@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 {910, title = {Pathogenic Variants in CEP85L Cause Sporadic and Familial Posterior Predominant Lissencephaly.}, journal = {Neuron}, volume = {106}, year = {2020}, month = {2020 04 22}, pages = {237-245.e8}, abstract = {

Lissencephaly (LIS), denoting a "smooth brain," is characterized by the absence of normal cerebral convolutions with abnormalities of cortical thickness. Pathogenic variants in over 20 genes are associated with LIS. The majority of posterior predominant LIS is caused by pathogenic variants in LIS1~(also known as PAFAH1B1), although a significant fraction remains without a known genetic etiology. We now implicate CEP85L as an important cause of~posterior predominant LIS, identifying 13 individuals with rare, heterozygous CEP85L variants, including 2 families with autosomal dominant inheritance. We show that CEP85L is a centrosome protein localizing to the pericentriolar material, and knockdown of Cep85l causes a neuronal migration defect in mice. LIS1 also localizes to the centrosome, suggesting that this organelle is key to the mechanism of posterior predominant LIS.

}, keywords = {Adolescent, Adult, Age of Onset, Animals, Centrosome, Child, Child, Preschool, Chromosome Aberrations, Classical Lissencephalies and Subcortical Band Heterotopias, Cytoskeletal Proteins, Female, Gene Knockdown Techniques, Genetic Variation, Heterozygote, Humans, Infant, Magnetic Resonance Imaging, Male, Mice, Mutation, Oncogene Proteins, Fusion, Pedigree, Seizures, Young Adult}, issn = {1097-4199}, doi = {10.1016/j.neuron.2020.01.027}, author = {Tsai, Meng-Han and Muir, Alison M and Wang, Won-Jing and Kang, Yi-Ning and Yang, Kun-Chuan and Chao, Nian-Hsin and Wu, Mei-Feng and Chang, Ying-Chao and Porter, Brenda E and Jansen, Laura A and Sebire, Guillaume and Deconinck, Nicolas and Fan, Wen-Lang and Su, Shih-Chi and Chung, Wen-Hung and Almanza Fuerte, Edith P and Mehaffey, Michele G and Ng, Ching-Ching and Chan, Chung-Kin and Lim, Kheng-Seang and Leventer, Richard J and Lockhart, Paul J and Riney, Kate and Damiano, John A and Hildebrand, Michael S and Mirzaa, Ghayda M and Dobyns, William B and Berkovic, Samuel F and Scheffer, Ingrid E and Tsai, Jin-Wu and Mefford, Heather C} } @article {719, title = {Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis.}, journal = {Am J Hum Genet}, volume = {105}, year = {2019}, month = {2019 Oct 03}, pages = {689-705}, abstract = {

Sphingomyelinases generate ceramide from sphingomyelin as a second messenger in intracellular signaling pathways involved in cell proliferation, differentiation, or apoptosis. Children from 12 unrelated families presented with microcephaly, simplified gyral pattern of the cortex, hypomyelination, cerebellar hypoplasia, congenital arthrogryposis, and early fetal/postnatal demise. Genomic analysis revealed bi-allelic loss-of-function variants in SMPD4, coding for the neutral sphingomyelinase-3 (nSMase-3/SMPD4). Overexpression of human Myc-tagged SMPD4 showed localization both to the outer nuclear envelope and the ER and additionally revealed interactions with several nuclear pore complex proteins by proteomics analysis. Fibroblasts from affected individuals showed ER cisternae abnormalities, suspected for increased autophagy, and were more susceptible to apoptosis under stress conditions, while treatment with siSMPD4 caused delayed cell cycle progression. Our data show that SMPD4 links homeostasis of membrane sphingolipids to cell fate by regulating the cross-talk between the ER and the outer nuclear envelope, while its loss reveals a pathogenic mechanism in microcephaly.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.08.006}, author = {Magini, Pamela and Smits, Daphne J and Vandervore, Laura and Schot, Rachel and Columbaro, Marta and Kasteleijn, Esmee and van der Ent, Mees and Palombo, Flavia and Lequin, Maarten H and Dremmen, Marjolein and de Wit, Marie Claire Y and Severino, Mariasavina and Divizia, Maria Teresa and Striano, Pasquale and Ordonez-Herrera, Natalia and Alhashem, Amal and Al Fares, Ahmed and Al Ghamdi, Malak and Rolfs, Arndt and Bauer, Peter and Demmers, Jeroen and Verheijen, Frans W and Wilke, Martina and van Slegtenhorst, Marjon and van der Spek, Peter J and Seri, Marco and Jansen, Anna C and Stottmann, Rolf W and Hufnagel, Robert B and Hopkin, Robert J and Aljeaid, Deema and Wiszniewski, Wojciech and Gawlinski, Pawel and Laure-Kamionowska, Milena and Alkuraya, Fowzan S and Akleh, Hanah and Stanley, Valentina and Musaev, Damir and Gleeson, Joseph G and Zaki, Maha S and Brunetti-Pierri, Nicola and Cappuccio, Gerarda and Davidov, Bella and Basel-Salmon, Lina and Bazak, Lily and Shahar, Noa Ruhrman and Bertoli-Avella, Aida and Mirzaa, Ghayda M and Dobyns, William B and Pippucci, Tommaso and Fornerod, Maarten and Mancini, Grazia M S} } @article {740, title = {Mutations in ANKLE2, a ZIKA Virus Target, Disrupt an Asymmetric Cell Division Pathway in Drosophila Neuroblasts to Cause Microcephaly.}, journal = {Dev Cell}, volume = {51}, year = {2019}, month = {2019 Dec 16}, pages = {713-729.e6}, abstract = {

