Baudisch Friederike, Draaken Markus, Bartels Enrika, Schmiedeke Eberhard, Bagci Soyhan, Bartmann Peter, Nöthen Markus M, Ludwig Michael, Reutter Heiko
Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.
Twin Res Hum Genet. 2013 Aug;16(4):802-7. doi: 10.1017/thg.2013.29. Epub 2013 May 9.
Early post-twinning mutational events can account for discordant phenotypes in monozygotic (MZ) twin pairs. Such mutational events may comprise genomic alterations of different sizes, ranging from single nucleotides to large copy-number variations (CNVs). Anorectal malformations (ARM) and the bladder exstrophy-epispadias complex (BEEC) represent the most severe end of the urorectal malformation spectrum. Recently, CNV studies in patients with sporadic ARM and the BEEC have identified de novo events that occur in specific chromosomal regions. We hypothesized that early arising, post-twinning CNVs might contribute to discordance in MZ twin pairs with ARM or the BEEC; knowledge of such CNVs might help to identify additional chromosomal regions involved in the development of these malformations. We investigated four discordant MZ twin pairs (three ARM and one BEEC) using molecular karyotyping arrays comprising 1,140,419 markers with a median marker spacing of 1.5 kb. Filtering the coding regions for possible disease-causing post-twinning de novo CNVs present only in the affected twin, but not in the unaffected twin or the parents, identified a total of 136 CNVs. These 136 CNVs were then filtered against publicly available databases and finally re-evaluated visually. No potentially causative CNV remained after applying these filter criteria. Our results suggest that post-twinning CNV events that affect coding regions of the genome did not contribute to the discordant phenotypes in MZ twin pairs that we investigated. Possible causes for the discordant phenotypes include changes in regulatory elements or smaller genetic changes within coding regions which may be detectable by whole-exome sequencing.
孪生后的早期突变事件可解释单卵（MZ）双胞胎对中不一致的表型。此类突变事件可能包括不同大小的基因组改变，范围从单核苷酸到大片段拷贝数变异（CNV）。肛门直肠畸形（ARM）和膀胱外翻-尿道上裂复合体（BEEC）代表泌尿直肠畸形谱系中最严重的一端。最近，对散发性ARM和BEEC患者的CNV研究已确定在特定染色体区域发生的新生事件。我们推测，孪生后早期出现的CNV可能导致患有ARM或BEEC的MZ双胞胎对出现不一致的情况；了解此类CNV可能有助于识别参与这些畸形发育的其他染色体区域。我们使用包含1,140,419个标记且标记间距中位数为1.5 kb的分子核型分析阵列，对四对不一致的MZ双胞胎（三对ARM和一对BEEC）进行了研究。筛选仅存在于受影响双胞胎而非未受影响双胞胎或其父母中的可能导致疾病的孪生后新生CNV的编码区域，共鉴定出136个CNV。然后将这136个CNV与公开可用的数据库进行比对，最后进行视觉重新评估。应用这些筛选标准后，没有留下潜在的致病CNV。我们的结果表明，影响基因组编码区域的孪生后CNV事件对我们所研究的MZ双胞胎对中不一致的表型没有影响。不一致表型的可能原因包括调控元件的变化或编码区域内较小的基因变化，这些变化可能通过全外显子测序检测到。
