title: Expansion of phenotype and genotypic data in CRB2-related syndrome.
abstract: Sequence variants in CRB2 cause a syndrome with greatly elevated maternal serum alpha-fetoprotein and amniotic fluid alpha-fetoprotein levels, cerebral ventriculomegaly and renal findings similar to Finnish congenital nephrosis. All reported patients have been homozygotes or compound heterozygotes for sequence variants in the Crumbs, Drosophila, Homolog of, 2 (CRB2) genes. Variants affecting CRB2 function have also been identified in four families with steroid resistant nephrotic syndrome, but without any other known systemic findings. We ascertained five, previously unreported individuals with biallelic variants in CRB2 that were predicted to affect function. We compiled the clinical features of reported cases and reviewed available literature for cases with features suggestive of CRB2-related syndrome in order to better understand the phenotypic and genotypic manifestations. Phenotypic analyses showed that ventriculomegaly was a common clinical manifestation (9/11 confirmed cases), in contrast to the original reports, in which patients were ascertained due to renal disease. Two children had minor eye findings and one was diagnosed with a B-cell lymphoma. Further genetic analysis identified one family with two affected siblings who were both heterozygous for a variant in NPHS2 predicted to affect function and separate families with sequence variants in NPHS4 and BBS7 in addition to the CRB2 variants. Our report expands the clinical phenotype of CRB2-related syndrome and establishes ventriculomegaly and hydrocephalus as frequent manifestations. We found additional sequence variants in genes involved in kidney development and ciliopathies in patients with CRB2-related syndrome, suggesting that these variants may modify the phenotype.
authors.affiliation: Department of Medical Genetics and Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Lamont
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Wen-Hann
authors.initials: WH
authors.lastname: Tan
authors.affiliation: Department of Medical Genetics and Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.
authors.forename: A Micheil
authors.initials: AM
authors.lastname: Innes
authors.affiliation: Department of Medical Genetics and Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Jillian S
authors.initials: JS
authors.lastname: Parboosingh
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.|Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Dina
authors.initials: D
authors.lastname: Schneidman-Duhovny
authors.affiliation: Center for Medical Genetics and Genomics, Magee-Womens Hospital of University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Rajkovic
authors.affiliation: Clinical Genetic Services, Department of Pediatrics, NYU School of Medicine, New York, NY, USA.
authors.forename: John
authors.initials: J
authors.lastname: Pappas
authors.affiliation: Department of Ophthalmology, Boston Children's Hospital, Boston, MA, USA.|Department of Ophthalmology, Pontificia Universidad Catolica de Chile, Santiago, Chile.
authors.forename: Pablo
authors.initials: P
authors.lastname: Altschwager
authors.affiliation: GeneDx, Inc., Gaithersburg, MD, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: DeWard
authors.affiliation: Department of Ophthalmology, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Fulton
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Gray
authors.affiliation: Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Max
authors.initials: M
authors.lastname: Krall
authors.affiliation: Division of Medical Genetics, Icahn School of Medicine at Mount Sinai & Mount Sinai Medical Center, New York, NY, USA.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Mehta
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Lance H
authors.initials: LH
authors.lastname: Rodan
authors.affiliation: Center for Medical Genetics and Genomics, Magee-Womens Hospital of University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Devereux N
authors.initials: DN
authors.lastname: Saller
authors.affiliation: Center for Medical Genetics and Genomics, Magee-Womens Hospital of University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Deanna
authors.initials: D
authors.lastname: Steele
authors.affiliation: Division of Nephrology, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Stein
authors.affiliation: Center for Medical Genetics and Genomics, Magee-Womens Hospital of University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Svetlana A
authors.initials: SA
authors.lastname: Yatsenko
authors.affiliation: Department of Medical Genetics and Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.
authors.forename: François P
authors.initials: FP
authors.lastname: Bernier
authors.affiliation: Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Slavotinek
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000235:genetics*; D003598:Cytoskeletal Proteins; D005260:Female; D005838:Genotype; D006801:Humans; D006849:Hydrocephalus / Q000175:diagnosis / Q000235:genetics*; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D009401:Nephrosis / Q000175:diagnosis / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011506:Proteins / Q000235:genetics; D013577:Syndrome
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C473308:Bbs7 protein, human; C492531:CRB2 protein, human; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D011506:Proteins