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Researchers Discover Chromothripsis in Healthy Mothers of Children with Congenital Abnormalities

NEW YORK (GenomeWeb) – While chromothripsis results in complex chromosome rearrangements and can lead to congenital abnormalities, it is also present in the genomes of healthy mothers of affected children, indicating that the genome may be able to tolerate a certain degree of extreme change, according to researchers from the University Medical Center Utrecht.

Researchers led by Utrecht's Wigard Kloosterman analyzed the genomes of three children who inherited chromothripsis rearrangements from their mothers and compared the rearrangements in their genomes to those in their mothers' genomes. As the researchers reported in the American Journal of Human Genetics today, the children inherited unbalanced rearrangements from their largely unaffected mothers and the resulting gene dosage imbalances likely led to their intellectual disabilities and other phenotypes.

"Our study shows that despite its dramatic effects on chromosomal architecture, chromothripsis — which involves the shattering of one or multiple chromosomes followed by random reassembly — does not necessarily lead to disease," Kloosterman said in a statement. "However, the presence of this phenomenon in healthy individuals impacts reproduction by leading to difficulties getting pregnant, miscarriages, and the birth of children with multiple birth defects, including intellectual disability."

Through a combination of microarray-based and G-banded chromosome analysis, Kloosterman and his colleagues examined the genomes of the three children and their parents and found that the children each had between two and five de novo copy-number changes affecting two or three chromosomes, as well as complex chromosomal rearrangements affecting between one and three chromosomes.

The mothers all had the derivative chromosomes found in their children — and two mothers had additional derivative chromosomes — while the three fathers had normal karyotypes.

Two of the moms, the researchers noted, were healthy, and the third had a milder phenotype than her child, though she still exhibited delayed psychomotor development and learning difficulties.

For all three mother-child pairs, the researchers performed whole-genome mate-pair sequencing and filtered the data against a control set of genomes to identify breakpoint junctions. Based on this, the researchers found that the mothers harbored balanced rearrangements involving between eight and 23 unique breakpoint junctions — the three mothers had a 1.1- to 2.6-fold increase in the number of rearrangements as compared to their more severely affected children.

Additionally, these breakpoint junctions affected between three and 13 protein-coding genes. Five of these genes had been linked to disease, according to their annotation in Online Mendelian Inheritance in Man, and three of those were found in the mother who exhibited symptoms.

Still, the two healthy mothers contained seven genes affected by intronic or exonic breakpoints, leading the researchers to note that most people contain about a hundred loss-of-function variants and that their findings serve to emphasize the "permissiveness of the genome to gene-disrupting changes."

Despite that permissiveness, children were affected by these large-scale rearrangements.

Kloosterman and his colleagues found that the kids didn't inherit all the breakpoints their mothers had. For instance, in one family, five of the 13 rearrangements were present in both mother and child, while another pair shared 16 of the 23 breakpoint junctions — the son harbored derived chromosomes 7 and 12, but not his mother's breakpoint junctions on derived chromosomes 6, 9, or 10.

Instead, they said that abnormalities in the children derived from CNVs that resulted from partial or unstable inheritance of the chromothripsis chromosomes.

For example, one child was found to have trisomy 16qter, which has been linked to psychomotor retardation, facial dysmorphisms, and other defects affecting the heart, kidneys, genitals, and more. Most of that child's symptoms, Kloosterman and his colleagues argued, could be accounted for by this trisomy.

Their finding, though, that largely healthy mothers could have chromothripsis chromosomes suggested to the researchers that such rare large-scale rearrangements could be more common than thought in the general population.

They also said that balanced complex chromosome rearrangements have been linked to fertility issues in otherwise healthy women — and two of the mothers in this study had had problems getting pregnant.

"The copy-number-neutral character of the chromothripsis rearrangements found in the mothers in this study shows the necessity of the use of a combination of detection methods rather than the use of CNV analysis alone for couples experiencing a broad range of reproductive problems," Kloosterman and his colleagues wrote in their paper.