A genotype-first approach identifies an intellectual disability-overweight syndrome caused by PHIP haploinsufficiency
Sandra Jansen
(1, 2)
,
Alexander Hoischen
(2)
,
Bradley Coe
(3)
,
Gemma Carvill
(4)
,
Hilde van Esch
(5)
,
Daniëlle Bosch
(1, 6)
,
Ulla Andersen
(7)
,
Carl Baker
(8)
,
Marijke Bauters
(9)
,
Raphael Bernier
(3)
,
Bregje van Bon
(2)
,
Hedi Claahsen-van der Grinten
(2)
,
Jozef Gecz
(10)
,
Christian Gilissen
(2)
,
Lucia Grillo
(11)
,
Anna Hackett
(12)
,
Tjitske Kleefstra
(13)
,
David Koolen
(1)
,
Malin Kvarnung
(14)
,
Martin J. Larsen
(15)
,
Carlo Marcelis
(2)
,
Fiona Mckenzie
(16)
,
Marie-Lorraine Monin
(17)
,
Caroline Nava
(17)
,
Janneke Schuurs-Hoeijmakers
(2)
,
Rolph Pfundt
(2)
,
Marloes Steehouwer
(2)
,
Servi Stevens
(18)
,
Connie Stumpel
(18)
,
Fleur Vansenne
(19)
,
Mirella Vinci
(20)
,
Maartje van de Vorst
(2)
,
Petra De Vries
(2)
,
Kali Witherspoon
(3)
,
Joris Veltman
(2, 21)
,
Han Brunner
(2, 18)
,
Heather Mefford
(3)
,
Corrado Romano
(20)
,
Lisenka Vissers
(2)
,
Evan Eichler
(3)
,
Bert de Vries
(2)
1
Donders Institute for Brain, Cognition and Behaviour
2 Radboud University Medical Center [Nijmegen]
3 University of Washington [Seattle]
4 [Northwestern University Medical School] - Feinberg School of Medicine [Northwestern University, Evanston]
5 KU Leuven - Catholic University of Leuven = Katholieke Universiteit Leuven
6 UMCU - University Medical Center [Utrecht]
7 SDU - University of Southern Denmark
8 GS - Department of Genome Sciences [Seattle]
9 University Hospitals Leuven [Leuven]
10 University of Adelaide
11 IRCCS - Istituto di Ricovero e Cura a Carattere Scientifico
12 Hunter Genetics
13 Department of Human Genetics [Nijmegen]
14 Karolinska Institutet [Stockholm]
15 OUH - Odense University Hospital
16 UWA - The University of Western Australia
17 ICM - Institut du Cerveau = Paris Brain Institute
18 MUMC - Maastricht University Medical Centre
19 UMCG - University Medical Center Groningen [Groningen]
20 I.R.C.C.S. - "Oasi Maria Santissima" Institute for Research and Prevention of Mental Retardation
21 Newcastle University [Newcastle]
2 Radboud University Medical Center [Nijmegen]
3 University of Washington [Seattle]
4 [Northwestern University Medical School] - Feinberg School of Medicine [Northwestern University, Evanston]
5 KU Leuven - Catholic University of Leuven = Katholieke Universiteit Leuven
6 UMCU - University Medical Center [Utrecht]
7 SDU - University of Southern Denmark
8 GS - Department of Genome Sciences [Seattle]
9 University Hospitals Leuven [Leuven]
10 University of Adelaide
11 IRCCS - Istituto di Ricovero e Cura a Carattere Scientifico
12 Hunter Genetics
13 Department of Human Genetics [Nijmegen]
14 Karolinska Institutet [Stockholm]
15 OUH - Odense University Hospital
16 UWA - The University of Western Australia
17 ICM - Institut du Cerveau = Paris Brain Institute
18 MUMC - Maastricht University Medical Centre
19 UMCG - University Medical Center Groningen [Groningen]
20 I.R.C.C.S. - "Oasi Maria Santissima" Institute for Research and Prevention of Mental Retardation
21 Newcastle University [Newcastle]
Christian Gilissen
- Fonction : Auteur
- PersonId : 1377566
- ORCID : 0000-0003-1693-9699
Martin J. Larsen
- Fonction : Auteur
- PersonId : 1377567
- ORCID : 0000-0003-4107-8771
Marie-Lorraine Monin
- Fonction : Auteur
- PersonId : 1211083
- ORCID : 0000-0002-0116-036X
- IdRef : 176085386
Corrado Romano
- Fonction : Auteur
- PersonId : 1377551
- ORCID : 0000-0003-1049-0683
Evan Eichler
- Fonction : Auteur
- PersonId : 1377568
- ORCID : 0000-0002-8246-4014
Résumé
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.