Advertisement

Whole-genome analysis of a putative rare and complex interchromosomal reciprocal insertion: thorough investigations for a straightforward interpretation

Published:November 29, 2021DOI:https://doi.org/10.1016/j.rbmo.2021.11.016

      Abstract

      Research question

      Should whole-genome investigations be considered systematically before a complex chromosomal abnormality preimplantation genetic testing for structural chromosomal rearrangements (PGT-SR) management is carried out using conventional cytogenetic techniques?

      Design

      A male carrying a putative rare interchromosomal reciprocal insertion (IRI) 46,XY,ins(14;?)(q11;?).ish der(14)ins(14;22)(q11.2;q11.2q11.2)(xcp14+,xcp22+,N25+,3’TRA/D+),der(22)ins(22;14)(q11.2;q11.2q11.2)(xcp22+,xcp14+,N25-,5’TRA/D+), and his partner were referred to our centre for preimplantation genetic testing analysis after three spontaneous miscarriages. Whole-genome sequencing was used to distinguish between the proposed IRI and an alternative explanation of reciprocal translocation. Fluorescence in-situ hybridization was used to detect all chromosome segments involved in this chromosomal rearrangement, to identify transferable normal and balanced embryos.

      Results

      Whole-genome sequencing allowed the determination of the number of chromosomal breakpoints involved in chromosomal rearrangement between chromosomes 14 and 22. Finally, only two breakpoints were identified instead of four in IRI rearrangements, which suggests a reciprocal translocation rearrangement. A probe strategy was established to highlight all chromosomal imbalances, whether IRI or reciprocal translocation, and preimplantation genetic testing cycles were achieved.

      Conclusion

      Conventional cytogenetic techniques are not capable of identifying all complex chromosomal rearrangements, especially those involving centromeric regions and short arms of acrocentric chromosomes. The advent of new sequencing technologies has allowed for a better appreciation of genome complexity. In this study, whole-genome analysis provided additional information to explain the occurrence of genomic events and confirmed that the initial diagnosis of IRI identified by conventional cytogenetic techniques was, in fact, a simple reciprocal translocation. A reliable PGT-SR strategy was proposed for this couple to achieve their parental project.

      KEYWORDS

      To read this article in full you will need to make a payment

      Subscribe:

