Newborn Screening for Sex Chromosome Disorders

DESCRIPTION (provided by applicant): Turner syndrome (TS) is the most common genetic problem affecting women and occurs when an entire, or a portion of an X-chromosome is deleted. The incidence of TS 1 in 1,500 to 2,000 live female births. Features include primary hypogonadism, renal abnormalities and cardiac problems. Girls with TS are short and have an average adult height of 4 feet 6 inches. Yet, with growth hormone therapy, acceptable adult stature can be achieved. Currently, many girls with TS are diagnosed after 10 years of age. Thus recognition of associated cardiac, renal, and other problems may be delayed. Final height will be compromised by late-onset of adjunctive therapy with growth hormone, which if begun at an early age, allows girls with TS to achieve normal adult height. Recently, we developed a strategy to detect TS and other sex chromosome abnormalities that relies on genomic DNA screening using informative single nucleotide polymorphism (SNP) markers spanning the X- and Y-chromosomes. This is followed by quantitative assessment of allele signal strength and number from SNPs via pyrosequencing. We hypothesize that using this new sex chromosome screening test we can develop an effective, low-cost screening test for detecting TS with broad commercial application. To optimize this approach for high-throughput screening at the lowest possible cost with high sensitivity, we recently completed Phase I studies that were highly successful, and show that we can detect ALL of the reported genotypes of TS. In Phase II of this SBIR project, we propose to extend our diagnostic test to clinical trials and develop a testing and referral program. We will test our assay in 1. Pediatric Endocrinology Clinics. (a) Test samples from girls known to have TS. (b) Test samples from girls with short stature. 2. Perform Newborn Screening Trials. and 3. Develop Testing and Notification Programs We anticipate that this Phase II application will lead to implementation of an inexpensive test that is suitable for detection of sex chromosome disorders by physicians and newborn screening programs. Turner syndrome (TS) is the most common genetic problem affecting women. The incidence of TS 1 in 1,500 to 2,000 live female births, and TS occurs when an entire, or a portion of an X-chromosome is deleted. Currently, many girls with TS are diagnosed after 10 years of age. Thus recognition of associated cardiac, renal, and learning problems may be delayed. Final height will be compromised by late-onset of adjunctive therapy with growth hormone, which if begun at an early age, allows girls with TS to achieve normal adult height. We propose the development of a new low-cost screening test for detecting TS with broad commercial application.