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Texas Children’s Hospital and Baylor College of Medicine researchers solve a 40-year medical mystery

Nicholas Lewis, a Houstonian in his forties, has struggled all his life with a mysterious neurological condition with symptoms ranging from developmental delay, intellectual disability, speech delay, and migraines to bilateral hearing loss. Despite decades of searching for answers, he and his family could not find a definite diagnosis for his mystery condition until recently.

The x-rays taken at birth and as a newborn showed Nick had developmental defects and brain malformations such as microcephaly (abnormally small head) and partial loss of corpus callosum, a broad band of nerves that connect two halves of the brain. This was before CT scans and MRIs were in vogue and genetic testing could only detect major chromosomal anomalies like Down’s syndrome.

“Although we were told Nick would be immobile and unable to talk, with the help of several early interventions and therapy programs, he started crawling when he was two,” his mom, Ms. Mercedes Alejandro, said. “We were elated when he started talking and walking with the aid of ankle-foot orthosis braces at three. We then enrolled him in special education classes which he continued until he was 21.”

“We are very proud that despite his disabilities, over the years, Nick has volunteered extensively in the community, has held several jobs over the years, and has grown into an empathetic, perceptive, and kind individual.”

When Nick was fourteen, he participated in an MRI study and was diagnosed with holoprosencephaly – a condition where the two halves of the developing brain fail to divide sufficiently resulting in a single-lobed structure. But he and his family still had no clue as to what had caused this defect. Interestingly, Nick’s facial features, brain anomalies, and microcephaly were very similar to children diagnosed with fetal alcohol spectrum disorders and so, for decades his mom thought that the occasional drinks she had consumed before she knew she was pregnant were to blame.

Using fruit flies and genomic sequencing to solve ‘mystery’ conditions

In 2015, the National Institutes of Health funded a nationwide research study called the Undiagnosed Diseases Network with the goal of finding answers for patients and their families affected by ‘mystery’ conditions. Baylor College of Medicine is one of the 12 UDN clinical sites and provides genome sequencing services. Under the leadership of Baylor faculty and researchers at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Drs. Hugo Bellen, Michael Wangler, and Shinya Yamamoto, UDN’s Model Organism Core has leveraged fruit flies to find a diagnosis for patients like Nick.

Although Nick and his family were aware of this study and were keen to enroll, for years they could not participate due to financial reasons. These genetic tests are expensive and are not covered by many private insurances and Medicaid, unless prescribed for an immediate medical reason.

The Texome Project researchers find the real culprit

Meanwhile, recognizing the high cost of these tests is an obstacle for many families, with the support of the National Institute of Health as well as private donations to the Neurological Research Institute of Texas Children Hospital at Baylor College of Medicine (BCM), Drs. Wangler and Bellen launched the Texome Project in 2021. The goal of this community-wide genomics initiative is to broaden access to the state-of-the-art genetic tests to low-income individuals and to those whose insurance will not cover these costs. With this initiative, they plan to offer free genetic testing to 100 individuals with undiagnosed medical conditions each year for the next five years.

Nick’s physician at the Baylor Adult Genetics clinic, Dr. Sandesh Nagamani and Baylor College genetic counselor, Lisa Saba, referred him to Dr. Wangler. He was enrolled in this study and the family finally received a precise diagnosis for his neurological condition in late 2022. Dr. Wangler collaborated with Drs. Chaya Murali, Seema Lalani, Carlos Bacino, and Nichole Owen; Ms. Blake Vuocolo, and Mr. Ryan German at Baylor College of Medicine and Texas Children’s Hospital to find a diagnosis for Nick's condition.

The team conducted exome sequencing tests which found Nick had a mutation in the ZIC2 gene, whose variants had been previously linked to holoprosencephaly. This finding validated the clinical diagnoses Nick had received earlier and more importantly, provided him and his family with a definitive molecular cause for this condition and a much-needed closure after decades of searching for answers. Knowing the true cause also helped in identifying targeted medications and therapies that work best for this specific condition.

“For decades, I carried an enormous sense of guilt and thought that somehow, I was to blame for Nick’s condition. Although I took excellent care of my health during pregnancy, I could never erase the guilt that perhaps a few drinks I had before I knew I was pregnant were the cause for Nick’s health issues. I’m so thankful to Dr. Wangler and his team for finding the real culprit and finally relieving me of this huge burden,” she said, “I feel exonerated!”

“Based on my decades of volunteer and advocacy experiences, I know I’m not the only mother of a child with a neurological condition who feels this way,” Ms. Alejandro added. “I speak for many mothers when I say we are all grateful to the Texome Project at Texas Children’s Hospital which has given families like mine easier access to cutting-edge genetic tests and an opportunity to receive precise medical diagnoses - which is life-altering and brings many tangible and intangible benefits to the patients and their families.”

Rajalaxmi Natarajan, PhD