CLINICAL CORRELATIONS OF CONTIGUOUS GENE SYNDROMES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 人类的染色体重排是多样的、频繁的，并经常导致表型异常。连续基因综合征(CGS)是由染色体重排引起的疾病，包括缺失和复制，导致正常基因剂量的改变。临床上，每一种CGS都有一种特殊且往往复杂的表型，在大多数病例中，这种表型在细胞遗传学病因之前就被认为是一种遗传综合征。负责的染色体片段通常在细胞遗传学规模上很小(&lt；5Mb)，但包含多个基因，其中一些是剂量敏感的，并独立地影响表型。对于大多数常染色体基因座来说，缺失会导致基因剂量减少，形成结构和功能单体。Smith-Magenis综合征(SMS)的del(17)(p11.2p11.2)和单体1p-del(1)(P36)在临界区间的特定基因单倍体不足。SMS的临床表现包括身材矮小、眼科、耳鼻喉科、心脏和肾脏异常、发育迟缓以及包括破坏性行为和睡眠障碍在内的神经行为异常。虽然不同的SMS患者的表型可能不同，但通过分子分析，大多数(&gt；90%)的SMS患者存在相同大小的缺失。与1号染色体短臂最远端条带缺失相关的临床特征最近已被描述。患者表现出各种各样的特征，包括不同程度的智力低下、生长迟缓、癫痫发作和/或异常脑电、低眼压、发育迟缓、青春期早期、口面部裂开或腭裂、前颧骨扩大、畸形、耳聋和心肌病。1p36缺失的大小各不相同，正在进行的基因型-表型相关性可能会阐明该区域的致病基因。 染色体片段的复制会导致剂量和基因表达的增加。Sms区(17p11.2)的重复在我们实验室已经被分子鉴定为Sms缺失的重组倒数。患有这种细胞遗传学异常的人比患有短信的人受到的影响较小，似乎没有主要的器官系统异常或睡眠障碍，并且可能具有正常或边缘智力。同样，我们实验室已经发现了1p36重复的人，他们的表型异常与他们的缺失对应的人不同。德克萨斯州儿童医院(TCH)的综合临床研究中心(GCRC)已经完成了对短信患者的严格评估。对异常大小的短信息缺失个体的进一步评估也将确定基因与表型的相关性。对重复17p11.2的患者进行评估是完全确定这一新的分子定义综合征的特征所必需的。GCRC也对缺失1p36的人进行了研究，到目前为止只有一名患者报告了该区域的重复。由于这些患者有不同大小的缺失，必须对更多的数字进行研究，以准确定义临床谱系和基因-表型的相关性。细胞遗传学和分子研究与这些临床分析同时进行，从而补充了这项临床研究。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Chromosomal rearrangements in humans are diverse, frequent, and often result in phenotypic abnormalities. Contiguous gene syndromes (CGS) are disorders caused by chromosomal rearrangements, including deletions and duplications, which result in an alteration of normal gene dosage. Clinically, each CGS is characterized by a specific and often complex phenotype, which was recognized in most cases as a genetic syndrome prior to knowledge of the cytogenetic etiology. The responsible chromosomal segment is usually small on a cytogenetic scale (<5 Mb), but encompasses multiple genes, some of which are dosage sensitive and contribute to the phenotype independently. For most autosomal loci, deletion causes a reduction of gene dosage to structural and functional monosomy. Haploinsufficiency for specific genes in the critical interval is implicated for del(17)(p11.2p11.2) in Smith-Magenis syndrome (SMS) and for monosomy 1p-del(1)(p36). The spectrum of clinical findings in SMS includes short stature, ophthalmologic, otolaryngologic, cardiac, and renal anomalies, developmental delay, and neurobehavioral abnormalities including destructive behavior and sleep disturbances. Although the phenotype may vary between SMS patients, the majority (>90%) of persons with SMS harbor the same sized deletion by molecular analysis. The clinical features associated with deletion of the most distal band on the short arm of chromosome 1 have been recently delineated. Patients show a wide range of features including variable degrees of mental retardation, growth delay, seizures and/or abnormal EEGs, hypotonia, developmental delay, early puberty, orofacial clefting or palatal anomalies, enlarged anterior fontanel, dysmorphic features, deafness, and cardiomyopathy. The 1p36 deletions vary in size and ongoing genotype-phenotype correlation will likely elucidate the causative genes in this region. Duplication of chromosomal segments causes increased dosage and gene expression. Duplication of the SMS region (17p11.2) has been molecularly identified in our laboratory as the recombination reciprocal of the SMS deletion. Persons with this cytogenetic abnormality are less severely affected than persons with SMS, do not seem to have major organ system anomalies or sleep disturbance, and can have normal or borderline intelligence. Likewise, persons with duplications of 1p36 have been identified in our laboratory and have different phenotypic anomalies than their deletion counterparts. Rigorous evaluations of patients with SMS have been completed through the General Clinical Research Center (GCRC) at the Texas Children's Hospital (TCH). Further evaluation of individuals with unusual sized SMS deletions will also determine genotype-phenotype correlation. Evaluations of patients with duplication 17p11.2 is necessary to completely characterize this novel molecularly defined syndrome. Persons with deletion of 1p36 have also been studied through the GCRC and duplication of this region has so far only been reported in one patient. As these patients have deletions of various sizes, a greater number must be studied to accurately define the clinical spectrum and genotype-phenotype correlation. Cytogenetic and molecular studies are performed concurrently with these clinical analyses and thus complement this clinical research.