Article open access publication

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

European Journal of Human Genetics, Springer Nature, ISSN 1018-4813

Volume 26, 1, 2018

DOI:10.1038/s41431-017-0039-5, Dimensions: pub.1095859071, PMC: PMC5839042, PMID: 29209020,



  1. (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. (2) Radboud University Nijmegen Medical Centre, grid.10417.33
  3. (3) University of Washington, grid.34477.33
  4. (4) Northwestern University, grid.16753.36
  5. (5) KU Leuven, grid.5596.f
  6. (6) University Medical Center Utrecht, grid.7692.a
  7. (7) University of Southern Denmark, grid.10825.3e, SDU
  8. (8) South Australian Health and Medical Research Institute, grid.430453.5
  9. (9) University of Adelaide, grid.1010.0
  10. (10) Laboratory of Medical Genetics, Oasi Research Institute (IRCCS), Via Conte Ruggero, 73, Postal Code 94018, Troina, Italy
  11. (11) University of Newcastle Australia, grid.266842.c
  12. (12) Karolinska Institute, grid.4714.6
  13. (13) Karolinska University Hospital, grid.24381.3c
  14. (14) Odense University Hospital, grid.7143.1, Southern Denmark Region
  15. (15) King Edward Memorial Hospital, grid.415259.e
  16. (16) University of Western Australia, grid.1012.2
  17. (17) Pitié-Salpêtrière Hospital, grid.411439.a
  18. (18) Maastricht University Medical Centre, grid.412966.e
  19. (19) University Medical Center Groningen, grid.4494.d
  20. (20) Newcastle University, grid.1006.7
  21. (21) Pediatrics and Medical Genetics, Oasi Research Institute (IRCCS), Via Conte Ruggero, 73, Postal Code 94018, Troina, Italy


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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