Researchers Pinpoint Novel Genetic Variant as the Cause for LGS and Mild Intellectual Impairments in Korean Family

Researchers Pinpoint Novel Genetic Variant as the Cause for LGS and Mild Intellectual Impairments in Korean Family
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A previously unknown inherited variation of a gene linked to Lennox-Gastaut Syndrome (LGS) was found as the underlying cause of the condition and mild intellectual disabilities in three generations of a Korean family, according to a recent study.

The findings were published in an article, “A Novel X-Linked Variant of IQSEC2 is Associated with Lennox–Gastaut Syndrome and Mild Intellectual Disability in Three Generations of a Korean Family,” in the journal Genetic Testing and Molecular Biomarkers

Identifying genes that cause LGS and associated intellectual disability is critical to the development of therapies to treat these conditions. However, genes related to LGS remain largely unknown.

Accordingly, recent studies have reported on variants of a gene found on the X chromosome, called IQ motif and Sec7 domain 2 or IQSEC2, that encodes for a protein found in nerve cell synapses in the brain and spinal cord. Synapses are the junctions between two nerve cells that allow them to communicate.

Variants of this gene have been linked with disorders such as intellectual disability, epilepsy, and LGS. So far, a total of eight IQSEC2 variants have been detected in people with LGS and LGS-like conditions, and all of these variants occurred spontaneously in one of the parents. 

One technique used to identify additional LGS variants is to analyze the genes of families with members living with LGS and intellectual disabilities.

This was the approach used by a team of researchers in Korea who identified a local family in which one male member was diagnosed with LGS, and two female members (his mother and grandmother) had mild intellectual disabilities.

Blood samples were withdrawn from five family members and the DNA sequence of their entire genomes was analyzed by whole-exome sequencing (WES). 

The DNA analysis uncovered a new variant of IQSEC2 — not yet reported in previous studies or found in databases — associated with LGS and intellectual disability. 

This variant occurred by a change in one nucleotide (DNA building block), leading to a change in one amino acid (protein building block) in a critical part of the IQSEC2 protein. 

A series of computer programs designed to predict the disease-causing potential of a new disease-linked variant confirmed this change as the cause of LGS and mild intellectual impairment in this family. 

The authors pointed to a previously reported IQSEC2 variant, which is similar to the new variant and associated with epilepsy. In this case, the change was smaller compared to the new variant. They noted how this small change “might result in differences in the symptoms.”

As this IQSEC2 variant was linked to the X-chromosome, it was inherited from the patients’ grandmother and his mother. Each of the women carried one copy of the variant which resulted in their mild intellectual disability. However, the son, who had only one X chromosome, developed LGS.

The patient’s father and sister were not carriers of the new IQSEC2 variant.

“These findings indicate that the variant of IQSEC2 triggered both LGS and intellectual disability dependent on sex and variant types in this family,” the researchers wrote.

“This variant enhances the spectrum of variants in the IQ-like motif of IQSEC2 and needs to be included in the targeted or broader sequencing analysis pipeline of both LGS and intellectual disability,” they said. 

Steve holds a PhD in Biochemistry from the Faculty of Medicine at the University of Toronto, Canada. He worked as a medical scientist for 18 years, within both industry and academia, where his research focused on the discovery of new medicines to treat inflammatory disorders and infectious diseases. Steve recently stepped away from the lab and into science communications, where he’s helping make medical science information more accessible for everyone.
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Ana de Barros, PhD Ana holds a PhD in Immunology from the University of Lisbon and worked as a postdoctoral researcher at Instituto de Medicina Molecular (iMM) in Lisbon, Portugal. She graduated with a BSc in Genetics from the University of Newcastle and received a Masters in Biomolecular Archaeology from the University of Manchester, England. After leaving the lab to pursue a career in Science Communication, she served as the Director of Science Communication at iMM.
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Steve holds a PhD in Biochemistry from the Faculty of Medicine at the University of Toronto, Canada. He worked as a medical scientist for 18 years, within both industry and academia, where his research focused on the discovery of new medicines to treat inflammatory disorders and infectious diseases. Steve recently stepped away from the lab and into science communications, where he’s helping make medical science information more accessible for everyone.
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