Detection of a novel unbalanced X;21 translocation in a girl with Turner syndrome phenotype

Abstract

Objective

To describe a novel unbalanced X;21 translocation resulting in a derivative pseudodicentric chromosome X;21 lacking the critical region for ovarian development and function, in a 16-year-old girl referred for cytogenetic analysis due to primary amenorrhea and Turner-like features.

Methods

Cytogenetic analysis of the proband and her parents was performed on peripheral blood lymphocytes by GTG banding. Molecular cytogenetic FISH analysis was performed on metaphase preparations, using X chromosome centromeric probe and telomeric and pancentromeric peptide nucleic acid (PNA) analog probes. The HUMARA assay as well as methylation studies for PCSK1N and FMR-1 loci were performed.

Results

Cytogenetic analysis revealed a de novo unbalanced X;21 translocation, described as 45,X,der(X)t(X;21)(q22.2;p11.2),-21. FISH analysis showed that the derivative X chromosome carried both the X and 21 centromeres, as well as, the Xp and 21q telomeres. The karyotype was thus reevaluated as 45,X,psu dic(21;X)(21qter→21p13::Xq22.2→Xpter),-21. X inactivation studies revealed that the derivative chromosome was of paternal origin and confirmed the selective inactivation of the derivative X segment of the pseudodicentric chromosome.

Conclusions

Primary amenorrhea and other Turner-like characteristics of the proband are apparently due to the loss of the Xq22.2→Xqter critical region which contains critical genes for the ovarian development and function. The chromosome X segment of the derivative pseudodicentric chromosome is selectively inactivated, but inactivation does not seem to spread onto the translocated chromosome 21, accounting probably for the lack of severe clinical consequences which would result from monosomy 21.

摘要

目的：对一名原发闭经和Turner样特征的16岁女孩进行细胞遗传学分析, 描述一例新的X;21不平衡易位导致衍生的假双着丝粒染色体X;21缺乏卵巢发育和功能的关键区域。

方法：采用GTG显带技术对先证者及其父母的外周血淋巴细胞进行细胞遗传学分析。采用X染色体着丝粒探针、端粒和泛着丝粒多肽核酸（PNA）类似探针对中期染色体标本进行分子细胞遗传学FISH分析。对PCSK1N和FMR-1基因座进行HUMARA分析和甲基化研究。

结果：细胞遗传学分析显示X;21从头不平衡易位, 描述为45,X,der(X)t(X;21)(q22.2;p11.2),-21。FISH分析表明, 衍生的X染色体携带X和21着丝粒, 以及Xp和21q端粒。因此, 核型重新确定为45,X,psu dic(21;X)(21qter→21p13::Xq22.2→Xpert),-21。X失活研究表明衍生染色体来源于父系, 证实了假双着丝粒染色体衍生X片段的选择性失活。

结论：原发闭经和先证者的其他Turner样特征显然是由于包含卵巢发育和功能基因的Xq22.2→Xqter关键区域丢失所致。衍生的假双着丝粒染色体的X染色体片段被选择性地失活, 但失活似乎没有扩散到易位的21号染色体上, 这可能是因为21号单体不会导致严重的临床后果。

Keywords:

• X;autosome translocation
• X inactivation
• pseudodicentric chromosome
• Turner syndrome

Acknowledgements

The authors thank the parents of the child for their permission to participate in the present study, Ioanna Haralampous for technical assistance and Prof. E. Kanavakis for his contribution to Genetic Counseling.

Ethical approval

The research was conducted in accordance with the World Medical Association Declaration of Helsinki.

Disclosure statement

The authors have no conflicts of interest to declare.

Author contributions

EK and SZ contributed to study design, cytogenetic analyses, interpretation of the results, data collection, data analysis and manuscript preparation; NS contributed to cytogenetic analyses and interpretation of the results; DV contributed to methylation analyses; CS contributed to methylation analyses design and interpretation of the haplotype results; TE performed FISH analyses; ET and GT contributed to clinical data acquisition; SG contributed to study design, interpretation of the results, figure collection and manuscript preparation; AM contributed to manuscript revising and she had the overall study supervision. All authors approved the final version of the manuscript.