How fruit flies and modern genomic technology helped to find a diagnosis for my daughter
My daughter, Bristol, is a cute and vivacious 5-year-old girl with sparkling brown eyes and bouncy curls who lights up a room. The first time we met Dr. Hsiao-Tuan Chao, her neurologist, and Dr. Michael Wangler, geneticist at Texas Children’s Hospital, she eagerly held onto Dr. Wangler’s stethoscope and proudly announced, “I’m the doctor now.”
Bristol was recently diagnosed with a neurodevelopmental condition, a disorder so new she is the first patient to be identified with it at Texas Children’s or anywhere else in the world! Here is an account of her difficult medical odyssey.
Bristol was a perfectly healthy newborn, but by the time she was 3 months old, we noticed she was failing to reach her milestones and was beginning to show worrisome symptoms. Her body was unusually floppy and flexible. She could not lift her head up or sit upright. When Bristol was about 4 months old, I was alarmed to see that sometimes her left eye turned inwards, even though her vision was fine.
As she grew older, we found Bristol was slow to crawl, stand and walk. She had difficulties in chewing, swallowing and talking. Although she would laugh and giggle, she could never smile. She also seemed to be resistant to physical pain and would never cry when she fell down, bumped into things, or received her vaccine shots.
Bristol was diagnosed with congenital hypotonia, which explained the poor muscle tone throughout her body and some of her other symptoms. She was referred to physical, occupational and speech therapists and underwent corrective eye surgery.
I am very thankful Bristol started these therapies very early on. I firmly believe early intervention and excellent rehabilitative care is the main reason she can now sit, walk and communicate.
Hypotonia is a symptom that can be caused by various neurological or non-neurological conditions. I wanted to know why Bristol had developed hypotonia and consulted many specialists who performed a battery of diagnostic tests and assessments for cerebral palsy, Down syndrome, autism, muscular dystrophy and many others, all of which were negative. Initially, even whole exome sequencing, a test that looks for misspellings in a gene, was inconclusive.
For five years, we kept looking for explanations about Bristol’s medical condition and a glimpse of what we could expect as she grew older, until a few months ago when we were referred to Drs. Chao and Wangler, who are also scientists at the Jan and Dan Duncan Neurological Research Institute (NRI) at Texas Children’s. They work under Dr. Hugo J. Bellen, professor of Baylor College of Medicine/NRI to study rare neurological disorders. Dr. 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 reexamining 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.
Interestingly, soon afterwards, the team was informed 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 my Bristol. So, they 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 damaging mutations in the EBF3 gene! Since so many individuals have been identified within a short time, it raises the possibility that mutation(s) in EBF3 gene could be the reason behind a few cognitive or speech disorders and hypotonia of unknown origin.
While the journey to find a cure for this condition has just begun, we are happy to finally have some answers. Also, 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.
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.