PDF(Pubmed)
Abstract：
Atypical femur fractures (AFFs) are rare complications of anti-resorptive therapy. Devastating to the affected individual, they pose a public health concern because of reduced uptake of an effective treatment for osteoporosis due to patient concern. The risk of AFF is increased sixfold to sevenfold in patients of Asian ethnicity compared with Europeans. Genetic factors may underlie the AFF phenotype. Given the rarity of AFFs, studying familial AFF cases is valuable in providing insights into any genetic predisposition. We present two Singaporean families, one comprising a mother (1-a) and a daughter (1-b), and the other comprising two sisters (2-a and 2-b). All four cases presented with bisphosphonate-associated AFF. Whole-exome sequencing (WES) was performed on 1-b, 2-a, and 2-b. DNA for 1-a was not available. Variants were examined using a candidate gene approach comprising a list of genes previously associated with AFF in the literature, as well as using unbiased filtering based on dominant and/or recessive inheritance patterns. Using a candidate gene approach, rare variants shared between all three cases were not identified. A rare variant in TMEM25, shared by the two sisters (2-a and 2-b), was identified. A rare heterozygous PLOD2 variant was present in the daughter case with AFF (1-b), but not in the sisters. A list of potential genetic variants for AFF was identified after variant filtering and annotation analysis of the two sisters (2-a and 2-b), including a Gly35Arg variant in TRAF4, a gene required for normal skeletal development. Although the findings from this genetic analysis are inconclusive, a familial aggregation of AFFs is suggestive of a genetic component in AFF pathogenesis. We provide a comprehensive list of rare variants identified in these AFF familial cases to aid future genetic studies. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
摘要：
非典型股骨骨折（AFFs）是抗吸收治疗的罕见并发症。毁灭受影响的个人，它们引起公众健康关注，因为由于患者的关注，骨质疏松症的有效治疗方法减少了。与欧洲人相比，亚洲种族患者的AFF风险增加了六到七倍。遗传因素可能是AFF表型的基础。鉴于AFF的稀有性，研究家族性AFF病例对于提供对任何遗传易感性的见解很有价值。我们介绍两个新加坡家庭，一个包括母亲(1-a)和女儿(1-b)，另一个包括两个姐妹(2-a和2-b)。所有四例均表现为双膦酸盐相关AFF。对1-b进行全外显子组测序（WES），2-a,2-b1-a的DNA不可用。使用候选基因方法检查变体，该方法包括文献中先前与AFF相关的基因列表。以及使用基于显性和/或隐性继承模式的无偏过滤。使用候选基因方法，未发现3例病例共有的罕见变异.TMEM25中的一种罕见变体，由两姐妹（2-a和2-b）共享，已确定。在AFF（1-b）的子病例中存在罕见的杂合PLOD2变体，但不是姐妹。在对两个姐妹（2-a和2-b）进行变异过滤和注释分析后，确定了AFF的潜在遗传变异列表，包括TRAF4中的Gly35Arg变体，这是正常骨骼发育所需的基因。虽然这个基因分析的结果没有定论，AFFs的家族聚集提示AFF发病机制中的遗传成分。我们提供了在这些AFF家族病例中发现的罕见变异的完整列表，以帮助未来的遗传研究。©2022作者JBMRPlus由WileyPeriodicalsLLC代表美国骨骼和矿物研究学会出版。