The apical Par complex, which contains atypical protein kinase C (aPKC), Bazooka (Par-3), and Par-6, is required for establishing polarity during asymmetric division of neuroblasts in Drosophila, and its activity depends on L(2)gl. We show that loss of Ankle2, a protein associated with microcephaly in humans and known to interact with Zika protein NS4A, reduces brain volume in flies and impacts the function of the Par complex. Reducing Ankle2 levels disrupts endoplasmic reticulum (ER) and nuclear envelope morphology, releasing the kinase Ballchen-VRK1 into the cytosol. These defects are associated with reduced phosphorylation of aPKC, disruption of Par-complex localization, and spindle alignment defects. Importantly, removal of one copy of ballchen or l(2)gl suppresses Ankle2 mutant phenotypes and restores viability and brain size. Human mutational studies implicate the above-mentioned genes in microcephaly and motor neuron disease. We suggest that NS4A, ANKLE2, VRK1, and LLGL1 define a pathway impinging on asymmetric determinants of neural stem cell division.

}, issn = {1878-1551}, doi = {10.1016/j.devcel.2019.10.009}, author = {Link, Nichole and Chung, Hyunglok and Jolly, Angad and Withers, Marjorie and Tepe, Burak and Arenkiel, Benjamin R and Shah, Priya S and Krogan, Nevan J and Aydin, Hatip and Geckinli, Bilgen B and Tos, Tulay and Isikay, Sedat and Tuysuz, Beyhan and Mochida, Ganesh H and Thomas, Ajay X and Clark, Robin D and Mirzaa, Ghayda M and Lupski, James R and Bellen, Hugo J} } @article {685, title = {Redefining the Etiologic Landscape of Cerebellar Malformations.}, journal = {Am J Hum Genet}, volume = {105}, year = {2019}, month = {2019 Sep 05}, pages = {606-615}, abstract = {

Cerebellar malformations are diverse congenital anomalies frequently associated with developmental disability. Although genetic and prenatal non-genetic causes have been described, no systematic analysis has been performed. Here, we present a large-exome sequencing study of Dandy-Walker malformation (DWM) and cerebellar hypoplasia (CBLH). We performed exome sequencing in 282 individuals from 100 families with DWM or CBLH, and we established a molecular diagnosis in 36 of 100 families, with a significantly higher yield for CBLH (51\%) than for DWM (16\%). The 41 variants impact 27 neurodevelopmental-disorder-associated genes, thus demonstrating that CBLH and DWM are often features of monogenic neurodevelopmental disorders. Though only seven monogenic causes (19\%) were identified in more than one individual, neuroimaging review of 131 additional individuals confirmed cerebellar abnormalities in 23 of 27 genetic disorders (85\%). Prenatal risk factors were frequently found among individuals without a genetic diagnosis (30 of 64 individuals [47\%]). Single-cell RNA sequencing of prenatal human cerebellar tissue revealed gene enrichment in neuronal and vascular cell types; this suggests that defective vasculogenesis may disrupt cerebellar development. Further, de novo gain-of-function variants in PDGFRB, a tyrosine kinase receptor essential for vascular progenitor signaling, were associated with CBLH, and this discovery links genetic and non-genetic etiologies. Our results suggest that genetic defects impact specific cerebellar cell types and implicate abnormal vascular development as a mechanism for cerebellar malformations. We also confirmed a major contribution for non-genetic prenatal factors in individuals with cerebellar abnormalities, substantially influencing diagnostic evaluation and counseling regarding recurrence risk and prognosis.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.07.019}, author = {Aldinger, Kimberly A and Timms, Andrew E and Thomson, Zachary and Mirzaa, Ghayda M and Bennett, James T and Rosenberg, Alexander B and Roco, Charles M and Hirano, Matthew and Abidi, Fatima and Haldipur, Parthiv and Cheng, Chi V and Collins, Sarah and Park, Kaylee and Zeiger, Jordan and Overmann, Lynne M and Alkuraya, Fowzan S and Biesecker, Leslie G and Braddock, Stephen R and Cathey, Sara and Cho, Megan T and Chung, Brian H Y and Everman, David B and Zarate, Yuri A and Jones, Julie R and Schwartz, Charles E and Goldstein, Amy and Hopkin, Robert J and Krantz, Ian D and Ladda, Roger L and Leppig, Kathleen A and McGillivray, Barbara C and Sell, Susan and Wusik, Katherine and Gleeson, Joseph G and Nickerson, Deborah A and Bamshad, Michael J and Gerrelli, Dianne and Lisgo, Steven N and Seelig, Georg and Ishak, Gisele E and Barkovich, A James and Curry, Cynthia J and Glass, Ian A and Millen, Kathleen J and Doherty, Dan and Dobyns, William B} } @article {614, title = {Analysis of 17 genes detects mutations in 81\% of 811 patients with lissencephaly.}, journal = {Genet Med}, volume = {20}, year = {2018}, month = {2018 11}, pages = {1354-1364}, abstract = {

