@article {769, title = {Delineation of a Human Mendelian Disorder of the DNA Demethylation Machinery: TET3 Deficiency.}, journal = {Am J Hum Genet}, volume = {106}, year = {2020}, month = {2020 02 06}, pages = {234-245}, abstract = {

Germline pathogenic variants in chromatin-modifying enzymes are a common cause of pediatric developmental disorders. These enzymes catalyze reactions that regulate epigenetic inheritance via histone post-translational modifications and DNA methylation. Cytosine methylation (5-methylcytosine [5mC]) of DNA is the quintessential epigenetic mark, yet no human Mendelian disorder of DNA demethylation has yet been delineated. Here, we describe in detail a Mendelian disorder caused by the disruption of DNA demethylation. TET3 is a methylcytosine dioxygenase that initiates DNA demethylation during early zygote formation, embryogenesis, and neuronal differentiation and is intolerant to haploinsufficiency in mice and humans. We identify and characterize 11 cases of human TET3 deficiency in eight families with the common phenotypic features of intellectual disability and/or global developmental delay; hypotonia; autistic traits; movement disorders; growth abnormalities; and facial dysmorphism. Mono-allelic frameshift and nonsense variants in TET3 occur throughout the coding region. Mono-allelic and bi-allelic missense variants localize to conserved residues; all but one such variant occur within the catalytic domain, and most display hypomorphic function in an assay of catalytic activity. TET3 deficiency and other Mendelian disorders of the epigenetic machinery show substantial phenotypic overlap, including features of intellectual disability and abnormal growth, underscoring shared disease mechanisms.

}, keywords = {Adult, Amino Acid Sequence, Autistic Disorder, Child, Child, Preschool, Developmental Disabilities, Dioxygenases, DNA Demethylation, Embryonic Development, Female, Gene Expression Regulation, Developmental, Growth Disorders, Humans, Infant, Male, Middle Aged, Movement Disorders, Pedigree, Protein Conformation, Sequence Homology, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.12.007}, author = {Beck, David B and Petracovici, Ana and He, Chongsheng and Moore, Hannah W and Louie, Raymond J and Ansar, Muhammad and Douzgou, Sofia and Sithambaram, Sivagamy and Cottrell, Trudie and Santos-Cortez, Regie Lyn P and Prijoles, Eloise J and Bend, Renee and Keren, Boris and Mignot, Cyril and Nougues, Marie-Christine and {\~O}unap, Katrin and Reimand, Tiia and Pajusalu, Sander and Zahid, Muhammad and Saqib, Muhammad Arif Nadeem and Buratti, Julien and Seaby, Eleanor G and McWalter, Kirsty and Telegrafi, Aida and Baldridge, Dustin and Shinawi, Marwan and Leal, Suzanne M and Schaefer, G Bradley and Stevenson, Roger E and Banka, Siddharth and Bonasio, Roberto and Fahrner, Jill A} } @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} }