title: Expanding the phenotype of CRB2 mutations - A new ciliopathy syndrome?
abstract: Recessive CRB2 mutations were recently reported to cause both steroid resistant nephrotic syndrome and prenatal onset ventriculomegaly with kidney disease. We report two Ashkenazi Jewish siblings clinically diagnosed with ciliopathy. Both presented with severe congenital hydrocephalus and mild urinary tract anomalies. One affected sibling also has lung hypoplasia and heart defects. Exome sequencing and further CRB2 analysis revealed that both siblings are compound heterozygotes for CRB2 mutations p.N800K and p.Gly1036Alafs*43, and heterozygous for a deleterious splice variant in the ciliopathy gene TTCB21. CRB2 is a polarity protein which plays a role in ciliogenesis and ciliary function. Biallelic CRB2 mutations in animal models result in phenotypes consistent with ciliopathy. This report expands the phenotype of CRB2 mutations to include lung hypoplasia and uretero-pelvic renal anomalies, and confirms cardiac malformation as a feature. We suggest that CRB2-associated disease is a new ciliopathy syndrome with possible digenic/triallelic inheritance, as observed in other ciliopathies. Clinically, CRB2 should be assessed when ciliopathy is suspected, especially in Ashkenazi Jews, where we found that p.N800K carrier frequency is 1 of 64. Patients harboring CRB2 mutations should be tested for the complete range of ciliopathy manifestations.
authors.affiliation: Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: R
authors.initials: R
authors.lastname: Jaron
authors.affiliation: Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel.|Faculty of Medicine, The Hebrew University of Jerusalem Medical School, Jerusalem, Israel.
authors.forename: N
authors.initials: N
authors.lastname: Rosenfeld
authors.affiliation: Department of Genetics, The Alexander Silberman Institute of Life Sciences, Faculty of Science Jerusalem, Edmond J. Safra Campus, Givat Ram, The Hebrew University of Jerusalem, Jerusalem, Israel.|Hereditary Research Lab, Life Sciences Department, Bethlehem University, Bethlehem, Israel.
authors.forename: F
authors.initials: F
authors.lastname: Zahdeh
authors.affiliation: Braun School of Public Health, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: S
authors.initials: S
authors.lastname: Carmi
authors.affiliation: Pediatric Neurosurgery, Shaare Zedek Medical Center, Jerusalem, Israel.|Pediatric Neurology Unit, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: L
authors.initials: L
authors.lastname: Beni-Adani
authors.affiliation: Department of Pathology, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: V
authors.initials: V
authors.lastname: Doviner
authors.affiliation: Faculty of Medicine, The Hebrew University of Jerusalem Medical School, Jerusalem, Israel.|Pediatric Pulmonary Institute, Department of Pediatrics, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Picard
authors.affiliation: Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel.|Faculty of Medicine, The Hebrew University of Jerusalem Medical School, Jerusalem, Israel.
authors.forename: R
authors.initials: R
authors.lastname: Segel
authors.affiliation: Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: S
authors.initials: S
authors.lastname: Zeligson
authors.affiliation: Department of Genetics, The Alexander Silberman Institute of Life Sciences, Faculty of Science Jerusalem, Edmond J. Safra Campus, Givat Ram, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: L
authors.initials: L
authors.lastname: Carmel
authors.affiliation: Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: P
authors.initials: P
authors.lastname: Renbaum
authors.affiliation: Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel.|Faculty of Medicine, The Hebrew University of Jerusalem Medical School, Jerusalem, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Levy-Lahad
mesh_terms: D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D000072661:Ciliopathies / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D006579:Heterozygote; D006801:Humans; D007585:Jews / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D035781:Siblings
chemical_list: C492531:CRB2 protein, human; D002352:Carrier Proteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C000594121:TTC21B protein, human
keywords: CRB2; ciliopathy; hydrocephalus; polarity protein; pulmonary hypoplasia; renal disease