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Exome Sequencing Uncovers De Novo Mutations in Individuals With Rare Facial Paralysis Syndrome

NEW YORK (GenomeWeb) – A study published online today in Nature Communications supports the notion that a rare neurological facial paralysis condition called Möbius syndrome can stem from new genetic glitches not found in parents of individuals with the disease.

An international team led by investigators in the Netherlands did exome sequencing on two children with Möbius syndrome and their unaffected parents, along with candidate gene sequencing in half a dozen isolated individuals with the condition. After narrowing in on a handful of genes with suspicious de novo mutations, the group did screening in another 103 affected individuals to find still more de novo mutations in two genes coding for components of hindbrain development pathways: PLXND1 and REV3L.

In follow-up experiments in a mouse model system, meanwhile, the researchers found that interfering with the corresponding mouse genes could produce symptoms resembling those found in individuals with Möbius syndrome. That not only suggests the newfound genetic glitches could be causative, they argued, but underlines the potential of finding such alterations through family sequencing-based approaches.

"Taken together, the present data establish de novo mutations as a cause for [Möbius syndrome]," the study's authors wrote, "providing a rationale for exome sequencing in patient-parent trios to identify de novo mutations in other genes underlying [Möbius syndrome]."

In the past, the researchers noted that there has been some debate about the relative importance of genetic and environmental factors in producing Möbius syndrome. The congenital condition has been linked to oxygen deprivation in the hindbrain due to exposure to certain drugs during pregnancy, for example, though an inherited syndrome resembling Möbius syndrome can also result from recessive mutations affecting the HOXB1 gene.

To dig into potential genetic causes further, the study's authors started by using the Life Technologies SOLiD 4 system to sequence protein-coding genes that had been captured with the Agilent SureSelect Human All Exon v2 50 Mb kit from two individuals with Möbius syndrome and their parents. They also did Sanger sequencing on several candidate genes in another six individuals with isolated Möbius syndrome.

Within one of the trios, the team tracked down de novo mutations in the chromosome 3 gene PLXND1, while three of the unrelated individuals had de novo mutations in the PLXND1, REV3L, and CCDC160 genes.

When the researchers sequenced all three genes in 103 more Möbius syndrome cases, they narrowed in on two more de novo mutations in PLXND1 and another two REV3L de novo mutations, prompting them to take these genes forward for further functional testing in mutant mice missing the genes.

Indeed, the animals appeared to show some symptoms resembling Möbius syndrome, such as facial and vertebral abnormalities, nerve problems, and diminished motor neuron representation, in the case of the PLXND1-free mice. Mice lacking REV3L, meanwhile, had high levels of DNA damage and other features related to stress response.

Given their findings so far, those involved in the study reasoned that "[w]hile vascular disruptions caused by various teratogens can explain the [Möbius syndrome] phenotype in some patients, our current data indicate that exome sequencing in patient-parent trios is a powerful approach for identifying causative mutations in [Möbius syndrome]."

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