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Developmental Disorder Study Uncovers Cases Marked by Mobile Genetic Element Insertions

NEW YORK – A team from the Wellcome Sanger Institute, the National Health Service Regional Genetics service, and elsewhere has uncovered so-called jumping genes — mobile genetic elements that bounce around the genome through retrotransposition, producing sequence insertions in the process. 

After sequencing and analyzing protein-coding portions of the genome in more than 9,700 children with developmental disorders and their unaffected parents, the researchers focused in on nine mobile genetic elements, including mobile genetic elements in the NSD1, MEF2C, and ARID2 genes that appeared to be behind the developmental disorders in three of the individuals who had not been diagnosed previously. Their results were published online today in Nature Communications.

"Previously, the role of transposons in rare developmental disorders has been poorly understood, and we have developed a strategy to analyze patient genomes for transposons that cause their symptoms," senior author Matthew Hurles, human genetics head at the Sanger Institute, said in a statement. "Our study suggests that routine clinical sequencing could assess patient genomes for damaging transposon events, which could allow more children to be diagnosed."

Through the Deciphering Developmental Disorders effort, the researchers came up with a sequencing and analysis pipeline aimed at identifying suspicious mobile element insertions or processed pseudogenes — produced by the same replicative machinery used by "long interspersed nuclear element 1" repeats — in children with undiagnosed developmental disorders.

When they applied this exome sequencing-centered strategy to 9,738 affected individuals and their parents, the investigators narrowed in on more than 1,100 variants involving mobile element insertions and nearly 600 polymorphic processed pseudogenes, which they examined in more detail using PCR, long read sequence, and expression data.

From a clinical perspective, the team's computational analyses suggested that four cases of developmental delay could be traced back to de novo retrotransposon-related gene changes, including three cases that had not been diagnosed before, first author Eugene Gardner, a postdoc in Hurles' Sanger lab, explained in a statement.

"These are significant diagnoses for the families involved, and this study is another step along the path to understanding the causes of developmental disorders," Gardner said.

The investigators noted that their current focus on exome sequences likely misses many more mobile element insertions peppered across patient genomes. Consequently, the authors suggested, "it remains an open question as to what contribution [retrotransposon] mutations in the non-coding genome play in the etiology of [developmental disorders]."

Recognizing that mobile element insertions and related sequences are not typically assessed in clinical sequencing settings, the team is reportedly making its retrotransposon analysis software openly available to other investigators.

"De novo [mobile element insertions] are typically readily interpretable with modest informatics expertise, and represent a clinically relevant class of variation to assay in clinical bioinformatics pipelines," the authors concluded. "While we ultimately find that the overall burden of [retrotransposon]-attributable disease is relatively low in the human population, it is nonetheless an important consideration when elucidating the genetic basis of disease in individual patients."