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A New Homozygous IGF1R Variant Defines a Clinically Recognizable Incomplete Dominant form of SHORT Syndrome
Author(s) -
Prontera Paolo,
Micale Lucia,
Verrotti Alberto,
Napolioni Valerio,
Stangoni Gabriela,
Merla Giuseppe
Publication year - 2015
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.22853
Subject(s) - insulin like growth factor 1 receptor , biology , missense mutation , proband , phenotype , genetics , exome sequencing , mutation , genetic heterogeneity , dwarfism , pi3k/akt/mtor pathway , exome , short stature , gene , endocrinology , receptor , signal transduction , growth factor
Here, we describe a child, born from consanguineous parents, with clinical features of SHORT syndrome, high IGF1 levels, developmental delay, CNS defects, and marked progeroid appearance. By exome sequencing, we identified a new homozygous c.2201G>T missense mutation in the IGF1R gene. Proband's parents and other relatives, all heterozygous carriers of the mutation, presented with milder phenotype including high IGFI levels, short stature, and type 2 diabetes. Functional studies using patient's cell lines showed a lower IGF1R expression that leads to the alteration of IGF1R‐mediated PI3K/AKT/mTOR downstream pathways, including autophagy. This study defines a clinically recognizable incomplete dominant form of SHORT syndrome, and provides relevant insights into the pathophysiological and phenotypical consequences of IGF1R mutations.