Duplication of exon 2 of the GPC3 gene in a case of Simpson‐Golabi‐Behmel syndrome

Abstract

In the May issue of the Journal, Mateos et al. [2013] reported a case of Simpson-Golabi-Behmel syndrome (SGBS), with a novel mutation of theGPC3 gene consisting of a duplication of exons 2–4 which causes a frameshift leading to a protein truncated of its last 183 amino-acids including the C-terminus. This report pinpointed that duplication of the GPC3 gene had not been reported before. We would like to emphasize that duplication screening should be part of the molecular analysis in SGBS by describing another duplication of GPC3. In a recent paper [Cottereau et al., 2013] we reported a large series of patientswith SGBS including one casewith aduplication of exon 2. This duplication was detected bymultiplex ligation-dependent probe amplification (MLPA) analysis in a series of 48 patients referred for SGBS, in whom no GPC3 deletion or point mutation had been identified (Fig. 1). This result was confirmed by quantitativemultiplex fluorescent PCR (PCR of exons 2, 3, and 8 ofGPC3 compared with exon 22 of the CFTR gene as internal control) (results not shown). RT-PCR analysis performed on mRNA extracted from a lymphoblastoid cell line of the patient, with primers designed in exons 1 and 3, respectively, showed a fragment with a size increase of around 160 pb compared to a normal control (Fig. 2). Sequencing of this fragment showed that it was a tandem duplication of exon 2. Unlike the previously reported case, this duplication conserves the reading frame and leads to an insertion of 54 residues from Gly59 to Gln112, in the GPC3 protein. This insertion includes, in the fourteen cysteine motif, three additional cysteine residues (p.Cys65, p.Cys72 and p.Cys73) which probably disrupt the conserved glypican three-dimensional structure of the protein thus altering its function [Filmus and Capurro, 2008]. This duplication was observed in a sporadic case (DNA of his mother was unavailable) who had a clinical picture typical of SGBS. He had been examined at the age of 20 years for tall stature. The diagnosis of SGBS had been suggested on themedical history of the patient because of macrosomia at birth followed by advanced statural growth (height at 214 cm) but normal OFC (þ0.8 SD) and BMI (20.1), diaphragmatic hernia operated on in the neonatal period, cryptorchidism, and on examination pectus excavatum, one pair of extra nipples, inguinal hernia, large hands, and suggestive dysmorphic features (macrognathia, median groove of the