New Cytogenetics Tests Can Help Clarify Pediatric Diagnosis of Complex Developmental Abnormalities

Breakthroughs in cytogenetic technologies, which focus on subtle alterations in genes and chromosomes, are enabling a new level of detail and accuracy in the diagnosis of complex and unexplained developmental problems in children.

The availability of this new information can help clinicians shift to a "genotype first" model of diagnosis, according to David H. Ledbetter, PhD, Woodruff professor of human genetics at Emory University and director of the Division of Medical Genetics.

Ledbetter's editorial on "Cytogenetic Technology--Genotype and Phenotype," is published online this week by the New England Journal of Medicine. It accompanies an article by Heather Mefford and colleagues about using new cytogenetic technologies to identify microdeletions and microduplications in a specific region of chomosome 1q21.1 in patients with unexplained mental retardation, autism or congenital anomalies

Cytogenetic arrays that reveal DNA microdeletions and additions, including single-copy changes of a few hundred base pairs, beadchips that detect single-nucleotide polymorphisms (SNPs) and tests called comparative genomic hybridization have led to an exciting renaissance of genetics-based syndrome delineation, says Ledbetter in his editorial.
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"In the early 1960s we began discovering the relationship between chromosome imbalance and diseases and syndromes, such as Down syndrome," says Ledbetter. "This was based on identifying multiple patients with the same cytogenetic abnormality and similar clinical symptoms. Ever since then, technology breakthroughs have allowed us to identify new syndromes and ever more subtle genetic differences."

The current proliferation of new genetic information has led researchers to discover that many small genetic variations are common and mostly benign in the human population. This means the relationship between DNA variations and disease must be analyzed even more carefully in order to find accurate connections. In order to prove that a genetic difference is directly related to a particular syndrome, notes Ledbetter, researchers must show that the difference is never found in normal control individuals or at least is found with significantly less frequency.

Also, researchers have found that a particular genetic variation may have only a mild effect in a parent but a much more severe effect in a child who inherits the same variant. And a group of children may have a variety of different problems resulting from the same gene variation. Whole-genome cytogenetic arrays are becoming much more common, however, which is bringing genetic testing to the level of everyday medicine.

"So many variations of developmental disorders and syndromes have been discovered that genetic testing has become essential for making a specific clinical diagnosis," says Ledbetter. "Although more information has made the job of a diagnostician even more challenging, it also is leading to more accurate diagnoses and should lead to much more effective treatments."
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