Mutation update for theGPC3gene involved in Simpson-Golabi-Behmel syndrome and review of the literature

Abstract

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked multiple congenital anomalies and overgrowth syndrome caused by a defect in the glypican-3 gene (GPC3). Until now, GPC3 mutations have been reported in isolated cases or small series and the global genotypic spectrum of these mutations has never been delineated. In this study, we review the 57 previously described GPC3 mutations and significantly expand this mutational spectrum with the description of 29 novel mutations. Compiling our data and those of the literature, we provide an overview of 86 distinct GPC3 mutations identified in 120 unrelated families, ranging from single nucleotide variations to complex genomic rearrangements and dispersed throughout the entire coding region of GPC3. The vast majority of them are deletions or truncating mutations (frameshift, nonsense mutations) predicted to result in a loss-of-function. Missense mutations are rare and the two which were functionally characterized, impaired GPC3 function by preventing GPC3 cleavage and cell surface addressing respectively. This report by describing for the first time the wide mutational spectrum of GPC3 could help clinicians and geneticists in interpreting GPC3 variants identified incidentally by high-throughput sequencing technologies and also reinforces the need for functional validation of non-truncating mutations (missense, in frame mutations, duplications).

Simpson−Golabi−Behmel syndrome type 1 with subclinical hypothyroidism

“…[3,4] Diagnosis of SGBS1 in males is established by observable clinical manifestations and/or detection of a pathogenic variant of GPC3, or a large duplication of GPC3 and/or GPC4. [5,6] In the present report, we describe a neonate of SGBS1 with a nonsense mutation in GPC3 presenting hypothyroidism and subclinical hypothyroidism.…”

Syndromic Wilms tumor: a review of predisposing conditions, surveillance and treatment

“…Children with BWS are also at risk of developing hepatoblastoma ( 24). An x-linked overgrowth syndrome associated with the GPC3 gene, patients with SGBS exhibit macrosomia, macrocephaly, organomegaly, distinct facial features, and abnormalities across most organ systems, including genitourinary anomalies (25). Newborns may experience hypoglycemia or have airway issues secondary to micrognathia and glossoptosis.…”

CUGC for Simpson-Golabi-Behmel syndrome (SGBS)

“…Up to now, GPC3 remains the only gene surely involved in SGBS. To date, 86 distinct GPC3 variants have been reported in 120-unrelated patients [6]. These variants, mostly inherited, are dispersed throughout the whole-coding region of the gene with no obvious variant hotspots.…”

“…SGBS is very rare and its exact prevalence is unknown. In a recent review of the literature we have identified 152 male patients, belonging to 120-unrelated families, with a GPC3 variant [6]. In their review, Tenorio et al [7] mentioned that 250 patients had been reported in the literature, but they included patients for whom misdiagnosis was possible as no confirmation by a molecular analysis was performed.…”