2. Academic Validation
  3. A genotype-first approach identifies an intellectual disability-overweight syndrome caused by PHIP haploinsufficiency

A genotype-first approach identifies an intellectual disability-overweight syndrome caused by PHIP haploinsufficiency

  • Eur J Hum Genet. 2018 Jan;26(1):54-63. doi: 10.1038/s41431-017-0039-5.
Sandra Jansen 1,  Alexander Hoischen 2 3,  Bradley P Coe 4,  Gemma L Carvill 5,  Hilde Van Esch 6,  Daniëlle G M Bosch 1 7,  Ulla A Andersen 8,  Carl Baker 4,  Marijke Bauters 6,  Raphael A Bernier 9,  Bregje W van Bon 1,  Hedi L Claahsen-van der Grinten 10,  Jozef Gecz 11 12,  Christian Gilissen 1,  Lucia Grillo 13,  Anna Hackett 14,  Tjitske Kleefstra 1,  David Koolen 1,  Malin Kvarnung 15 16,  Martin J Larsen 17,  Carlo Marcelis 1,  Fiona McKenzie 18 19,  Marie-Lorraine Monin 20,  Caroline Nava 21 22,  Janneke H Schuurs-Hoeijmakers 1,  Rolph Pfundt 1,  Marloes Steehouwer 1,  Servi J C Stevens 23,  Connie T Stumpel 23,  Fleur Vansenne 24,  Mirella Vinci 13,  Maartje van de Vorst 1,  Petra de Vries 1,  Kali Witherspoon 4,  Joris A Veltman 1 25,  Han G Brunner 1 23,  Heather C Mefford 26,  Corrado Romano 27,  Lisenka E L M Vissers 1,  Evan E Eichler 4 28,  Bert B A de Vries 29
Affiliations

Affiliations

  • 1 Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
  • 2 Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands.
  • 3 Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands.
  • 4 Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, 98195, USA.
  • 5 Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
  • 6 Centre for Human Genetics, KU Leuven, Herestraat 49, B-3000, Leuven, Belgium.
  • 7 Currently working at the Department of Genetics, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands.
  • 8 Department of Psychiatry, Odense, Institute of clinical research, University of Southern Denmark, J.B. Winsløwsvej 18, 5000, Odense C, Denmark.
  • 9 Department of Psychiatry, University of Washington, Seattle, WA, USA.
  • 10 Department of Paediatric Endocrinology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
  • 11 Adelaide Medical School and the Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia.
  • 12 South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia.
  • 13 Laboratory of Medical Genetics, Oasi Research Institute (IRCCS), Via Conte Ruggero, 73, Postal Code 94018, Troina, Italy.
  • 14 The GOLD service Hunter Genetics, University of Newcastle, Newcastle, NSW, Australia.
  • 15 Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, SE-171 76, Stockholm, Sweden.
  • 16 Department of Clinical Genetics, Karolinska University Hospital, 171 77, Stockholm, Sweden.
  • 17 Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
  • 18 School of Paediatrics and Child Health, The University of Western Australia, Crawley, WA, Australia.
  • 19 Genetic Services of Western Australia, King Edward Memorial Hospital, Subiaco, WA, Australia.
  • 20 Department of Genetics, Pitié-Salpêtrière University Hospital, 47-83 Boulevard de l'Hôpital, 75651, Paris Cedex 13, France.
  • 21 Département de Génétique, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, 75013, Paris, France.
  • 22 INSERM, U 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, ICM, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, 75013, Paris, France.
  • 23 Department of Clinical Genetics and GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, P. Debyelaan 25, 6229 HX, Maastricht, The Netherlands.
  • 24 Department of Genetics, University of Groningen, University Medical Center Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands.
  • 25 Institute of Genetic Medicine, International Centre for Life, Newcastle University, Central Parkway, Newcastle, NE1 3BZ, United Kingdom.
  • 26 Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, United States.
  • 27 Pediatrics and Medical Genetics, Oasi Research Institute (IRCCS), Via Conte Ruggero, 73, Postal Code 94018, Troina, Italy.
  • 28 Howard Hughes Medical Institute, University of Washington, Seattle, WA, 98195, USA.
  • 29 Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands. [email protected].
PMID: 29209020 DOI: 10.1038/s41431-017-0039-5
Abstract

Genotype-first combined with reverse phenotyping has shown to be a powerful tool in human genetics, especially in the era of next generation sequencing. This combines the identification of individuals with mutations in the same gene and linking these to consistent (endo)phenotypes to establish disease causality. We have performed a MIP (molecular inversion probe)-based targeted re-sequencing study in 3,275 individuals with intellectual disability (ID) to facilitate a genotype-first approach for 24 genes previously implicated in ID.Combining our data with data from a publicly available database, we confirmed 11 of these 24 genes to be relevant for ID. Amongst these, PHIP was shown to have an enrichment of disruptive mutations in the individuals with ID (5 out of 3,275). Through international collaboration, we identified a total of 23 individuals with PHIP mutations and elucidated the associated phenotype. Remarkably, all 23 individuals had developmental delay/ID and the majority were overweight or obese. Other features comprised behavioral problems (hyperactivity, aggression, features of autism and/or mood disorder) and dysmorphisms (full eyebrows and/or synophrys, upturned nose, large ears and tapering fingers). Interestingly, PHIP encodes two protein-isoforms, PHIP/DCAF14 and NDRP, each involved in neurodevelopmental processes, including E3 ubiquitination and neuronal differentiation. Detailed genotype-phenotype analysis points towards haploinsufficiency of PHIP/DCAF14, and not NDRP, as the underlying cause of the phenotype.Thus, we demonstrated the use of large scale re-sequencing by MIPs, followed by reverse phenotyping, as a constructive approach to verify candidate disease genes and identify novel syndromes, highlighted by PHIP haploinsufficiency causing an ID-overweight syndrome.

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