FGFR3 gene mutation plus GRB10 gene duplication in a patient with achondroplasia plus growth delay with prenatal onset

Yuan, Haiming; Huang, Liwu; Hu, Xizi; Li, Qian; Sun, Xiaofang; Xie, Yuan; Kong, Shu

doi:10.1186/s13023-016-0465-4

Cited by 8 publications

(3 citation statements)

References 26 publications

(26 reference statements)

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“…The CNV maps about 130 kb from the promoter of GRB10 ( Figure 3B-1 ), an imprinted gene with biallelic expression in many tissues, but with maternal expression in muscle and placenta (Blagitko et al, 2000; Monk et al, 2009). Genomic imbalances affecting GRB10 , in particular, maternal duplications involving GRB10 , lead to SRS-like features and growth retardation (Tumer et al, 2018; Yuan et al, 2016). Since the duplication is inherited from the healthy maternal grandfather via the healthy mother, an imprinting transmission pattern might be envisaged.…”

Section: Discussionmentioning

confidence: 99%

Molecular Etiology Disclosed by Array CGH in Patients With Silver–Russell Syndrome or Similar Phenotypes

et al. 2019

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Introduction: Silver–Russell syndrome (SRS) is an imprinting disorder primarily caused by genetic and epigenetic aberrations on chromosomes 11 and 7. SRS is a rare growth retardation disorder often misdiagnosed due to its heterogeneous and non-specific clinical features. The Netchine–Harbison clinical scoring system (NH-CSS) is the recommended tool for differentiating patients into clinical SRS or unlikely SRS. However, the clinical diagnosis is molecularly confirmed only in about 60% of patients, leaving the remaining substantial proportion of SRS patients with unknown genetic etiology. Materials and Methods: A cohort of 34 Italian patients with SRS or SRS-like features scored according to the NH-CSS and without any SRS-associated (epi)genetic alterations was analyzed by high-resolution array-based comparative genomic hybridization (CGH) in order to identify potentially pathogenic copy number variants (CNVs). Results and Discussion: In seven patients, making up 21% of the initial cohort, five pathogenic and two potentially pathogenic CNVs were found involving distinct genomic regions either previously associated with growth delay conditions (1q24.3-q25.3, 17p13.3, 17q22, and 22q11.2-q11.22) and with SRS spectrum (7p12.1 and 7p15.3-p14.3) or outlined for the first time (19q13.42), providing a better definition of reported and as yet unreported SRS overlapping syndromes. All the variants involve genes with a defined role in growth pathways, and for two genes mapping at 7p, IGF2BP3 and GRB10, the association with SRS turns out to be reinforced. The deleterious effect of the two potentially pathogenic variants, comprising GRB10 and ZNF331 genes, was explored by targeted approaches, though further studies are needed to validate their pathogenic role in the SRS etiology. In conclusion, we reconfirm the utility of performing a genome-wide scan to achieve a differential diagnosis in patients with SRS or similar features and to highlight novel chromosome alterations associated with SRS and growth retardation disorders.

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Section: Discussionmentioning

confidence: 99%

Molecular Etiology Disclosed by Array CGH in Patients With Silver–Russell Syndrome or Similar Phenotypes

et al. 2019

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“…Five to 10% of SRS patients are reported to have duplication (Monk et al, 2000;Eggermann et al, 2012b) or mUPD on chromosome 7 (Yuan et al, 2016), where growth factor receptorbound protein 10 [GRB10; also known as maternally expressed gene 1 (MEG1)] resides. SRS patients with mUPD7 are more likely to have verbal dyspraxia, learning difficulties, myoclonus dystonia and autistic spectrum disorder compared to other SRS subgroups (Wakeling et al, 2017).…”

Section: Mupd7 and Duplication Of Chromosomementioning

confidence: 99%

Modeling human epigenetic disorders in mice: Beckwith-Wiedemann Syndrome and Silver-Russell Syndrome

Chang

Bartolomei

2020

Disease Models &Amp; Mechanisms

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Genomic imprinting, a phenomenon in which the two parental alleles are regulated differently, is observed in mammals, marsupials and a few other species, including seed-bearing plants. Dysregulation of genomic imprinting can cause developmental disorders such as Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS). In this Review, we discuss (1) how various (epi)genetic lesions lead to the dysregulation of clinically relevant imprinted loci, and (2) how such perturbations may contribute to the developmental defects in BWS and SRS. Given that the regulatory mechanisms of most imprinted clusters are well conserved between mice and humans, numerous mouse models of BWS and SRS have been generated. These mouse models are key to understanding how mutations at imprinted loci result in pathological phenotypes in humans, although there are some limitations. This Review focuses on how the biological findings obtained from innovative mouse models explain the clinical features of BWS and SRS.

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“…The common pathogenic genes of fetal short limb deformity have been identified. For example, the pathogenic genes of achondroplasia, fatal dwarf and osteogenetic dysplasia are FGFR3 and COL1A1/COL1A12 [19][20][21][22][23][24]. DDSH is generally caused by functional null mutations in the gene, HSPG2.…”

Section: Discussionmentioning

confidence: 99%

Prenatal identification of novel HSPG2 variants associated with dyssegmental dysplasia Silverman-Handmaker type

Wang¹

2022

Clin. Exp. Obstet. Gynecol.

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Background: We aimed to analyze mutations of the pathogenic gene in dyssegmental dysplasia Silverman-Handmaker (DDSH) type associated with the Heparin sulfate proteoglycan 2 (HSPG2) gene. Case: Prenatal testing for genetic mutations associated with fetal DDSH were performed on a pregnant woman with previous history of carrying a fetus with short limb malformation at the 17th week of gestation. DNA was extracted from amniotic fluid and next-generation sequencing-based deep panel sequencing was performed on the Illumina NextSeq platform to identify possible causative mutations of DDSH. Results: Two novel heterozygous mutations in HSPG2 gene, c.6001dupC (p. R2001pfs*19) and c.11207G>A (p. R373Q), were identified and associated with the DDSH diagnosis. Conclusion: This is the first report to prenatally identify novel mutations in HSPG2 that confirms a DDSH diagnosis.

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FGFR3 gene mutation plus GRB10 gene duplication in a patient with achondroplasia plus growth delay with prenatal onset

Cited by 8 publications

References 26 publications

Molecular Etiology Disclosed by Array CGH in Patients With Silver–Russell Syndrome or Similar Phenotypes

Molecular Etiology Disclosed by Array CGH in Patients With Silver–Russell Syndrome or Similar Phenotypes

Modeling human epigenetic disorders in mice: Beckwith-Wiedemann Syndrome and Silver-Russell Syndrome

Prenatal identification of novel HSPG2 variants associated with dyssegmental dysplasia Silverman-Handmaker type

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