title: Molecular analysis of a novel intragenic deletion in GPC3 in three cousins with Simpson-Golabi-Behmel syndrome.
abstract: Simpson-Golabi-Behmel syndrome (SGBS) is characterized by multiple congenital abnormalities, pre/postnatal overgrowth, distinctive craniofacial features intellectual disability (ID) of variable degree, and an increased risk for embryonal tumors. SGBS is X-linked recessive and caused by deletions, duplications, and point mutations in GPC3, encoding a membrane associated cell surface heparan sulfate proteoglycan named glypican 3. GPC3 plays essential roles in the regulation of cell growth signaling and cell division. Here, we report on a family with three affected cousins who show variable clinical signs of SGBS and ID. Initial microarray-CGH revealed a deletion of approximately 30-50 kb that includes at least one exon of GPC3. By subsequent Sanger sequencing of genomic DNA we could map the chromosomal break points to define a deletion size of 43,617 bp including exons 5 and 6 of the GPC3 gene. RT-PCR analysis on RNA derived from whole blood could further confirm the deletion of both exons on transcript level. This loss of two exons results in a frameshift and a premature stop of translation. Based on our results we have established a breakpoint spanning PCR that could identify the mutation in the mothers and grandmother of the patients. Thus, we provided a molecular test that allows accurate genetic counselling and prenatal diagnosis for this family.
authors.affiliation: Institut für Humangenetik, Universität zu Lübeck, Lübeck, Germany.
authors.forename: Julia
authors.identifier: http://orcid.org/0000-0002-5942-2924
authors.initials: J
authors.lastname: Schmidt
authors.affiliation: Sektion für Funktionelle Genetik am Institut für Humangenetik Lübeck, Universität zu Lübeck, Lübeck, Germany.
authors.forename: Ronja
authors.initials: R
authors.lastname: Hollstein
authors.affiliation: Sektion für Funktionelle Genetik am Institut für Humangenetik Lübeck, Universität zu Lübeck, Lübeck, Germany.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Kaiser
authors.affiliation: Institut für Humangenetik, Universität zu Lübeck, Lübeck, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gillessen-Kaesbach
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000503:physiopathology; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D019457:Chromosome Breakage; D005091:Exons / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D050172:Genes, X-Linked; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000503:physiopathology; D005877:Gigantism / Q000235:genetics* / Q000503:physiopathology; D053673:Glypicans / Q000235:genetics*; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D010375:Pedigree; D010641:Phenotype; D017384:Sequence Deletion
chemical_list: C105937:GPC3 protein, human; D053673:Glypicans
keywords: GPC3; Simpson-Golabi-Behmel syndrome; organomegaly; overgrowth