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Study Determines Dx Yield of Exome Sequencing, Chromosomal Microarrays in Short-Statured Individuals

NEW YORK — A new meta-analysis to determine the diagnostic yield of exome sequencing and chromosomal microarrays in people of short stature suggests that these tests deliver molecular diagnoses for about 40 percent of patients.

According to the researchers, who published their findings in the Journal of the American Medical Association (JAMA) Pediatrics on Monday, the new results can serve as a reference for clinicians to recommend genetic tests for the condition and may guide doctors in deciding on precision treatments for patients.

For their study, lead author Qing Li, a researcher at Peking Union Medical College Hospital in China, and colleagues evaluated 20 studies comprising 1,350 patients with short stature who underwent exome sequencing and another 1,070 who completed chromosomal microarray testing.

Short stature, defined as height less than two standard deviations from the mean for the respective age and sex, can be caused by genetic and environmental factors. While several previous studies had noted the diagnostic yield of exome sequencing and chromosomal microarrays for the condition, their results had differed widely.

For their study, the researchers considered articles published up to January 2023, a search that drew nearly 5,000 studies. However, after removing duplicates and implementing stringent inclusion criteria, they narrowed the list to 20 studies.

Their meta-analysis for the exome sequencing category, which included 10 cohorts, showed an overall diagnostic yield of nearly 27 percent. Patients in these studies had pathogenic or likely pathogenic variants in 250 unique genes. Subsequent subgroup analysis indicated exome sequencing as the first-tier approach yielded slightly more positive diagnoses than those using it as a last-resort strategy, but the results were not statistically significant.

Meanwhile, a meta-analysis for chromosomal microarray tests from 14 cohorts showed an overall diagnostic yield of nearly 14 percent. This test identifies pathogenic copy number variants and is neither a first-tier strategy nor a last-resort option but complementary to exome sequencing, the authors noted. 

According to them, the findings emphasize the potential of exome sequencing and chromosomal microarray testing early in the diagnostic process for more timely and accurate genetic diagnoses. "It also provides a baseline diagnostic yield for healthcare payors and medical associations to determine cost-effectiveness, design medical insurance policies, and establish a consensus on diagnosing a specific short stature disorder," they wrote.

However, they noted that their findings may have a selection bias as they excluded cohorts that had studied short-statured patients with a particular type of syndrome. Moreover, variations in the inclusion criteria among individual studies make it difficult to extrapolate the findings to all short-stature patients.

In an accompanying editorial, Monica Wojcik, a physician at Boston Children's Hospital, and Ann Wu, an associate professor at Harvard Medical School, pointed out that the nonspecific nature of short stature makes it challenging to infer widespread conclusions from the study's findings. "Short stature is one indicator of a potential genetic condition, as are other nonspecific features, such as hypotonia, for which genome-wide sequencing has also been proposed as the ideal first-line diagnostic tool," they wrote. "Rather, these data provide further support of genome-wide testing as a first-tier test for anyone suspected to have a rare genetic condition."