Institute of Medical and Molecular Genetics, Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, and Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, 28046 Madrid, Spain.
J Clin Endocrinol Metab. 2011 Feb;96(2):E404-12. doi: 10.1210/jc.2010-1689. Epub 2010 Dec 8.
Léri-Weill dyschondrosteosis (LWD) is a skeletal dysplasia characterized by disproportionate short stature and the Madelung deformity of the forearm. SHOX mutations and pseudoautosomal region 1 deletions encompassing SHOX or its enhancers have been identified in approximately 60% of LWD and approximately 15% of idiopathic short stature (ISS) individuals. Recently SHOX duplications have been described in LWD/ISS but also in individuals with other clinical manifestations, thus questioning their pathogenicity.
The objective of the study was to investigate the pathogenicity of SHOX duplications in LWD and ISS.
Multiplex ligation-dependent probe amplification is routinely used in our unit to analyze for SHOX/pseudoautosomal region 1 copy number changes in LWD/ISS referrals. Quantitative PCR, microsatellite marker, and fluorescence in situ hybridization analysis were undertaken to confirm all identified duplications.
During the routine analysis of 122 LWD and 613 ISS referrals, a total of four complete and 10 partial SHOX duplications or multiple copy number (n > 3) as well as one duplication of the SHOX 5' flanking region were identified in nine LWD and six ISS cases. Partial SHOX duplications appeared to have a more deleterious effect on skeletal dysplasia and height gain than complete SHOX duplications. Importantly, no increase in SHOX copy number was identified in 340 individuals with normal stature or 104 overgrowth referrals.
MLPA analysis of SHOX/PAR1 led to the identification of partial and complete SHOX duplications or multiple copies associated with LWD or ISS, suggesting that they may represent an additional class of mutations implicated in the molecular etiology of these clinical entities.
Léri-Weill 软骨发育不全症（LWD）是一种骨骼发育不良症，其特征为不成比例的身材矮小和前臂的 Madelung 畸形。大约 60%的 LWD 和大约 15%的特发性身材矮小症（ISS）患者中已发现 SHOX 突变和包含 SHOX 或其增强子的假常染色体区域 1 缺失。最近，在 LWD/ISS 中也描述了 SHOX 重复，但也在具有其他临床表现的个体中描述了 SHOX 重复，因此质疑其致病性。
本研究旨在研究 SHOX 重复在 LWD 和 ISS 中的致病性。
我们单位常规使用多重连接依赖性探针扩增来分析 LWD/ISS 转诊中 SHOX/假常染色体区域 1 的拷贝数变化。进行定量 PCR、微卫星标记和荧光原位杂交分析以确认所有鉴定的重复。
在对 122 例 LWD 和 613 例 ISS 转诊的常规分析中，在 9 例 LWD 和 6 例 ISS 病例中总共鉴定出 4 个完整和 10 个部分 SHOX 重复或多个拷贝数（n > 3）以及一个 SHOX 5'侧翼区域的重复。部分 SHOX 重复似乎对骨骼发育不良和身高增长的影响比完整 SHOX 重复更大。重要的是，在 340 名身高正常的个体或 104 名过度生长转诊中未发现 SHOX 拷贝数增加。
SHOX/PAR1 的 MLPA 分析导致了与 LWD 或 ISS 相关的部分和完整 SHOX 重复或多个拷贝的鉴定，表明它们可能代表了与这些临床实体的分子病因学相关的另一类突变。