PURPOSE: To estimate diagnostic yield and genotype-phenotype correlations in a cohort of 811 patients with lissencephaly or subcortical band heterotopia.

METHODS: We collected DNA from 756 children with lissencephaly over 30 years. Many were tested for deletion 17p13.3 and mutations of LIS1, DCX, and ARX, but few other genes. Among those tested, 216 remained unsolved and were tested by a targeted panel of 17 genes (ACTB, ACTG1, ARX, CRADD, DCX, LIS1, TUBA1A, TUBA8, TUBB2B, TUBB, TUBB3, TUBG1, KIF2A, KIF5C, DYNC1H1, RELN, and VLDLR) or by whole-exome sequencing. Fifty-five patients studied at another institution were added as a validation cohort.

RESULTS: The overall mutation frequency in the entire cohort was 81\%. LIS1 accounted for 40\% of patients, followed by DCX (23\%), TUBA1A (5\%), and DYNC1H1 (3\%). Other genes accounted for 1\% or less of patients. Nineteen percent remained unsolved, which suggests that several additional genes remain to be discovered. The majority of unsolved patients had posterior pachygyria, subcortical band heterotopia, or mild frontal pachygyria.

CONCLUSION: The brain-imaging pattern correlates with mutations in single lissencephaly-associated genes, as well as in biological pathways. We propose the first LIS classification system based on the underlying molecular mechanisms.

}, keywords = {Brain, Classical Lissencephalies and Subcortical Band Heterotopias, DNA Mutational Analysis, Female, Genetic Association Studies, Humans, Lissencephaly, Male, Mutation, Whole Exome Sequencing}, issn = {1530-0366}, doi = {10.1038/gim.2018.8}, author = {Di Donato, Nataliya and Timms, Andrew E and Aldinger, Kimberly A and Mirzaa, Ghayda M and Bennett, James T and Collins, Sarah and Olds, Carissa and Mei, Davide and Chiari, Sara and Carvill, Gemma and Myers, Candace T and Rivi{\`e}re, Jean-Baptiste and Zaki, Maha S and Gleeson, Joseph G and Rump, Andreas and Conti, Valerio and Parrini, Elena and Ross, M Elizabeth and Ledbetter, David H and Guerrini, Renzo and Dobyns, William B} } @article {543, title = {Functional Dysregulation of CDC42 Causes Diverse Developmental Phenotypes.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 Feb 01}, pages = {309-320}, abstract = {

