Very short DNA segments can be detected and handled by the repair machinery during germline chromothriptic chromosome reassembly

TY - JOUR

T1 - Very short DNA segments can be detected and handled by the repair machinery during germline chromothriptic chromosome reassembly

AU - Slamova, Zuzana

AU - Nazaryan-Petersen, Lusine

AU - Mehrjouy, Mana M.

AU - Drabova, Jana

AU - Hancarova, Miroslava

AU - Marikova, Tatana

AU - Novotna, Drahuse

AU - Vlckova, Marketa

AU - Vlckova, Zdenka

AU - Bak, Mads

AU - Zemanova, Zuzana

AU - Tommerup, Niels

AU - Sedlacek, Zdenek

PY - 2018

Y1 - 2018

N2 - Analyses at nucleotide resolution reveal unexpected complexity of seemingly simple and balanced chromosomal rearrangements. Chromothripsis is a rare complex aberration involving local shattering of one or more chromosomes and reassembly of the resulting DNA segments. This can influence gene expression and cause abnormal phenotypes. We studied the structure and mechanism of a seemingly balanced de novo complex rearrangement of four chromosomes in a boy with developmental and growth delay. Microarray analysis revealed two paternal de novo deletions of 0.7 and 2.5 Mb at two of the breakpoints in 1q24.3 and 6q24.1-q24.2, respectively, which could explain most symptoms of the patient. Subsequent whole-genome mate-pair sequencing confirmed the chromothriptic nature of the rearrangement. The four participating chromosomes were broken into 29 segments longer than 1 kb. Sanger sequencing of all breakpoint junctions revealed additional complexity compatible with the involvement of different repair pathways. We observed translocation of a 33 bp long DNA fragment, which may have implications for the definition of the lower size limit of structural variants. Our observations and literature review indicate that even very small fragments from shattered chromosomes can be detected and handled by the repair machinery during germline chromothriptic chromosome reassembly.

AB - Analyses at nucleotide resolution reveal unexpected complexity of seemingly simple and balanced chromosomal rearrangements. Chromothripsis is a rare complex aberration involving local shattering of one or more chromosomes and reassembly of the resulting DNA segments. This can influence gene expression and cause abnormal phenotypes. We studied the structure and mechanism of a seemingly balanced de novo complex rearrangement of four chromosomes in a boy with developmental and growth delay. Microarray analysis revealed two paternal de novo deletions of 0.7 and 2.5 Mb at two of the breakpoints in 1q24.3 and 6q24.1-q24.2, respectively, which could explain most symptoms of the patient. Subsequent whole-genome mate-pair sequencing confirmed the chromothriptic nature of the rearrangement. The four participating chromosomes were broken into 29 segments longer than 1 kb. Sanger sequencing of all breakpoint junctions revealed additional complexity compatible with the involvement of different repair pathways. We observed translocation of a 33 bp long DNA fragment, which may have implications for the definition of the lower size limit of structural variants. Our observations and literature review indicate that even very small fragments from shattered chromosomes can be detected and handled by the repair machinery during germline chromothriptic chromosome reassembly.

KW - alternative non-homologous end joining

KW - chromothripsis

KW - complex chromosome aberration

KW - DNA repair

KW - small insertions

KW - whole-genome sequencing

U2 - 10.1002/humu.23408

DO - 10.1002/humu.23408

M3 - Journal article

C2 - 29405539

AN - SCOPUS:85042196690

SN - 1059-7794

VL - 39

SP - 709

EP - 716

JO - Human Mutation

JF - Human Mutation

IS - 5

ER -