      Subscribe to Reproductive BioMedicine Online
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Angell R.R.
        • Templeton A.A.
        Chromosome abnormalities in human embryos after in vitro fertilization.
        Nature. 1983; 303: 336-338https://doi.org/10.1038/303336a0
        • Bernardini L.
        • Palka C.
        • Ceccarini C.
        • Capalbo A.
        • Bottillo I.
        • Mingarelli R.
        • Dallapiccola B.
        Complex rearrangement of chromosomes 7q21.13-q22.1 confirms the ectrodactyly-deafness locus and suggests new candidate genes.
        Am. J. Med. Genet. A. 2008; 146A: 238-244https://doi.org/10.1002/ajmg.a.32093
        • Chen K.
        • Wallis J.W.
        • McLellan M.D.
        • Larson D.E.
        • Kalicki J.M.
        • Pohl C.S.
        • Mardis E.R.
        BreakDancer: an algorithm for high-resolution mapping of genomic structural variation.
        Nat. Methods. 2009; 6: 677-681https://doi.org/10.1038/nmeth.1363
        • Dong Z.
        • Chau M.H.K.
        • Zhang Y.
        • Dai P.
        • Zhu X.
        • Leung T.Y.
        • Choy K.W.
        Deciphering the complexity of simple chromosomal insertions by genome sequencing.
        Hum. Genet. 2020; https://doi.org/10.1007/s00439-020-02210-x
        • Dvorkina T.
        • Kunyavskaya O.
        • Bzikadze A.V.
        • Alexandrov I.
        • Pevzner P.A.
        CentromereArchitect: inference and analysis of the architecture of centromeres.
        Bioinformatics. 2021; 37: i196-i204https://doi.org/10.1093/bioinformatics/btab265
        • Harbuz R.
        • Bilan F.
        • Couet D.
        • Charraud V.
        • Kitzis A.
        • Gilbert-Dussardier B.
        Osteogenesis imperfecta, tricho-dento-osseous syndrome and intellectual disability: a familial case with 17q21.33-q22 (COL1A1 and DLX3) deletion and 7q32.3-q33 duplication resulting from a reciprocal interchromosomal insertion.
        Am. J. Med. Genet. A. 2013; 161A: 2504-2511https://doi.org/10.1002/ajmg.a.36122
        • Kang S.H.
        • Shaw C.
        • Ou Z.
        • Eng P.A.
        • Cooper M.L.
        • Pursley A.N.
        • Cheung S.W.
        Insertional translocation detected using FISH confirmation of array-comparative genomic hybridization (aCGH) results.
        Am. J. Med. Genet. A. 2010; 152A: 1111-1126https://doi.org/10.1002/ajmg.a.33278
        • Li H.
        • Durbin R.
        Fast and accurate long-read alignment with Burrows-Wheeler transform.
        Bioinformatics. 2010; 26: 589-595https://doi.org/10.1093/bioinformatics/btp698
        • McKinlay
        • Gardner R.J.
        • Amor D.J
        Chromosome Abnormalities and Genetic Counseling.
        Oxford University Press, 2018
        • Neill N.J.
        • Ballif B.C.
        • Lamb A.N.
        • Parikh S.
        • Ravnan J.B.
        • Schultz R.A.
        • Shaffer L.G.
        Recurrence, submicroscopic complexity, and potential clinical relevance of copy gains detected by array CGH that are shown to be unbalanced insertions by FISH.
        Genome Res. 2011; 21: 535-544https://doi.org/10.1101/gr.114579.110
        • Ogilvie C.
        • Bint S.
        Care needed in interpretation of chromosome rearrangements.
        Reprod. Biomed. Online. 2018; 37: 651https://doi.org/10.1016/j.rbmo.2018.09.005
        • Ou Z.
        • Martin D.M.
        • Bedoyan J.K.
        • Cooper M.L.
        • Chinault A.C.
        • Stankiewicz P.
        • Cheung S.W.
        Branchiootorenal syndrome and oculoauriculovertebral spectrum features associated with duplication of SIX1, SIX6, and OTX2 resulting from a complex chromosomal rearrangement.
        Am. J. Med. Genet. A. 2008; 146A: 2480-2489https://doi.org/10.1002/ajmg.a.32398
        • Pellestor F.
        • Anahory T.
        • Lefort G.
        • Puechberty J.
        • Liehr T.
        • Hedon B.
        • Sarda P.
        Complex chromosomal rearrangements: origin and meiotic behavior.
        Hum. Reprod. Update. 2011; 17: 476-494https://doi.org/10.1093/humupd/dmr010
        • Redon R.
        • Ishikawa S.
        • Fitch K.R.
        • Feuk L.
        • Perry G.H.
        • Andrews T.D.
        • Hurles M.E.
        Global variation in copy number in the human genome.
        Nature. 2006; 444: 444-454https://doi.org/10.1038/nature05329
