@article {912, title = {Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.}, journal = {Genet Med}, volume = {22}, year = {2020}, month = {2020 07}, pages = {1215-1226}, abstract = {

PURPOSE: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts.

METHODS: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts.

RESULTS: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts.

CONCLUSION: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies.

}, keywords = {Exome, Germ Cells, Humans, Intellectual Disability, Mutation, Missense, Phenotype, Transcriptome, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins}, issn = {1530-0366}, doi = {10.1038/s41436-020-0792-7}, author = {Castilla-Vallmanya, Laura and Selmer, Kaja K and Dimartino, Cl{\'e}mantine and Rabionet, Raquel and Blanco-S{\'a}nchez, Bernardo and Yang, Sandra and Reijnders, Margot R F and van Essen, Antonie J and Oufadem, Myriam and Vigeland, Magnus D and Stadheim, Barbro and Houge, Gunnar and Cox, Helen and Kingston, Helen and Clayton-Smith, Jill and Innis, Jeffrey W and Iascone, Maria and Cereda, Anna and Gabbiadini, Sara and Chung, Wendy K and Sanders, Victoria and Charrow, Joel and Bryant, Emily and Millichap, John and Vitobello, Antonio and Thauvin, Christel and Mau-Them, Frederic Tran and Faivre, Laurence and Lesca, Gaetan and Labalme, Audrey and Rougeot, Christelle and Chatron, Nicolas and Sanlaville, Damien and Christensen, Katherine M and Kirby, Amelia and Lewandowski, Raymond and Gannaway, Rachel and Aly, MAH and Lehman, Anna and Clarke, Lorne and Graul-Neumann, Luitgard and Zweier, Christiane and Lessel, Davor and Lozic, Bernarda and Aukrust, Ingvild and Peretz, Ryan and Stratton, Robert and Smol, Thomas and Dieux-Co{\"e}slier, Anne and Meira, Joanna and Wohler, Elizabeth and Sobreira, Nara and Beaver, Erin M and Heeley, Jennifer and Briere, Lauren C and High, Frances A and Sweetser, David A and Walker, Melissa A and Keegan, Catherine E and Jayakar, Parul and Shinawi, Marwan and Kerstjens-Frederikse, Wilhelmina S and Earl, Dawn L and Siu, Victoria M and Reesor, Emma and Yao, Tony and Hegele, Robert A and Vaske, Olena M and Rego, Shannon and Shapiro, Kevin A and Wong, Brian and Gambello, Michael J and McDonald, Marie and Karlowicz, Danielle and Colombo, Roberto and Serretti, Alessandro and Pais, Lynn and O{\textquoteright}Donnell-Luria, Anne and Wray, Alison and Sadedin, Simon and Chong, Belinda and Tan, Tiong Y and Christodoulou, John and White, Susan M and Slavotinek, Anne and Barbouth, Deborah and Morel Swols, Dayna and Parisot, M{\'e}lanie and Bole-Feysot, Christine and Nitschk{\'e}, Patrick and Pingault, V{\'e}ronique and Munnich, Arnold and Cho, Megan T and Cormier-Daire, Val{\'e}rie and Balcells, Susanna and Lyonnet, Stanislas and Grinberg, Daniel and Amiel, Jeanne and Urreizti, Roser and Gordon, Christopher T} } @article {589, title = {Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability.}, journal = {Am J Hum Genet}, volume = {104}, year = {2019}, month = {2019 03 07}, pages = {530-541}, abstract = {

Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.01.010}, author = {Cogn{\'e}, Benjamin and Ehresmann, Sophie and Beauregard-Lacroix, Eliane and Rousseau, Justine and Besnard, Thomas and Garcia, Thomas and Petrovski, Slav{\'e} and Avni, Shiri and McWalter, Kirsty and Blackburn, Patrick R and Sanders, Stephan J and Uguen, K{\'e}vin and Harris, Jacqueline and Cohen, Julie S and Blyth, Moira and Lehman, Anna and Berg, Jonathan and Li, Mindy H and Kini, Usha and Joss, Shelagh and von der Lippe, Charlotte and Gordon, Christopher T and Humberson, Jennifer B and Robak, Laurie and Scott, Daryl A and Sutton, Vernon R and Skraban, Cara M and Johnston, Jennifer J and Poduri, Annapurna and Nordenskj{\"o}ld, Magnus and Shashi, Vandana and Gerkes, Erica H and Bongers, Ernie M H F and Gilissen, Christian and Zarate, Yuri A and Kvarnung, Malin and Lally, Kevin P and Kulch, Peggy A and Daniels, Brina and Hernandez-Garcia, Andres and Stong, Nicholas and McGaughran, Julie and Retterer, Kyle and Tveten, Kristian and Sullivan, Jennifer and Geisheker, Madeleine R and Stray-Pedersen, Asbjorg and Tarpinian, Jennifer M and Klee, Eric W and Sapp, Julie C and Zyskind, Jacob and Holla, {\O}ystein L and Bedoukian, Emma and Filippini, Francesca and Guimier, Anne and Picard, Arnaud and Busk, {\O}yvind L and Punetha, Jaya and Pfundt, Rolph and Lindstrand, Anna and Nordgren, Ann and Kalb, Fayth and Desai, Megha and Ebanks, Ashley Harmon and Jhangiani, Shalini N and Dewan, Tammie and Coban Akdemir, Zeynep H and Telegrafi, Aida and Zackai, Elaine H and Begtrup, Amber and Song, Xiaofei and Toutain, Annick and Wentzensen, Ingrid M and Odent, Sylvie and Bonneau, Dominique and Latypova, X{\'e}nia and Deb, Wallid and Redon, Sylvia and Bilan, Fr{\'e}d{\'e}ric and Legendre, Marine and Troyer, Caitlin and Whitlock, Kerri and Caluseriu, Oana and Murphree, Marine I and Pichurin, Pavel N and Agre, Katherine and Gavrilova, Ralitza and Rinne, Tuula and Park, Meredith and Shain, Catherine and Heinzen, Erin L and Xiao, Rui and Amiel, Jeanne and Lyonnet, Stanislas and Isidor, Bertrand and Biesecker, Leslie G and Lowenstein, Dan and Posey, Jennifer E and Denomm{\'e}-Pichon, Anne-Sophie and F{\'e}rec, Claude and Yang, Xiang-Jiao and Rosenfeld, Jill A and Gilbert-Dussardier, Brigitte and Audebert-Bellanger, S{\'e}verine and Redon, Richard and Stessman, Holly A F and Nellaker, Christoffer and Yang, Yaping and Lupski, James R and Goldstein, David B and Eichler, Evan E and Bolduc, Francois and B{\'e}zieau, St{\'e}phane and K{\"u}ry, S{\'e}bastien and Campeau, Philippe M} } @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} } @article {74, title = {Mosaic Activating Mutations in FGFR1 Cause Encephalocraniocutaneous Lipomatosis.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 Mar 03}, pages = {579-587}, abstract = {

Encephalocraniocutaneous lipomatosis (ECCL) is a sporadic condition characterized by ocular, cutaneous, and central nervous system anomalies. Key clinical features include a well-demarcated hairless fatty nevus on the scalp, benign ocular tumors, and central nervous system lipomas. Seizures, spasticity, and intellectual disability can be present, although affected individuals without seizures and with normal intellect have also been reported. Given the patchy and asymmetric nature of the malformations, ECCL has been hypothesized to be due to a post-zygotic, mosaic mutation. Despite phenotypic overlap with several other disorders associated with mutations in the RAS-MAPK and PI3K-AKT pathways, the molecular etiology of ECCL remains unknown. Using exome sequencing of DNA from multiple affected tissues from five unrelated individuals with ECCL, we identified two mosaic mutations, c.1638C>A (p.Asn546Lys) and c.1966A>G (p.Lys656Glu) within the tyrosine kinase domain of FGFR1, in two affected individuals each. These two residues are the most commonly mutated residues in FGFR1 in human cancers and are associated primarily with CNS tumors. Targeted resequencing of FGFR1 in multiple tissues from an independent cohort of individuals with ECCL identified one additional individual with a c.1638C>A (p.Asn546Lys) mutation in FGFR1. Functional studies of ECCL fibroblast cell lines show increased levels of phosphorylated FGFRs and phosphorylated FRS2, a direct substrate of FGFR1, as well as constitutive activation of RAS-MAPK signaling. In addition to identifying the molecular etiology of ECCL, our results support the emerging overlap between mosaic developmental disorders and tumorigenesis.

}, keywords = {Adolescent, Cell Line, Tumor, Central Nervous System Neoplasms, Child, Preschool, Exome, Eye, Eye Diseases, Female, Humans, Infant, Lipomatosis, Male, Mutation, Mutation, Missense, Neurocutaneous Syndromes, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Receptor, Fibroblast Growth Factor, Type 1, Seizures, Sequence Analysis, DNA}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.02.006}, author = {Bennett, James T and Tan, Tiong Yang and Alcantara, Diana and T{\'e}trault, Martine and Timms, Andrew E and Jensen, Dana and Collins, Sarah and Nowaczyk, Malgorzata J M and Lindhurst, Marjorie J and Christensen, Katherine M and Braddock, Stephen R and Brandling-Bennett, Heather and Hennekam, Raoul C M and Chung, Brian and Lehman, Anna and Su, John and Ng, SuYuen and Amor, David J and Majewski, Jacek and Biesecker, Les G and Boycott, Kym M and Dobyns, William B and O{\textquoteright}Driscoll, Mark and Moog, Ute and McDonell, Laura M} }