Deleted DNA may lead to intellectual disabilities

Feng Li of Hopkins' McKusick-Nathans Institute of Genetic Medicine, along with researchers at other universities, recently completed a genetic study of the correlation between Intellectual Disability and submicroscopial duplication of Xp22.31 of the X-chromosome.

Intellectual Disability (ID) is a mental disorder characterized by significantly below-average test scores and limitations in certain skills, such as communication, self-care and social abilities. Although children with ID can still learn, they develop much more slowly than average.

There are two classifications of ID: syndromic, which includes phenotypic abnormalities, and non-syndromic, when altered cognitive abilities are the only symptom. Although both types may be caused by the same genetic abnormalities, the innumerable genetic differences amongst different people make pinpointing the exact genetic determinant difficult.

The disproportionate ratio of males to females affected (1.4 for moderate to severe ID; 1.9 for mild) suggests that ID could be caused by an X-linked chromosomal defect.

An region of the X-chromosome called Xp22.31 that spans approximately 1.5 million base pairs has been found to be deleted in numerous individuals with ID, attention deficit hyperactivity disorder (ADHD), autism and other forms of cognitive abnormalities.

In addition, other studies propose that a duplication of the same region may be linked to patients with both abnormal phenotypic and cognitive features.

While some authors considered Xp22.31 duplication to be pathogenic, others classified it as a benign variant.

In this study, 7793 people from 13 clinical centers with developmental delay (DD), ID, autism and multiple congenital abnormalities were studied. The research team performed standard protocols of chromosome analysis, microarray and X-inactivation analysis on the individuals' blood cultures.

Results suggest a possible causal relationship between duplication of Xp22.31 and abnormal phenotype of people with ID. However, it is also probable that this irregularity is a rare population variation. Although there is no conclusive proof, evidence still suggests this genetic aberration is a risk factor for ID and other conditions.

"We are still at a very early stage of understanding the clinical significance of genomic imbalances," said Yiping Shen, a researcher at Harvard Medical School who participated in the study. "There are many things we could do to better understand the genotype-phenotype correlations regarding these novel genomic imbalances."

"The 'genotype-first' approach we did with the Xp22.31 duplications where we evaluate[d] the clinical phenotypes of individuals carrying the similar genomic imbalances is an effort tool towards that goal," Shen said.