Scientists Develop A New Diagnostic Approach For rs Of Recessive Genetic D

[Guest guest]

Scientists Develop A New Diagnostic Approach For rs Of

Recessive Genetic Disorders

http://www.medicalnewstoday.com/medicalnews.php?newsid=46454

Disruption of global gene expression patterns in carriers may be a

significant source of human variation

Scientists Vivian Cheung and Warren Ewens from the University of

Pennsylvania have developed a new approach for the diagnosis of

medical disorders that are inherited in a recessive manner. Their

method is based on identifying subtle but distinct differences in

genome-wide expression profiles using microarray technology. An

article describing the approach appears online this week in the

journal Genome Research.

As a model for their work, Cheung and Ewens used a rare recessive

disease known as Nijmegen breakage syndrome (NBS). Only one gene -

called NBS1 - is known to be causative for NBS, although there are

multiple disease-initiating variants of this gene in different human

populations. Individuals who possess deleterious mutations in both

copies of NBS1 exhibit reduced head sizes, slowed growth rates,

immunodeficiency, and a predisposition to cancer. Heterozygous

carriers - who possess only one copy of the causative gene variant -

appear normal, although some reports have suggested that

heterozygotes may have an increased risk of cancer.

Using microarray technology, which simultaneously ascertains the

expression patterns of thousands of genes, Cheung and Ewens

discovered that heterozygous carriers of NBS exhibited distinct gene

expression patterns when compared to controls. Of 3,928 genes that

were expressed in the NBS carriers and controls, 520 consistently

exhibited differences between the two groups.

Cheung and Ewens identified a set of 16 genes whose expression

patterns could reliably discriminate between carriers and non-

carriers of NBS. The genes could also distinguish carriers of NBS

from carriers of a closely related syndrome known as ataxia

telangiectasia. Therefore, these 16 predictive genes can be used to

develop clinical tests to identify carriers of NBS.

Similar approaches can be extended for developing diagnostic tests

for carriers of other recessive genetic disorders. Even though most

recessive diseases are rare, many individuals are carriers for

recessive genetic disorders: on average, each person is a carrier for

three or four deleterious, disease-causing mutations. An approach to

effectively identify carriers of these diseases would be welcomed by

the medical community, especially in cases where the disease-causing

mutation is unknown or uncharacterized at the DNA level.

Based on the results of the study, Cheung and Ewens also suggest that

recessive mutations can significantly contribute to human

variation. " If each of us is a carrier for three or four harmful

recessive mutations, and if the expression levels of several hundred

genes are altered for each of these mutations, then heterozygosity

for recessive mutations plays a significant role in human variation

and in the overall genetic architecture of complex human traits and

diseases, " explains Cheung.