Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism.

Autor:	Chopra M; Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris (AP-HP), and Institut Imagine, Paris 75015, France; Laboratory of embryology and genetics of human malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Université de Paris, Paris 75015, France; Rosamund Stone Zander Translational Neuroscience Center, Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA. Electronic address: maya.chopra@childrens.harvard.edu., McEntagart M; Department of Medical Genetics, St George's University Hospitals NHS FT, London SW17 ORE, UK., Clayton-Smith J; Manchester Centre for Genomic Medicine, University of Manchester, St Mary's Hospital, Manchester M13 9WL, UK; Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester M13 9WL, UK., Platzer K; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig 04129, Germany., Shukla A; Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, India., Girisha KM; Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, India., Kaur A; Genetics Metabolic Unit, Department of Pediatrics, PGIMER, Chandigarh 160012, India., Kaur P; Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, India., Pfundt R; Department of Human Genetics, Radboud University Medical Centre, 6500 HB Nijmegen, the Netherlands., Veenstra-Knol H; Department of Genetics University of Groningen, University Medical Centre Groningen, Groningen CB50, the Netherlands., Mancini GMS; Department of Clinical Genetics, Erasmus Medical Center, University Medical Center Rotterdam, Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands., Cappuccio G; Department of Translational Medicine, Section of Pediatrics, Federico II University of Naples, Naples 80131, Italy; Telethon Institute of Genetics and Medicine, Pozzuoli, Naples 80078, Italy., Brunetti-Pierri N; Department of Translational Medicine, Section of Pediatrics, Federico II University of Naples, Naples 80131, Italy; Telethon Institute of Genetics and Medicine, Pozzuoli, Naples 80078, Italy., Kortüm F; Institute of Human Genetics and Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany., Hempel M; Institute of Human Genetics and Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany., Denecke J; Institute of Human Genetics and Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany., Lehman A; Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada., Kleefstra T; Department of Human Genetics, Radboud University Medical Centre, 6500 HB Nijmegen, the Netherlands., Stuurman KE; Department of Clinical Genetics, Erasmus Medical Center, University Medical Center Rotterdam, Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands., Wilke M; Department of Clinical Genetics, Erasmus Medical Center, University Medical Center Rotterdam, Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands., Thompson ML; HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA., Bebin EM; University of Alabama at Birmingham, Department of Neurology and Pediatrics, Birmingham, AL 35294, USA., Bijlsma EK; Department of Clinical Genetics, Leiden University Medical Centre, 2300 RC Leiden, the Netherlands., Hoffer MJV; Department of Clinical Genetics, Leiden University Medical Centre, 2300 RC Leiden, the Netherlands., Peeters-Scholte C; Department of Neurology, Leiden University Medical Centre, 2300 RC Leiden, the Netherlands., Slavotinek A; Division of Genetics, Department of Pediatrics, UCSF, San Francisco, CA 94158, USA., Weiss WA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94110, USA., Yip T; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA., Hodoglugil U; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA., Whittle A; Department of Pediatrics, Zuckerberg San Francisco General, San Francisco, UCSF, San Francisco, CA 94143, USA., diMonda J; Department of Human Genetic, Emory University, Atlanta, GA 30322, USA., Neira J; Department of Human Genetic, Emory University, Atlanta, GA 30322, USA., Yang S; Clinical Genomics Program, GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA., Kirby A; Section on Medical Genetics, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA., Pinz H; Division of Medical Genetics, Saint Louis University School of Medicine, St. Louis, MO 63104, USA., Lechner R; Department of Clinical Genetics, Erasmus Medical Center, University Medical Center Rotterdam, Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands., Sleutels F; Department of Clinical Genetics, Erasmus Medical Center, University Medical Center Rotterdam, Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands., Helbig I; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19014, USA; Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Neurology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA., McKeown S; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19014, USA., Helbig K; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19014, USA., Willaert R; Clinical Genomics Program, GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA., Juusola J; Clinical Genomics Program, GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA., Semotok J; Clinical Genomics Program, GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA., Hadonou M; St. George's Genomics Service, St George's University Hospitals NHS FT, London SW17 ORE, UK., Short J; St. George's Genomics Service, St George's University Hospitals NHS FT, London SW17 ORE, UK., Yachelevich N; NYU Clinical Genetics Services, 145 E 32(nd) St PH, New York, NY 10016, USA., Lala S; Division of Clinical Genetics, Nickelaus Children's Health System, 3100 SW 62(nd) Avenue, Coral Gables, FL 33155, USA., Fernández-Jaen A; Department of Pediatric Neurology. Hospital Universitario Quirónsalud, Madrid and Universidad Complutense, Madrid 28224, Spain., Pelayo JP; Genologica Center, Málaga 29016, Spain., Klöckner C; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig 04129, Germany., Kamphausen SB; Institute of Human Genetics, University Hospital Magdeburg, Magdeburg 39120, Germany., Abou Jamra R; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig 04129, Germany., Arelin M; Department for Women and Child Health, Hospital for Children and Adolescents, University Hospitals, University of Leipzig, Leipzig 04129, Germany., Innes AM; Department of Medical Genetics and Albert Children's Hospital Research Institute, Cumming School of Medicine, Calgary, AB T3B 6A8, Canada., Niskakoski A; Blueprint Genetics, Keilaranta 16 A-B, 02150 Espoo, Finland., Amin S; WE Genomic Medicine Centre, University Hospitals Bristol NHS Foundation Trust, Bristol B52 8EG, UK., Williams M; Bristol Genetics Laboratory, North Bristol NHS Trust, Pathology Sciences Building, Southmead Hospital, Bristol BS10 5NB, UK., Evans J; Bristol Genetics Laboratory, North Bristol NHS Trust, Pathology Sciences Building, Southmead Hospital, Bristol BS10 5NB, UK., Smithson S; WE Genomic Medicine Centre, University Hospitals Bristol NHS Foundation Trust, Bristol B52 8EG, UK., Smedley D; William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK., de Burca A; Oxford Centre for Genomic Medicine, Oxford and Spires Cleft Centre, Oxford OX3 9DU, UK., Kini U; Oxford Centre for Genomic Medicine, Oxford and Spires Cleft Centre, Oxford OX3 9DU, UK., Delatycki MB; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia; Department of Paediatrics, The University of Melbourne, Parkville, VIC 3052, Australia., Gallacher L; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia; Department of Paediatrics, The University of Melbourne, Parkville, VIC 3052, Australia., Yeung A; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia; Department of Paediatrics, The University of Melbourne, Parkville, VIC 3052, Australia., Pais L; Broad Institute - Center for Mendelian Genomics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA., Field M; NSW Genetics of Learning Disability Service, Waratah, NSW 2298, Australia., Martin E; NSW Genetics of Learning Disability Service, Waratah, NSW 2298, Australia., Charles P; Département de Génétique, Centre de Référence Déficiences Intellectuelles de Causes Rares, Groupe Hospitalier Pitié Salpêtrière, AP-HP, Sorbonne Université, Paris 75013, France., Courtin T; Département de génétique, Hôpital Pitié-Salpêtrière, AP-HP, Sorbonne Université, Paris 75013, France., Keren B; Département de génétique, Hôpital Pitié-Salpêtrière, AP-HP, Sorbonne Université, Paris 75013, France., Iascone M; Medical Genetics Laboratory, ASST Papa Giovanni XXIII, Bergamo 24127, Italy., Cereda A; Pediatric Department, ASST Papa Giovanni XXIII, Bergamo 24127, Italy., Poke G; Genetic Health Service, New Zealand, Central Hub Wellington Hospital, Wellington 6242, New Zealand., Abadie V; Department of Paediatrics, Necker-Enfants Malades University Hospital, AP-HP, Centre de référence du syndrome de Pierre Robin et troubles de succion-déglutition congénitaux (SPRATON), Paris 75015, France., Chalouhi C; Department of Paediatrics, Necker-Enfants Malades University Hospital, AP-HP, Centre de référence du syndrome de Pierre Robin et troubles de succion-déglutition congénitaux (SPRATON), Paris 75015, France., Parthasarathy P; Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand., Halliday BJ; Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand., Robertson SP; Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand., Lyonnet S; Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris (AP-HP), and Institut Imagine, Paris 75015, France; Laboratory of embryology and genetics of human malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Université de Paris, Paris 75015, France., Amiel J; Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris (AP-HP), and Institut Imagine, Paris 75015, France; Laboratory of embryology and genetics of human malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Université de Paris, Paris 75015, France., Gordon CT; Laboratory of embryology and genetics of human malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Université de Paris, Paris 75015, France. Electronic address: chris.gordon@inserm.fr.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2021 Jun 03; Vol. 108 (6), pp. 1138-1150. Date of Electronic Publication: 2021 Apr 27.
DOI:	10.1016/j.ajhg.2021.04.007
Abstrakt:	ANKRD17 is an ankyrin repeat-containing protein thought to play a role in cell cycle progression, whose ortholog in Drosophila functions in the Hippo pathway as a co-factor of Yorkie. Here, we delineate a neurodevelopmental disorder caused by de novo heterozygous ANKRD17 variants. The mutational spectrum of this cohort of 34 individuals from 32 families is highly suggestive of haploinsufficiency as the underlying mechanism of disease, with 21 truncating or essential splice site variants, 9 missense variants, 1 in-frame insertion-deletion, and 1 microdeletion (1.16 Mb). Consequently, our data indicate that loss of ANKRD17 is likely the main cause of phenotypes previously associated with large multi-gene chromosomal aberrations of the 4q13.3 region. Protein modeling suggests that most of the missense variants disrupt the stability of the ankyrin repeats through alteration of core structural residues. The major phenotypic characteristic of our cohort is a variable degree of developmental delay/intellectual disability, particularly affecting speech, while additional features include growth failure, feeding difficulties, non-specific MRI abnormalities, epilepsy and/or abnormal EEG, predisposition to recurrent infections (mostly bacterial), ophthalmological abnormalities, gait/balance disturbance, and joint hypermobility. Moreover, many individuals shared similar dysmorphic facial features. Analysis of single-cell RNA-seq data from the developing human telencephalon indicated ANKRD17 expression at multiple stages of neurogenesis, adding further evidence to the assertion that damaging ANKRD17 variants cause a neurodevelopmental disorder. (Copyright © 2021 American Society of Human Genetics. All rights reserved.)
Databáze:	MEDLINE
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