CLINICAL CORRELATIONS OF CONTIGUOUS GENE SYNDROMES

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。人类的染色体重排是多样的、频繁的，并且经常导致表型异常。连锁基因综合征（CGS）是由染色体重排引起的疾病，包括缺失和重复，导致正常基因剂量的改变。在临床上，每个CGS的特点是一个特定的，往往是复杂的表型，这是公认的，在大多数情况下，作为一个遗传综合征之前的知识的细胞遗传学病因。负责的染色体区段通常在细胞遗传学规模上很小（<5 Mb），但包含多个基因，其中一些是剂量敏感的，并且独立地促成表型。对于大多数常染色体基因座，缺失导致结构和功能单体的基因剂量减少。特定基因在临界区间的单倍不足与史密斯-马格尼斯综合征（SMS）中的del（17）（p11.2p11.2）和单体1 p-del（1）（p36）有关。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、发育迟缓和神经行为异常，包括破坏性行为和睡眠障碍。尽管SMS患者之间的表型可能不同，但通过分子分析，大多数（>90%）SMS患者具有相同大小的缺失。与1号染色体短臂上最远端带缺失相关的临床特征最近已被描述。患者表现出广泛的特征，包括不同程度的智力迟钝、生长迟缓、癫痫发作和/或异常EEG、张力减退、发育迟缓、青春期提前、口面裂或腭异常、前囟扩大、畸形特征、耳聋和心肌病。1 p36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。染色体片段的复制导致剂量和基因表达增加。在我们的实验室中，SMS区域（17p11.2）的复制已被分子鉴定为SMS缺失的重组倒数。患有这种细胞遗传学异常的人比SMS患者受影响的程度要轻，似乎没有主要的器官系统异常或睡眠障碍，并且可以具有正常或边缘智力。同样，在我们的实验室中已经鉴定出1 p36重复的人，并且与其缺失的对应物相比具有不同的表型异常。对SMS患者的严格评估已经通过德克萨斯儿童医院（TCH）的综合临床研究中心（GCRC）完成。对具有不寻常大小SMS缺失的个体的进一步评估也将确定基因型-表型相关性。有必要对重复17p11.2的患者进行评估，以完全描述这种新的分子定义的综合征。1 p36缺失的人也通过GCRC进行了研究，迄今为止仅在一名患者中报告了该区域的重复。由于这些患者有各种大小的缺失，必须研究更多的患者以准确定义临床谱和基因型-表型相关性。细胞遗传学和分子学研究与这些临床分析同时进行，因此补充了本临床研究。

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.