Cryptic breakpoint identified by whole-genome mate-pair sequencing in a rare paternally inherited complex chromosomal rearrangement

Abstract

BackgroundPrecise 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.Case presentationWe 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.ConclusionsIn 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.

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

“…Type IV CCR configurations must have formed during the pachytene stage of meiosis for the carrier in family 1 (Fig. 1d) [1,16].…”

“…Simple ABCR is a two-breakage rearrangement, whereas complex chromosomal rearrangement (CCR) involves chromosomal abnormalities with three or more breakpoints. CCRs are rare in the population, with only around 380 cases reported till date [1,2]. Although 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].…”

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

“…Type IV CCR configurations must have formed during the pachytene stage of meiosis for the carrier in family 1 (Fig. 1D) [1,16].…”

“…Simple ABCR is a two-breakage rearrangement, whereas complex chromosomal rearrangement (CCR) involves chromosomal abnormalities with three or more breakpoints. CCRs are rare in the population, with only around 380 cases reported till date [1,2].…”

Preimplantation genetic testing: method and two case studies of familial three-way complex translocations

“…Typically, CCR male carriers tend to be infertile or subfertile because of hypospermatogenesis or spermatogenic arrest caused by complex meiotic configurations. Consequently, the paternal transmission of CCRs is considered to be scarce, although there are reports of a few rare cases [24][25][26].…”