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.

Revealing the functions of novel mutations in RAB3GAP1 in Martsolf and Warburg micro syndromes

“…Supporting Information Table S1 demonstrates RAB3GAP1 mutations in the literature. To date 3 missense mutations, 27 nonsense mutations, 25 deletion/insertions, and 10 splicing mutations were identified in this gene (Aligianis et al, ; Asahina, Endoh, Matsubayashi, Fukuda, & Ogata, ; Gupta et al, ; Handley et al, ; Handley & Aligianis, ; Imagawa et al, ; Kadam & Chuan, ; Loiudice, Napoli, Ragone, Nardi, & Casini, ; Morris‐Rosendahl et al, ; Trkova et al, ).…”

Prenatal Diagnosis of Congenital Cataract: Sonographic Features and Perinatal Outcome in 41 Cases

“…In reviewing the literature, we identified 15 isolated congenital cataracts diagnosed antenatally (▶ Table 4) [6,9,[23][24][25][26][27][28][29][30]. Among these 15 cases, 8 cases had termination of pregnancy and 7 cases were liveborn.…”

Congenital Cataract and Narrow CSP: A Clue to Prenatal Diagnosis of RAB3GAP1-Associated Warburg Micro Syndrome

“…At 18 weeks, her fetal ultrasound showed bilateral echogenic lens and a narrow CSP measuring 1.4 mm in width (►Figs. 1,2). Antenatal developing corpus callosum was seen normally.…”

“…With advancement in fetal scanning, fetal eye and brain anomalies can be detected early in pregnancy and prenatal diagnosis of WMS has been made in cases of congenital cataracts. 1 Cavum septum pellucidum (CSP) is a very important landmark in fetal brain imaging and is present between 18 and 36 weeks of pregnancy. Abnormalities of CSP include its absence, enlargement, or echogenicity.…”