【作者】 梁德生；

【导师】 夏家辉；

【作者基本信息】 中南大学 ， 遗传学， 2006， 博士

【摘要】 我们对本室追踪了25年的具有智力障碍和轻微面部异常表型特征的一名男性先症者进行分析研究，高分辨G-显带染色体检查发现明显的臂间倒位46，XY，inv(12)(p11q14)和一段细胞遗传学水平上不能识别的额外染色体物质插入异常的12号染色体长臂，核型为[46，XY，inv(12)(pter→p11.2：：q14.1→p11.2：：?：：q14.1→qter)]。先症者的核型和表型都稳定地传递给了他的儿子。 为了鉴定额外染色体物质的来源，分析这种不明原因综合征的基因型／核型与表型的关系，探索智力障碍的发病机制，我们首先应用荧光原位杂交技术(FISH)对先症者及其儿子进行染色体断点定位研究，发现额外染色体物质来源于12号染色体短臂，将短臂断裂重接点／重复片断着丝粒端边界定位于12p11.22的124kb(chr12：28755133-28878898)内，长臂断裂重接点定位于12q14.1的70kb(chr12：58510500-58580370)内，重复片断端粒端起点定位于12p12.31(chr12：17695757-17725491)的29kb内[12p重复片断范围定位于12p12.31-p11.22的liMb(chr12-17695757-28878898)内，双色FISH确定重复片断反向插入长臂断裂重接点中。 进一步应用具有116，314个SNPs(分辨率为0.3-0.5Mb)的Mapping SNP Array全基因组CN检测技术进行分析，结果显示12号染色体短臂重复片断端粒端边界位于HindⅢ芯片的SNP_A-1662961和XabI芯片的SNP_A-1662196之间的232kb(chr12：17708381-17940493、)内，着丝粒端边界位于XabI芯片的SNP_A-1716707和SNP_A-1757551之间的165kb(chr12：28724178-28889151)内，重复片断位于SNP_A-1662961和SNP_A-1757551之间的11Mb(chr12：17708381-28889151)范围内，即dup(12)(p12.31p11.22)，结果与FISH分析高度吻合。这是10万个SNPs以上级别的Mapping SNPArray Copy Number检测技术应用于染色体病诊断方面的首次报道。 先症者父母的染色体检查未见异常。应用微卫星标记进行重复片段等位基因的亲-子传递分析，明确地显示先症者的染色体异常起源于母亲，并提示在母体配子形成期的第二次减数分裂中发生姐妹染色更多还原

【Abstract】 A male proband with mental retardation and mild facial features has been clinically investigated since 1981 and high resolution chromosome G-banding show that he carries an apparently pericentric inversion 46, XY, inv(12)(pllql4) and a cytogenetically unrecognizable extra chromosomal material inserted into 12q[46, XY, inv(12)(pter→ p11.2::q14.1→p11.2::?::q14.1→qter)]. Both of the karyotype and phenotype were steadfastly transmitted to his son. To identify the extra chromosomal material and the breakpoints, delineate the genotype/ karyotype-phenotype correlation for this unknown syndrome and find out the pathogenesis of mental retardation, the chromosomal painting for the breakpoints was carried out using fluorescence in situ hybridization (FISH) in both proband and his son, which implied that the extra segment was derived from 12p. Further FISH analysis mapped 12p breakpoint or the proximal end of 12p duplication to a 124kb (chr12: 28755133-28878898) region on 12p11.22, 12q breakpoint to a 70kb (chr12: 58510500-58580370) on 12q14.1 and the distal end of 12p duplication to a 29kb (chr12: 17695757-17725491) on 12p12.31, resulting in a HMb(chr12: 17695757-28878898) of 12p duplication [dup(12) (p12.31p11.22)], which was shown to insert reversely at one of the reunion points in the long arm of the inv(12) chromosome by double-color FISH.We further performed the genome-wide copy number detection in both the proband and his son by GeneChip Mapping 100K Array with 116,314 SNPs and a resolution of 0.3-0.5Mb, which showed the proximal end of 12p duplication within a 165kb(chr12: 28724178-28889151) between SNP_A-1716707 and SNP_A-1757551 of XabI array on 12p11.22 and the distal end of 12p duplication within a 232kb (chr12: 17708381-17940493) between SNP_A-1662961 of HindIII array and SNP_A-1662196 of XabI array on 12p12.31, resulting in a 11Mb(chr12: 17708381-28889151) of 12p duplication between SNP_A-1662961 and SNP_A-1757551 (12p12.31-p11.22). The results were co-confirmed with those by FISH. It is the first report to analyze copy number using更多还原