Newborn Screening for Sex Chromosome Disorders

描述（由申请人提供）： 特纳综合征（TS）是影响女性的最常见的遗传问题，发病率为1/1，500至2，000活产女性，当整个X染色体或部分X染色体缺失时发生。表型特征包括原发性性腺功能减退、肾功能异常和严重的身材矮小。然而，通过生长激素治疗，可以达到可接受的成年身高。目前，许多患有TS的女孩在10岁后被诊断出来。因此，心脏、肾脏和学习问题的识别可能会延迟，最终身高可能会受到影响。如果存在Y染色体，患有TS的女孩也有发生性腺肿瘤的风险。最近，我们开发了一种策略来筛选Tuner综合征和其他性染色体异常，该策略依赖于使用跨越X和Y染色体的信息性单核苷酸多态性（SNP）标记进行基因组DNA筛选。随后通过焦磷酸测序定量评估等位基因、来自单个核苷酸的信号强度。因此，我们建议开发一种有效的，低成本的新生儿筛查试验（性染色体疾病筛查试验）检测TS的商业应用。我们的Phasel里程碑将是（1）测试和优化检测灵敏度和准确性，（2）测试选择性（假阳性率）。(3)创建多重标记集，以最大限度地降低成本。我们预计，这一1期申请将导致开发一种适用于高通量人群筛查性染色体疾病的检测方法。在接下来的步骤中，我们预计将提交第二阶段申请，用于试点大规模新生儿筛查研究。如果成功，这一战略将适用于每年在美国出生的200万名女婴，这些女婴接受了州新生儿筛查计划的检测，并适用于数十万名接受商业新生儿筛查服务的婴儿。

DESCRIPTION (provided by applicant): Turner syndrome (TS) is the most common genetic problem effecting women, with an incidence of 1 in 1,500 to 2,000 live female births and occurs when an entire, or portions of an X-chromosome is deleted. Phenotypic features include primary hypogonadism, renal abnormalities, and profound short stature. 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 cardiac, renal, and learning problems may be delayed, and final height may be compromised. Girls with TS are also at risk for gonadal tumor development if Y-chromosomal is present. Recently we developed a strategy to screen for Tuner syndrome and other sex chromosome abnormalities that relies on genomic DNA screening using informative single nucleotide polymorphism (SNP) markers that span the X and Y-chromosomes. This is followed by quantitative assessment of allele, signal strength from single nucleotides via pyrosequencing. Thus, we propose to develop an effective, low-cost newborn screening test (the sex chromosome disorder screening test) for detecting TS with commercial application. Our Phasel milestones will be to (1) test for and optimize assay sensitivity and accuracy, (2) test for selectivity (rate of false-positives). (3) Create multiplex marker sets to minimize cost. We anticipate that this Phase 1 application will lead to the development of an assay that is suitable for high-throughput population screening for sex chromosome disorders. In next steps, we anticipate submitting a Phase 2 application for piloting large-scale newborn screening studies. If successful, this strategy will be applicable to the 2 million female infants born each year in the United States tested by state newborn screening programs, and to the several hundred thousand infants tested by commercial newborn screening services.