title: A recessive syndrome of intellectual disability, moderate overgrowth, and renal dysplasia predisposing to Wilms tumor is caused by a mutation in FIBP gene.
abstract: Clinical classification of overgrowth syndromes represents a challenge since a wide spectrum of disorders result in marked overgrowth. Therefore, there is a continuous effort to identify the genetic basis of these disorders that will eventually facilitate their molecular classification. Here, we have identified the genetic etiology and the pathogenetic mechanism underlying a rare autosomal recessive overgrowth syndrome in three affected siblings. The overgrowth phenotype in the patients was accompanied by developmental delay, learning disabilities, and variable congenital abnormalities. To elucidate the genetic etiology of the disorder, whole-genome genotyping and whole-exome sequencing were used. The disease was mapped to 3p21.1-p14.2 and 11q13.1-q13.4, where an in-frame insertion (c.175_176insTAA) in FIBP gene was revealed. The resulting indel (p.H59LN) was predicted to change the protein conformation with likely deleterious effect on its function as one of the fibroblast growth factor signaling mediators. In vitro cellular proliferation assay and in situ hypridization in vivo were then performed to understand the pathophysiology of the disease. The patients' skin fibroblasts showed an increased proliferation capacity compared to the controls' explaining the observed overgrowth phenotype. In addition, we detected Fibp expression most notably in the brains of mice embryos suggesting a possible effect on cognitive functions early in development. To date, only one patient has been reported with a homozygous nonsense mutation in FIBP exhibiting an overgrowth syndrome with multiple congenital abnormalities. Taken all together, these findings provide convincing evidence implicating FIBP aberrations in the newly recognized overgrowth syndrome and expand the associated phenotypes to include possible Wilms tumor predisposition. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.
authors.forename: Nadia
authors.initials: N
authors.lastname: Akawi
authors.affiliation: Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.
authors.forename: Salma
authors.initials: S
authors.lastname: Ben-Salem
authors.affiliation: Department of Biosciences, University of Helsinki, Helsinki, Finland.
authors.forename: Laura
authors.initials: L
authors.lastname: Lahti
authors.affiliation: Department of Biosciences, University of Helsinki, Helsinki, Finland.
authors.forename: Juha
authors.initials: J
authors.lastname: Partanen
authors.affiliation: Department of Biosciences, University of Helsinki, Helsinki, Finland.
authors.forename: Bassam R
authors.initials: BR
authors.lastname: Ali
authors.affiliation: Department of Paediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.
authors.forename: Lihadh
authors.initials: L
authors.lastname: Al-Gazali
mesh_terms: D000293:Adolescent; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D005808:Genes, Recessive; D056726:Genetic Association Studies; D005838:Genotype; D006130:Growth Disorders / Q000175:diagnosis / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D007668:Kidney / Q000002:abnormalities*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D013577:Syndrome; D009396:Wilms Tumor / Q000175:diagnosis / Q000209:etiology*
chemical_list: D002352:Carrier Proteins; C116274:FIBP protein, human; D008565:Membrane Proteins
keywords: FIBP; Wilms tumor; autosomal recessive; learning disabilities; mutation; overgrowth