ArticleEuropean journal of human genetics : EJHG2018
A genotype-first approach identifies an intellectual disability-overweight syndrome caused by PHIP haploinsufficiency.
Article in European journal of human genetics : EJHG, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 57 citations in OpenAlex.
- Chung-Jansen Syndrome in a Young Woman with a PHIP Variant: Severe Obesity, Intellectual Disability, and Endocrine Abnormalities.Journal of clinical medicine · 2026Article
- A clinical protocol for the detection of comorbidities associated with monogenic causes of male infertility.Human reproduction (Oxford, England) · 2026Article
- Differential phosphorylation of PHIP phosphopeptides with implications in insulin signaling.BMC molecular and cell biology · 2026Article
- Identification of de novo variants from parent-proband duos via long-read sequencing.American journal of human genetics · 2026Article
- Sleep-Disordered Breathing in Chung-Jansen Syndrome.International journal of molecular sciences · 2026Article
- Novel Insights: A Novel PHIP Variant in a Family with Severe Early-Onset Obesity.Hormone research in paediatrics · 2026Article
- Clinical exome sequencing efficacy and phenotypic expansions involving non-isolated congenital anomalies of kidney and urinary tract (CAKUT+).European journal of human genetics : EJHG · 2025Article
- Patient reported outcomes that matter to individuals with (genetic) intellectual disabilities: a qualitative study.Journal of neurodevelopmental disorders · 2025Article
- Neuroendocrinology and the Genetics of Obesity.Endocrinology · 2025Review
- Detecting monogenic obesity: a systematic exome-wide workup of over 500 individuals.International journal of obesity (2005) · 2025Article
- Abundant Parent-of-origin Effect eQTL: The Framingham Heart Study.bioRxiv : the preprint server for biology · 2025Article
- Cullin-RING Ubiquitin Ligases in Neurodevelopment and Neurodevelopmental Disorders.Biomedicines · 2025Review
- The expanding landscape of genetic causes of obesity.Pediatric research · 2025Review
- Broadening theChildren (Basel, Switzerland) · 2024Article
- Updates on Rare Genetic Variants, Genetic Testing, and Gene Therapy in Individuals With Obesity.Current obesity reports · 2024Review
- Pathogenic PHIP Variants are Variably Associated With CAKUT.Kidney international reports · 2024Article
- The detection of a strong episignature for Chung-Jansen syndrome, partially overlapping with Börjeson-Forssman-Lehmann and White-Kernohan syndromes.Human genetics · 2024Article
- A Comprehensive Review of Syndromic Forms of Obesity: Genetic Etiology, Clinical Features and Molecular Diagnosis.Current obesity reports · 2024Review
- Clinical phenotypes of individuals with Chung-Jansen syndrome across age groups.American journal of medical genetics. Part A · 2024Article
- Increased burden of rare protein-truncating variants in constrained, brain-specific and synaptic genes in extremely impulsively violent males with antisocial personality disorder.Genes, brain, and behavior · 2024Article
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Authors and funding
41 authors at 16 institutions in 9 countries.
Funding
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.
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