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首页> 外文期刊>Molecular cytogenetics >Cryptic breakpoint identified by whole-genome mate-pair sequencing in a rare paternally inherited complex chromosomal rearrangement
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Cryptic breakpoint identified by whole-genome mate-pair sequencing in a rare paternally inherited complex chromosomal rearrangement

机译：罕见的患者遗传复合染色体重排中全基因组伴侣对鉴定的隐秘断点

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Precise characterization of apparently balanced complex chromosomal rearrangements in non-affected individuals is crucial as they may result in reproductive failure, recurrent miscarriages or affected offspring. We present a family, where the non-affected father and daughter were found, using FISH and karyotyping, to be carriers of a three-way complex chromosomal rearrangement [t(6;7;10)(q16.2;q34;q26.1), de novo in the father]. The family suffered from two stillbirths, one miscarriage, and has a son with severe intellectual disability. In the present study, the family was revisited using whole-genome mate-pair sequencing. Interestingly, whole-genome mate-pair sequencing revealed a cryptic breakpoint on derivative (der) chromosome 6 rendering the rearrangement even more complex. FISH using a chromosome (chr) 6 custom-designed probe and a chr10 control probe confirmed that the interstitial chr6 segment, created by the two chr6 breakpoints, was translocated onto der(10). Breakpoints were successfully validated with Sanger sequencing, and small imbalances as well as microhomology were identified. Finally, the complex chromosomal rearrangement breakpoints disrupted the SIM1, GRIK2, CNTNAP2, and PTPRE genes without causing any phenotype development. In contrast to the majority of maternally transmitted complex chromosomal rearrangement cases, our study investigated a rare case where a complex chromosomal rearrangement, which most probably resulted from a Type IV hexavalent during the pachytene stage of meiosis I, was stably transmitted from a fertile father to his non-affected daughter. Whole-genome mate-pair sequencing proved highly successful in identifying cryptic complexity, which consequently provided further insight into the meiotic segregation of chromosomes and the increased reproductive risk in individuals carrying the specific complex chromosomal rearrangement. We propose that such complex rearrangements should be characterized in detail using a combination of conventional cytogenetic and NGS-based approaches to aid in better prenatal preimplantation genetic diagnosis and counseling in couples with reproductive problems.
机译：在非受影响的个体中显然平衡的复杂染色体重排的精确表征至关重要，因为它们可能导致生殖失败，复发性流产或受影响的后代。我们展示了一个家庭，在那里使用鱼和核型发现非受影响的父女，是三元复杂染色体重排的载体[T（6; 7; 10）（Q16.2; Q34; Q26。 1），在父亲中的de novo]。这个家庭遭受了两次死产，一个流产，并拥有一个严重智力残疾的儿子。在本研究中，使用全基因组伴侣对测序重新审视家庭。有趣的是，全基因组合对对测序揭示了衍生物（Der）染色体6上的密码断裂点，使得重排更加复杂。使用染色体（CHR）6定制设计的探针和CHR10对照探针证实，由两个CHR6断点产生的间隙CHR6段易于转移到DER（10）上。用Sanger测序成功验证断点，并确定了小的不平衡以及微观组学。最后，复杂的染色体重排断点破坏SIM1，GRIK2，CNTNAP2和PTPRE基因，而不会导致任何表型发育。与大多数母体传播的复杂染色体重排病例相比，我们的研究研究了一种罕见的染色体重新排列，其中大部分可能由IV型六价在MeIosis I的嗜血症阶段中的六价导致，稳定地从肥沃的父亲传播他的非受影响的女儿。在识别隐秘复杂性方面证明了全基因组伴对对测序的高度成功，因此提供了进一步了解染色体的减数分裂的偏见以及携带特异性复杂染色体重排的个体的繁殖风险增加。我们建议使用常规细胞遗传学和基于NGS的方法的组合来详细描述这些复排重排，以帮助更好的产前预致癌遗传诊断和伴侣的生殖问题。

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