Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes.
Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes.
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DOI：
10.1056/nejmoa0805384
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发表时间：
2008-10-16
期刊：
影响因子：
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通讯作者：
Eichler EE
中科院分区：
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作者：
Mefford HC;Sharp AJ;Baker C;Itsara A;Jiang Z;Buysse K;Huang S;Maloney VK;Crolla JA;Baralle D;Collins A;Mercer C;Norga K;de Ravel T;Devriendt K;Bongers EM;de Leeuw N;Reardon W;Gimelli S;Bena F;Hennekam RC;Male A;Gaunt L;Clayton-Smith J;Simonic I;Park SM;Mehta SG;Nik-Zainal S;Woods CG;Firth HV;Parkin G;Fichera M;Reitano S;Lo Giudice M;Li KE;Casuga I;Broomer A;Conrad B;Schwerzmann M;Räber L;Gallati S;Striano P;Coppola A;Tolmie JL;Tobias ES;Lilley C;Armengol L;Spysschaert Y;Verloo P;De Coene A;Goossens L;Mortier G;Speleman F;van Binsbergen E;Nelen MR;Hochstenbach R;Poot M;Gallagher L;Gill M;McClellan J;King MC;Regan R;Skinner C;Stevenson RE;Antonarakis SE;Chen C;Estivill X;Menten B;Gimelli G;Gribble S;Schwartz S;Sutcliffe JS;Walsh T;Knight SJ;Sebat J;Romano C;Schwartz CE;Veltman JA;de Vries BB;Vermeesch JR;Barber JC;Willatt L;Tassabehji M;Eichler EE
人类基因组中的复制和缺失可导致疾病或使人易患病。检测这些变化的技术进步允许在大量患者中常规识别亚显微失衡。我们测试了两组不明原因的精神发育迟滞、自闭症或先天性异常患者和未受影响的人染色体1q21.1特定区域的微缺失和微重复的存在。我们从5218例患者中筛选出25例1q21.1内复发性1.35-Mb缺失。微缺失在8名患者中从头出现，在3名患者中从轻度受影响的父母遗传，在6名患者中从明显未受影响的父母遗传，在8名患者中遗传未知。在4737名对照者中，缺失（P = 1.1×10−7）。我们发现微缺失的表型表达水平存在相当大的差异;表型包括轻度至中度智力低下、小头畸形、心脏异常和白内障。9名智力低下或自闭症谱系障碍及其他可变特征的儿童中，相互重复的频率较高（P = 0.02）。我们在788例精神发育迟滞和先天性异常患者的独立样本中发现了1q21.1区域的三个缺失和三个重复。我们已经确定了逃避综合征分类的复发性分子病变，其疾病表现必须在更广泛的发展背景下考虑，而不是被分配到一个特定的疾病。这些病变患者的临床诊断最容易根据基因型而不是表型实现。
Duplications and deletions in the human genome can cause disease or predispose persons to disease. Advances in technologies to detect these changes allow for the routine identification of submicroscopic imbalances in large numbers of patients. We tested for the presence of microdeletions and microduplications at a specific region of chromosome 1q21.1 in two groups of patients with unexplained mental retardation, autism, or congenital anomalies and in unaffected persons. We identified 25 persons with a recurrent 1.35-Mb deletion within 1q21.1 from screening 5218 patients. The microdeletions had arisen de novo in eight patients, were inherited from a mildly affected parent in three patients, were inherited from an apparently unaffected parent in six patients, and were of unknown inheritance in eight patients. The deletion was absent in a series of 4737 control persons (P = 1.1×10−7). We found considerable variability in the level of phenotypic expression of the microdeletion; phenotypes included mild-to-moderate mental retardation, microcephaly, cardiac abnormalities, and cataracts. The reciprocal duplication was enriched in the nine children with mental retardation or autism spectrum disorder and other variable features (P = 0.02). We identified three deletions and three duplications of the 1q21.1 region in an independent sample of 788 patients with mental retardation and congenital anomalies. We have identified recurrent molecular lesions that elude syndromic classification and whose disease manifestations must be considered in a broader context of development as opposed to being assigned to a specific disease. Clinical diagnosis in patients with these lesions may be most readily achieved on the basis of genotype rather than phenotype.