De novo IGF2 mutation on the paternal allele in a patient with Silver–Russell syndrome and ectrodactyly. Issue 8 (29th May 2017)

• Record Type: Journal Article
• Authors: Yamoto, Kaori; Saitsu, Hirotomo; Nakagawa, Norio; Nakajima, Hisakazu; Hasegawa, Tatsuji; Fujisawa, Yasuko; Kagami, Masayo; Fukami, Maki; Ogata, Tsutomu
• Is Part Of: Human mutation. Volume 38:Issue 8(2017)
• Page Start: 953
• Page End: 958
• Publication Date: 2017-05-29
• Subjects: frameshift mutation -- ectrodactyly -- IGF2 -- imprinting -- Silver–Russell syndrome; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23253
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract : We performed whole exome sequencing in a patient with Silver‐Russell syndrome, ectrodactyly, undermasculinized genitalia, developmental delay, and placental hypoplasia, revealing a de novo IGF2 frameshift mutation (NM_000612.5:c.110_117delinsAGGTAA, p.(Leu37Glnfs*31)) on the paternal allele. The results, together with those in patients with variable H19 ‐DMR 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. Abstract: 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 Sma I and Sal I sites before and after Sma I/ Sal I 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.