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Exome Sequencing Uncovers Monogenic Condition Marked By Speech Problems, Intellectual Delay

NEW YORK (GenomeWeb) – Newly acquired mutations in the gene CHAMP1 can cause a condition characterized by speech impairment, intellectual disability, and specific facial features, according to a study appearing in today's issue of the American Journal of Human Genetics.

A team from Germany and the Netherlands performed exome sequencing on five unrelated individuals with a combination of severe speech impairment, intellectual disability, and unusual but similar facial features. Compared with protein-coding sequences from their parents, these affected children all showed de novo frameshift or nonsense mutations in a chromosome alignment-related gene called CHAMP1.

The results suggest CHAMP1 testing may be advantageous in children with symptoms that overlap with known genetic syndromes such as Prader-Willi syndrome (PWS) or Angelman syndrome (AS) but test negative for mutations in genes associated with those conditions, the study's authors explained.

"[W]e suggest that the genetic analysis of CHAMP1 should be considered in individuals with unclassified, non-syndromic, or mild dysmorphic forms of [intellectual disability/global developmental delay], especially if muscular hypotonia and severe speech delay are present and PWS and AS testing have given normal results," they wrote.

Many de novo mutations have been implicated in various forms of intellectual disability and other types of developmental delay. For the current study, the researchers focused on a form of delay marked by certain lip, nose, and other facial features, speech problems, and altered movement.

Using either Illumina HiSeq 2500 or ABI SOLiD 5500XL instruments, they sequenced gene coding portions of the genome captured from each affected individual and his or her unaffected parents with the Agilent SureSelect XT Human All Exon V5 kit.

The team tracked down two frameshift mutations and three nonsense mutations in the chromosome 13 gene CHAMP1 when it analyzed these exomes. The CHAMP1 alterations turned up only in those with the condition and were missing in parental exome sequences.

Unexpectedly, the researchers found that two of the unrelated individuals had identical nonsense mutations in CHAMP1.

The CHAMP1 glitches shared other similarities, too. Each was predicted to upend zinc finger domain function in the CHAMP1 gene product — a protein that normally localizes to chromosomes and the mitotic spindle during cell division to mediate the kinetochore attachment to microtubules that is needed for appropriate chromosome segregation.

Since other conditions characterized by developmental delay have been linked to alterations in genes involved in chromosome and spindle alignment, the authors of the analysis argued that "CHAMP1 represents an attractive functional candidate gene for a developmental disorder."

The team noted that loss-of-function mutations in the gene did not turn up in databases such as dbSNP136 or the Broad Institute's Exome Aggregation Consortium (ExAC) database, nor were they found in 1000 Genomes Project sequence data. 

Together, the researchers said, "our data further highlight the importance of the kinetochores and chromosomal alignment for proper human neuronal development and function."