Cytogenetics Laboratory, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy.
Department of Biomedical and Biotechnological Sciences, Medical Genetics, University of Catania, Catania, Italy; Oasi Research Institute-IRCCS, Troina, Italy.
Eur J Med Genet. 2022 Nov;65(11):104596. doi: 10.1016/j.ejmg.2022.104596. Epub 2022 Sep 5.
We describe a 5-year-old girl who was diagnosed at birth with 18q de novo homogeneous deletion at G-banding karyotype. Her clinical condition, characterized by hypotonia, psychomotor retardation, short stature, deafness secondary to bilateral atresia of the external auditory canals, was in agreement with the 18q deletion syndrome though presence of coloboma of a single eye only suggested a mosaic condition as an unusual sign. By combining multiple technologies including array-CGH, FISH, and WGS, we found that the terminal deletion 18q21.32q23 (21 Mb) was in segmental mosaicism of the proximal region 18q21.31q21.32 (2.7 Mb), which showed a variable number of copies: one, two, or three, in 7, 41 and 55% of the cells respectively. Breakpoint junction analysis demonstrated the presence of an inv-dup del (18q) with a disomic segment of 4.7 kb between the inverted and non-inverted copies of the duplicated region 18q21.31q21.32. From these results, we propose that all three types of abnormal chr18 (the inv-dup del and the two 18q terminal deletions of different sizes) arisen from breaks in a dicentric mirror chromosome 18q, either in more than one embryo cell or from subsequent breaking-fusion-bridge cycles. The duplication region was with identical polymorphisms as in all non-recurrent inv-dup del rearrangements though, in contrast with most of them, the 18q abnormality was of maternal origin. Taking into account that distal 18q deletions are not rarely associated with inv-dup del(18q) cell lines, and that the non-disjunction of chromosome 18 takes place especially at maternal meiosis II rather than meiosis I, multiple rescue events starting from trisomic zygotes could be considered alternative to the postmitotic ones. From the clinical point of view, our case, as well as those of del(18q) in mosaic with the dic(18q), shows that the final phenotype is the sum of the different cell lines that acted on embryonic development with signs typical of both the 18q deletion syndrome and trisomy 18. Asymmetrical malformations, such as coloboma of the iris only in the right eye, confirm the underlying mosaicism regardless of whether it is still detectable in the blood.
我们描述了一位 5 岁女孩，她在出生时被诊断出患有 18q 从头同种缺失，G 带核型分析。她的临床状况表现为肌张力低下、精神运动发育迟缓、身材矮小、双侧外耳道闭锁导致的耳聋，这与 18q 缺失综合征一致，但只有一只眼睛的虹膜裂仅提示镶嵌状态是一种不寻常的表现。通过结合包括 array-CGH、FISH 和 WGS 在内的多种技术，我们发现末端缺失 18q21.32q23（21Mb）在近端区域 18q21.31q21.32（2.7Mb）中呈片段性镶嵌，其拷贝数不同：分别有一个、两个或三个，在 7%、41%和 55%的细胞中。断裂点连接分析表明存在 inv-dup del（18q），在重复区域 18q21.31q21.32 的倒置和非倒置拷贝之间存在一个 4.7kb 的双体片段。从这些结果中，我们提出所有三种异常 chr18（inv-dup del 和两种不同大小的 18q 末端缺失）都源自双中心镜染色体 18q 的断裂，要么发生在多个胚胎细胞中，要么发生在随后的断裂-融合-桥循环中。重复区域与所有非重复 inv-dup del 重排中的相同多态性相同，但与大多数重排不同的是，18q 异常为母源来源。考虑到远端 18q 缺失与 inv-dup del（18q）细胞系并不罕见，并且 18 号染色体的非分离尤其发生在母本减数分裂 II 期，而不是减数分裂 I 期，从三体受精卵开始的多种挽救事件可以被认为是后有丝分裂事件的替代事件。从临床角度来看，我们的病例以及与 dic（18q）镶嵌的 del（18q）病例表明，最终表型是作用于胚胎发育的不同细胞系的总和，具有 18q 缺失综合征和三体 18 的典型特征。不对称性畸形，如只有右眼虹膜裂，无论其在血液中是否仍可检测到，均可确认潜在的镶嵌状态。
