Child with rare epileptic disorder receives long-awaited diagnosis

(Press-News.org) Researchers at Baylor College of Medicine, the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children's Hospital, Baylor Genetics and collaborating institutions provided a long-awaited and rare genetic diagnosis in a child with Lennox-Gastaut syndrome, a type of developmental epileptic encephalopathy (DEE), associated with a severe, complex form of epilepsy and developmental delay.

Their recent study reports that a highly complex rearrangement of fragments from chromosomes 3 and 5 altered the typical organization of genes in the q14.3 region of chromosome 5, leading to a rare condition known as 5q14.3 microdeletion syndrome. This is the first reported case of chromosomes 3 and 5 reshuffling leading to a form of DEE due to the disruption of 5q14.3. The study appeared in the American Journal of Medical Genetics: Part A.

“About half of the children with severe epilepsy do not have a diagnosis; there is no explanation for their condition. We wanted to change this situation,” said co-corresponding author Dr. Hsiao-Tuan Chao, assistant professor of pediatrics-neurology, molecular and human genetics and neuroscience at Baylor. “For the last five years my lab has been working with Texas Children’s and Baylor Genetics to improve our ability to uncover new genetic causes for childhood epilepsy through our Undiagnosed Epilepsy Genetics Initiative supported by the Cain Pediatric Neurology Research Foundation.”

In the current study, the team reports the case of a young child with developmental epileptic encephalopathy whose previous genomic studies did not provide a genetic diagnosis.

“The child and the family came to Texas Children’s and the Duncan NRI for answers and our team took a closer look at their genome,” said Chao, who also is a Cain investigator at the Duncan NRI and a McNair Scholar. “Using genome sequencing and fluorescently labeled DNA analyses, we reevaluated the child’s genomic condition and found a highly complex reshuffling of chromosomes 3 and 5 resulting in 5q14.3 microdeletion syndrome.”

This reshuffling of chromosomes, or chromothripsis, is a very intricate chromosomal rearrangement. For reasons that are not yet clear, one or several chromosomes can suddenly break down simultaneously into up to thousands of fragments (Thripsis in Greek means destruction into small parts). The cell then pieces the fragments of the chromosomes back together but in a reshuffled order that is different from the original. This reshuffling usually disrupts the normal function of genes in the chromosome fragments, leading to disease.

Two previous pediatric cases with neurodevelopmental conditions have been reported with loss of the chromosome 5q14.3 region, but in one case the chromosomal reshuffling involved chromosomes 5 and 15 and the other included chromosomes 3, 5, 7, 9 and 18. The case reported in the current study is the first 5q14.3 microdeletion syndrome due to reshuffling of chromosomes 3 and 5.

Chromothripsis is more commonly found in cancer. This and other studies increasingly support that chromothripsis also is involved in neurodevelopmental disorders.

“We also found that the chromosomal reshuffling did not directly affect the gene MEFC2 in chromosome 5, which we know when disrupted causes epilepsy and 5q14.3 microdeletion syndrome, but it impacted a non-coding gene right next to it, called MEF2C-AS1, that regulates the levels of MEFC2,” Chao said. “Loss of MEF2C-AS1 is expected to decrease expression of MEF2C. Our finding further supports emerging evidence that disrupting MEF2C-AS1 can result in neurological characteristics like those seen when the actual MEF2C is disrupted.”

The findings highlight the diagnostic importance of identifying chromothripsis in neurological disorders, such as DEE, that are associated with chromosomal alterations. Precise diagnosis is prognostically important because chromothripsis can be associated with increased cancer risk, which may require these individuals to receive enhanced cancer screenings throughout their lives.

Other contributors to this work include Melina L. Corriveau, Joshua C. Korb, Sydney L. Michener, Nichole M. Owen, Erica L. Wilson, Jamie Kubala, Alicia Turner, Danielle S. Takacs, Lorraine Potocki, John W. Swann, Mingshan Xue and Hongzheng Dai. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, the Duncan NRI, Baylor Genetics and the Robert and Janice McNair Foundation.

Funding support was provided by the Gordan and Mary Cain Foundation, Anne and Bob Graham Foundation, Elkins Foundation, Robert and Janice McNair Foundation and Burroughs Wellcome Fund.

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