NEW YORK (GenomeWeb) – Mosaic mutations found in some, but not all, tissues appear to account for a subset of the de novo alterations associated with autism spectrum disorder (ASD), a new study suggests.
As they reported online today in PLOS Genetics, researchers from Johns Hopkins School of Medicine and the Kennedy Krieger Institute scrutinized protein-coding sequences in members of almost 2,400 ASD-affected families. Most de novo mutations they detected seemed to stem from alterations in sperm and egg cells, though a small subset appeared to have occurred post-zygotically, leading to mosaicism in a child's tissues.
"[W]e show that de novo variation in a large whole-exome sequencing dataset is frequently mosaic and that such mosaic variation is likely to contribute to disease diagnoses in some affected individuals," senior author Jonathan Pevsner and co-author Donald Freed, wrote.
Based on prior observations pointing to an over-representation of de novo copy number changes in individuals with ASD, the pair set out to see if some of the de novo mutations might originate post-zygotically, as some have postulated in the past.
Using Agilent SureSelect kits, Pevsner and Freed captured protein-coding portions of the genome in post-mortem frontal cortex, heart, and/or kidney samples from the University of Maryland Brain and Tissue Bank, representing a dozen individuals with ASD and four without. They then sequenced the exomes to 95-fold coverage, on average, with Illumina HiSeq instruments.
The researchers sifted through hundreds of potential mosaic mutations found in 32 of those samples, but ruled out tissue-specific candidates as false positives.
After demonstrating that a haplotype calling method could pick up mosaic mutations from genome sequences, though, the team used the analytical approach to characterize de novo variants in exomes for 2,388 individuals with ASD, 1,774 unaffected siblings, and 4,776 parents from the Simons Simplex Collection.
With the help of Sanger sequencing, the researchers explored the veracity of their mosaic and germline de novo mutation calls — information they used to come up with a high-confidence call set containing 221 mosaic de novo variants.
Compared with germline de novo variants, the mosaic mutations tended to involve deletions. They were also a bit more common in the ASD cases than in unaffected siblings. Based on patterns in the Simons Simplex Collection dataset, the team speculated that mosaic de novo mutations may be behind some 5.1 percent of ASD cases, while germline de novo mutations were implicated in 5.6 percent of cases.
Almost 100 genes were apparently affected by missense or likely disruptive mosaic mutations, the study's authors noted. That included three — KMT2C, NCKAP1, and MYH10 — that have been linked to ASD risk in the past.
"[C]ontributory mosaic mutation implies some expected level of discordance between monozygotic twins due to heritable factors arising post-zygotically," they wrote. "Furthermore, high-confidence identification of contributory mosaic mutation in affected probands implies a lower risk of familial recurrence in some families."