel disease genes by genome-wide assay.

}, keywords = {Cohort Studies, DNA Copy Number Variations, Exons, Genetic Diseases, Inborn, Genome, Human, Homeodomain Proteins, Humans, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Neurodevelopmental Disorders, Protein-Serine-Threonine Kinases, Retrospective Studies, Transcription Factors, Whole Genome Sequencing}, issn = {1756-994X}, doi = {10.1186/s13073-017-0472-7}, author = {Gambin, Tomasz and Yuan, Bo and Bi, Weimin and Liu, Pengfei and Rosenfeld, Jill A and Coban-Akdemir, Zeynep and Pursley, Amber N and Nagamani, Sandesh C S and Marom, Ronit and Golla, Sailaja and Dengle, Lauren and Petrie, Heather G and Matalon, Reuben and Emrick, Lisa and Proud, Monica B and Treadwell-Deering, Diane and Chao, Hsiao-Tuan and Koillinen, Hannele and Brown, Chester and Urraca, Nora and Mostafavi, Roya and Bernes, Saunder and Roeder, Elizabeth R and Nugent, Kimberly M and Bader, Patricia I and Bellus, Gary and Cummings, Michael and Northrup, Hope and Ashfaq, Myla and Westman, Rachel and Wildin, Robert and Beck, Anita E and Immken, LaDonna and Elton, Lindsay and Varghese, Shaun and Buchanan, Edward and Faivre, Laurence and Lefebvre, Mathilde and Schaaf, Christian P and Walkiewicz, Magdalena and Yang, Yaping and Kang, Sung-Hae L and Lalani, Seema R and Bacino, Carlos A and Beaudet, Arthur L and Breman, Amy M and Smith, Janice L and Cheung, Sau Wai and Lupski, James R and Patel, Ankita and Shaw, Chad A and Stankiewicz, Pawe{\l}} } @article {338, title = {Mutations in EBF3 Disturb Transcriptional Profiles and Cause Intellectual Disability, Ataxia, and Facial Dysmorphism.}, journal = {Am J Hum Genet}, volume = {100}, year = {2017}, month = {2017 Jan 05}, pages = {117-127}, abstract = {

From a GeneMatcher-enabled international collaboration, we identified ten individuals affected by intellectual disability, speech delay, ataxia, and facial dysmorphism and carrying a deleterious EBF3 variant detected by whole-exome sequencing. One 9-bp duplication and one splice-site, five missense, and two nonsense variants in EBF3 were found; the mutations occurred de novo in eight individuals, and the missense variant c.625C>T (p.Arg209Trp) was inherited by two affected siblings from their healthy mother, who is mosaic. EBF3 belongs to the early B cell factor family (also known as Olf, COE, or O/E) and is a transcription factor involved in neuronal differentiation and maturation. Structural assessment predicted that the five amino acid substitutions have damaging effects on DNA binding of EBF3. Transient expression of EBF3 mutant proteins in HEK293T cells revealed mislocalization of all but one mutant in the cytoplasm, as well as nuclear localization. By transactivation assays, all EBF3 mutants showed significantly reduced or no ability to activate transcription of the reporter gene CDKN1A, and in~situ subcellular fractionation experiments demonstrated that EBF3 mutant proteins were less tightly associated with chromatin. Finally, in RNA-seq and ChIP-seq experiments, EBF3 acted as a transcriptional regulator, and mutant EBF3 had reduced genome-wide DNA binding and gene-regulatory activity. Our findings demonstrate that variants disrupting EBF3-mediated transcriptional regulation cause intellectual disability and developmental delay and are present in \~{}0.1\% of individuals with unexplained neurodevelopmental disorders.

}, keywords = {Adolescent, Adult, Amino Acid Substitution, Ataxia, Child, Child, Preschool, Chromatin, Cyclin-Dependent Kinase Inhibitor p21, Developmental Disabilities, Exome, Face, Female, Gene Expression Regulation, Genes, Reporter, HEK293 Cells, Humans, Intellectual Disability, Language Development Disorders, Male, Models, Molecular, Mosaicism, Mutation, Neurodevelopmental Disorders, Protein Transport, Syndrome, Transcription Factors, Transcription, Genetic}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.11.012}, author = {Harms, Frederike Leonie and Girisha, Katta M and Hardigan, Andrew A and Kort{\"u}m, Fanny and Shukla, Anju and Alawi, Malik and Dalal, Ashwin and Brady, Lauren and Tarnopolsky, Mark and Bird, Lynne M and Ceulemans, Sophia and Bebin, Martina and Bowling, Kevin M and Hiatt, Susan M and Lose, Edward J and Primiano, Michelle and Chung, Wendy K and Juusola, Jane and Akdemir, Zeynep C and Bainbridge, Matthew and Charng, Wu-Lin and Drummond-Borg, Margaret and Eldomery, Mohammad K and El-Hattab, Ayman W and Saleh, Mohammed A M and B{\'e}zieau, St{\'e}phane and Cogn{\'e}, Benjamin and Isidor, Bertrand and K{\"u}ry, S{\'e}bastien and Lupski, James R and Myers, Richard M and Cooper, Gregory M and Kutsche, Kerstin} }