title: Early detection of bilateral cataracts in utero may represent a manifestation of severe congenital disease.
abstract: We observed bilateral cataracts on second trimester ultrasound, in two consecutive pregnancies, with no other structural defects detected. The parents were unrelated and had no family history for the disease. The first pregnancy was terminated in week 22. Copy number variation analysis revealed, in both the aborted fetus and the mother, a 495 kb duplication at 22q11.23 encompassing CRYBB3 and CRYBB2, and not present in variation databases. In the second pregnancy, lens hyperechogenicity was detected by ultrasound at week 13 and 4 days. The identical duplication at 22q11.23 was found in the fetus and considered as possibly pathogenic. At weeks 22 and 30, smaller orbit measurements were elucidated on ultrasound, raising concerns as to the underlying molecular genetic cause, necessitating further investigation. Whole-exome sequencing, using DNA of the first fetus, was performed shortly after the birth of a male child, and two truncating RAB3GAP1 mutations were detected: c.538G>T; p. (Glu180*) and c.943C>T; p. (Arg315*). Neither mutation has been previously reported to be disease-causing; however, evaluation in the context of previously published literature indicated their deleterious nature, implying a clinical diagnosis of Warburg micro syndrome or Martsolf syndrome. Sanger sequencing confirmed segregation of the two mutations within the family, consistent with autosomal recessive inheritance. The child born from the second pregnancy showed features typical of Warburg micro syndrome, with the exception of microcephaly, at age 31 months. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Gennet, Centre for Fetal Medicine and Reproductive Genetics, Prague, Czech Republic.
authors.forename: Marie
authors.initials: M
authors.lastname: Trkova
authors.affiliation: Gennet, Centre for Fetal Medicine and Reproductive Genetics, Prague, Czech Republic.|Department of Gynecology and Obstetrics, Thomayer Hospital, Prague, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Hynek
authors.affiliation: Institute of Inherited Metabolic Diseases, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Czech Republic.
authors.forename: Lubica
authors.initials: L
authors.lastname: Dudakova
authors.affiliation: Gennet, Centre for Fetal Medicine and Reproductive Genetics, Prague, Czech Republic.
authors.forename: Vera
authors.initials: V
authors.lastname: Becvarova
authors.affiliation: Department of Ophthalmology, Second Faculty of Medicine, Charles University in Prague and Motol Hospital in Prague, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Hlozanek
authors.affiliation: Gennet, Centre for Fetal Medicine and Reproductive Genetics, Prague, Czech Republic.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Raskova
authors.affiliation: Faculty of Medical and Health Sciences, Department of Ophthalmology, New Zealand National Eye Centre, University of Auckland, Auckland, New Zealand.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Vincent
authors.affiliation: Institute of Inherited Metabolic Diseases, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Czech Republic.|Department of Ophthalmology, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Liskova
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D037881:Aborted Fetus / Q000503:physiopathology; D002386:Cataract / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D003315:Cornea / Q000002:abnormalities* / Q000503:physiopathology; D056915:DNA Copy Number Variations / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D007006:Hypogonadism / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D007223:Infant; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008831:Microcephaly / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation; D009896:Optic Atrophy / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D011247:Pregnancy; D017422:Sequence Analysis, DNA; D016216:Ultrasonography, Prenatal; D038206:beta-Crystallin B Chain / Q000235:genetics*; D020692:rab3 GTP-Binding Proteins / Q000235:genetics*
chemical_list: C103908:CRYBB3 protein, human; D038206:beta-Crystallin B Chain; C113634:beta-crystallin B2; C580955:RAB3GAP1 protein, human; D020692:rab3 GTP-Binding Proteins
keywords: CRYBB2; CRYBB3; DNA copy number variations; RAB3GAP1; Warburg micro syndrome; high-throughput nucleotide sequencing; prenatal ultrasonography