November 30, 2011 (Montreal, Quebec) — Partial or complete deletion of a specific gene, the MBD5 gene, on a specific region of chromosome 2 has been identified in every single individual affected by a microdeletion syndrome characterized by intellectual disability, epilepsy, and autism spectrum disorder (ASD). Researchers reported this finding here at the 12th International Congress of Human Genetics and the 61st American Society of Human Genetics Annual Meeting, which was published in the October 7 issue of the American Journal of Human Genetics.

Sarah Elsea, PhD, associate professor of pediatrics and human and molecular genetics at the Virginia Commonwealth University School of Medicine in Richmond, and colleagues assembled a collaborative team of clinical diagnostic laboratories and research facilities in Canada, Europe, and the United States to characterize the genetic content and phenotypic outcomes associated with a spectrum of genetic alterations with the 2q23.1 deletion syndrome region.

"We demonstrate that MBD5,...encoding the methyl-CpG-binding domain 5 protein, is a clear causal locus within the 2q23.1 deletion region and represents a previously unrecognized contributor to the genetic etiology of ASD," they report.

Microdeletion Syndrome

As Dr. Elsea told Medscape Medical News, the 2q23.1 microdeletion syndrome manifests as intellectual disability, epilepsy, ASD, and significant speech impairment. "Depending on the size of the deletion, the severity of these features varies," she explained. Individuals with very large deletions in the region are more severely affected with additional manifestations. Regardless of the size of the deletion, the MBD5 gene is the primary contributor to the core features of the syndrome, she added.

The team also found that partial or complete deletion of the same gene was associated with haploinsufficiency of messenger RNA expression, "meaning individuals with this microdeletion disorder have only 1 functioning copy of the gene, so there is only 50% function." Genetic and phenotypic analyses suggest that the majority of individuals affected by the 2q23.1 deletion syndrome exhibit autistic-like behaviors. In a sample of 2275 subjects with ASD, researchers observed a "highly similar" rate of 4 microdeletions of MBD5.

In contrast, they found no deletions of the 2q23.1 segment, the full MBD5 locus, or any MBD5 coding exons in 7878 control subjects with no psychiatric diagnosis. The team also identified novel changes in the MBD5 DNA sequence in 0.8% of autism cases.

Conservatively estimated, they believe that approximately 1% of individuals with ASD have an alteration of the MBD5 gene. As Dr. Elsea noted, one of the immediate benefits of their findings is that healthcare professionals are now able to provide a diagnosis for a subset of children with developmental problems.

"A proper diagnosis provides comfort and relief and some insight into the etiology behind the developmental problems, and it puts families in contact with other families whose children have similar problems," she noted. It will also allow children in the future to obtain a proper diagnosis.

Commenting on the study during a press conference, Evan Eichler, PhD, professor of genome science at the University of Washington School of Medicine in Seattle, observed that just like cancer, in any given family, there can be 1 or 2 genes that are responsible for the phenotype for many neuropsychiatric diseases.

"There are many different ways to get to Rome in terms of disease," he said, adding that "in some cases, it may be the same mutation in the same gene, but [occurring in] a different pathway. This is important because it tells us something fundamental in terms of understanding the biology of neuropsychiatric disease and its relationship with intellectual disability, for example."

The hope is that if these individuals cannot be cured, then at least their quality of life can be improved. By focusing on pathways involved in autism, for example, there are going to be far fewer pathways through which an individual arrives at autism than there are genes responsible for it.

Identification of these pathways provides a far more tractable way forward to treat the pathway, Dr. Eichler noted.

Dr. Elsea and Dr. Eichler have disclosed no relevant financial relationships.

Am J Hum Genet. 2011;89:551-563. Abstract

12th International Congress of Human Genetics (ICHG) and the 61st American Society of Human Genetics (ASHG) Annual Meeting. Presented October 11, 2011.


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