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De novo IGF2 mutation on the paternal allele in a patient with Silver–Russell syndrome and ectrodactyly
Author(s) -
Yamoto Kaori,
Saitsu Hirotomo,
Nakagawa Norio,
Nakajima Hisakazu,
Hasegawa Tatsuji,
Fujisawa Yasuko,
Kagami Masayo,
Fukami Maki,
Ogata Tsutomu
Publication year - 2017
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23253
Subject(s) - biology , ectrodactyly , genetics , frameshift mutation , exome sequencing , mutation , allele , phenotype , nonsense mutation , indel mutation , gene , ectodermal dysplasia , missense mutation , genotype , single nucleotide polymorphism
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.