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, Danielle 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 - de Vries, Petra
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.
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.
KW - DE-NOVO MUTATIONS
KW - DOMAIN-INTERACTING PROTEIN
KW - LINKED MENTAL-RETARDATION
KW - AUTISM SPECTRUM DISORDERS
KW - OF-FUNCTION MUTATIONS
KW - DEVELOPMENTAL DELAY
KW - SIGNALING PATHWAYS
KW - UBIQUITIN LIGASE
KW - GENES
KW - SCHIZOPHRENIA
U2 - 10.1038/s41431-017-0039-5
DO - 10.1038/s41431-017-0039-5
M3 - Article
C2 - 29209020
SN - 1018-4813
VL - 26
SP - 54
EP - 63
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 1
ER -