Institute of Human Genetics, University of Bonn, Bonn, Germany.
Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.
Horm Res Paediatr. 2017;88(6):408-417. doi: 10.1159/000480505. Epub 2017 Oct 26.
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.
Clinical phenotyping followed by NGS in 17 families including 6 affected sib pairs.
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.
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.
背景/目的：通过对与生长相关的基因进行系统的、靶向的下一代测序（NGS）重测序，阐明严重原发性胰岛素样生长因子-I 缺乏症（SPIGFD）的遗传原因。
对 17 个家族进行临床表型分析，然后对 6 对受累同胞进行 NGS。
我们在 2 名综合征性 SPIGFD 男性患者中发现了 HRAS（p.Gly13Cys）和 FAM111A（p.Arg569His）的杂合性、新生、致病变异。在一个近亲家族的 2 个同胞中检测到了先前描述的 GHR 无义变异（p.Glu198*）。此外，我们在一个受影响较轻的父亲及其受影响的女儿中发现了 IGF2 基因（p.Arg156Cys）的一个遗传新变异，该基因是一个母系印迹基因。我们还在 SH2B1 和 SOCS2 中检测到了另外 2 个新的错义变异，它们都来自一个未受影响的父母。
使用基于 NGS 的大规模靶向重测序对与生长相关的基因进行筛查，确定了 HRAS、FAM111A 和 GHR 中的致病变异。鉴于 HRAS 突变的受试者发生肿瘤的风险增加，必须进行密切的临床监测，并对使用重组 IGF-I 治疗的风险/获益比进行彻底讨论。分离分析被证明是解释潜在的 SPIGFD 相关基因变异的关键。
