DataSheet1_Molecular Genetics and Pathogenesis of the Floating Harbor Syndrome: Case Report of Long-Term Growth Hormone Treatment and a Literature Review.pdf

Introduction: Floating Harbor syndrome (FHS) is an extremely rare disorder, with slightly more than a hundred cases reported worldwide. FHS is caused by heterozygous mutations in the SRCAP gene; however, little is known about the pathogenesis of FHS or the effectiveness of its treatment.
Methods: Whole-exome sequencing (WES) was performed for the definitive molecular diagnosis of the disease. Identified variants were validated using Sanger sequencing. In addition, systematic literature and public data on genetic variation in SRCAP and the effects of growth hormone (GH) treatment was conducted.
Results: We herein report the first case of FHS in the Russian Federation. The male proband presented with most of the typical phenotypic features of FHS, including short stature, skeletal and facial features, delayed growth and bone age, high pitched voice, and intellectual impairment. The proband also had partial growth hormone deficiency. We report the history of treatment of the proband with GH, which resulted in modest improvement in growth prior to puberty. WES revealed a pathogenic c.7466C>G (p.Ser2489*) mutation in the last exon of the FHS-linked SRCAP gene. A systematic literature review and analysis of available genetic variation datasets highlighted an unusual distribution of pathogenic variants in SRCAP and confirmed the lack of pathogenicity for variants outside of exons 33 and 34. Finally, we suggested a new model of FHS pathogenesis which provides possible basis for the dominant negative nature of FHS-causing mutations and explains limited effects of GH treatment in FHS.
Conclusion: Our findings expand the number of reported FHS cases and provide new insights into disease genetics and the efficiency of GH therapy for FHS patients.

引言：浮动港综合征（Floating Harbor syndrome, FHS）是一种极为罕见的疾病，全球范围内仅报道过百余例病例。该疾病由SRCAP基因的杂合突变引发，但目前学界对其发病机制及治疗有效性的认知仍十分有限。方法：本研究采用全外显子测序（Whole-exome sequencing, WES）对该疾病进行明确的分子诊断，并通过桑格测序（Sanger sequencing）对鉴定得到的变异位点进行验证。此外，本研究还针对SRCAP基因的遗传变异及生长激素（growth hormone, GH）的治疗效果开展了系统的文献调研与公共数据集分析。结果：本文首次报道了俄罗斯联邦境内的FHS病例。该男性先证者表现出FHS的多数典型表型特征，包括身材矮小、骨骼与面部异常、生长及骨龄发育迟缓、高调语音以及智力障碍。该先证者同时存在部分生长激素缺乏症。本文还记录了该先证者接受GH治疗的病史，该治疗在青春期前对其生长产生了轻度改善效果。WES检测显示，在与FHS相关的SRCAP基因的最后一个外显子中，存在一处致病的c.7466C>G（p.Ser2489*）突变。对现有遗传变异数据集的系统文献回顾与分析揭示了SRCAP致病变异的异常分布模式，并证实了第33、34号外显子之外的变异不具备致病性。最后，本研究提出了一种全新的FHS发病机制模型，该模型为FHS致病突变的显性负效特性提供了潜在理论基础，同时解释了GH治疗在FHS患者中效果有限的原因。结论：本研究的发现扩充了已报道的FHS病例数量，并为该疾病的遗传学研究及FHS患者的GH治疗有效性提供了全新的认知视角。