High-throughput test may lead to earlier diagnosis of Turner’s syndrome

Rivkees SA. J Clin Endocrinol Metab. 2011;doi:10.1210/jc.2010-1554.

A new high-throughput test based on a quantitative method of genotyping to detect X chromosome abnormalities demonstrated high sensitivity and specificity in the detection of Turner’s syndrome, according to recent data.

“We have developed a novel approach for diagnosing Turner’s syndrome that can be used to practically test large numbers of girls and is much quicker and less expensive than current methods,” Scott A. Rivkees, MD, of Yale University School of Medicine in New Haven, Conn., said in a press release. “The new test would also provide the benefit of early detection of other health conditions associated with Turner’s syndrome, such as potential renal and cardiac problems.”

A quantitative, pyrosequencing-based method

According to researchers, the test utilizes pyrosequencing to quantitate relative allele strength from single nucleotide polymorphisms using 18 X chromosome and one Y chromosome single nucleotide polymorphism markers. They based relative allele strength cutoff ranges for the markers on homozygous and heterozygous genotypes for a cohort of 496 apparently healthy men and women. Values between these cutoffs were considered out of range.

The researchers deemed people as having Turner's syndrome if homozygosity was present in all 18 markers or if at least one marker was out of range, as this indicated mosaicism or partial deletion of the X chromosome.

Clinical utility of test

To evaluate the test’s efficacy, the researchers included 132 girls and women without Turner’s syndrome and 74 with Turner’s syndrome in their analysis. Results indicated that, of the 90 clinically confirmed cases of the condition, the assay exhibited 96% sensitivity and 97% specificity.

Buccal swab DNA from 19 girls and women without Turner’s syndrome and 69 with the condition was also used to assess the test’s efficacy. In this cohort, the assay demonstrated 97.1% sensitivity and 84.2% specificity.

“Our data confirm that high-throughput testing using quantitative genotyping by pyrosequencing allows for accurate identification of [Turner’s syndrome] with clinically meaningful sensitivity and specificity,” the researchers wrote.

Rivkees said there are other positive ramifications.

“Because of the small amount of DNA needed for the test, ample DNA can be extracted from cheek swabs or from newborn screening blood spots that are routinely collected,” he said. “If broadly used in the clinical setting at young ages, this test can prevent the delayed recognition of Turner’s syndrome.”

Disclosure: Dr. Rivkees has a direct financial interest in the high-throughput test. He is a founder of and an equity holder in JS Genetics. Yale University has been recently issued a patent convering this method with an exclusive sublicense granted to JS Genetics.

For more information:

• Rivkees SA. J Clin Endocrinol Metab. 2011;doi:10.1210/jc.2010-1554.

The report by Rivkees and colleagues is a highly important step toward much desired and needed earlier diagnosis of Turner’s syndrome (1 in 1,500 life births). Currently, it is woefully late, with a median age of diagnosis at 12 to 14 years of age, according to different studies. Earlier detection is desirable because medical care for Turner’s syndrome can be initiated earlier. Currently, only too often, short girls are diagnosed with Turner’s syndrome at the peripubertal age when the accumulated height deficit is so large that there is insufficient time to achieve catch-up growth and get these girls to an adult height of 5 feet or more.

The high-throughput assay is the first method that has a reasonably good specificity/sensitivity profile to allow mass testing and be able to detect Turner’s syndrome, even in the frequent cases of mosaicism (up to 40%). It is unclear if the method can also be applied to dried filter paper samples available from mandated neonatal screening tests. Buccal smears as utilized here in the detection of Turner’s syndrome (homozygous or heterozygous) are actually much more onerous and do not lend themselves readily for newborn screening. While 18 single nucleotide polymorphisms spanning the entire X chromosome were included in the panel, only one Y chromosome marker was used. This may not be enough, as we need to know more about Y chromosomal material, including SRY and GBY, the gonadoblastoma gene, which are on different regions of the Y chromosome.

Nonetheless, this is a robust and significant breakthrough that should readily lend itself to the earlier diagnosis of another even more frequent sex chromosome abnormality (1 in 600 life births) that is only too often diagnosed very late in life, Klinefelter’s syndrome. A short turnaround time of only 3 days is also helpful.

– Paul Saenger, MD, MACE
Endocrine Today Editorial Board member

Disclosure: Dr. Saenger reports no relevant financial disclosures.

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