title: CRB2 mutations produce a phenotype resembling congenital nephrosis, Finnish type, with cerebral ventriculomegaly and raised alpha-fetoprotein.
abstract: We report five fetuses and a child from three families who shared a phenotype comprising cerebral ventriculomegaly and echogenic kidneys with histopathological findings of congenital nephrosis. The presenting features were greatly elevated maternal serum alpha-fetoprotein (MSAFP) or amniotic fluid alpha-fetoprotein (AFAFP) levels or abnormalities visualized on ultrasound scan during the second trimester of pregnancy. Exome sequencing revealed deleterious sequence variants in Crumbs, Drosophila, Homolog of, 2 (CRB2) consistent with autosomal-recessive inheritance. Two fetuses with cerebral ventriculomegaly and renal microcysts were compound heterozygotes for p.Asn800Lys and p.Trp759Ter, one fetus with renal microcysts was a compound heterozygote for p.Glu643Ala and p.Asn800Lys, and one child with cerebral ventriculomegaly, periventricular heterotopias, echogenic kidneys, and renal failure was homozygous for p.Arg633Trp in CRB2. Examination of the kidneys in one fetus showed tubular cysts at the corticomedullary junction and diffuse effacement of the epithelial foot processes and microvillous transformation of the renal podocytes, findings that were similar to those reported in congenital nephrotic syndrome, Finnish type, that is caused by mutations in nephrin (NPHS1). Loss of function for crb2b and nphs1 in Danio rerio were previously shown to result in loss of the slit diaphragms of the podocytes, leading to the hypothesis that nephrosis develops from an inability to develop a functional glomerular barrier. We conclude that the phenotype associated with CRB2 mutations is pleiotropic and that the condition is an important consideration in the evaluation of high MSAFP/AFAFP where a renal cause is suspected.
authors.affiliation: Department of Pediatrics, Division of Genetics, University of California, San Francisco, San Francisco, CA 94143-2711, USA; Institute for Human Genetics, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0794, USA. Electronic address: slavotia@ucsf.edu.
authors.forename: Anne
authors.initials: A
authors.lastname: Slavotinek
authors.affiliation: Molecular Genetics Pathology Laboratory, Arkansas Children's Hospital, 1 Children's Way, Slot 820, Little Rock, AR 72202, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Kaylor
authors.affiliation: GeneDx, Inc., 207 Perry Parkway, Gaithersburg, MD 20877, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Pierce
authors.affiliation: Division of Medical Genetics, Icahn School of Medicine at Mount Sinai & Mount Sinai Medical Center, 1 Gustave Levy Place, New York, NY 10029, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Cahr
authors.affiliation: GeneDx, Inc., 207 Perry Parkway, Gaithersburg, MD 20877, USA.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: DeWard
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Dina
authors.initials: D
authors.lastname: Schneidman-Duhovny
authors.affiliation: Department of Pediatrics, Division of Genetics, University of California, San Francisco, San Francisco, CA 94143-2711, USA.
authors.forename: Adnan
authors.initials: A
authors.lastname: Alsadah
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai & Mount Sinai Medical Center, 1 Gustave Levy Place, New York, NY 10029, USA.
authors.forename: Fadi
authors.initials: F
authors.lastname: Salem
authors.affiliation: Division of Rheumatology, Department of Medicine, UCSF and the San Francisco VA Hospital, 4150 Clement St, Mailstop 111R, San Francisco, CA 94121, USA.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Schmajuk
authors.affiliation: Division of Medical Genetics, Icahn School of Medicine at Mount Sinai & Mount Sinai Medical Center, 1 Gustave Levy Place, New York, NY 10029, USA.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Mehta
mesh_terms: D000653:Amniotic Fluid / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002648:Child; D005260:Female; D005333:Fetus; D014644:Genetic Variation; D006801:Humans; D006849:Hydrocephalus / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009404:Nephrotic Syndrome / Q000235:genetics*; D010641:Phenotype; D011247:Pregnancy; D017433:Protein Structure, Secondary; D000509:alpha-Fetoproteins / Q000378:metabolism*
chemical_list: C492531:CRB2 protein, human; D002352:Carrier Proteins; D008565:Membrane Proteins; D000509:alpha-Fetoproteins