2. Academic Validation
  3. Pathogenic Variants in GPC4 Cause Keipert Syndrome

Pathogenic Variants in GPC4 Cause Keipert Syndrome

  • Am J Hum Genet. 2019 May 2;104(5):914-924. doi: 10.1016/j.ajhg.2019.02.026.
David J Amor 1,  Sarah E M Stephenson 1,  Mirna Mustapha 2,  Martin A Mensah 3,  Charlotte W Ockeloen 4,  Wei Shern Lee 1,  Rick M Tankard 5,  Dean G Phelan 1,  Marwan Shinawi 6,  Arjan P M de Brouwer 7,  Rolph Pfundt 4,  Cari Dowling 8,  Tomi L Toler 6,  V Reid Sutton 9,  Emanuele Agolini 10,  Martina Rinelli 10,  Rossella Capolino 11,  Diego Martinelli 12,  Giuseppe Zampino 13,  Miroslav Dumić 14,  William Reardon 15,  Charles Shaw-Smith 16,  Richard J Leventer 17,  Martin B Delatycki 1,  Tjitske Kleefstra 7,  Stefan Mundlos 3,  Geert Mortier 18,  Melanie Bahlo 5,  Nicola J Allen 8,  Paul J Lockhart 19
Affiliations

Affiliations

  • 1 Murdoch Children's Research Institute, Flemington Road, Parkville, Victoria 3052, Australia; Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Flemington Road, Parkville, Victoria 3052, Australia.
  • 2 Department of Otolaryngology-Head and Neck Surgery, Stanford University, Stanford, CA 94305, USA.
  • 3 Institut für Medizinische Genetik, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin 13353, Germany.
  • 4 Department of Human Genetics, Radboud University Medical Center, Nijmegen 6500 HB, the Netherlands.
  • 5 The Walter and Eliza Hall Institute of Medical Research, Royal Parade, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.
  • 6 Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 7 Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500HB Nijmegen, The Netherlands.
  • 8 Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
  • 9 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
  • 10 Laboratory of Medical Genetics, Department of Laboratories, IRCCS Bambino Gesù Children's Hospital, Rome 00165, Italy.
  • 11 Medical Genetics, Department of Pediatrics, IRCCS Bambino Gesù Children's Hospital, Rome 00165, Italy.
  • 12 Division of Metabolism, Department of Pediatric Subspecialties, IRCCS Bambino Gesù Children's Hospital Rome 00165, Italy.
  • 13 Center for Rare Disease and Congenital Defects, Fondazione Policlinico Universitario A. Gemelli, Catholic University, Rome 00168, Italy.
  • 14 Department of Pediatrics Rebro, University of Zagreb Medical School, Kispaticeva 12, 10 000 Zagreb, Croatia.
  • 15 Department of Clinical Genetics, Our Lady's Children Hospital Crumlin, Dublin, D12, V004, Ireland.
  • 16 Department of Clinical Genetics, Royal Devon and Exeter National Health Service Foundation Trust, Exeter EX1 2ED, UK.
  • 17 Murdoch Children's Research Institute, Flemington Road, Parkville, Victoria 3052, Australia; Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Flemington Road, Parkville, Victoria 3052, Australia; Department of Neurology, Royal Children's Hospital, Flemington Road, Parkville, Victoria 3052, Australia.
  • 18 Department of Medical Genetics, Antwerp University Hospital and University of Antwerp, B-2650 Antwerp (Edegem), Belgium.
  • 19 Murdoch Children's Research Institute, Flemington Road, Parkville, Victoria 3052, Australia; Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Flemington Road, Parkville, Victoria 3052, Australia. Electronic address: [email protected].
PMID: 30982611 DOI: 10.1016/j.ajhg.2019.02.026
Abstract

Glypicans are a family of cell-surface heparan sulfate proteoglycans that regulate growth-factor signaling during development and are thought to play a role in the regulation of morphogenesis. Whole-exome sequencing of the Australian family that defined Keipert syndrome (nasodigitoacoustic syndrome) identified a hemizygous truncating variant in the gene encoding glypican 4 (GPC4). This variant, located in the final exon of GPC4, results in premature termination of the protein 51 amino acid residues prior to the stop codon, and in concomitant loss of functionally important N-linked glycosylation (Asn514) and glycosylphosphatidylinositol (GPI) anchor (Ser529) sites. We subsequently identified seven affected males from five additional kindreds with novel and predicted pathogenic variants in GPC4. Segregation analysis and X-inactivation studies in carrier females provided supportive evidence that the GPC4 variants caused the condition. Furthermore, functional studies of recombinant protein suggested that the truncated proteins p.Gln506∗ and p.Glu496∗ were less stable than the wild type. Clinical features of Keipert syndrome included a prominent forehead, a flat midface, hypertelorism, a broad nose, downturned corners of mouth, and digital abnormalities, whereas cognitive impairment and deafness were variable features. Studies of Gpc4 knockout mice showed evidence of the two primary features of Keipert syndrome: craniofacial abnormalities and digital abnormalities. Phylogenetic analysis demonstrated that GPC4 is most closely related to GPC6, which is associated with a bone dysplasia that has a phenotypic overlap with Keipert syndrome. Overall, we have shown that pathogenic variants in GPC4 cause a loss of function that results in Keipert syndrome, making GPC4 the third human glypican to be linked to a genetic syndrome.

Keywords

GPC4; Keipert syndrome; Nasodigitoacoustic syndrome; glypicans.

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