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Molecular analysis of a novel intragenic deletion in GPC3 in three cousins with Simpson–Golabi–Behmel syndrome
Author(s) -
Schmidt Julia,
Hollstein Ronja,
Kaiser Frank J.,
GillessenKaesbach Gabriele
Publication year - 2017
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.38188
Subject(s) - exon , sanger sequencing , genetics , biology , breakpoint , frameshift mutation , gene duplication , point mutation , glypican 3 , gene , exon trapping , exome sequencing , genomic dna , mutation , microbiology and biotechnology , chromosome , alternative splicing , cancer
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.