%0 Journal Article %J Am J Hum Genet %D 2019 %T Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability. %A Cogné, Benjamin %A Ehresmann, Sophie %A Beauregard-Lacroix, Eliane %A Rousseau, Justine %A Besnard, Thomas %A Garcia, Thomas %A Petrovski, Slavé %A Avni, Shiri %A McWalter, Kirsty %A Blackburn, Patrick R %A Sanders, Stephan J %A Uguen, Kévin %A Harris, Jacqueline %A Cohen, Julie S %A Blyth, Moira %A Lehman, Anna %A Berg, Jonathan %A Li, Mindy H %A Kini, Usha %A Joss, Shelagh %A von der Lippe, Charlotte %A Gordon, Christopher T %A Humberson, Jennifer B %A Robak, Laurie %A Scott, Daryl A %A Sutton, Vernon R %A Skraban, Cara M %A Johnston, Jennifer J %A Poduri, Annapurna %A Nordenskjöld, Magnus %A Shashi, Vandana %A Gerkes, Erica H %A Bongers, Ernie M H F %A Gilissen, Christian %A Zarate, Yuri A %A Kvarnung, Malin %A Lally, Kevin P %A Kulch, Peggy A %A Daniels, Brina %A Hernandez-Garcia, Andres %A Stong, Nicholas %A McGaughran, Julie %A Retterer, Kyle %A Tveten, Kristian %A Sullivan, Jennifer %A Geisheker, Madeleine R %A Stray-Pedersen, Asbjorg %A Tarpinian, Jennifer M %A Klee, Eric W %A Sapp, Julie C %A Zyskind, Jacob %A Holla, Øystein L %A Bedoukian, Emma %A Filippini, Francesca %A Guimier, Anne %A Picard, Arnaud %A Busk, Øyvind L %A Punetha, Jaya %A Pfundt, Rolph %A Lindstrand, Anna %A Nordgren, Ann %A Kalb, Fayth %A Desai, Megha %A Ebanks, Ashley Harmon %A Jhangiani, Shalini N %A Dewan, Tammie %A Coban Akdemir, Zeynep H %A Telegrafi, Aida %A Zackai, Elaine H %A Begtrup, Amber %A Song, Xiaofei %A Toutain, Annick %A Wentzensen, Ingrid M %A Odent, Sylvie %A Bonneau, Dominique %A Latypova, Xénia %A Deb, Wallid %A Redon, Sylvia %A Bilan, Frédéric %A Legendre, Marine %A Troyer, Caitlin %A Whitlock, Kerri %A Caluseriu, Oana %A Murphree, Marine I %A Pichurin, Pavel N %A Agre, Katherine %A Gavrilova, Ralitza %A Rinne, Tuula %A Park, Meredith %A Shain, Catherine %A Heinzen, Erin L %A Xiao, Rui %A Amiel, Jeanne %A Lyonnet, Stanislas %A Isidor, Bertrand %A Biesecker, Leslie G %A Lowenstein, Dan %A Posey, Jennifer E %A Denommé-Pichon, Anne-Sophie %A Férec, Claude %A Yang, Xiang-Jiao %A Rosenfeld, Jill A %A Gilbert-Dussardier, Brigitte %A Audebert-Bellanger, Séverine %A Redon, Richard %A Stessman, Holly A F %A Nellaker, Christoffer %A Yang, Yaping %A James R Lupski %A Goldstein, David B %A Eichler, Evan E %A Bolduc, Francois %A Bézieau, Stéphane %A Küry, Sébastien %A Campeau, Philippe M %K Adaptor Proteins, Signal Transducing %K Adolescent %K Adult %K Amino Acid Sequence %K Autistic Disorder %K Child %K Child, Preschool %K Female %K Genetic Association Studies %K Humans %K Infant %K Intellectual Disability %K Male %K Mutation, Missense %K Nuclear Proteins %K Prognosis %K Sequence Homology %K Syndrome %K Young Adult %X

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.

