Breakthrough in Genetic Diagnosis for Child with Epileptic Disorder

Researchers have made significant strides in diagnosing a rare genetic disorder in a child suffering from Lennox-Gastaut syndrome, a severe form of developmental epileptic encephalopathy (DEE) characterized by complex epilepsy and developmental delays. This diagnosis comes after extensive genomic studies failed to yield answers for the family over several years.

The study reveals that a complex rearrangement of genetic material from chromosomes 3 and 5 resulted in a condition known as 5q14.3 microdeletion syndrome. This finding marks the first documented case where the rearrangement of chromosomes 3 and 5 has been linked to DEE due to the disruption of the 5q14.3 genetic region. The results of this study were published in the American Journal of Medical Genetics: Part A.

Approximately half of children with severe epilepsy remain undiagnosed, lacking explanations for their conditions. Researchers aimed to change this statistic. A team from Baylor College of Medicine, in collaboration with Texas Children's Hospital and Baylor Genetics, has spent five years enhancing methods to identify new genetic causes for childhood epilepsy through the Undiagnosed Epilepsy Genetics Initiative, supported by the Cain Pediatric Neurology Research Foundation.

This case involved a young child with DEE whose prior genomic assessments had not identified a genetic cause. The family sought answers at Texas Children's Hospital, leading to a comprehensive reevaluation of the child's genome.

Using advanced genome sequencing techniques, the research team uncovered a highly complex chromosomal reshuffling involving chromosomes 3 and 5, which resulted in the 5q14.3 microdeletion syndrome. This phenomenon, known as chromothripsis, involves the simultaneous fragmentation of one or multiple chromosomes into potentially thousands of pieces, which are then incorrectly reassembled by the cell, resulting in genetic disruptions that can lead to various health issues.

While chromothripsis has been linked predominantly to cancer, emerging evidence suggests its involvement in neurodevelopmental disorders as well. In the cases previously reported, the loss of the 5q14.3 region was noted, but they involved different chromosomes and did not precisely replicate the child's condition.

Interestingly, the chromosomal reshuffling did not directly impact the MEFC2 gene, which is known to cause epilepsy and 5q14.3 microdeletion syndrome when disrupted. Instead, the study showed that the alteration affected a neighboring non-coding gene, MEF2C-AS1, which regulates MEFC2 levels. The loss of MEF2C-AS1 is anticipated to decrease MEFC2 expression, further supporting the emerging understanding that disturbances in MEF2C-AS1 can lead to neurological issues akin to those caused by disruptions in MEFC2 itself.

These findings underscore the diagnostic significance of identifying chromothripsis in neurological disorders associated with chromosomal changes. Accurate diagnosis is crucial, as chromothripsis may correlate with an elevated risk of cancer, which can necessitate increased cancer screenings throughout a patient's life.