From The Labs

The number of rare variant genes contributes to symptoms of genetic disease

How the burden of rare variants works
How the burden of rare variants works. Graphic courtesy of Cell Reports.


By Ruth SoRelle, M.P.H.

Genetic or Mendelian mutation in a gene is often the cause of disease, but the symptoms of that disorder may stem from the burden of rare genetic variation – minute changes in the genetic material that make up a gene and occur in only a few people.

The report from an international consortium of researchers led by those at Baylor College of Medicine appears in the journal Cell Reports. .

Whole exome sequencing

Concentrating on the peripheral nerve-affecting disorder Charcot-Marie-Tooth disease, which is associated with mutations in different genes and a broad clinical spectrum,

Dr. James Lupski
Dr. James Lupski

Dr. James R. Lupski, Cullen professor of molecular and human genetics at Baylor,

Dr. Claudia Gonzaga-Jauregui
Dr. Claudia Gonzaga-Jauregui

and Dr. Claudia Gonzaga-Jauregui, the first author working in his laboratory, analyzed the results of whole exome sequencing in 40 people with pathology similar to that seen in Charcot-Marie-Tooth disease from 37 families who were unrelated and whose disease cause had not been identified by ordinary molecular testing. Whole exome sequencing identified gene mutations that might be the cause in 17 of the families.

(Rare gene variants are minute changes in the genetic material that make up a gene and that occur in very few people. Whole exome sequencing is the complete blueprint for the protein-making repertoire of an organism.)

In addition, the researchers proposed three new genes that appeared to cause the disease in both genetic tests and studies in living model organisms.

Increased rare variants

When they put together the mutation data, they found a significantly increased number of rare variants across 58 genes associated with pathology in nerves (neuropathy) in people with the disease when compared to those who did not have it.

“Charcot-Marie-Tooth varies greatly in its symptoms,” said Gonzaga-Jauregui. “Some people have sensory neuropathy or decreased sensitivity or strength in their hands. Others are bound to wheelchairs early life.”

Variability in the disease

Her studies in the original 37 families found that rare variants and the accumulation of such in genes participating in the same pathways that cause disease could contribute to variability in the way the disease is expressed.

To further test the theory, she and her colleagues tested combinations of the genes in zebrafish (popular model organisms).

“If we injected a concentration of a molecule to inactivate one gene, we got a mild disease. When we inject molecules to inactivate two genes together, we got a severe disease,” she said. “The idea is that rare variants are sensitizing the system. Patients have more mutations other than the main driver that causes neuropathy.”

Surprisingly, she said, they found some people with enrichment for rare recessive variants in neuropathy genes  in the general population.

Another insult

“We propose that with another insult – environmental or disease as in diabetes or chemotherapy – the mutation burden takes organisms to the edge of developing neuropathy,” she said.

“Now that we have exome sequencing, we can see beyond the one single gene causing disease,” she said. “Genes are playing a role in a greater context contributing to disease. Different proteins interplay and interact in the cell. One gene might malfunction and another does not quite function normally, and they both come together in how the cell works. We want to understand how all this comes together to give you disease.”

Others who from Baylor who took part in this work include: Tamar Harel, Tomasz Gambin, Shalini Jhangiani, Eric Boerwinkle, Matthew N. Bainbridge, Davut Pehlivan, Yuji Okamoto, Marjorie Withers, Wojciech Wiszniewski, Donna Muzny, the Baylor-Hopkins Center for Mendelian Genomics and Richard A. Gibbs.

Funding for this work came from the U.S. National Institute of Neurological Disorders and Stroke (Grant R01S058529, K23NS078056; U54NS065712 and R01NS075764); National Heart, Lung and Blood Institute (NIH U54H G006542), National Human Genome Research Institute (Grant U54HG003273); NIH P50MH094268; the Muscular Dystrophy Association (Grant MDA294479); NIH (Grants T32GM7526-37; GM007315; GM07863 and F30 NRSA NS092238.)

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