Y-chromosome microdeletions are not associated with SHOX haploinsufficiency
Y-chromosome microdeletions are not associated with SHOX haploinsufficiency
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DOI：
10.1093/humrep/det322
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发表时间：
2013-11-01
影响因子：
6.1
通讯作者：
Krausz, C.
中科院分区：
文献类型：
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作者：
Chianese, C.;Lo Giacco, D.;Krausz, C.
Y染色体微缺失是否与SHOX单倍性不足相关，从而代表携带者及其男性后代骨骼异常的风险？目前的研究表明SHOX单倍不足不太可能与Y染色体微缺失有关，Y染色体微缺失通常不是除生精障碍以外的任何病理状态的主要分子遗传学原因。然而，最近有人提出，它们不仅与不育有关，而且与假常染色体区域（PAR）的异常有关，其中SHOX单倍不足在具有正常核型的微缺失携带者中以5.4的频率突出。这一发现意味着Y染色体缺陷男性所生的儿子不仅会出现生育问题，而且还可能患有与SHOX相关的疾病。（佛罗伦萨、明斯特、巴塞罗那、帕多瓦和安科纳），常规进行Y染色体微缺失筛查，在一项多中心研究中，分析了224例携带Y-染色体的患者的PAR连锁和SHOX拷贝数变异（CNVs）。使用定制的X染色体特异性阵列CGH平台和/或针对SHOX和SRY基因的qPCR检测，我们的数据显示224个（98.2）微缺失携带者中有220个（98.2）具有正常的SHOX拷贝数，所有对照也是如此。在任何检查的受试者（患者和对照）中均未发现SHOX缺失，因此排除了与SHOX单倍不足的相关性。在1.78例患者（n 4）中检测到SHOX重复，其中2例核型异常，2例核型正常。这可能表明，Y染色体微缺失有较高的发生率为SHOX重复，无论患者的核型。然而，在这方面，在我们的四名SHOX重复的患者中观察到的唯一临床状况是不育。为了评估在两名具有Y染色体微缺失和正常核型的男性中发现的SHOX重复是否代表中性多态性或实际上与微缺失的存在相关，分析的对照数量相当低。染色体微缺失可以求助于人工生殖技术（ART）来养育他们的亲生子女。然而，不孕夫妇必须意识到隐含的风险，这使得遗传咨询成为患者管理的关键一步。这项研究并没有证实以前令人震惊的数据，表明Y染色体微缺失和SHOX单倍不足之间的关联。我们的研究结果表明，缺失携带者患SHOX相关疾病的风险没有增加（身材矮小和骨骼异常），并表明没有必要在尝试ART的Yq微缺失携带者的遗传咨询中进行根本性的改变，因为到目前为止，对雄性后代的唯一风险仍然是精子发生受损。这项工作得到了意大利大学部的支持，（将PRIN 2010 - 2012授予C.K.），托斯卡纳地区健康研究计划（Progetto Salute 2009），G.F.，西班牙卫生部（FIS-11/02254号赠款）和欧洲联盟生殖训练玛丽居里网络（项目编号：289880，C.K.）。作者声明不存在利益冲突。
Are Y-chromosome microdeletions associated with SHOX haploinsufficiency, thus representing a risk of skeletal anomalies for the carriers and their male descendents?The present study shows that SHOX haploinsufficiency is unlikely to be associated with Y-chromosome microdeletions.Y-chromosome microdeletions are not commonly known as a major molecular genetic cause of any pathological condition except spermatogenic failure. However, it has been recently proposed that they are associated not only with infertility but also with anomalies in the pseudoautosomal regions (PAR), among which SHOX haploinsufficiency stands out with a frequency of 5.4 in microdeletion carriers bearing a normal karyotype. This finding implies that sons fathered by men with Y-chromosome defects will not only exhibit fertility problems, but might also suffer from SHOX-related conditions.Five European laboratories (Florence, Mnster, Barcelona, Padova and Ancona), routinely performing Y-chromosome microdeletion screening, were enrolled in a multicenter study.PAR-linked and SHOX copy number variations (CNVs) were analyzed in 224 patients carrying Y-chromosome microdeletions and 112 controls with an intact Y chromosome, using customized X-chromosome-specific array-CGH platforms and/or qPCR assays for SHOX and SRY genes.Our data show that 220 out of 224 (98.2) microdeletion carriers had a normal SHOX copy number, as did all the controls. No SHOX deletions were found in any of the examined subjects (patients as well as controls), thus excluding an association with SHOX haploinsufficiency. SHOX duplications were detected in 1.78 of patients (n 4), of whom two had an abnormal and two a normal karyotype. This might suggest that Y-chromosome microdeletions have a higher incidence for SHOX duplications, irrespective of the patients karyotype. However, the only clinical condition observed in our four SHOX-duplicated patients was infertility.The number of controls analyzed is rather low to assess whether the SHOX duplications found in the two men with Y-chromosome microdeletions and a normal karyotype represent a neutral polymorphism or are actually associated with the presence of the microdeletion.Men suffering from infertility due to the presence of Y-chromosome microdeletions can resort to artificial reproductive technology (ART) to father their biological children. However, infertile couples must be aware of the risks implied and this makes genetic counseling a crucial step in the patients management. This study does not confirm previous alarming data that showed an association between Y-chromosome microdeletions and SHOX haploinsufficiency. Our results imply that deletion carriers have no augmented risk of SHOX-related pathologies (short stature and skeletal anomalies) and indicate that there is no need for radical changes in genetic counseling of Yq microdeletion carriers attempting ART, since the only risk established so far for their male offspring remains impaired spermatogenesis.This work was supported by the Italian Ministry of University (grant PRIN 2010-2012 to C.K.), Tuscan Regional Health Research Program (Progetto Salute 2009) to G.F., the Spanish Ministry of Health (grant FIS-11/02254) and the European Union Reprotrain Marie Curie Network (project number: 289880 to C.K.). The authors declare that no conflicting interests exist.