@article {697, title = {De Novo Variants Disturbing the Transactivation Capacity of POU3F3 Cause a Characteristic Neurodevelopmental Disorder.}, journal = {Am J Hum Genet}, volume = {105}, year = {2019}, month = {2019 Aug 01}, pages = {403-412}, abstract = {

POU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. Brain abnormalities were observed in seven of eleven MRI reports. POU3F3 is an intronless gene, insensitive to nonsense-mediated decay, and 13 individuals carried protein-truncating variants. All truncating variants that we tested in cellular models led to aberrant subcellular localization of the encoded protein. Luciferase assays demonstrated negative effects of these alleles on transcriptional activation of a reporter with a FOXP2-derived binding motif. In addition to the loss-of-function variants, five individuals had missense variants that clustered at specific positions within the functional domains, and one small in-frame deletion was identified. Two missense variants showed reduced transactivation capacity in our assays, whereas one variant displayed gain-of-function effects, suggesting a distinct pathophysiological mechanism. In bioluminescence resonance energy transfer (BRET) interaction assays, all the truncated POU3F3 versions that we tested had significantly impaired dimerization capacities, whereas all missense variants showed unaffected dimerization with wild-type POU3F3. Taken together, our identification and functional cell-based analyses of pathogenic variants in POU3F3, coupled with a clinical characterization, implicate disruptions of this gene in a characteristic neurodevelopmental disorder.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.06.007}, author = {Snijders Blok, Lot and Kleefstra, Tjitske and Venselaar, Hanka and Maas, Saskia and Kroes, Hester Y and Lachmeijer, Augusta M A and van Gassen, Koen L I and Firth, Helen V and Tomkins, Susan and Bodek, Simon and {\~O}unap, Katrin and Wojcik, Monica H and Cunniff, Christopher and Bergstrom, Katherine and Powis, Z{\"o}e and Tang, Sha and Shinde, Deepali N and Au, Catherine and Iglesias, Alejandro D and Izumi, Kosuke and Leonard, Jacqueline and Abou Tayoun, Ahmad and Baker, Samuel W and Tartaglia, Marco and Niceta, Marcello and Dentici, Maria Lisa and Okamoto, Nobuhiko and Miyake, Noriko and Matsumoto, Naomichi and Vitobello, Antonio and Faivre, Laurence and Philippe, Christophe and Gilissen, Christian and Wiel, Laurens and Pfundt, Rolph and Deriziotis, Pelagia and Brunner, Han G and Fisher, Simon E} } @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 {380, title = {Unraveling genetic predisposition to familial or early onset gastric cancer using germline whole-exome sequencing.}, journal = {Eur J Hum Genet}, volume = {25}, year = {2017}, month = {2017 11}, pages = {1246-1252}, abstract = {

Recognition of individuals with a genetic predisposition to gastric cancer (GC) enables preventive measures. However, the underlying cause of genetic susceptibility to gastric cancer remains largely unexplained. We performed germline whole-exome sequencing on leukocyte DNA of 54 patients from 53 families with genetically unexplained diffuse-type and intestinal-type GC to identify novel GC-predisposing candidate genes. As young age at diagnosis and familial clustering are hallmarks of genetic tumor susceptibility, we selected patients that were diagnosed below the age of 35, patients from families with two cases of GC at or below age 60 and patients from families with three GC cases at or below age 70. All included individuals were tested negative for germline CDH1 mutations before or during the study. Variants that were possibly deleterious according to in silico predictions were filtered using several independent approaches that were based on gene function and gene mutation burden in controls. Despite a rigorous search, no obvious candidate GC predisposition genes were identified. This negative result stresses the importance of future research studies in large, homogeneous cohorts.

}, keywords = {Adult, Aged, Antigens, CD, Cadherins, Early Detection of Cancer, Exome, Female, Genetic Predisposition to Disease, Genetic Testing, Germ-Line Mutation, Humans, Male, Middle Aged, Sequence Analysis, DNA, Stomach Neoplasms}, issn = {1476-5438}, doi = {10.1038/ejhg.2017.138}, author = {Vogelaar, Ingrid P and van der Post, Rachel S and van Krieken, J Han Jm and Spruijt, Liesbeth and van Zelst-Stams, Wendy Ag and Kets, C Marleen and Lubinski, Jan and Jakubowska, Anna and Teodorczyk, Urszula and Aalfs, Cora M and van Hest, Liselotte P and Pinheiro, Hugo and Oliveira, Carla and Jhangiani, Shalini N and Muzny, Donna M and Gibbs, Richard A and Lupski, James R and de Ligt, Joep and Vissers, Lisenka E L M and Hoischen, Alexander and Gilissen, Christian and van de Vorst, Maartje and Goeman, Jelle J and Schackert, Hans K and Ranzani, Guglielmina N and Molinaro, Valeria and G{\'o}mez Garc{\'\i}a, Encarna B and Hes, Frederik J and Holinski-Feder, Elke and Genuardi, Maurizio and Ausems, Margreet G E M and Sijmons, Rolf H and Wagner, Anja and van der Kolk, Lizet E and Bj{\o}rnevoll, Inga and H{\o}berg-Vetti, Hildegunn and van Kessel, Ad Geurts and Kuiper, Roland P and Ligtenberg, Marjolijn J L and Hoogerbrugge, Nicoline} } @article {127, title = {Novel genetic causes for cerebral visual impairment.}, journal = {Eur J Hum Genet}, volume = {24}, year = {2016}, month = {2016 May}, pages = {660-5}, abstract = {

