Barber John C K, Maloney Viv, Hollox Edward J, Stuke-Sontheimer Annegret, du Bois Gabi, Daumiller Eva, Klein-Vogler Ute, Dufke Andreas, Armour John A L, Liehr Thomas
Wessex Regional Genetics Laboratory, Salisbury Hospital NHS Trust, Salisbury, Wiltshire, UK.
Eur J Hum Genet. 2005 Oct;13(10):1131-6. doi: 10.1038/sj.ejhg.5201475.
It has been proposed that duplications of 8p23.1 are either euchromatic variants of the 8p23.1 defensin domain with no phenotypic consequences or true duplications associated with developmental delay and heart defects. Here, we provide evidence for both alternatives in two new families. A duplication of most of band 8p23.1 (circa 5 Mb) was found in a girl of 8 years with pulmonary stenosis and mild language delay. BAC fluorescence in situ hybridisation (FISH) and multiplex amplifiable probe hybridisation (MAPH) showed that the two copies of the duplicated segment were sited, in an alternating fashion, between three copies of a circa 300-450 kb segment from 8p23.1 distal to REPD. Copy number of the variable 8p23.1 defensin domain was consistent with duplication but within the normal range. Duplication of the GATA-binding protein 4 gene (GATA4) in this patient and others with and without heart defects, suggests it is a dosage-sensitive gene with variable penetrance. A cytogenetically similar duplication of 8p23.1 was found at prenatal diagnosis in a fetus, father and grandmother. There was no duplication using BAC FISH but MAPH showed 11 copies of the 360 kb variable defensin domain which is within the expanded range found in previous euchromatic variant carriers. Semiquantitative FISH (SQ-FISH) was consistent with a simultaneous expansion of the adjacent olfactory receptor repeats. These results distinguish duplications of 8p23.1 with clinically significant consequences from benign copy number variants, which have not yet been associated with qualitative or quantitative traits.
有人提出，8p23.1的重复要么是8p23.1防御素结构域的常染色质变体，无表型后果，要么是与发育迟缓及心脏缺陷相关的真正重复。在此，我们在两个新家族中为这两种情况均提供了证据。在一名患有肺动脉狭窄和轻度语言发育迟缓的8岁女孩中发现了8p23.1大部分条带（约5 Mb）的重复。BAC荧光原位杂交（FISH）和多重可扩增探针杂交（MAPH）显示，重复片段的两个拷贝以交替方式位于来自8p23.1远端REPD的约300 - 450 kb片段的三个拷贝之间。可变的8p23.1防御素结构域的拷贝数与重复一致，但在正常范围内。该患者以及其他有或无心脏缺陷的患者中GATA结合蛋白4基因（GATA4）的重复表明，它是一个具有可变外显率的剂量敏感基因。在一名胎儿、其父亲和祖母的产前诊断中发现了细胞遗传学上相似的8p23.1重复。BAC FISH未检测到重复，但MAPH显示360 kb可变防御素结构域有11个拷贝，这在先前常染色质变体携带者中发现的扩增范围内。半定量FISH（SQ - FISH）与相邻嗅觉受体重复序列的同时扩增一致。这些结果区分了具有临床显著后果的8p23.1重复与尚未与定性或定量性状相关的良性拷贝数变体。
