Demaerel Wolfram, Hestand Matthew S, Vergaelen Elfi, Swillen Ann, López-Sánchez Marcos, Pérez-Jurado Luis A, McDonald-McGinn Donna M, Zackai Elaine, Emanuel Beverly S, Morrow Bernice E, Breckpot Jeroen, Devriendt Koenraad, Vermeesch Joris R
Department of Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium.
Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain; Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, Barcelona, Spain.
Am J Hum Genet. 2017 Oct 5;101(4):616-622. doi: 10.1016/j.ajhg.2017.09.002. Epub 2017 Sep 28.
Inversion polymorphisms between low-copy repeats (LCRs) might predispose chromosomes to meiotic non-allelic homologous recombination (NAHR) events and thus lead to genomic disorders. However, for the 22q11.2 deletion syndrome (22q11.2DS), the most common genomic disorder, no such inversions have been uncovered as of yet. Using fiber-FISH, we demonstrate that parents transmitting the de novo 3 Mb LCR22A-D 22q11.2 deletion, the reciprocal duplication, and the smaller 1.5 Mb LCR22A-B 22q11.2 deletion carry inversions of LCR22B-D or LCR22C-D. Hence, the inversions predispose chromosome 22q11.2 to meiotic rearrangements and increase the individual risk for transmitting rearrangements. Interestingly, the inversions are nested or flanking rather than coinciding with the deletion or duplication sizes. This finding raises the possibility that inversions are a prerequisite not only for 22q11.2 rearrangements but also for all NAHR-mediated genomic disorders.
低拷贝重复序列（LCRs）之间的倒位多态性可能使染色体易发生减数分裂非等位基因同源重组（NAHR）事件，从而导致基因组疾病。然而，对于最常见的基因组疾病——22q11.2缺失综合征（22q11.2DS），目前尚未发现此类倒位。我们利用纤维荧光原位杂交技术（fiber-FISH）证明，传递新生的3 Mb LCR22A-D 22q11.2缺失、相互重复以及较小的1.5 Mb LCR22A-B 22q11.2缺失的父母携带LCR22B-D或LCR22C-D倒位。因此，这些倒位使22q11.2染色体易发生减数分裂重排，并增加了传递重排的个体风险。有趣的是，这些倒位是嵌套或侧翼的，而不是与缺失或重复大小一致。这一发现增加了这样一种可能性，即倒位不仅是22q11.2重排的先决条件，也是所有NAHR介导的基因组疾病的先决条件。
