Turkunova Mariia E, Barbitoff Yury A, Serebryakova Elena A, Polev Dmitrii E, Berseneva Olga S, Bashnina Elena B, Baranov Vladislav S, Glotov Oleg S, Glotov Andrey S
Federal State Budget Institution of Higher Education "North-Western State Medical University Named After I.I Mechnikov" Under the Ministry of Public Health of the Russian Federation, Saint-Petersburg, Russia.
Department of Genomic Medicine, D.O.Ott Research Institute of Obstetrics, Gynaecology and Reproductology, St. Petersburg, Russia.
Front Genet. 2022 May 18;13:846101. doi: 10.3389/fgene.2022.846101. eCollection 2022.
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 gene; however, little is known about the pathogenesis of FHS or the effectiveness of its treatment. 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 and the effects of growth hormone (GH) treatment was conducted. 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 gene. A systematic literature review and analysis of available genetic variation datasets highlighted an unusual distribution of pathogenic variants in 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. 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.
弗洛廷港综合征（FHS）是一种极为罕见的疾病，全球报告的病例略多于100例。FHS由该基因的杂合突变引起；然而，关于FHS的发病机制或其治疗效果知之甚少。进行全外显子组测序（WES）以明确该疾病的分子诊断。使用桑格测序法验证鉴定出的变异。此外，还对该基因的遗传变异以及生长激素（GH）治疗效果进行了系统的文献和公共数据研究。我们在此报告俄罗斯联邦首例FHS病例。男性先证者表现出FHS的大多数典型表型特征，包括身材矮小、骨骼和面部特征、生长和骨龄延迟、高音调嗓音以及智力障碍。先证者还存在部分生长激素缺乏。我们报告了该先证者接受GH治疗的病史，这导致青春期前生长有适度改善。WES揭示了FHS相关基因最后一个外显子中的致病性c.7466C>G（p.Ser2489*）突变。系统的文献综述和对可用遗传变异数据集的分析突出了该基因致病性变异的异常分布，并证实外显子33和34以外的变异缺乏致病性。最后，我们提出了一种新的FHS发病机制模型，该模型为导致FHS的突变的显性负性性质提供了可能的基础，并解释了GH治疗对FHS患者效果有限的原因。我们的研究结果增加了报告的FHS病例数量，并为疾病遗传学以及FHS患者的GH治疗效率提供了新的见解。
