DDX3X: When Whole Exome Sequencing Reveals a Gene Variant that Science Hasn’t Caught Up To

A cutl little girl wearing a headdress and smiling

Originally posted at Global Genes

In August 2011, we welcomed our third child into our family. After an uneventful pregnancy, I delivered Peyton Grace via scheduled C-section and we brought her home four days later. It became apparent pretty early on that Peyton was not developing similarly to our other children. She had an extremely difficult time sleeping and could not be soothed unless she was tightly bundled or in a swing on the highest speed setting. She also had trouble keeping her feedings down and other concerning digestive issues. She later would fail to meet all of her milestones. On her first birthday, Peyton could not sit without support for more than a few seconds and was not babbling. We called in Early Intervention and began every type of therapy imaginable. Progress came painfully slow.

When she did make progress, it was followed by months of no new development. At this time we also began genetic testing and other medical testing under the advisement of our pediatric neurologist. Peyton developed difficult to control seizures that would later result in her being put on the ketogenic diet. After a few years without results, we decided to have the Whole Exome Sequencing (WES) run. Eight months later, we received a non-result. Peyton had a variant on her DDX3X gene line, but it was not yet known if this gene was the cause of her struggles or not. Science had not caught up with the technology. We did know that this was a de novo finding, meaning that it was not inherited from either parent. After the results came in, we continued on with life, doing everything possible to help Peyton be her best self.
In May 2015 we received a surpising phone call from our Genetic Counselor. Other girls had some of the same struggles as Peyton and their WES testing was also turning up findings on their DDX3X gene line. A paper was soon to be published in The American Journal of Human Genetics (Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling-August 2015) and a clinic in Pennsylvania was planning a DDX3X family day to go over the findings. The Clinic for Special Children, located in Lancaster, Pennsylvania, put on an amazing day with a variety of specialists. The Genetics Counselor, Karlla W. Briggati, welcomed us with open arms and patiently answered our questions. Eight families, including mine, were fortunate enough to attend the day. We learned that approximately 50 girls in the world are currently affected by a variant on their DDX3X gene line.

Credit to Dan Marschka -Staff Photographer LancasterOnline.Com

Credit to Dan Marschka -Staff Photographer LancasterOnline.Com

This number is expected to grow as WES becomes more readily available. Like beautiful snowflakes, each of our girls is remarkably similar, yet exceptionally unique. This specific condition is not inherited and affects only girls. (Boys can inherite a variant on their DDX3X gene line from their unaffected mother)
*100% of the girls have Intelictual Disability in varying severity as well as having limited to no speech
*32% have low weight
*76% have hypotonia
*16% have epilepsy
*45% have movement disorders with some being unable to walk
*53% have behavior issues
A list of other symptoms includes, but is not limited to: abnormal findings in brain MRI, skin abnormalities, hyperlaxity, visual problems, hearing loss, cleft lip or palate, precocious puberty, and scoliosis.
In addition to the amazing knowledge that I gained while visiting The Clinic for Special Children, I found a support system of people who understand exactly what we are going through. A DDX3X mom from South Dakota started a Facebook page for our girls. We now can log on and talk to other families and rally support for one another from near and far. Families from the United States, Cananda, Ireland, the U.K. and the Netherlands are lending a caring ear and offering up suggestions on therapies, procedures, medical equipment, and more. As this group continues to grow, so does our understanding of how complex DDX3X is.
This is just the beginning of our story with DDX3X, but we have so much hope for the future and now know that our daughter is not alone in her journey. Until all of our daughters can share their own stories, we will be the voices for our DDX3X girls!

(via Global Genes)