Suzuki Erina, Shima Hirohito, Toki Machiko, Hanew Kunihiko, Matsubara Keiko, Kurahashi Hiroki, Narumi Satoshi, Ogata Tsutomu, Kamimaki Tsutomu, Fukami Maki
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
Cytogenet Genome Res. 2016;150(2):86-92. doi: 10.1159/000455026. Epub 2017 Jan 19.
Our current understanding of the phenotypic consequences and the molecular basis of germline complex chromosomal rearrangements remains fragmentary. Here, we report the clinical and molecular characteristics of 2 women with germline complex X-chromosomal rearrangements. Patient 1 presented with nonsyndromic ovarian dysfunction and hyperthyroidism; patient 2 exhibited various Turner syndrome- associated symptoms including ovarian dysfunction, short stature, and autoimmune hypothyroidism. The genomic abnormalities of the patients were characterized by array-based comparative genomic hybridization, high-resolution karyotyping, microsatellite genotyping, X-inactivation analysis, and bisulfite sequencing. Patient 1 carried a rearrangement of unknown parental origin with a 46,X,der(X)(pter→ p22.1::p11.23→q24::q21.3→q24::p11.4→pter) karyotype, indicative of a catastrophic chromosomal reconstruction due to chromothripsis/chromoanasynthesis. Patient 2 had a paternally derived isochromosome with a 46,X,der(X)(pter→ p22.31::q22.1→q10::q10→q22.1::p22.31→pter) karyotype, which likely resulted from 2 independent, sequential events. Both patients showed completely skewed X inactivation. CpG sites at Xp22.3 were hypermethylated in patient 2. The results indicate that germline complex X-chromosomal rearrangements underlie nonsyndromic ovarian dysfunction and Turner syndrome. Disease-causative mechanisms of these rearrangements likely include aberrant DNA methylation, in addition to X-chromosomal mispairing and haploinsufficiency of genes escaping X inactivation. Notably, our data imply that germline complex X-chromosomal rearrangements are created through both chromothripsis/chromoanasynthesis-dependent and -independent processes.
我们目前对种系复杂染色体重排的表型后果和分子基础的理解仍然支离破碎。在此，我们报告了2例患有种系复杂X染色体重排的女性的临床和分子特征。患者1表现为非综合征性卵巢功能障碍和甲状腺功能亢进；患者2表现出各种特纳综合征相关症状，包括卵巢功能障碍、身材矮小和自身免疫性甲状腺功能减退。通过基于阵列的比较基因组杂交、高分辨率核型分析、微卫星基因分型、X染色体失活分析和亚硫酸氢盐测序对患者的基因组异常进行了表征。患者1携带一种来源不明的重排，核型为46,X,der(X)(pter→ p22.1::p11.23→q24::q21.3→q24::p11.4→pter)，表明由于染色体碎裂/染色体组分析导致灾难性的染色体重建。患者2有一条父源等臂染色体，核型为46,X,der(X)(pter→ p22.31::q22.1→q10::q10→q22.1::p22.31→pter)，这可能是由2个独立的连续事件导致的。两名患者均表现出完全偏态的X染色体失活。患者2中Xp22.3处的CpG位点高度甲基化。结果表明，种系复杂X染色体重排是非综合征性卵巢功能障碍和特纳综合征的基础。这些重排的致病机制可能除了X染色体错配和逃避X染色体失活的基因单倍剂量不足外，还包括异常的DNA甲基化。值得注意的是，我们的数据表明种系复杂X染色体重排是通过染色体碎裂/染色体组分析依赖性和非依赖性过程产生的。
