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

Cottereau, Edouard; Moizard, Marie‐Pierre; David, Albert; Raynaud, Martine; Marmin, Nadine; Toutain, Annick

doi:10.1002/ajmg.a.36199

Cited by 10 publications

(9 citation statements)

References 16 publications

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“…These findings confirm that the recurrent PIGA germline mutation c.1234C>T results in a recognizable clinical phenotype (summarized in Table ) and causes SGBS2. Our data corroborate the long suspected assumption that SGBS2 is a condition distinct from SGBS1 [Cottereau et al, ]. These results also indicate that SGBS2 is not allelic to orofaciodigital syndrome type 1 (MIM #311200), which was speculated by Budny et al [] and as is currently assigned in the OMIM database [Cottereau et al, ].…”

Section: Discussionsupporting

confidence: 91%

A recurrent germline mutation in the PIGA gene causes Simpson‐Golabi‐Behmel syndrome type 2

Fauth

Steindl

Toutain

et al. 2015

American J of Med Genetics Pt A

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Hypomorphic germline mutations in the PIGA (phosphatidylinositol glycan class A) gene recently were recognized as the cause of a clinically heterogeneous spectrum of X-linked disorders including (i) early onset epileptic encephalopathy with severe muscular hypotonia, dysmorphism, multiple congenital anomalies, and early death ("MCAHS2"), (ii) neurodegenerative encephalopathy with systemic iron overload (ferro-cerebro-cutaneous syndrome, "FCCS"), and (iii) intellectual disability and seizures without dysmorphism. Previous studies showed that the recurrent PIGA germline mutation c.1234C>T (p.Arg412*) leads to a clinical phenotype at the most severe end of the spectrum associated with early infantile lethality. We identified three additional individuals from two unrelated families with the same PIGA mutation. Major clinical findings include early onset intractable epileptic encephalopathy with a burst-suppression pattern on EEG, generalized muscular hypotonia, structural brain abnormalities, macrocephaly and increased birth weight, joint contractures, coarse facial features, widely spaced eyes, a short nose with anteverted nares, gingival overgrowth, a wide mouth, short limbs with short distal phalanges, and a small penis. Based on the phenotypic overlap with Simpson-Golabi-Behmel syndrome type 2 (SGBS2), we hypothesized that both disorders might have the same underlying cause. We were able to confirm the same c.1234C>T (p.Arg412*) mutation in the DNA sample from an affected fetus of the original family affected with SGBS2. We conclude that the recurrent PIGA germline mutation c.1234C>T leads to a recognizable clinical phenotype with a poor prognosis and is the cause of SGBS2.

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Section: Discussionsupporting

confidence: 91%

A recurrent germline mutation in the PIGA gene causes Simpson‐Golabi‐Behmel syndrome type 2

Fauth

Steindl

Toutain

et al. 2015

American J of Med Genetics Pt A

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“…Five rearrangements, one deletion and four duplications, were studied at the cDNA level. cDNA analysis confirmed the in silico predictions for deletion of exons 5 to 6 (Schmidt et al., ) and showed that duplications of exon 2 to 4, exon 3 to 6, and exon 7 also lead to the truncation of the protein with a complete absence of GPI anchoring domain ((Mateos et al., ; Vuillaume et al., ), whereas duplication of exon 2 maintains the open reading frame with an insertion of 54 amino acids which probably disrupts the conserved glypican three‐dimensional structure (Cottereau et al., ).…”

Section: Mutational Spectrummentioning

confidence: 70%

“…The vast majority of these mutations are deletions or truncating mutations (frameshift, nonsense mutations) predicted to result in a loss‐of‐function. Other types of mutations such as missenses mutations or duplications are less frequent and were also shown to alter GPC3 function when they were functionally characterized (Cottereau et al., ; Mateos et al., ; Veugelers et al., ; Vuillaume et al., ). These observations should be taken into account for the interpretation of novel GPC3 variants as a lot of variants are nowadays identified by next‐generation sequencing.…”

Section: Functional Impact Of Gpc3 Mutationsmentioning

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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“…However, only one duplication of all 9 GPC4 exons, of which the functional consequences have not been assessed, has been reported in the original family described by Golabi and Rosen [4]. Moreover, no GPC4 point variants have been reported so far, questioning the exact role of this gene in the pathogenesis of SGBS [5].…”

Section: Mutational Spectrummentioning

confidence: 99%

“…The variant detection rate in SGBS is highly variable depending on the reports [5]. Low detection rates may reflect less stringent clinical criteria used by the laboratories and/or clinical misdiagnosis due to the unfamiliarity with the phenotype amongst the clinicians requesting GPC3 analysis.…”

Section: Clinical Sensitivity (Proportion Of Positive Tests If the DImentioning

confidence: 99%

CUGC for Simpson-Golabi-Behmel syndrome (SGBS)

et al. 2019

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

Cited by 10 publications

References 16 publications

A recurrent germline mutation in the PIGA gene causes Simpson‐Golabi‐Behmel syndrome type 2

A recurrent germline mutation in the PIGA gene causes Simpson‐Golabi‐Behmel syndrome type 2

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

CUGC for Simpson-Golabi-Behmel syndrome (SGBS)

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