@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 {906, title = {Monogenic variants in dystonia: an exome-wide sequencing study.}, journal = {Lancet Neurol}, volume = {19}, year = {2020}, month = {2020 11}, pages = {908-918}, abstract = {

BACKGROUND: Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia.

METHODS: For this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow.

FINDINGS: We sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19\%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45\%] of 222; excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19\%] of 98) or isolated (16 [4\%] of 388) dystonia. Across all categories of dystonia, 104 (65\%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism.

INTERPRETATION: In this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations.

FUNDING: Else Kr{\"o}ner-Fresenius-Stiftung, Technische Universit{\"a}t M{\"u}nchen, Helmholtz Zentrum M{\"u}nchen, Medizinische Universit{\"a}t Innsbruck, Charles University in Prague, Czech Ministry of Education, the Slovak Grant and Development Agency, the Slovak Research and Grant Agency.

}, keywords = {Adolescent, Child, Child, Preschool, Dystonia, Exome, Female, Genetic Variation, Humans, Infant, Infant, Newborn, Male, Pedigree, Whole Exome Sequencing, Young Adult}, issn = {1474-4465}, doi = {10.1016/S1474-4422(20)30312-4}, author = {Zech, Michael and Jech, Robert and Boesch, Sylvia and {\v S}korv{\'a}nek, Matej and Weber, Sandrina and Wagner, Matias and Zhao, Chen and Jochim, Angela and Necp{\'a}l, J{\'a}n and Dincer, Yasemin and Vill, Katharina and Distelmaier, Felix and Stoklosa, Malgorzata and Krenn, Martin and Grunwald, Stephan and Bock-Bierbaum, Tobias and Fe{\v c}{\'\i}kov{\'a}, Anna and Havr{\'a}nkov{\'a}, Petra and Roth, Jan and P{\v r}{\'\i}hodov{\'a}, Iva and Adamovi{\v c}ov{\'a}, Miriam and Ulmanov{\'a}, Olga and Bechyn{\v e}, Karel and Danhofer, Pavl{\'\i}na and Vesel{\'y}, Branislav and Ha{\v n}, Vladim{\'\i}r and Pavelekova, Petra and Gdovinov{\'a}, Zuzana and Mantel, Tobias and Meindl, Tobias and Sitzberger, Alexandra and Schr{\"o}der, Sebastian and Blaschek, Astrid and Roser, Timo and Bonfert, Michaela V and Haberlandt, Edda and Plecko, Barbara and Leineweber, Birgit and Berweck, Steffen and Herberhold, Thomas and Langguth, Berthold and {\v S}vantnerov{\'a}, Jana and Min{\'a}r, Michal and Ramos-Rivera, Gonzalo Alonso and Wojcik, Monica H and Pajusalu, Sander and {\~O}unap, Katrin and Schatz, Ulrich A and P{\"o}lsler, Laura and Milenkovic, Ivan and Laccone, Franco and Pilshofer, Veronika and Colombo, Roberto and Patzer, Steffi and Iuso, Arcangela and Vera, Julia and Troncoso, Monica and Fang, Fang and Prokisch, Holger and Wilbert, Friederike and Eckenweiler, Matthias and Graf, Elisabeth and Westphal, Dominik S and Riedhammer, Korbinian M and Brunet, Theresa and Alhaddad, Bader and Berutti, Riccardo and Strom, Tim M and Hecht, Martin and Baumann, Matthias and Wolf, Marc and Telegrafi, Aida and Person, Richard E and Zamora, Francisca Millan and Henderson, Lindsay B and Weise, David and Musacchio, Thomas and Volkmann, Jens and Szuto, Anna and Becker, Jessica and Cremer, Kirsten and Sycha, Thomas and Zimprich, Fritz and Kraus, Verena and Makowski, Christine and Gonzalez-Alegre, Pedro and Bardakjian, Tanya M and Ozelius, Laurie J and Vetro, Annalisa and Guerrini, Renzo and Maier, Esther and Borggraefe, Ingo and Kuster, Alice and Wortmann, Saskia B and Hackenberg, Annette and Steinfeld, Robert and Assmann, Birgit and Staufner, Christian and Opladen, Thomas and R{\r u}{\v z}i{\v c}ka, Ev{\v z}en and Cohn, Ronald D and Dyment, David and Chung, Wendy K and Engels, Hartmut and Ceballos-Baumann, Andres and Ploski, Rafal and Daumke, Oliver and Haslinger, Bernhard and Mall, Volker and Oexle, Konrad and Winkelmann, Juliane} } @article {427, title = {Identification of STAC3 variants in non-Native American families with overlapping features of Carey-Fineman-Ziter syndrome and Moebius syndrome.}, journal = {Am J Med Genet A}, volume = {173}, year = {2017}, month = {2017 Oct}, pages = {2763-2771}, abstract = {

Horstick et al. (2013) previously reported a homozygous p.Trp284Ser variant in STAC3 as the cause of Native American myopathy (NAM) in 5 Lumbee Native American families with congenital hypotonia and weakness, cleft palate, short stature, ptosis, kyphoscoliosis, talipes deformities, and susceptibility to malignant hyperthermia (MH). Here we present two non-Native American families, who were found to have STAC3 pathogenic variants. The first proband and her affected older sister are from a consanguineous Qatari family with a suspected clinical diagnosis of Carey-Fineman-Ziter syndrome (CFZS) based on features of hypotonia, myopathic facies with generalized weakness, ptosis, normal extraocular movements, cleft palate, growth delay, and kyphoscoliosis. We identified the homozygous c.851G>C;p.Trp284Ser variant in STAC3 in both sisters. The second proband and his affected sister are from a non-consanguineous, Puerto Rican family who was evaluated for a possible diagnosis of Moebius syndrome (MBS). His features included facial and generalized weakness, minimal limitation of horizontal gaze, cleft palate, and hypotonia, and he has a history of MH. The siblings were identified to be compound heterozygous for STAC3 variants c.851G>C;p.Trp284Ser and c.763_766delCTCT;p.Leu255IlefsX58. Given the phenotypic overlap of individuals with CFZS, MBS, and NAM, we screened STAC3 in 12 individuals diagnosed with CFZS and in 50 individuals diagnosed with MBS or a congenital facial weakness disorder. We did not identify any rare coding variants in STAC3. NAM should be considered in patients presenting with facial and generalized weakness, normal or mildly abnormal extraocular movement, hypotonia, cleft palate, and scoliosis, particularly if there is a history of MH.

}, keywords = {Adaptor Proteins, Signal Transducing, Adolescent, Adult, Child, Female, Humans, Male, Mobius Syndrome, Muscular Diseases, Mutation, Pedigree, Pierre Robin Syndrome, Prognosis, Young Adult}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38375}, author = {Telegrafi, Aida and Webb, Bryn D and Robbins, Sarah M and Speck-Martins, Carlos E and FitzPatrick, David and Fleming, Leah and Redett, Richard and Dufke, Andreas and Houge, Gunnar and van Harssel, Jeske J T and Verloes, Alain and Robles, Angela and Manoli, Irini and Engle, Elizabeth C and Jabs, Ethylin W and Valle, David and Carey, John and Hoover-Fong, Julie E and Sobreira, Nara L M} }