Supplementary Material for: Targeted Resequencing of Putative Growth-Related Genes Using Whole Exome Sequencing in Patients with Severe Primary IGF-I Deficiency

<b><i>Background/Aims:</i></b> 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. <b><i>Methods:</i></b> Clinical phenotyping followed by NGS in 17 families including 6 affected sib pairs. <b><i>Results:</i></b> We identified disease-causing, heterozygous, de novo variants in <i>HRAS</i> (p.Gly13Cys) and <i>FAM111A</i> (p.Arg569His) in 2 male patients with syndromic SPIGFD. A previously described homozygous <i>GHR</i> nonsense variant was detected in 2 siblings of a consanguineous family (p.Glu198*). Furthermore, we identified an inherited novel variant in the <i>IGF2</i> 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 <i>SH2B1</i> and <i>SOCS2,</i> both were inherited from an unaffected parent. <b><i>Conclusions:</i></b> Screening of growth-related genes using NGS-based, large-scale, targeted resequencing identified disease-causing variants in <i>HRAS, FAM111A</i>, and <i>GHR</i>. Considering the increased risk of subjects with <i>HRAS</i> 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