Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 22529 Hamburg, Germany.
Department of Medicine III, Technische Universität Dresden Medical Center, 01307 Dresden, Germany.
J Clin Endocrinol Metab. 2022 Jun 16;107(7):e3048-e3057. doi: 10.1210/clinem/dgac147.
Many different inherited and acquired conditions can result in premature bone fragility/low bone mass disorders (LBMDs).
We aimed to elucidate the impact of genetic testing on differential diagnosis of adult LBMDs and at defining clinical criteria for predicting monogenic forms.
Four clinical centers broadly recruited a cohort of 394 unrelated adult women before menopause and men younger than 55 years with a bone mineral density (BMD) Z-score < -2.0 and/or pathological fractures. After exclusion of secondary causes or unequivocal clinical/biochemical hallmarks of monogenic LBMDs, all participants were genotyped by targeted next-generation sequencing.
In total, 20.8% of the participants carried rare disease-causing variants (DCVs) in genes known to cause osteogenesis imperfecta (COL1A1, COL1A2), hypophosphatasia (ALPL), and early-onset osteoporosis (LRP5, PLS3, and WNT1). In addition, we identified rare DCVs in ENPP1, LMNA, NOTCH2, and ZNF469. Three individuals had autosomal recessive, 75 autosomal dominant, and 4 X-linked disorders. A total of 9.7% of the participants harbored variants of unknown significance. A regression analysis revealed that the likelihood of detecting a DCV correlated with a positive family history of osteoporosis, peripheral fractures (> 2), and a high normal body mass index (BMI). In contrast, mutation frequencies did not correlate with age, prevalent vertebral fractures, BMD, or biochemical parameters. In individuals without monogenic disease-causing rare variants, common variants predisposing for low BMD (eg, in LRP5) were overrepresented.
The overlapping spectra of monogenic adult LBMD can be easily disentangled by genetic testing and the proposed clinical criteria can help to maximize the diagnostic yield.
许多不同的遗传性和获得性疾病可导致早发性骨脆弱/低骨量疾病（LBMD）。
我们旨在阐明遗传检测对成人 LBMD 鉴别诊断的影响，并确定预测单基因形式的临床标准。
四个临床中心广泛招募了一组 394 名绝经前的无亲缘关系的成年女性和 55 岁以下的男性，这些患者的骨密度（BMD）Z 评分<−2.0 和/或有病理骨折。排除继发性原因或单基因 LBMD 的明确临床/生化特征后，所有参与者均通过靶向下一代测序进行基因分型。
共有 20.8%的参与者携带已知引起成骨不全症（COL1A1、COL1A2）、低磷酸酶症（ALPL）和早发性骨质疏松症（LRP5、PLS3 和 WNT1）的致病罕见变异（DCV）。此外，我们还在 ENPP1、LMNA、NOTCH2 和 ZNF469 中发现了罕见的 DCV。3 例为常染色体隐性遗传，75 例为常染色体显性遗传，4 例为 X 连锁遗传疾病。共有 9.7%的参与者携带意义不明的变异。回归分析显示，检测到 DCV 的可能性与骨质疏松症阳性家族史、外周骨折（>2 处）和高正常体重指数（BMI）相关。相比之下，突变频率与年龄、常见的椎体骨折、BMD 或生化参数无关。在没有单基因疾病致病罕见变异的个体中，低 BMD 的常见变异（如 LRP5 中的变异）更为常见。
遗传检测可轻易区分单基因成人 LBMD 的重叠谱，所提出的临床标准有助于最大限度地提高诊断效果。
