Silver Russel syndrome in an aboriginal patient from Australia

Poulton, Cathryn; Azmanov, Dimitar N.; Atkinson, Vanessa; Beilby, John; Ewans, Lisa; Gration, Dylan; Dreyer, Lauren; Shetty, Vinutha B; Peake, Ciara; McCormack, Emma; Palmer, Richard L.; Lewis, Barry; Dawkins, Hugh; Broley, Stephanie; Baynam, Gareth

doi:10.1002/ajmg.a.40502

Cited by 15 publications

(17 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Body asymmetry, a frequent characteristic in SRS caused by mosaic IC1 hypomethylation, was absent in the index patient and his affected mother. This is in agreement with the previous clinical findings in patients with the p.Arg279Leu variant [4,5], the sporadic case from Japan [6] and other patients with SRS and genomic mutations of IGF2 which were not mosaic [20][21][22][23][24]. In agreement with a previous report [5], IGF-1 serum levels were normal in the index patient and his mother.…”

Section: Discussionsupporting

confidence: 93%

See 1 more Smart Citation

Novel mutation points to a hot spot in CDKN1C causing Silver–Russell syndrome

et al. 2020

View full text Add to dashboard Cite

Background Pathogenic CDKN1C gain-of-function variants on the maternal allele were initially reported as a cause of IMAGe syndrome characterized by intrauterine growth retardation, metaphyseal dysplasia, primary adrenal insufficiency and genital anomalies. Recently, a maternally inherited CDKN1C missense mutation (p.Arg279Leu) was identified in several members of a single family clinically diagnosed with Silver–Russell syndrome (SRS) but without adrenal insufficiency. Thereafter, two half siblings from UK with familial SRS were described who carried the same mutation. This specific amino acid change is located within a narrow functional region containing the mutations previously associated with IMAGe syndrome. Results Here, we describe a third familial case with maternally inherited SRS due to a missense variant affecting the same amino acid position 279 but leading to a different amino acid substitution (p. (Arg279Ser)). The two affected family members (mother and son) presented with the complete SRS phenotype (both Netchine–Harbison CSS score 5 of 6) but without body asymmetry or adrenal insufficiency. Conclusions In comparison with loss-of-function genomic IGF2 mutations, CDKN1C gain-of-function mutations are a less frequent cause of SRS and seem to affect a cluster of few amino acids.

show abstract

Section: Discussionsupporting

confidence: 93%

“…Since the first report of a genomic IGF2 mutation in familial SRS by Begemann et al [12], eleven additional IGF2 mutations in only sporadic cases were reported [13,[20][21][22][23][24]. This number is not high, but higher than the three families and one sporadic case reported with genomic CDKN1C mutations and SRS ( [4][5][6], this study).…”

Section: Discussionmentioning

confidence: 49%

Novel mutation points to a hot spot in CDKN1C causing Silver–Russell syndrome

et al. 2020

View full text Add to dashboard Cite

show abstract

“…A maternal CDKN1C gain-of-function variant has been reported as a rare cause of SRS (Eggermann et al, 2014). Recently, five reports have identified IGF2 loss-of-function variants as new contributors to the molecular etiology of SRS, on the basis of studies including individuals of German, Japanese, Chinese, and Australian Aboriginal descent ( Table 1 ) (Begemann et al, 2015; Liu et al, 2017; Yamoto et al, 2017; Abi Habib et al, 2018; Poulton et al, 2018). In our SRS patient from China, we found a novel IGF2 splicing variant, NM_000612.4: c.157+5G > A, which is located on the paternal allele.…”

Section: Discussionmentioning

confidence: 99%

“…Subsequently, five reports revealed SRS-associated IGF2 variants. However, the variants and phenotypic spectrum remain very limited (Liu et al, 2017; Yamoto et al, 2017; Abi Habib et al, 2018; Poulton et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Rare De Novo IGF2 Variant on the Paternal Allele in a Patient With Silver–Russell Syndrome

Xia

Lyu

et al. 2019

Front. Genet.

View full text Add to dashboard Cite

Silver–Russell syndrome (SRS) is a rare, well-recognized disorder characterized by growth restriction, including intrauterine and postnatal growth. Most SRS cases are caused by hypomethylation of the paternal imprinting center 1 (IC1) in chromosome 11p15.5 and maternal uniparental disomy in chromosome 7 (UPD7). Here, we report on a Chinese family with a 4 year old male proband presenting with low birth weight, growth retardation, short stature, a narrow chin, delayed bone age, and speech delays, as a result of a rare molecular etiology. Whole-exome sequencing was conducted, and a novel de novo IGF2 splicing variant, NM_000612.4: c.157+5G > A, was identified on the paternal allele. In vitro functional analysis by RT-PCR and Sanger sequencing revealed that the variant leads to an aberrant RNA transcript lacking exon 2. Our results further confirm the IGF2 variant mediates SRS and expand the pathogenic variant and phenotypic spectrum of IGF2-mediated SRS. The results indicate that, beyond DNA methylation and UPD7 and CDKN1C variant tests, IGF2 gene screening should also be considered for SRS molecular diagnoses.

show abstract

“…Through exome analysis, the authors identified an IGF2 nonsense mutation in all patients, inherited from their healthy fathers (OMIM 616489) (51). After this first report, other five studies identified variants in IGF2 gene on the paternal allele causing SRS-like (52)(53)(54)(55)(56). Up to now, one missense and six loss-of-function variants (3 frameshift, 2 nonsense and 1 splice-site) in the IGF2 gene were reported.…”

Section: Igf2 Defectsmentioning

confidence: 98%

Update on new GH-IGF axis genetic defects

Vasques¹,

Andrade²,

Correa³

et al. 2019

Archives of Endocrinology and Metabolism

View full text Add to dashboard Cite

The somatotropic axis is the main hormonal regulator of growth. Growth hormone (GH), also known as somatotropin, and insulin-like growth factor 1 (IGF-1) are the key components of the somatotropic axis. This axis has been studied for a long time and the knowledge of how some molecules could promote or impair hormones production and action has been growing over the last decade. The enhancement of large-scale sequencing techniques has expanded the spectrum of known genes and several other candidate genes that could affect the GH-IGF1-bone pathway. To date, defects in more than forty genes were associated with an impairment of the somatotropic axis. These defects can affect from the secretion of GH to the bioavailability and action of IGF-1. Affected patients present a large heterogeneous group of conditions associated with growth retardation. In this review, we focus on the description of the GH-IGF axis genetic defects reported in the last decade.

show abstract

Silver Russel syndrome in an aboriginal patient from Australia

Cited by 15 publications

References 5 publications

Novel mutation points to a hot spot in CDKN1C causing Silver–Russell syndrome

Novel mutation points to a hot spot in CDKN1C causing Silver–Russell syndrome

Rare De Novo IGF2 Variant on the Paternal Allele in a Patient With Silver–Russell Syndrome

Update on new GH-IGF axis genetic defects

Contact Info

Product

Resources

About