种系或组成型生色发生相关的复杂染色体重排(CCR)很少见,显然是“一次性”,在单个细胞周期中发生的灾难性事件,表现出意想不到的复杂性,有时与严重的异常表型相关。术语显色发生包括三种不同的现象,即染色体,染色体异步,和染色体。在这里,我们在一名表型类似常染色体显性遗传MRD44(OMIM617061)的患者中,在超复杂t(5;7;21)dn中发现了嗜铬细胞和嗜铬细胞的标志,涉及多个无序断点连接(BPJ),并伴有一些微缺失和神经发育基因的破坏.G带染色体和FISH表明,CCR暗示5p15.2→pter片段易位到7q11.23;反过来,der(7)的片段7q11.23→qter分为两部分:q11.23→q32转移到5p15.2上,并在der(5)中融合到21q22.1→ter,而远端7q32→qter段在q22.1转移到der(21)上。随后的全基因组测序揭示了CCT5,CMBL,来自der(5)的RETREG1,MYO10和TRIO,IMMP2L,TES,VPS37D,DUS4L,TYW1B,和der(7)的FEZF1-AS1,以及der(21)的TIAM1和SOD1,被BPJ打断了,而其他一些基因(预测是单倍体或无关紧要的)被完全删除。虽然值得注意的是CCT5,TRIO,TES,MYO10和TIAM1(甚至VPS37D)在正常神经元发育的关键生物过程中合作,例如细胞粘附,迁移,增长,和/或细胞骨架形成,TRIO的破坏最有可能导致患者的MRD44样表型,包括智力残疾,小头畸形,手指异常,和面部畸形。我们的观察代表了与显色发生事件相关的TRIO的首次截断,因此扩展了该关键基因的突变谱。此外,我们的发现表明,超复杂重排的结构建模涉及一种以上的机制。
Germline or constitutional chromoanagenesis-related complex chromosomal rearrangements (CCRs) are rare, apparently \"all-at-once\", catastrophic events that occur in a single cell cycle, exhibit an unexpected complexity, and sometimes correlate with a severe abnormal phenotype. The term chromoanagenesis encompasses three distinct phenomena, namely chromothripsis, chromoanasynthesis, and chromoplexy. Herein, we found hallmarks of chromothripsis and chromoplexy in an ultra-complex t(5;7;21)dn involving several disordered breakpoint junctions (BPJs) accompanied by some microdeletions and the disruption of neurodevelopmental genes in a patient with a phenotype resembling autosomal dominant MRD44 (OMIM 617061). G-banded chromosomes and FISH showed that the CCR implied the translocation of the 5p15.2→pter segment onto 7q11.23; in turn, the fragment 7q11.23→qter of der(7) separated into two pieces: the segment q11.23→q32 translocated onto 5p15.2 and fused to 21q22.1→ter in the der(5) while the distal 7q32→qter segment translocated onto der(21) at q22.1. Subsequent whole-genome sequencing unveiled that CCT5, CMBL, RETREG1, MYO10, and
TRIO from der(5), IMMP2L, TES, VPS37D, DUS4L, TYW1B, and FEZF1-AS1 from der(7), and TIAM1 and SOD1 from der(21), were disrupted by BPJs, whereas some other genes (predicted to be haplosufficient or inconsequential) were completely deleted. Although remarkably CCT5,
TRIO, TES, MYO10, and TIAM1 (and even VPS37D) cooperate in key biological processes for normal neuronal development such as cell adhesion, migration, growth, and/or cytoskeleton formation, the disruption of
TRIO most likely caused the patient\'s MRD44-like phenotype, including intellectual disability, microcephaly, finger anomalies, and facial dysmorphia. Our observation represents the first truncation of
TRIO related to a chromoanagenesis event and therefore expands the mutational spectrum of this crucial gene. Moreover, our findings indicate that more than one mechanism is involved in modeling the architecture of ultra-complex rearrangements.