Cerebral visual impairment (CVI) is a major cause of low vision in children due to impairment in projection and/or interpretation of the visual input in the brain. Although acquired causes for CVI are well known, genetic causes underlying CVI are largely unidentified. DNAs of 25 patients with CVI and intellectual disability, but without acquired (eg, perinatal) damage, were investigated by whole-exome sequencing. The data were analyzed for de novo, autosomal-recessive, and X-linked variants, and subsequently classified into known, candidate, or unlikely to be associated with CVI. This classification was based on the Online Mendelian Inheritance in Man database, literature reports, variant characteristics, and functional relevance of the gene. After classification, variants in four genes known to be associated with CVI (AHDC1, NGLY1, NR2F1, PGAP1) in 5 patients (20\%) were identified, establishing a conclusive genetic diagnosis for CVI. In addition, in 11 patients (44\%) with CVI, variants in one or more candidate genes were identified (ACP6, AMOT, ARHGEF10L, ATP6V1A, DCAF6, DLG4, GABRB2, GRIN1, GRIN2B, KCNQ3, KCTD19, RERE, SLC1A1, SLC25A16, SLC35A2, SOX5, UFSP2, UHMK1, ZFP30). Our findings show that diverse genetic causes underlie CVI, some of which will provide insight into the biology underlying this disease process.

}, keywords = {Adolescent, Blindness, Cortical, Child, Child, Preschool, Female, Genetic Loci, Humans, Male, Polymorphism, Single Nucleotide, Young Adult}, issn = {1476-5438}, doi = {10.1038/ejhg.2015.186}, author = {Bosch, Dani{\"e}lle G M and Boonstra, F Nienke and de Leeuw, Nicole and Pfundt, Rolph and Nillesen, Willy M and de Ligt, Joep and Gilissen, Christian and Jhangiani, Shalini and Lupski, James R and Cremers, Frans P M and de Vries, Bert B A} } @article {12, title = {Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis.}, journal = {Genet Med}, volume = {18}, year = {2016}, month = {2016 11}, pages = {1158-1162}, abstract = {

PURPOSE: We aimed to identify a novel genetic cause of tooth agenesis (TA) and/or orofacial clefting (OFC) by combining whole-exome sequencing (WES) and targeted resequencing in a large cohort of TA and OFC patients.

METHODS: WES was performed in two unrelated patients: one with severe TA and OFC and another with severe TA only. After deleterious mutations were identified in a gene encoding low-density lipoprotein receptor-related protein 6 (LRP6), all its exons were resequenced with molecular inversion probes in 67 patients with TA, 1,072 patients with OFC, and 706 controls.

RESULTS: We identified a frameshift (c.4594delG, p.Cys1532fs) and a canonical splice-site mutation (c.3398-2A>C, p.?) in LRP6, respectively, in the patient with TA and OFC and in the patient with severe TA only. The targeted resequencing showed significant enrichment of unique LRP6 variants in TA patients but not in nonsyndromic OFC patients. Of the five variants in patients with TA, two affected the canonical splice site and three were missense variants; all variants segregated with the dominant phenotype, and in one case the missense mutation occurred de novo.

CONCLUSION: Mutations in LRP6 cause TA in humans.Genet Med 18 11, 1158-1162.

}, keywords = {Adolescent, Anodontia, Child, Exome, Female, Frameshift Mutation, Genetic Predisposition to Disease, Humans, Low Density Lipoprotein Receptor-Related Protein-6, Male, Mutation, Missense, Pedigree, Sequence Analysis, DNA, Wnt Signaling Pathway}, issn = {1530-0366}, doi = {10.1038/gim.2016.10}, author = {Ockeloen, Charlotte W and Khandelwal, Kriti D and Dreesen, Karoline and Ludwig, Kerstin U and Sullivan, Robert and van Rooij, Iris A L M and Thonissen, Michelle and Swinnen, Steven and Phan, Milien and Conte, Federica and Ishorst, Nina and Gilissen, Christian and RoaFuentes, Laury and van de Vorst, Maartje and Henkes, Arjen and Steehouwer, Marloes and van Beusekom, Ellen and Bloemen, Marjon and Vankeirsbilck, Bruno and Berg{\'e}, Stefaan and Hens, Greet and Schoenaers, Joseph and Poorten, Vincent Vander and Roosenboom, Jasmien and Verdonck, An and Devriendt, Koen and Roeleveldt, Nel and Jhangiani, Shalini N and Vissers, Lisenka E L M and Lupski, James R and de Ligt, Joep and Von den Hoff, Johannes W and Pfundt, Rolph and Brunner, Han G and Zhou, Huiqing and Dixon, Jill and Mangold, Elisabeth and van Bokhoven, Hans and Dixon, Michael J and Kleefstra, Tjitske and Hoischen, Alexander and Carels, Carine E L} }