Exome sequencing has markedly enhanced the discovery of genes implicated in Mendelian disorders, particularly for individuals in whom a known clinical entity could not be assigned. This has led to the recognition that phenotypic heterogeneity resulting from allelic mutations occurs more commonly than previously appreciated. Here, we report that missense variants in CDC42, a gene encoding a small GTPase functioning as an intracellular signaling node, underlie a clinically heterogeneous group of phenotypes characterized by variable growth dysregulation, facial dysmorphism, and neurodevelopmental, immunological, and hematological anomalies, including a phenotype resembling Noonan syndrome, a developmental disorder caused by dysregulated RAS signaling. In silico, in~vitro, and in~vivo analyses demonstrate that mutations variably perturb CDC42 function by altering the switch between the active and inactive states of the GTPase and/or affecting CDC42 interaction with effectors, and differentially disturb cellular and developmental processes. These findings reveal the remarkably variable impact that dominantly acting CDC42 mutations have on cell function and development, creating challenges in syndrome definition, and exemplify the importance of functional profiling for syndrome recognition and delineation.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.12.015}, author = {Martinelli, Simone and Krumbach, Oliver H F and Pantaleoni, Francesca and Coppola, Simona and Amin, Ehsan and Pannone, Luca and Nouri, Kazem and Farina, Luciapia and Dvorsky, Radovan and Lepri, Francesca and Buchholzer, Marcel and Konopatzki, Raphael and Walsh, Laurence and Payne, Katelyn and Pierpont, Mary Ella and Vergano, Samantha Schrier and Langley, Katherine G and Larsen, Douglas and Farwell, Kelly D and Tang, Sha and Mroske, Cameron and Gallotta, Ivan and Di Schiavi, Elia and Della Monica, Matteo and Lugli, Licia and Rossi, Cesare and Seri, Marco and Cocchi, Guido and Henderson, Lindsay and Baskin, Berivan and Alders, Marielle and Mendoza-Londono, Roberto and Dupuis, Lucie and Nickerson, Deborah A and Chong, Jessica X and Meeks, Naomi and Brown, Kathleen and Causey, Tahnee and Cho, Megan T and Demuth, Stephanie and Digilio, Maria Cristina and Gelb, Bruce D and Bamshad, Michael J and Zenker, Martin and Ahmadian, Mohammad Reza and Hennekam, Raoul C and Tartaglia, Marco and Mirzaa, Ghayda M} } @article {558, title = {MACF1 Mutations Encoding Highly Conserved Zinc-Binding Residues of the GAR Domain Cause Defects in Neuronal Migration and Axon Guidance.}, journal = {Am J Hum Genet}, volume = {103}, year = {2018}, month = {2018 12 06}, pages = {1009-1021}, abstract = {

To date, mutations in 15 actin- or microtubule-associated genes have been associated with the cortical malformation lissencephaly and variable brainstem hypoplasia. During a multicenter review, we recognized a rare lissencephaly variant with a complex brainstem malformation in three unrelated children. We searched our large brain-malformation databases and found another five children with this malformation (as well as one with a less severe variant), analyzed available whole-exome or -genome sequencing data, and tested ciliogenesis in two affected individuals. The brain malformation comprised posterior predominant lissencephaly and midline crossing defects consisting of absent anterior commissure and a striking W-shaped brainstem malformation caused by small or absent pontine crossing fibers. We discovered heterozygous de novo missense variants or an in-frame deletion involving highly conserved zinc-binding residues within the GAR domain of MACF1 in the first eight subjects. We studied cilium formation and found a higher proportion of mutant cells with short cilia than of control cells with short cilia. A ninth child had similar lissencephaly but~only subtle brainstem dysplasia associated with a heterozygous de novo missense variant in the spectrin repeat domain of MACF1. Thus, we report variants of the microtubule-binding GAR domain of MACF1 as the cause of a distinctive and most likely pathognomonic brain malformation. A~gain-of-function or dominant-negative mechanism appears likely given that many heterozygous mutations leading to protein truncation are included in the ExAC Browser. However, three de novo variants in MACF1 have been observed in large schizophrenia cohorts.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.10.019}, author = {Dobyns, William B and Aldinger, Kimberly A and Ishak, Gisele E and Mirzaa, Ghayda M and Timms, Andrew E and Grout, Megan E and Dremmen, Marjolein H G and Schot, Rachel and Vandervore, Laura and van Slegtenhorst, Marjon A and Wilke, Martina and Kasteleijn, Esmee and Lee, Arthur S and Barry, Brenda J and Chao, Katherine R and Szcza{\l}uba, Krzysztof and Kobori, Joyce and Hanson-Kahn, Andrea and Bernstein, Jonathan A and Carr, Lucinda and D{\textquoteright}Arco, Felice and Miyana, Kaori and Okazaki, Tetsuya and Saito, Yoshiaki and Sasaki, Masayuki and Das, Soma and Wheeler, Marsha M and Bamshad, Michael J and Nickerson, Deborah A and Engle, Elizabeth C and Verheijen, Frans W and Doherty, Dan and Mancini, Grazia M S} } @article {58, title = {Association of MTOR Mutations With Developmental Brain Disorders, Including Megalencephaly, Focal Cortical Dysplasia, and Pigmentary Mosaicism.}, journal = {JAMA Neurol}, volume = {73}, year = {2016}, month = {2016 07 01}, pages = {836-845}, abstract = {

IMPORTANCE: Focal cortical dysplasia (FCD), hemimegalencephaly, and megalencephaly constitute a spectrum of malformations of cortical development with shared neuropathologic features. These disorders are associated with significant childhood morbidity and mortality.

