Simpson–Golabi–Behmel syndrome: a prenatal diagnosis in a foetus with <i><scp>GPC3</scp></i> and <i><scp>GPC4</scp></i> gene microduplications

Mujezinović, Faris; Krgovic, Danijela; Blatnik, Ana; Zagradišnik, Boris; Vipotnik, TV; Golec, Tč; Tul, N.; Vokač, Nadja Kokalj

doi:10.1111/cge.12725

Cited by 14 publications

(16 citation statements)

References 7 publications

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“…Our patient had a small duplication involving the entirety of GPC3 and GPC4 , similar to those recently reported by other groups (Mujezinovic et al., ; Vuillaume et al., ), although we note that those previously reported patients had break points within GPC3 , more likely to cause haploinsufficiency. However, while patients with haploinsufficiency of GPC3 / GPC4 usually have overgrowth with SGBS, our patient's clinical phenotype was one of microcephaly and undergrowth.…”

Section: Discussionsupporting

confidence: 91%

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Xq26 duplications lead to undergrowth or overgrowth via competing pathways including GPC3/GPC4

Karna

Myers

2019

Annals of Human Genetics

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The Xq26 locus has importance in human growth with multiple genes and regions playing important roles, which potentially leads to macrosomia or microsomia if disrupted. One region of Xq26.2 comprises the genes GPC3 and GPC4; deletion or duplication of this region has been recently been shown to result in overgrowth, specifically Simpson-Golabi-Behmel syndrome. We describe a male patient with two maternally inherited Xq26 microduplications; the first was 0.8 Mb at Xq26.2 affecting only GPC3 and GPC4, and the second, a distal 0.6 Mb duplication at Xq26.3 affecting seven genes. Rather than having Simpson-Golabi-Behmel syndrome, our patient had microcephaly and undergrowth, with development that was within normal limits at 25 months of age. This finding suggests that the molecular pathway leading to overgrowth secondary to GPC3/GPC4 haploinsufficiency can be overpowered by a disruption to the distal Xq26.3 region. Of the genes in that region, we propose that SLC9A6 is the most likely to play an important role as mutations in this gene lead to Christianson syndrome, in which patients may have microcephaly and weight loss. K E Y W O R D SGPC3 protein (human), GPC4 protein (human), microcephaly, Simpson-Golabi-Behmel syndrome, SLC9A6 protein, trisomy Xq26, X chromosome ( human) RESULTSThe patient is a now 25-month-old boy, born at term following a pregnancy notable only because the fetus was small Ann Hum Genet. 2020;84:201-204.

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Section: Discussionsupporting

confidence: 91%

“…() and Mujezinovic et al. () cases demonstrate that, in isolation, GPC3 / GPC4 duplications produce overgrowth (Simpson–Golabi–Behmel syndrome), while the Madrigal et al. () case indicates that distal Xq26.3 duplications result in undergrowth.…”

Section: Resultsmentioning

confidence: 99%

Xq26 duplications lead to undergrowth or overgrowth via competing pathways including GPC3/GPC4

