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Single Gene Mutations Implicated in New Intellectual Disability Syndrome

NEW YORK (GenomeWeb) – Investigators have described a new genetic syndrome marked by de novo mutations in a single gene called WDR26 that appear to cause intellectual disability, developmental delays, and movement-related symptoms.

At first, investigators from GeneDx, the Children's Hospital of Philadelphia, and University Medical Center Utrecht saw suspicious WDR26 mutations in two individuals with intellectual disability and mild dysmorphism. Then, a CHOP- and University of Pennsylvania-led research team expanded the search for WDR26 mutations in exome sequence data from tens of thousands of individuals, including 21,400 with intellectual disability.

As they reported online today in the American Journal of Human Genetics, the researchers narrowed in on 15 individuals with de novo mutations affecting one copy of WDR26, using exome sequence data for the affected individuals and their unaffected parents. These mutations were missing from population databases but seemed to produce some features that overlapped with an already described microdeletion syndrome that removes a stretch of chromosome 1 sequence that often encompasses WDR26.

Individuals with the WDR26 haploinsufficiency syndrome had symptoms such as motor delay, intellectual disability, a raised upper lip, teeth set far apart, bursts of stiff-legged movement, seizures, and speech delay.

"This discovery is just the first step in understanding why changes in WDR26 cause intellectual disability and seizures," senior author Matthew Deardorff, a pediatric geneticist affiliated with CHOP and UPenn's Perelman School of Medicine, said in a statement. "With further investigation, our goal is to better understand the biology and identify specific treatments for these children."

The team scoured exome sequences for 28,700 individuals, leading to 10 females and five males between the ages of two and 34 who had de novo WDR26 mutations not found in their unaffected parents. Across the full set of clinical exomes, the alterations affected roughly one in 2,000 individuals, the authors reported, though it was more common in the individuals with intellectual disability.

The researchers began characterizing expression patterns and other features in lymphoblastoid cell lines from individuals with or without the WDR26 mutations. Their results suggest that nonsense mutations lead to gene transcripts that are removed by nonsense-mediated decay, for example, while missense mutations in the gene were not necessarily dealt with through this pathway.

"Our studies are very much in the early stage, but as we continue to gain more clinical and scientific knowledge about this condition, we will be able to better explain to parents what to expect," Deardorff said, noting that potential treatment strategies might advance as the syndrome becomes more broadly recognized and diagnosed in additional individuals. "It may be possible that early intervention with special education can help address a child's intellectual disability, although we do not yet have enough clinical data to develop full guidelines for medical management. 

With that in mind, CHOP has established a registry to bring together more clinical data on individuals with the rare syndrome and to provide resources for families affected by the condition.

"[W]e report the recognition of a role for WDR26 in human syndromic intellectual disability," Deardorff and his co-authors wrote. "This recognition was dependent upon the presence of de novo variants, the utilization of broad reference datasets that included this variably annotated gene, and a concerted effort of international collaborators to identify individuals and characterize the clinical features."