The LRP4 gene encodes the highly conserved low‐density lipoprotein receptor‐related protein 4 (LRP4), which acts as a co‐receptor for sclerostin. Sclerostin and LRP4 negatively regulate WNT/β‐catenin signaling pathway and lack of their inhibitory activity leads to constant osteoblastic differentiation. Consequently, increased bone formation occurs, which in the case of LRP4 mutations results in sclerosteosis type 2 (SOST2). Alterations within the LRP4 may also cause Cenani‐Lenz syndactyly syndrome (CLSS), congenital myasthenia or isolated syndactyly. Here, we have reported a patient, in whom we found a novel homozygous splice‐site variant c.1048+6T>C in LRP4 using whole exome sequencing. The patient was initially misdiagnosed with isolated CLSS‐like or Malik‐Percin‐like syndactyly. However, we have finally refined the diagnosis after comprehensive radiological examination and molecularly confirmed SOST2. Additionally, we have pointed here to the splicing variants as important causative alterations that may be overlooked in the molecular analysis due to the lack of advanced, reliable algorithms, built‐into the standard diagnostic pipelines. Using advanced in silico prediction tools of splice‐site alterations, including Alamut Visual software, we have demonstrated that the c.1048+6T>C LRP4 variant affects the native donor site and impairs an SC35 enhancer activity. Based on our experience, we recommend comprehensive radiological imaging, including X‐ray of the skull in each case of isolated syndactyly resulting from pathogenic variants of LRP4. We suggest that all previously reported patients carrying biallelic LRP4 mutations, who were diagnosed with isolated syndactyly, could actually present with SOST2 that had been unrecognized due to the incomplete clinical and radiological assessment.

中文翻译：

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LRP4 基因中的一种新的双等位基因剪接位点变体导致硬化性骨病 2。

LRP4基因编码高度保守的低密度脂蛋白受体相关蛋白 4 (LRP4)，它是硬化素的共同受体。硬化蛋白和 LRP4 负调节 WNT/β-catenin 信号通路，缺乏抑制活性导致成骨细胞不断分化。因此，骨形成增加，在LRP4突变的情况下导致 2 型硬化性骨病 (SOST2)。LRP4内的改变也可能导致 Cenani-Lenz 并指综合征 (CLSS)、先天性肌无力或孤立性并指。在这里，我们报告了一名患者，我们在该患者中发现了LRP4中的一种新的纯合剪接位点变体 c.1048+6T>C使用全外显子组测序。该患者最初被误诊为孤立的 CLSS 样或 Malik-Percin 样并指。然而，经过全面的放射学检查和分子证实的SOST2，我们终于完善了诊断。此外，我们在此指出剪接变体是重要的致病改变，由于缺乏内置于标准诊断管道中的先进、可靠的算法，可能会在分子分析中被忽视。使用先进的剪接位点改变计算机预测工具，包括 Alamut Visual 软件，我们已经证明 c.1048+6T>C LRP4变体影响天然供体位点并削弱 SC35 增强子活性。根据我们的经验，我们建议进行全面的放射成像，包括对由LRP4致病性变异引起的孤立并指的每例颅骨 X 线检查。我们建议所有先前报道的携带双等位基因LRP4突变的患者，被诊断为孤立的并指，实际上可能出现由于临床和放射学评估不完整而未被识别的 SOST2。