Karna

Myers

2019

Annals of Human Genetics

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“…Table details GPC3 mutations published between March 1996 and December 2017 in the international peer‐reviewed literature (PubMed database) and The Human Gene Mutation Database (HGMD professional 2016.4) following HGVS nomenclature guidelines (http://www.HGVS.org) and the reference sequence GenBank entry NM_004484.3. We collected 57 distinct GPC3 mutations detected in 71 unrelated families (Agatep et al., ; Das Bhowmik & Dalal, ; Day & Fryer, ; DiMaio, Yang, Mahoney, McGrath, & Li, ; Ganesamoorthy et al., ; Garavelli et al., ; Gertsch, Kirmani, Ackerman, & Babovic‐Vuksanovic, ; Gurrieri et al., ; Halayem et al., ; Hughes‐Benzie et al., ; Kehrer et al., ; Kosaki et al., ; Li et al., ; Lindsay et al., ; Magini et al., ; Mariani et al., ; Mateos et al., ; Mujezinović et al., ; Ochiai et al., ; Okamoto, Yagi, Imura, & Wada, ; Pilia et al., ; Rodríguez‐Criado et al., ; Romanelli et al., ; Sakazume et al., ; Schmidt, Hollstein, Kaiser, & Gillessen‐Kaesbach, ; Shimojima et al., ; Spencer, Fieggen, Vorster, & Beighton, ; Støve et al., ; Thomas et al., ; Vaisfeld, Pomponi, Pietrobono, Tabolacci, & Neri, ; Veugelers et al., , ; Villarreal et al., ; Weichert et al., ; Xuan, Hughes‐Benzie, & MacKenzie, ; Yano et al., ; Young, Wishnow, & Nigro, ). In this study, we also report 38 GPC3 mutations in 63 additional male patients from 49 unrelated families (Cf.…”

Section: Mutational Spectrummentioning

confidence: 99%

“…Nine were detected prenatally by chromosomal microarray (DiMaio et al., ; Ganesamoorthy et al., ; Magini et al., ; Mujezinović et al., ; Støve et al., ; Weichert et al., ) or whole exome sequencing (Magini et al., ) in fetuses with abnormal ultrasound findings. In these fetuses, clinical features including notably fetal overgrowth, craniofacial abnormalities (DiMaio et al., ; Magini et al., ; Mujezinović et al., ; Støve et al., ; Weichert et al., ), and congenital diaphragmatic hernia (Ganesamoorthy et al., ) were retrospectively in line with SGBS diagnosis. Two other variants were detected postnatally by next‐generation sequencing.…”

Section: Conclusion and Future Prospectsmentioning

confidence: 99%

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

et al. 2018

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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).

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“…Several authors have reported certain features on prenatal ultrasound that can facilitate SGB syndrome diagnosis before birth [Chen et al, 1993;Yamashita et al, 1995;Enns et al, 1998;Weichert et al, 2011;Garavelli et al, 2012;Cottereau et al, 2013;Kehrer et al, 2016;Magini et al, 2016;Mujezinović et al, 2016;Støve et al, 2017;Zimmermann and Stanek, 2017]. Table 1 summarizes the described prenatal findings from previously published cases and our cases.…”

Section: Discussionmentioning

confidence: 91%

Two Consecutive Pregnancies with Simpson-Golabi-Behmel Syndrome Type 1: Case Report and Review of Published Prenatal Cases

et al. 2018

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Fetal overgrowth and numerous congenital malformations can be detected in every trimester of pregnancy. New technologies in molecular testing, such as chromosomal microarray analysis and next-generation sequencing, continually demonstrate advantages for definitive diagnosis in fetal life. Simpson-Golabi-Behmel (SGB) syndrome is a rare but well-known overgrowth condition that is rarely diagnosed in the prenatal setting. We report 3 cases of SGB syndrome in 2 consecutive pregnancies. In our series, distinctive prenatal sonographic findings led to molecular diagnosis. Exome sequencing from fetal DNA revealed a hemizygous splice site variant in the GPC3 gene: NM_004484.3:c.1166+ 1G>T. The mother is a heterozygous carrier. We also provide an overview of the previously published 57 prenatal cases of SGB syndrome with prevalence estimation of the symptoms to aid prenatal differential diagnosis of fetal overgrowth syndromes.

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Simpson–Golabi–Behmel syndrome: a prenatal diagnosis in a foetus with GPC3 and GPC4 gene microduplications

Cited by 14 publications

References 7 publications

Xq26 duplications lead to undergrowth or overgrowth via competing pathways including GPC3/GPC4

Xq26 duplications lead to undergrowth or overgrowth via competing pathways including GPC3/GPC4

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

Two Consecutive Pregnancies with Simpson-Golabi-Behmel Syndrome Type 1: Case Report and Review of Published Prenatal Cases

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