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“My 5-year old daughter is such a cute, vivacious little girl who lights up a room,” said mom Evonia Dunlap. “When Bristol was born, she was perfectly healthy but by the time she was 3 months old, she was failing to reach her milestones and began showing worrisome symptoms.”

Bristol could not lift her head up or sit upright, her body was unusually floppy and flexible, and her left eye began turning inward, even though her vision was fine. As Bristol grew older, she was slow to crawl, stand and walk, and had difficulties in chewing, swallowing and talking.

“My daughter seemed to be very resistant to physical pain,” Dunlap said. “She would never cry when she fell down, bumped into things or received her vaccine shots, which was very, very unusual.”

Bristol was diagnosed with congenital hypotonia, a symptom that can be caused by various neurological or non-neurological conditions, which explained the poor muscle tone throughout her body. She had corrective eye surgery and Dunlap credits the physical, occupational and speech therapies with helping her daughter sit, walk and communicate.

But there was one thing Dunlap wanted to know. What caused Bristol to develop hypotonia?

After consulting many specialists who performed a battery of diagnostic tests and assessments for cerebral palsy, Down syndrome, autism, muscular dystrophy and many others, the results came back negative. Whole exome sequencing, a test that looks for misspellings in a gene, was inconclusive.

After five years searching for answers, Dunlap’s medical odyssey ended at Texas Children’s when Bristol was referred to neurologist Dr. Hsiao-Tuan Chao and geneticist Dr. Michael Wangler, physician scientists in Dr. Hugo Bellen’s lab at the Jan and Dan Duncan Neurological Research Institute (NRI) at Texas Children’s.

Bellen’s team is an important part of the Undiagnosed Disease Project, a national network established by the National Institutes of Health. Through this initiative, they came to know of a 7-year-old boy who had symptoms remarkably similar to Bristol’s and carried a point mutation in the Early B-Cell Factor 3 (EBF3) gene.

After closely re-examining Bristol’s exome sequencing results, they found she also carried the exact same mutation that produces defective EBF3 protein. Since EBF3 is a master regulator of hundreds of other genes, even the tiniest alteration in its function could potentially cause widespread damage to the developing nervous system and muscles.

The team also learned of another little girl at NYU’s Langone Medical Center who had a similar medical history and was found to carry the exact same EBF3 mutation. The NRI team thought this was truly remarkable and postulated that variation in EBF3 could be the possible link between these two children and Bristol.

The team extensively studied the fruit fly and mammalian versions of EBF3 and concluded the point mutation in EBF3 was indeed the culprit behind the symptoms exhibited by Bristol and the others. In the last six months alone, at least 20 patients around the world have been found to carry the damaging mutations in the EBF3 gene.

While the journey to find a cure for this condition has just begun, Dunlap is happy to finally have some answers.

“Thanks to this study, physicians around the world will now have some understanding of this condition, which we anticipate, will help to diagnose many children in the future,” Dunlap said. “I fervently hope I can now connect with other families of children with EBF3-related disorders so we can learn from and support each other.”