Research History

This is the original paper that supports DDX3X Gene mutations as a cause for Intellectual Disability (ID) in females. This paper created a correlation, a community, and this organization.

The paper is available here.

Technical Summary:

Intellectual disability (ID) affects approximately 1%–3% of humans with a gender bias toward males. Previous studies have identified mutations in more than 100 genes on the X chromosome in males with ID, but there is less evidence for de novo mutations on the X chromosome causing ID in females. In this study we present 35 unique deleterious de novo mutations in DDX3X identified by whole exome sequencing in 38 females with ID and various other features including hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Based on our findings, mutations in DDX3X are one of the more common causes of ID, accounting for 1%–3% of unexplained ID in females. Although no de novo DDX3X mutations were identified in males, we present three families with segregating missense mutations in DDX3X, suggestive of an X-linked recessive inheritance pattern. In these families, all males with the DDX3Xvariant had ID, whereas carrier females were unaffected. To explore the pathogenic mechanisms accounting for the differences in disease transmission and phenotype between affected females and affected males with DDX3X missense variants, we used canonical Wnt defects in zebrafish as a surrogate measure of DDX3X function in vivo. We demonstrate a consistent loss-of-function effect of all tested de novo mutations on the Wnt pathway, and we further show a differential effect by gender. The differential activity possibly reflects a dose-dependent effect of DDX3X expression in the context of functional mosaic females versus one-copy males, which reflects the complex biological nature of DDX3X mutations.

Dr. Sherr at University of California, San Francisco

Liz Berger, a mother of a beautiful DDX3X child, has been with working with Dr. Sherr, neurologist at University of California, San Francisco whose lab is running Brain Development Research Program. They included our girls in their research.

If you’d like to be involved:

  • Here is the intake form to be included in the study
  • You will be asked to provide your girl’s MRI and family history form.
  • Once you submit the Intake Form you will be in touch with with Dr. Sherr’s research assistant Lindsey Suit (Lindsey.Suit@ucsf.edu) or Brieana Frégeau (brieana.fregeau@ucsf.edu)]
  • Please join our patient registry as well!

Skin Sample Study at the Coriell Institute

Karlla Welch Brigatti, a genetic researcher, has arranged for skin biopsy samples from DDX3X children and parents to be stored at the Coriell Institute as the group accumulates enough samples to begin a larger study.

“The Coriell Institute is a very large public biobank where I’ve had a long and successful experience banking patient samples for a host of different genetic disorders. This is a great place to ‘store’ the samples, and researchers from around the world can access them for free if they’ve also contributed to the bank (or the researcher who has contributed gives them access). Look up more information here.”

if you are interested in donating a skin and/or blood sample to the repository, you can contact Tara Schmidlen at tschmidlen@coriell.org or by phone at 856-757-4822. She is the genetic counselor and coordinator who works closely with a host of patient registries and individual families and can help work out the logistics with you. Please mention that you received her information from Karlla Brigatti and was advised to contact her regarding inclusion of your DDX3X sample to their biobank.

One Mother’s Experience

Beth, a DDX3X mother, had this to say about the process of taking a skin biopsy.

“Hi everyone! Yesterday we did the skin cell samples at the Clinic for Special Children to be sent to Coriell. It was pretty easy! Dr. Strauss gave us a shot for pain (like novocaine at the dentist) in our upper arm and that was the worst part, but for me the process was easier than getting blood taken. Then they take a little sample out of your arm and send it off and put a bandaid over the spot and it is over. Virginia didn’t even cry!”

How to get in touch

If you have any questions about any of these research opportunities, or want to simply get in touch to learn more, please don’t hesitate to contact us.