OBJECTIVE: To identify the underlying molecular cause of FCD, hemimegalencephaly, and diffuse megalencephaly.

DESIGN, SETTING, AND PARTICIPANTS: Patients with FCD, hemimegalencephaly, or megalencephaly (mean age, 11.7 years; range, 2-32 years) were recruited from Pediatric Hospital A. Meyer, the University of Hong Kong, and Seattle Children{\textquoteright}s Research Institute from June 2012 to June 2014. Whole-exome sequencing (WES) was performed on 8 children with FCD or hemimegalencephaly using standard-depth (50-60X) sequencing in peripheral samples (blood, saliva, or skin) from the affected child and their parents and deep (150-180X) sequencing in affected brain tissue. Targeted sequencing and WES were used to screen 93 children with molecularly unexplained diffuse or focal brain overgrowth. Histopathologic and functional assays of phosphatidylinositol 3-kinase-AKT (serine/threonine kinase)-mammalian target of rapamycin (mTOR) pathway activity in resected brain tissue and cultured neurons were performed to validate mutations.

MAIN OUTCOMES AND MEASURES: Whole-exome sequencing and targeted sequencing identified variants associated with this spectrum of developmental brain disorders.

RESULTS: Low-level mosaic mutations of MTOR were identified in brain tissue in 4 children with FCD type 2a with alternative allele fractions ranging from 0.012 to 0.086. Intermediate-level mosaic mutation of MTOR (p.Thr1977Ile) was also identified in 3 unrelated children with diffuse megalencephaly and pigmentary mosaicism in skin. Finally, a constitutional de novo mutation of MTOR (p.Glu1799Lys) was identified in 3 unrelated children with diffuse megalencephaly and intellectual disability. Molecular and functional analysis in 2 children with FCD2a from whom multiple affected brain tissue samples were available revealed a mutation gradient with an epicenter in the most epileptogenic area. When expressed in cultured neurons, all MTOR mutations identified here drive constitutive activation of mTOR complex 1 and enlarged neuronal size.

CONCLUSIONS AND RELEVANCE: In this study, mutations of MTOR were associated with a spectrum of brain overgrowth phenotypes extending from FCD type 2a to diffuse megalencephaly, distinguished by different mutations and levels of mosaicism. These mutations may be sufficient to cause cellular hypertrophy in cultured neurons and may provide a demonstration of the pattern of mosaicism in brain and substantiate the link between mosaic mutations of MTOR and pigmentary mosaicism in skin.

}, keywords = {Adolescent, Adult, Amino Acids, Animals, Cells, Cultured, Cerebral Cortex, Child, Child, Preschool, Developmental Disabilities, Embryo, Mammalian, Female, Gene Expression Regulation, Genetic Association Studies, Humans, Intercellular Signaling Peptides and Proteins, Male, Malformations of Cortical Development, Mechanistic Target of Rapamycin Complex 1, Megalencephaly, Mosaicism, Multiprotein Complexes, Mutation, Nerve Tissue Proteins, Neurons, Rats, Retrospective Studies, TOR Serine-Threonine Kinases, Young Adult}, issn = {2168-6157}, doi = {10.1001/jamaneurol.2016.0363}, author = {Mirzaa, Ghayda M and Campbell, Catarina D and Solovieff, Nadia and Goold, Carleton and Jansen, Laura A and Menon, Suchithra and Timms, Andrew E and Conti, Valerio and Biag, Jonathan D and Adams, Carissa and Boyle, Evan August and Collins, Sarah and Ishak, Gisele and Poliachik, Sandra and Girisha, Katta M and Yeung, Kit San and Chung, Brian Hon Yin and Rahikkala, Elisa and Gunter, Sonya A and McDaniel, Sharon S and Macmurdo, Colleen Forsyth and Bernstein, Jonathan A and Martin, Beth and Leary, Rebecca and Mahan, Scott and Liu, Shanming and Weaver, Molly and Doerschner, Michael and Jhangiani, Shalini and Muzny, Donna M and Boerwinkle, Eric and Gibbs, Richard A and Lupski, James R and Shendure, Jay and Saneto, Russell P and Novotny, Edward J and Wilson, Christopher J and Sellers, William R and Morrissey, Michael and Hevner, Robert F and Ojemann, Jeffrey G and Guerrini, Renzo and Murphy, Leon O and Winckler, Wendy and Dobyns, William B} }