%B Am J Hum Genet %V 104 %P 530-541 %8 2019 Mar 07 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/30827496?dopt=Abstract %R 10.1016/j.ajhg.2019.01.010 %0 Journal Article %J Am J Hum Genet %D 2017 %T Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies. %A Xu, Mingchu %A Xie, Yajing Angela %A Abouzeid, Hana %A Gordon, Christopher T %A Fiorentino, Alessia %A Sun, Zixi %A Lehman, Anna %A Osman, Ihab S %A Dharmat, Rachayata %A Riveiro-Álvarez, Rosa %A Bapst-Wicht, Linda %A Babino, Darwin %A Arno, Gavin %A Busetto, Virginia %A Zhao, Li %A Li, Hui %A Lopez-Martinez, Miguel A %A Azevedo, Liliana F %A Hubert, Laurence %A Pontikos, Nikolas %A Eblimit, Aiden %A Lorda-Sanchez, Isabel %A Kheir, Valeria %A Plagnol, Vincent %A Oufadem, Myriam %A Soens, Zachry T %A Yang, Lizhu %A Bole-Feysot, Christine %A Pfundt, Rolph %A Allaman-Pillet, Nathalie %A Nitschké, Patrick %A Cheetham, Michael E %A Lyonnet, Stanislas %A Agrawal, Smriti A %A Li, Huajin %A Pinton, Gaëtan %A Michaelides, Michel %A Besmond, Claude %A Li, Yumei %A Yuan, Zhisheng %A von Lintig, Johannes %A Webster, Andrew R %A Le Hir, Hervé %A Stoilov, Peter %A Amiel, Jeanne %A Hardcastle, Alison J %A Ayuso, Carmen %A Sui, Ruifang %A Chen, Rui %A Allikmets, Rando %A Schorderet, Daniel F %K Abnormalities, Multiple %K Adolescent %K Animals %K Child %K Child, Preschool %K Cyclophilins %K Female %K Humans %K Male %K Mice %K Mutation %K Pedigree %K Peptidylprolyl Isomerase %K Retinal Degeneration %K Young Adult %X

Pre-mRNA splicing factors play a fundamental role in regulating transcript diversity both temporally and spatially. Genetic defects in several spliceosome components have been linked to a set of non-overlapping spliceosomopathy phenotypes in humans, among which skeletal developmental defects and non-syndromic retinitis pigmentosa (RP) are frequent findings. Here we report that defects in spliceosome-associated protein CWC27 are associated with a spectrum of disease phenotypes ranging from isolated RP to severe syndromic forms. By whole-exome sequencing, recessive protein-truncating mutations in CWC27 were found in seven unrelated families that show a range of clinical phenotypes, including retinal degeneration, brachydactyly, craniofacial abnormalities, short stature, and neurological defects. Remarkably, variable expressivity of the human phenotype can be recapitulated in Cwc27 mutant mouse models, with significant embryonic lethality and severe phenotypes in the complete knockout mice while mice with a partial loss-of-function allele mimic the isolated retinal degeneration phenotype. Our study describes a retinal dystrophy-related phenotype spectrum as well as its genetic etiology and highlights the complexity of the spliceosomal gene network.

%B Am J Hum Genet %V 100 %P 592-604 %8 2017 Apr 06 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/28285769?dopt=Abstract %R 10.1016/j.ajhg.2017.02.008 %0 Journal Article %J Am J Hum Genet %D 2013 %T Mutations in KCTD1 cause scalp-ear-nipple syndrome. %A Marneros, Alexander G %A Beck, Anita E %A Turner, Emily H %A McMillin, Margaret J %A Edwards, Matthew J %A Field, Michael %A de Macena Sobreira, Nara Lygia %A Perez, Ana Beatriz A %A Fortes, Jose A R %A Lampe, Anne K %A Giovannucci Uzielli, Maria Luisa %A Gordon, Christopher T %A Plessis, Ghislaine %A Le Merrer, Martine %A Amiel, Jeanne %A Reichenberger, Ernst %A Shively, Kathryn M %A Cerrato, Felecia %A Labow, Brian I %A Tabor, Holly K %A Smith, Joshua D %A Shendure, Jay %A Nickerson, Deborah A %A Bamshad, Michael J %K Abnormalities, Multiple %K Amino Acid Sequence %K Branchio-Oto-Renal Syndrome %K Co-Repressor Proteins %K Ear, External %K Ectodermal Dysplasia %K Exome %K Female %K Humans %K Hypospadias %K Male %K Molecular Sequence Data %K Muscle Hypotonia %K Mutation, Missense %K Nipples %K Pedigree %K Phenotype %K Protein Structure, Tertiary %K Repressor Proteins %K Scalp %K Sequence Homology, Amino Acid %X

Scalp-ear-nipple (SEN) syndrome is a rare, autosomal-dominant disorder characterized by cutis aplasia of the scalp; minor anomalies of the external ears, digits, and nails; and malformations of the breast. We used linkage analysis and exome sequencing of a multiplex family affected by SEN syndrome to identify potassium-channel tetramerization-domain-containing 1 (KCTD1) mutations that cause SEN syndrome. Evaluation of a total of ten families affected by SEN syndrome revealed KCTD1 missense mutations in each family tested. All of the mutations occurred in a KCTD1 region encoding a highly conserved bric-a-brac, tram track, and broad complex (BTB) domain that is required for transcriptional repressor activity. KCTD1 inhibits the transactivation of the transcription factor AP-2α (TFAP2A) via its BTB domain, and mutations in TFAP2A cause cutis aplasia in individuals with branchiooculofacial syndrome (BOFS), suggesting a potential overlap in the pathogenesis of SEN syndrome and BOFS. The identification of KCTD1 mutations in SEN syndrome reveals a role for this BTB-domain-containing transcriptional repressor during ectodermal development.

%B Am J Hum Genet %V 92 %P 621-6 %8 2013 Apr 04 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/23541344?dopt=Abstract %R 10.1016/j.ajhg.2013.03.002