The genetic cause of intellectual deficiency and/or congenital malformations in two parental reciprocal translocation carriers and implications for assisted reproduction
The genetic cause of intellectual deficiency and/or congenital malformations in two parental reciprocal translocation carriers and implications for assisted reproduction
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两个亲代易位携带者智力缺陷和/或先天畸形的遗传原因及其对辅助生殖的影响
DOI：
10.1007/s10815-020-01986-1
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发表时间：
2020-10-22
影响因子：
3.1
通讯作者：
Tan, Yue-Qiu
中科院分区：
文献类型：
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作者：
Cheng, Dehua;Yuan, Shimin;Tan, Yue-Qiu
目的 阐明两对双亲易位携带者智力缺陷和/或先天畸形的遗传原因，并提供适当的辅助生殖治疗（ART）策略。 材料与方法 两对相似的夫妇，其孩子出现全面性发育迟缓/智力障碍症状，分别于 2017 年和 2019 年到中信湘雅生殖遗传医院（中国长沙）就诊，以确定影响孩子的病症的原因并寻求 ART 以生出健康的婴儿。两对健康夫妇均非近亲结婚，否认有毒物接触史，无不良生活史。本研究经中信湘雅生殖遗传医院伦理委员会批准，并获得家长书面知情同意。通过核型分析、染色体易位断点图谱分析、单核苷酸多态性（SNP）微阵列分析和全外显子组测序（WES）对两个孩子进行遗传诊断，并在两个家庭中进行不同的适当生殖策略。结果核型分析显示，两个患者均携带亲本相互易位[46,XY,t(7;16)(p13;q24)pat和46,XY,t(13;17)(q12.3;p11.2)pat，分别]。后续断点图谱分析显示相关基因没有中断，SNP 微阵列分析发现两名患者没有显着的拷贝数变异 (CNV)。此外，WES 结果显示，患者 1 和 2 分别携带 MCOLN1[c.195G>C (p.K65N) 和 c.1061G>A (p.W354*)] 和 MCPH1[c.877A>G (p.S293G) 和 c.1869_1870delAT (p.C624*)] 的候选复合杂合突变，这些突变遗传自他们的父母以前没有报道过。此外，患者1的父母在ART周期中获得了10个胚胎，根据植入前结构重排和单基因缺陷的基因检测，核型正常且非MCOLN1突变携带者的胚胎成功移植，产下健康男孩。患者2的父母选择使用供体精子进行ART，以降低复发风险。结论对两名遗传性染色体易位携带者进行系统的基因诊断并结合临床表型，揭示了他们的病因，这对于这些家庭的遗传咨询和进一步的ART至关重要。
PurposeTo elucidate the genetic cause of intellectual deficiency and/or congenital malformations in two parental reciprocal translocation carriers and provide appropriate strategies of assisted reproductive therapy (ART).Materials and methodsTwo similar couples having a child with global developmental delay/intellectual disability symptoms attended the Reproductive and Genetic Hospital of CITIC-Xiangya (Changsha, China) in 2017 and 2019, respectively, in order to determine the cause(s) of the conditions affecting their child and to seek ART to have a healthy baby. Both of the healthy couples were not of consanguineous marriage, denied exposure to toxicants, and had no adverse life history. This study was approved by the Institutional Ethics Committee of the Reproductive & Genetic Hospital of CITIC-Xiangya, and written informed consent was obtained from the parents. Genetic diagnoses were performed by karyotype analysis, breakpoint mapping analysis of chromosomal translocation(s), single-nucleotide polymorphism (SNP) microarray analysis, and whole-exome sequencing (WES) for the two children and different appropriate reproductive strategies were performed in the two families.ResultsKaryotype analysis revealed that both patients carried parental reciprocal translocations [46,XY,t(7;16)(p13;q24)pat and 46,XY,t(13;17)(q12.3;p11.2)pat, respectively]. Follow-up breakpoint mapping analysis showed no interruption of associated genes, and SNP microarray analysis identified no significant copy number variations (CNVs) in the two patients. Moreover, WES results revealed that patients 1 and 2 harbored candidate compound heterozygous mutations ofMCOLN1[c.195G>C (p.K65N) and c.1061G>A (p.W354*)] andMCPH1[c.877A>G (p.S293G) and c.1869_1870delAT (p.C624*)], respectively, that were inherited from their parents and not previously reported. Furthermore, the parents of patient 1 obtained 10 embryos during ART cycle, and an embryo of normal karyotype and non-carrier of observedMCOLN1mutations according to preimplantation genetic testing for structural rearrangement and monogenic defect was successfully transferred, resulting in the birth of a healthy boy. The parents of patient 2 chose to undergo ART with donor sperm to reduce the risk of recurrence.ConclusionsSystematic genetic diagnosis of two carriers of inherited chromosomal translocations accompanied by clinical phenotypes revealed their cause of disease, which was critical for genetic counseling and further ART for these families.