Journal
HORMONE RESEARCH IN PAEDIATRICS
Volume 88, Issue 6, Pages 408-417Publisher
KARGER
DOI: 10.1159/000480505
Keywords
Whole exome sequencing; Severe primary insulin-like growth factor deficiency; Growth disorder; Growth hormone receptor; HRAS; IGF2; FAM111A; Short stature; Trio-based analysis
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Funding
- BONFOR program of the University of Bonn [O-149.0104]
- Else-Kroner-Fresenius Stiftung (EKFS) [2014_A14]
- German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) [RE 1723/1-1, RE 1723/2-1]
- DFG [LU 731/3-1]
- Ipsen
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Background/Aims: To elucidate the genetic causes of severe primary insulin-like growth factor-I deficiency (SPIGFD) by systematic, targeted, next-generation sequencing (NGS)based resequencing of growth-related genes. Methods: Clinical phenotyping followed by NGS in 17 families including 6 affected sib pairs. Results: We identified disease-causing, heterozygous, de novo variants in HRAS (p.Gly13Cys) and FAM111A (p.Arg569His) in 2 male patients with syndromic SPIGFD. A previously described homozygous GHR nonsense variant was detected in 2 siblings of a consanguineous family (p.Glu198*). Furthermore, we identified an inherited novel variant in the IGF2 gene (p.Arg156Cys) of a maternally imprinted gene in a less severely affected father and his affected daughter. We detected 2 other novel missense variants in SH2B1 and SOCS2, both were inherited from an unaffected parent. Conclusions: Screening of growth-related genes using NGS-based, large-scale, targeted resequencing identified disease-causing variants in HRAS, FAM111A, and GHR. Considering the increased risk of subjects with HRAS mutations for neoplasms, close clinical monitoring and a thorough discussion of the risk/benefit ratio of the treatment with recombinant IGF-I is mandatory. Segregation analysis proved to be critical in the interpretation of potential SPIGFD-associated gene variations. (C) 2017 S. Karger AG, Basel
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