No major contribution of <i>IGF2</i> variants to the etiology of sporadic 11p15‐associated imprinting disorders

Müller, Anne; Soellner, Lukas; Binder, Gerhard; Begemann, Matthias; Eggermann, Thomas

doi:10.1002/ajmg.a.37416

Cited by 4 publications

(4 citation statements)

References 12 publications

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“…(), argue that IGF2 mutation analysis is worth performing in SRS patients negative for H19 ‐DMR epimutations and UPD(7)mat, especially in those with severe limb/digital malformations and/or low to low‐normal serum IGF‐II values (clinical significance of IGF‐I/IGFBP‐3 values is uncertain at present), and without body asymmetry. While IGF2 mutations could lead to common SRS phenotype, previous IGF2 mutation screenings have failed to identify a pathogenic variant in a large number of patients with SRS or SRS‐like phenotype (Müller, Soellner, Binder, Begemann, & Eggermann, ; Obermann et al., ). Thus, further studies are required to determine whether IGF2 mutation analysis should be included in the routine diagnostic workup for SRS.…”

Section: Clinical Findings In Patients With Igf2 Mutations and In Thomentioning

confidence: 99%

De novoIGF2mutation on the paternal allele in a patient with Silver–Russell syndrome and ectrodactyly

et al. 2017

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Although paternally expressed IGF2 is known to play a critical role in placental and body growth, only a single mutation has been found in IGF2. We identified, through whole-exome sequencing, a de novo IGF2 indel mutation leading to frameshift (NM_000612.5:c.110_117delinsAGGTAA, p.(Leu37Glnfs*31)) in a patient with Silver-Russell syndrome, ectrodactyly, undermasculinized genitalia, developmental delay, and placental hypoplasia. Furthermore, we demonstrated that the mutation resided on the paternal allele by sequencing the long PCR product harboring the mutation- and methylation-sensitive SmaI and SalI sites before and after SmaI/SalI digestion. The results, together with the previous findings in four cases from a single family with a paternally inherited IGF2 nonsense mutation and those in patients with variable H19 differentially methylated region epimutations leading to compromised IGF2 expression, suggest that the whole phenotype of this patient is explainable by the IGF2 mutation, and that phenotypic severity is primarily determined by the IGF2 expression level in target tissues.

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Section: Clinical Findings In Patients With Igf2 Mutations and In Thomentioning

confidence: 99%

De novoIGF2mutation on the paternal allele in a patient with Silver–Russell syndrome and ectrodactyly

et al. 2017

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“…As no report regarding SRS caused by IGF2 mutation had been published, the authors are not sure about the contribution of IGF2 to prenatal and postnatal growth. In another study, the same authors argue that IGF2 mutation analysis is not indicated in sporadic SRS cases ( Muller et al, 2016 ). Recently, a Japanese team reported the first case of de novo IGF2 mutation in a patient with SRS, arguing that IGF2 mutation analysis is helpful in SRS patients negative for other etiologies ( Yamoto et al, 2017 ).…”

Section: Introductionmentioning

confidence: 98%

De Novo Mutation of Paternal IGF2 Gene Causing Silver–Russell Syndrome in a Sporadic Patient

Liu

Wang²,

Yang

et al. 2017

Front. Genet.

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Silver–Russell syndrome (SRS) is a rare, but well-recognized disease characterized by growth disorder. To date, there are two reports arguing IGF2 mutation for the onset of SRS. Herein, we present another sporadic case harboring IGF2 mutation. The male proband was the first and only child of a non-consanguineous Chinese couple. He was small for gestational age, with relative macrocephaly at birth. Severe feeding difficulties, low feeding, and growth retardation were revealed during neonatal period. At 4.5 years old, obvious body asymmetry was noted. Whole exome sequencing identified a novel de novo c.101G > A (p.Gly34Asp, NM_000612) variant in IGF2 and Sanger sequencing validated the variant. Amplification refractory mutation system polymerase chain reaction demonstrated that the IGF2 variant was on the paternal allele. Alignment shows the variant is evolutionarily conserved. Structural modeling argues that the variant site might be important for the binding of IGF2 to its receptor. Our study provides further evidence that IGF2 mutation may be another mechanism of SRS, and we consider that IGF2 should be included in a disease specific gene panel in case it is designed for SRS routine diagnostics.

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“…Maternally transmitted SRS was described in a four-generation family with a CDKN1C gain-of-function mutation 60 , and paternally transmitted SRS in a family with an IGF2 loss-of-function mutation 61 . However, no additional mutations have been reported to date in sporadic or familial cases of SRS 60,62,63 . Sequence analysis of either gene might be considered, particularly in familial cases of SRS where the inheritance pattern is consistent; however, coding variants in these genes are rare 60,62,63 .…”

Section: Additional Testingmentioning

confidence: 99%

“…However, no additional mutations have been reported to date in sporadic or familial cases of SRS 60,62,63 . Sequence analysis of either gene might be considered, particularly in familial cases of SRS where the inheritance pattern is consistent; however, coding variants in these genes are rare 60,62,63 .…”

Section: Additional Testingmentioning

confidence: 99%

Diagnosis and management of Silver–Russell syndrome: first international consensus statement

et al. 2016

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No major contribution of IGF2 variants to the etiology of sporadic 11p15‐associated imprinting disorders

Cited by 4 publications

References 12 publications

De novoIGF2mutation on the paternal allele in a patient with Silver–Russell syndrome and ectrodactyly

De novoIGF2mutation on the paternal allele in a patient with Silver–Russell syndrome and ectrodactyly

De Novo Mutation of Paternal IGF2 Gene Causing Silver–Russell Syndrome in a Sporadic Patient

Diagnosis and management of Silver–Russell syndrome: first international consensus statement

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