        • Robinson J.T.
        • Thorvaldsdottir H.
        • Winckler W.
        • Guttman M.
        • Lander E.S.
        • Getz G.
        • Mesirov J.P.
        Integrative genomics viewer.
        Nat. Biotechnol. 2011; 29: 24-26https://doi.org/10.1038/nbt.1754
        • Salaun G.
        • Tchirkov A.
        • Francannet C.
        • Pons H.
        • Brugnon F.
        • Pebrel-Richard C.
        • Goumy C.
        Sperm meiotic segregation of a balanced interchromosomal reciprocal insertion resulting in recurrent spontaneous miscarriage.
        Reprod. Biomed. Online. 2018; 37: 100-106https://doi.org/10.1016/j.rbmo.2018.03.019
        • Schluth-Bolard C.
        • Diguet F.
        • Chatron N.
        • Rollat-Farnier P.A.
        • Bardel C.
        • Afenjar A.
        • Sanlaville D.
        Whole genome paired-end sequencing elucidates functional and phenotypic consequences of balanced chromosomal rearrangement in patients with developmental disorders.
        J. Med. Genet. 2019; 56: 526-535https://doi.org/10.1136/jmedgenet-2018-105778
        • Scriven P.N.
        • Ogilvie C.M.
        FISH for pre-implantation genetic diagnosis.
        Methods Mol. Biol. 2010; 659: 269-282https://doi.org/10.1007/978-1-60761-789-1_20
        • Stephens P.J.
        • Greenman C.D.
        • Fu B.
        • Yang F.
        • Bignell G.R.
        • Mudie L.J.
        • Campbell P.J.
        Massive genomic rearrangement acquired in a single catastrophic event during cancer development.
        Cell. 2011; 144: 27-40https://doi.org/10.1016/j.cell.2010.11.055
        • Uguen K.
        • Jubin C.
        • Duffourd Y.
        • Bardel C.
        • Malan V.
        • Dupont J.M.
        • Sanlaville D.
        Genome sequencing in cytogenetics: Comparison of short-read and linked-read approaches for germline structural variant detection and characterization.
        Mol. Genet. Genomic Med. 2020; 8: e1114https://doi.org/10.1002/mgg3.1114
        • Van Esch H.
        • Groenen P.
        • Daw S.
        • Poffyn A.
        • Holvoet M.
        • Scambler P.
        • Devriendt K.
        Partial DiGeorge syndrome in two patients with a 10p rearrangement.
        Clin. Genet. 1999; 55: 269-276https://doi.org/10.1034/j.1399-0004.1999.550410.x
        • Van Hemel J.O.
        • Eussen H.J.
        Interchromosomal insertions. Identification of five cases and a review.
        Hum. Genet. 2000; 107: 415-432https://doi.org/10.1007/s004390000398
        • Wallis M.J.
        • Kelly A.L.
        • Peters G.B.
        • St Heaps L.
        • Nandini A.
        • McGaughran J.M.
        A balanced paternal interchromosomal reciprocal insertion between 5q12.1q13.2 and 20p12.3p12.1 resulting in separate genetic conditions in two siblings.
        Am. J. Med. Genet. A. 2016; 170: 1930-1933https://doi.org/10.1002/ajmg.a.37689
        • Wang Y.T.
        • Bajalica S.
        • Han F.Y.
        • Wang Z.C.
        • Bui T.H.
        • Xie Y.G.
        Direct and inverted reciprocal chromosome insertions between chromosomes 7 and 14 in a woman with recurrent miscarriages.
        Am. J. Med. Genet. 1994; 52: 349-351https://doi.org/10.1002/ajmg.1320520319
        • Zenagui R.
        • Bernicot I.
        • Ranisavljevic N.
        • Haquet E.
        • Ferrieres-Hoa A.
        • Pellestor F.
        • Anahory T.
        Inheritance of imbalances in recurrent chromosomal translocation t(11;22): clarification by PGT-SR and sperm-FISH analysis.
        Reprod. Biomed. Online. 2019; 39: 40-48https://doi.org/10.1016/j.rbmo.2019.02.010

      Biography

      Reda Zenagui, PhD, is a graduate in molecular genetics from Montpellier University, France. He currently works at the Preimplantation Genetic Testing (PGT) unit at Montpellier Hospital. His research focus is on improving reproductive care in patients with chromosomal abnormalities.
      Key message
      Whole-genome investigations of a putative interchromosomal reciprocal insertion by paired-end sequencing technologies have been beneficial for chromosomal rearrangement identification as a reciprocal translocation and genetic counselling improvement technique. These investigations have provided a targeted preimplantation genetic testing of structural rearrangement (PGT-SR) strategy to avoid embryonic risks related to unbalanced chromosomes.