TY - JOUR
T1 - A genotype-first approach identifies an intellectual disability-overweight syndrome caused by PHIP haploinsufficiency
AU - Jansen, Sandra
AU - Hoischen, Alexander
AU - Coe, Bradley P.
AU - Carvill, Gemma L.
AU - Van Esch, Hilde
AU - Bosch, Daniëlle G.M.
AU - Andersen, Ulla A.
AU - Baker, Carl
AU - Bauters, Marijke
AU - Bernier, Raphael A.
AU - Van Bon, Bregje W.
AU - Claahsen-Van Der Grinten, Hedi L.
AU - Gecz, Jozef
AU - Gilissen, Christian
AU - Grillo, Lucia
AU - Hackett, Anna
AU - Kleefstra, Tjitske
AU - Koolen, David
AU - Kvarnung, Malin
AU - Larsen, Martin J.
AU - Marcelis, Carlo
AU - McKenzie, Fiona
AU - Monin, Marie Lorraine
AU - Nava, Caroline
AU - Schuurs-Hoeijmakers, Janneke H.
AU - Pfundt, Rolph
AU - Steehouwer, Marloes
AU - Stevens, Servi J.C.
AU - Stumpel, Connie T.
AU - Vansenne, Fleur
AU - Vinci, Mirella
AU - Van De Vorst, Maartje
AU - Vries, Petra De
AU - Witherspoon, Kali
AU - Veltman, Joris A.
AU - Brunner, Han G.
AU - Mefford, Heather C.
AU - Romano, Corrado
AU - Vissers, Lisenka E.L.M.
AU - Eichler, Evan E.
AU - De Vries, Bert B.A.
N1 - Funding Information:
Acknowledgements We are grateful to all individuals and their parents for participating in this study. We are also grateful to the Rad-boud Genomics Technology Center for performing Sanger sequencing. We also want to thank Choli Lee for technical assistance with HiSeq sequencing. We thank Boris Keren, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Département de Génétique, Paris, France, for interpretation of the exome data of Individual 15. We thank Ineke van der Burgt, Human Genetics, Radboudumc, Nijmegen, The Netherlands and Christina Ringmann Fagerberg, Department of Clinical Genetics, Odense University Hospital, Denmark for clinical support. We are grateful to all of the families at the participating Simons Simplex Collection (SSC) sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren, E. Wijsman). We appreciate obtaining access to phenotypic data on SFARI Base. This work was financially supported by grants from the Netherlands Organisation for Health Research and Development (917-86-319 to B.B.A.d.V., 912-12-109 to B.B.A.d.V. and J.A.V., 907-00-365 to T.K., and 918-15-667 to J.A.V) and the European Research Council (ERC; starting grant DENOVO 281964 to J.A.V.). This research was supported, in part, by the following: Simons Foundation Autism Research Initiative (SFARI 303241) to E.E.E., National Institutes of Health (R01MH101221 to E. E.E. and R01MH100047 to R.A.B.). E.E.E. is an investigator of the Howard Hughes Medical Institute. J.G. is supported by NHMRC research fellowship 1041920 and Channel 7 Children’s Research Foundation. This work was supported by the Italian Ministry of Health and “5 per mille” funding. The authors would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at http://exac.broadinstitute.org/about.
Publisher Copyright:
© 2017 European Society of Human Genetics.
PY - 2018/1/1
Y1 - 2018/1/1
N2 - 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.
AB - 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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U2 - 10.1038/s41431-017-0039-5
DO - 10.1038/s41431-017-0039-5
M3 - Article
C2 - 29209020
AN - SCOPUS:85036653048
VL - 26
SP - 54
EP - 63
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
SN - 1018-4813
IS - 1
ER -