Whole-genome mate-pair sequencing of apparently balanced chromosome rearrangements reveals complex structural variations: two case studies

Ya-Qi Tan,Yue-Qiu Tan,De-Hua Cheng

doi:10.1186/s13039-020-00487-1

Ya-Qi Tan, Yue-Qiu Tan + Show 1 more

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https://doi.org/10.1186/s13039-020-00487-1

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Abstract

BackgroundApparently balanced chromosome rearrangements (ABCRs) in non-affected individuals are well-known to possess high reproductive risks such as infertility, abnormal offspring, and pregnancy loss. However, caution should be exercised in genetic counseling and reproductive intervention because cryptic unbalanced defects and genome structural variations beyond the resolution of routine cytogenetics may not be detected.Case presentationHere, we studied two familial cases of ABCRs were recruited in this study. In family 1, the couple suffered two abortions pregnancies and underwent labor induction. Single nucleotide polymorphism (SNP) array analysis of the aborted sample from the second pregnancy revealed a 10.8 Mb heterozygous deletion at 10q26.13q26.3 and a 5.5 Mb duplication at 19q13.41-q13.43. The non-affected father was identified as a carrier of three-way complex chromosomal rearrangement [t (6;10;19)(p22;q26;q13)] by karyotyping. Whole-genome mate-pair sequencing revealed a cryptic breakpoint on the derivative chromosome 19 (der19), indicating that the karyotype was a more complex structural rearrangement comprising four breakpoints. Three genes, FAM24B, CACNG8, and KIAA0556, were disrupted without causing any abnormal phenotype in the carrier. In family 2, the couple suffered from a spontaneous miscarriage. This family had an affected child with multiple congenital deformities and an unbalanced karyotype, 46,XY,der (11) t (6;11)(q13;p11.2). The female partner was identified as a balanced translocation carrier with the karyotype 46,XX,t (6;11)(q13;p11.2) dn. Further SNP array and fluorescent in situ hybridization (FISH) indicated a cryptic insertion between chromosome 6 and chromosome 11. Finally, whole-genome mate-pair sequencing revealed an extremely complex genomic structural variation, including a cryptic deletion and 12 breakpoints on chromosome 11, and 1 breakpoint on chromosome 6 .ConclusionsOur study investigated two rare cases of ABCRs and demonstrated the efficacy of whole-genome mate-pair sequencing in analyzing the genome complex structural variation. In case of ABCRs detected by conventional cytogenetic techniques, whole genome sequencing (WGS) based approaches should be considered for accurate diagnosis, effective genetic counseling, and correct reproductive intervention to avoid recurrence risks.

Highlights

Balanced chromosome rearrangements (ABCRs) in non-affected individuals are wellknown to possess high reproductive risks such as infertility, abnormal offspring, and pregnancy loss
Our study investigated two rare cases of Apparently balanced chromosome rearrangements (ABCRs) and demonstrated the efficacy of whole-genome mate-pair sequencing in analyzing the genome complex structural variation
In case of ABCRs detected by conventional cytogenetic techniques, whole genome sequencing (WGS) based approaches should be considered for accurate diagnosis, effective genetic counseling, and correct reproductive intervention to avoid recurrence risks

Summary

Introduction

Balanced chromosome rearrangements (ABCRs) in non-affected individuals are wellknown to possess high reproductive risks such as infertility, abnormal offspring, and pregnancy loss. Whole-genome matepair sequencing revealed a cryptic breakpoint on the derivative chromosome 19 (der19), indicating that the karyotype was a more complex structural rearrangement comprising four breakpoints. Most ABCRs are associated with a normal phenotype, they show high reproductive risks such as infertility, recurrent spontaneous miscarriage, and offspring with developmental defects and so on [3,4,5]. It is crucial to accurately diagnose the karyotype of ABCR carriers with normal phenotype to determine the reproductive risk and choose an appropriate approach to avoid birth defects, such approaches include spontaneous pregnancy combined with prenatal diagnosis, preimplantation genetic testing, and use of donor sperm or egg

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