Inserm U1132 and Université de Paris, Paris, France.
Department of Rheumatology, Hôpital Lariboisière, AP-HP, Paris, France.
Mol Genet Genomic Med. 2021 Jun;9(6):e1681. doi: 10.1002/mgg3.1681. Epub 2021 May 3.
Early-onset osteoporosis (EOOP) is defined by low bone mineral density (BMD), which increases the risk of fracture. Although the prevalence of osteoporosis at a young age is unknown, low BMD is highly linked to genetic background. Heterozygous pathogenic variants in low-density lipoprotein receptor-related protein 5 (LRP5) are associated with EOOP. This study aimed to investigate the genetic profile in patients with EOOP to better understand the variation in phenotype severity by using a targeted gene sequencing panel associated with bone fragility.
We used a sequencing panel with 17 genes reported to be related to bone fragility for analysis of 68 patients with EOOP. We found a high positivity rate of EOOP with LRP5 variants (14 patients, 20.6%). The remaining 79.4% of patients with EOOP but without LRP5 variants showed variable disease severity, as observed in patients with at least one variant in this gene. One patient, with multiple fractures and spine L1-L4 BMD Z-score -2.9, carried a novel pathogenic homozygous variant, c.2918T>C, p.(Leu973Pro), without any pseudoglioma. In addition to carrying the LRP5 variant, 2 other patients carried a heterozygous variant in Wnt signaling pathway genes: dickkopf WNT signaling pathway inhibitor 1 (DKK1) [NM_012242.4: c.359G>T, p.(Arg120Leu)] and Wnt family member 3A (WNT3A) [NM_033131.3: c.377G>A, p. (Arg126His)]. As compared with single-variant LRP5 carriers, double-variant carriers had a significantly lower BMD Z-score (-4.1 ± 0.8) and higher mean number of fractures (6.0 ± 2.8 vs. 2.2 ± 1.9). Analysis of the family segregation suggests the inheritance of BMD trait.
Severe forms of EOOP may occur with carriage of 2 pathogenic variants in genes encoding regulators of the Wnt signaling pathway. Two-variant carriers of Wnt pathway genes had severe EOOP. Moreover, DKK1 and WNT3A genes should be included in next-generation sequence analyses of bone fragility.
早发性骨质疏松症（EOOP）的定义是骨密度（BMD）低，这会增加骨折的风险。尽管年轻时骨质疏松症的患病率尚不清楚，但低 BMD 与遗传背景高度相关。载脂蛋白 B 受体相关蛋白 5（LRP5）的杂合致病性变体与 EOOP 相关。本研究旨在通过使用与骨脆性相关的靶向基因测序面板，研究 EOOP 患者的遗传特征，以更好地了解表型严重程度的变化。
我们使用了一个与骨脆性相关的 17 个基因的测序面板来分析 68 名 EOOP 患者。我们发现 LRP5 变体的 EOOP 阳性率很高（14 名患者，20.6%）。其余 79.4%的 EOOP 患者没有 LRP5 变体，但疾病严重程度不同，这在该基因至少有一个变体的患者中也观察到。一名患者有多处骨折和脊柱 L1-L4 BMD Z 评分-2.9，携带一种新的致病纯合变体 c.2918T>C，p.(Leu973Pro)，无假性神经胶质瘤。除携带 LRP5 变体外，另外 2 名患者携带 Wnt 信号通路基因的杂合变体：Dickkopf WNT 信号通路抑制剂 1（DKK1）[NM_012242.4：c.359G>T，p.(Arg120Leu)]和 Wnt 家族成员 3A（WNT3A）[NM_033131.3：c.377G>A，p.(Arg126His)]。与单变体 LRP5 携带者相比，双变体携带者的 BMD Z 评分明显更低（-4.1±0.8），骨折总数更高（6.0±2.8 比 2.2±1.9）。家系分析表明 BMD 性状的遗传。
携带编码 Wnt 信号通路调节剂的基因中的 2 种致病性变体可能会发生严重形式的 EOOP。Wnt 通路基因的双变体携带者患有严重的 EOOP。此外，应将 DKK1 和 WNT3A 基因纳入骨脆性的下一代测序分析中。
