Szoszkiewicz Anna, Szczepanek Małgorzata, Bukowska-Olech Ewelina, Sowińska-Seidler Anna, Socha Magdalena, Jamsheer Aleksander
Poznan University of Medical Sciences, Department of Medical Genetics, Rokietnicka 8, Poznan, Poland.
Poznan University of Medical Sciences, Doctoral School, Department of Medical Genetics, Poznan, Poland.
J Appl Genet. 2025 Apr 12. doi: 10.1007/s13353-025-00966-4.
Fibrodysplasia ossificans progressiva (FOP; OMIM #135100) is a rare genetic disorder characterized by congenital malformation of the great toes and progressive heterotopic ossification of soft tissues. To date, the disease has been linked to 15 pathogenic variants in the ACVR1 gene, which encodes a type I receptor for bone morphogenetic proteins. Most patients with FOP carry a recurrent single-nucleotide substitution (c.617G>A; p.Arg206His) in the ACVR1 gene. The genotype-phenotype correlations for atypical pathogenic variants of ACVR1 are poorly understood. In this study, we report the largest population of Polish patients affected by FOP and analyze their phenotypes and genotypes. We screened the whole ACVR1 coding sequence of 16 patients affected by FOP to confirm the presence of pathogenic variants. Thirteen individuals carried the classic pathogenic variant (p.Arg206His) and had a classic or FOP-plus phenotype. In agreement with the findings of previous studies, one patient with a p.Gly356Asp pathogenic variant had a variant FOP phenotype. We point to an unusual phenomenon in two patients who carried atypical pathogenic variants (p.Gly356Asp and p.Arg258Ser) and displayed a classic FOP phenotype. Our study extends the understanding of FOP's genotype-phenotype correlation, suggesting that classic FOP phenotypes are associated with non-classic pathogenic variants. We also summarize the recent advances in drug development for this condition. Therefore, the study may be valuable for clinicians consulting patients with FOP.
进行性骨化性纤维发育不良（FOP；OMIM #135100）是一种罕见的遗传性疾病，其特征为大脚趾先天性畸形以及软组织进行性异位骨化。迄今为止，该疾病已与ACVR1基因中的15种致病变异相关联，该基因编码骨形态发生蛋白的I型受体。大多数FOP患者在ACVR1基因中携带一个反复出现的单核苷酸替换（c.617G>A；p.Arg206His）。对于ACVR1非典型致病变异的基因型-表型相关性了解甚少。在本研究中，我们报告了受FOP影响的波兰患者的最大群体，并分析了他们的表型和基因型。我们筛选了16名受FOP影响患者的整个ACVR1编码序列，以确认致病变异的存在。13名个体携带经典致病变异（p.Arg206His），具有经典或FOP加表型。与先前研究的结果一致，一名携带p.Gly356Asp致病变异的患者具有变异型FOP表型。我们指出两名携带非典型致病变异（p.Gly356Asp和p.Arg258Ser）并表现出经典FOP表型的患者中存在一种不寻常的现象。我们的研究扩展了对FOP基因型-表型相关性的理解，表明经典FOP表型与非经典致病变异相关。我们还总结了针对这种疾病的药物开发的最新进展。因此，该研究对于为FOP患者提供咨询的临床医生可能具有价值。
