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

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

  • Am J Hum Genet. 2021 Jun 3;108(6):1138-1150. doi: 10.1016/j.ajhg.2021.04.007.
Maya Chopra 1,  Meriel McEntagart 2,  Jill Clayton-Smith 3,  Konrad Platzer 4,  Anju Shukla 5,  Katta M Girisha 5,  Anupriya Kaur 6,  Parneet Kaur 5,  Rolph Pfundt 7,  Hermine Veenstra-Knol 8,  Grazia M S Mancini 9,  Gerarda Cappuccio 10,  Nicola Brunetti-Pierri 10,  Fanny Kortüm 11,  Maja Hempel 11,  Jonas Denecke 11,  Anna Lehman 12,  CAUSES Study 12,  Tjitske Kleefstra 7,  Kyra E Stuurman 9,  Martina Wilke 9,  Michelle L Thompson 13,  E Martina Bebin 14,  Emilia K Bijlsma 15,  Mariette J V Hoffer 15,  Cacha Peeters-Scholte 16,  Anne Slavotinek 17,  William A Weiss 18,  Tiffany Yip 19,  Ugur Hodoglugil 19,  Amy Whittle 20,  Janette diMonda 21,  Juanita Neira 21,  Sandra Yang 22,  Amelia Kirby 23,  Hailey Pinz 24,  Rosan Lechner 9,  Frank Sleutels 9,  Ingo Helbig 25,  Sarah McKeown 26,  Katherine Helbig 26,  Rebecca Willaert 22,  Jane Juusola 22,  Jennifer Semotok 22,  Medard Hadonou 27,  John Short 27,  Genomics England Research Consortium 28,  Naomi Yachelevich 29,  Sajel Lala 30,  Alberto Fernández-Jaen 31,  Janvier Porta Pelayo 32,  Chiara Klöckner 4,  Susanne B Kamphausen 33,  Rami Abou Jamra 4,  Maria Arelin 34,  A Micheil Innes 35,  Anni Niskakoski 36,  Sam Amin 37,  Maggie Williams 38,  Julie Evans 38,  Sarah Smithson 37,  Damian Smedley 39,  Anna de Burca 40,  Usha Kini 40,  Martin B Delatycki 41,  Lyndon Gallacher 41,  Alison Yeung 41,  Lynn Pais 42,  Michael Field 43,  Ellenore Martin 43,  Perrine Charles 44,  Thomas Courtin 45,  Boris Keren 45,  Maria Iascone 46,  Anna Cereda 47,  Gemma Poke 48,  Véronique Abadie 49,  Christel Chalouhi 49,  Padmini Parthasarathy 50,  Benjamin J Halliday 50,  Stephen P Robertson 50,  Stanislas Lyonnet 51,  Jeanne Amiel 51,  Christopher T Gordon 52
Affiliations

Affiliations

  • 1 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: [email protected].
  • 2 Department of Medical Genetics, St George's University Hospitals NHS FT, London SW17 ORE, UK.
  • 3 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.
  • 4 Institute of Human Genetics, University of Leipzig Medical Center, Leipzig 04129, Germany.
  • 5 Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, India.
  • 6 Genetics Metabolic Unit, Department of Pediatrics, PGIMER, Chandigarh 160012, India.
  • 7 Department of Human Genetics, Radboud University Medical Centre, 6500 HB Nijmegen, the Netherlands.
  • 8 Department of Genetics University of Groningen, University Medical Centre Groningen, Groningen CB50, the Netherlands.
  • 9 Department of Clinical Genetics, Erasmus Medical Center, University Medical Center Rotterdam, Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands.
  • 10 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.
  • 11 Institute of Human Genetics and Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
  • 12 Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
  • 13 HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
  • 14 University of Alabama at Birmingham, Department of Neurology and Pediatrics, Birmingham, AL 35294, USA.
  • 15 Department of Clinical Genetics, Leiden University Medical Centre, 2300 RC Leiden, the Netherlands.
  • 16 Department of Neurology, Leiden University Medical Centre, 2300 RC Leiden, the Netherlands.
  • 17 Division of Genetics, Department of Pediatrics, UCSF, San Francisco, CA 94158, USA.
  • 18 Department of Neurology, University of California, San Francisco, San Francisco, CA 94110, USA.
  • 19 Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 20 Department of Pediatrics, Zuckerberg San Francisco General, San Francisco, UCSF, San Francisco, CA 94143, USA.
  • 21 Department of Human Genetic, Emory University, Atlanta, GA 30322, USA.
  • 22 Clinical Genomics Program, GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
  • 23 Section on Medical Genetics, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
  • 24 Division of Medical Genetics, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
  • 25 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.
  • 26 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.
  • 27 St. George's Genomics Service, St George's University Hospitals NHS FT, London SW17 ORE, UK.
  • 28 Genomics England, London EC1M 6BQ, UK; William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, UK.
  • 29 NYU Clinical Genetics Services, 145 E 32(nd) St PH, New York, NY 10016, USA.
  • 30 Division of Clinical Genetics, Nickelaus Children's Health System, 3100 SW 62(nd) Avenue, Coral Gables, FL 33155, USA.
  • 31 Department of Pediatric Neurology. Hospital Universitario Quirónsalud, Madrid and Universidad Complutense, Madrid 28224, Spain.
  • 32 Genologica Center, Málaga 29016, Spain.
  • 33 Institute of Human Genetics, University Hospital Magdeburg, Magdeburg 39120, Germany.
  • 34 Department for Women and Child Health, Hospital for Children and Adolescents, University Hospitals, University of Leipzig, Leipzig 04129, Germany.
  • 35 Department of Medical Genetics and Albert Children's Hospital Research Institute, Cumming School of Medicine, Calgary, AB T3B 6A8, Canada.
  • 36 Blueprint Genetics, Keilaranta 16 A-B, 02150 Espoo, Finland.
  • 37 WE Genomic Medicine Centre, University Hospitals Bristol NHS Foundation Trust, Bristol B52 8EG, UK.
  • 38 Bristol Genetics Laboratory, North Bristol NHS Trust, Pathology Sciences Building, Southmead Hospital, Bristol BS10 5NB, UK.
  • 39 William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
  • 40 Oxford Centre for Genomic Medicine, Oxford and Spires Cleft Centre, Oxford OX3 9DU, UK.
  • 41 Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia; Department of Paediatrics, The University of Melbourne, Parkville, VIC 3052, Australia.
  • 42 Broad Institute - Center for Mendelian Genomics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • 43 NSW Genetics of Learning Disability Service, Waratah, NSW 2298, Australia.
  • 44 Département de Génétique, Centre de Référence Déficiences Intellectuelles de Causes Rares, Groupe Hospitalier Pitié Salpêtrière, AP-HP, Sorbonne Université, Paris 75013, France.
  • 45 Département de génétique, Hôpital Pitié-Salpêtrière, AP-HP, Sorbonne Université, Paris 75013, France.
  • 46 Medical Genetics Laboratory, ASST Papa Giovanni XXIII, Bergamo 24127, Italy.
  • 47 Pediatric Department, ASST Papa Giovanni XXIII, Bergamo 24127, Italy.
  • 48 Genetic Health Service, New Zealand, Central Hub Wellington Hospital, Wellington 6242, New Zealand.
  • 49 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.
  • 50 Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand.
  • 51 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.
  • 52 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: [email protected].
PMID: 33909992 DOI: 10.1016/j.ajhg.2021.04.007
Abstract

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.

Keywords

ANKRD17; Hippo pathway; Mask; Yorkie; ankyrin repeats; dysmorphism; intellectual disability; neurodevelopmental syndrome; speech delay.

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