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

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.

Fig. 1

Photographs of individuals with a mutation in PHIP, overview of the PHIP gene with the 2 isoforms and location of mutations. a Photographs of 14 individuals with a mutation in PHIP of whom Individuals 18 and 19 were sisters. Shared facial features include a high forehead, full eyebrows/synophrys, characteristic upturned nose with thick alae nasi, a long philtrum and thin lips. Photographs are shown with informed consent of the individual or his/her parents. b Schematic representation of the PHIP gene (NM_017934.6) and the two protein isoforms PHIP/DCAF14 and NDRP. The point mutations are scattered throughout the coding sequence. The structural variants identified in Individuals 13 and 14 are depicted in detail in Supplemental Fig. 2. IRS, insulin receptor substrate domain; PH, pleckstrin homology domain