Background Mosaicism for chromosomal structural abnormalities, other than marker or ring chromosomes, is rarely inherited.
Methods We performed cytogenetics studies and breakpoint analyses on a family with transmission of mosaicism for a derivative chromosome 8 (der(8)), resulting from an unbalanced translocation between the long arms of chromosomes 8 and 21 over three generations.
Results The proband and his maternal half-sister had mosaicism for a der(8) cell line leading to trisomy of the distal 21q, and both had Down syndrome phenotypic features. Mosaicism for a cell line with the der(8) and a normal cell line was also detected in a maternal half-cousin. The der(8) was inherited from the maternal grandmother who had four abnormal cell lines containing the der(8), in addition to a normal cell line. One maternal half-aunt had the der(8) and an isodicentric chromosome 21 (idic(21)). Sequencing studies revealed microhomologies at the junctures of the der(8) and idic(21) in the half-aunt, suggesting a replicative mechanism in the rearrangement formation. Furthermore, interstitial telomeric sequences (ITS) were identified in the juncture between chromosomes 8 and 21 in the der(8).
Conclusion Mosaicism in the proband, his half-sister and half-cousin resulting from loss of chromosome 21 material from the der(8) appears to be a postzygotic event due to the genomic instability of ITS and associated with selective growth advantage of normal cells. The reversion of the inherited der(8) to a normal chromosome 8 in this family resembles revertant mosaicism of point mutations. We propose that ITS could mediate recurring revertant mosaicism for some constitutional chromosomal structural abnormalities.
- Genomic Instability
- Chromosome Aberrations
- Genetic Phenomena
- Human Genetics
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
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ERR and SWC are joint senior authors.
Contributors The study was conceived and designed and responsible for the overall content as the guarantor by WB and SWC. WB contributed to acquisition of data, data analysis and interpretation, figure and table preparation, and drafting of the manuscript. JBM, TQ, LMC, JW and PH contributed to acquisition of data. BY, XQ, SES, and FX contributed to sequencing analysis of the breakpoints. PL and JRL contributed their expertise on breakpoint analysis and data interpretation. GVNV, VO, VST and RWH also contributed to acquisition of data and data interpretation. ROL and SP assisted in patient recruitment and sample collection. ERR contributed to providing clinical information, patient recruitment, sample collection, critical review of the manuscript. SWC contributed to data interpretation, overseeing project development and critical review of the manuscript. JRL, ROL, GVNV, VO, BY, PL, SP and JBM contributed significantly to manuscript revisions. All authors reviewed the manuscript and approved the final version. WB and SWC conceived and designed the studies and are responsible for the overall content as guarantors. ERR is responsible for the clinical data as guarantor.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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