Newborn Screening for SCID in a High-Risk Population

描述（由申请人提供）：严重联合免疫缺陷（SCID）是一种罕见的，但危及生命的遗传性疾病，其中婴儿出生时没有T或B细胞功能。他们在出生后的头几个月发生严重感染，除非接受免疫重建治疗，如健康人的造血干细胞移植（HSCT），否则无法存活。出生后不久被诊断为SCID的婴儿，在发生感染之前，有最好的生存机会和较少的医疗并发症。然而，要在感染发生前识别出SCID，需要对新生儿进行普遍筛查。Puck博士开发了一种T细胞淋巴细胞减少症检测方法，该方法基于对从干血斑提取的DNA中的T细胞受体切除环（TRECs）进行定量。TRECs存在于新形成的T细胞中，但在患有SCID的婴儿的血液中基本上不存在，其中T细胞成熟受损。计划进行一项试点临床试验，以确定前瞻性、基于人群的TREC筛查的可行性。在母亲知情同意的情况下，将为在亚利桑那州西纳瓦霍保留地的2家医院出生的婴儿提供SCID筛查。我们计划在这里进行SCID筛查试验有5个原因：1。SCID是一种严重的疾病，在出生时并不明显，早期诊断可以改善健康结果。2.纳瓦霍婴儿的SCID发病率至少比一般人群高20倍，因为在阿萨巴斯卡血统的个体中发现了ARTEMIS基因突变。大约每2,000名纳瓦霍出生的婴儿中就有一人受到SCID的影响，这增加了在有限规模的试验中发现SCID的可能性。3.纳瓦霍保留地制定了有效的地方公共卫生和外联方案，以确保与家庭沟通，以便在需要时采取后续行动。4.纳瓦霍婴儿被诊断患有SCID，在UCSF儿童医院接受科万博士的骨髓移植，科万博士是治疗所有SCID，特别是ARTEMIS SCID的世界权威。科万博士和胡博士跟踪纳瓦霍SCID患者的结果。5. TREC检测方法需要在基于人群的研究中进行验证，以确定灵敏度和特异性。在SCID发病率高的人群中进行试验是衡量测试有效性的最有效方法。 公共卫生相关性：患有严重联合免疫缺陷（SCID）的婴儿无法抵抗感染。他们在出生后的头几个月里就病得很重，除非他们的免疫系统得到恢复，否则就无法生存。如果早期发现，可以通过骨髓移植治疗SCID。我们正在研究一种新生儿筛查测试，旨在在感染发生前诊断SCID。我们将在纳瓦霍印第安人保留地的高危人群中开展试点测试项目，那里每2,000名婴儿中就有1名出生时患有SCID。

DESCRIPTION (provided by applicant): Severe combined immunodeficiency (SCID) is a rare, but life-threatening inherited disorder in which infants are born without T or B cell function. They develop serious infections in their first months of life and do not survive past infancy unless they receive immune-reconstituting treatment, such as a hematopoietic stem cell transplant (HSCT) from a healthy person. Infants diagnosed with SCID soon after birth, and before developing infections, have the best chance of survival and fewer medical complications. To recognize SCID before onset of infections, however, requires universal screening of newborns. Dr. Puck has developed an assay for T cell lymphocytopenia based on quantitating T-cell receptor excision circles (TRECs) in DNA extracted from dried blood spots. TRECs are present in newly formed T cells, but essentially absent in the blood of infants with SCID, in whom T cell maturation is impaired. A pilot clinical trial to establish feasibility of prospective, population-based TREC screening is planned. With maternal informed consent, screening for SCID will be offered to infants born in 2 hospitals on the Western Navajo Reservation in Arizona. We plan a SCID screening trial here for 5 reasons: 1. SCID is a serious condition not readily apparent at birth for which early diagnosis can improve health outcome. 2. Navajo infants have at least a 20-fold higher incidence of SCID than the general population because of an ARTEMIS gene mutation found in individuals of Athabaskan ancestry. Around one per 2,000 Navajo births is affected with SCID, increasing the likelihood of finding SCID in a trial of limited size. 3. Effective local public health and outreach programs are in place on the Navajo Reservation to assure communication with families for follow-up when indicated. 4. Navajo infants diagnosed with SCID receive their bone marrow transplants at the UCSF Children's Hospital in the program of Dr. Cowan, a world authority on treatment of all SCID, and particularly ARTEMIS SCID. Dr. Cowan and Dr. Hu track the outcomes of the Navajo SCID patients. 5. The TREC assay methodology needs to be validated in population-based studies to establish sensitivity and specificity. A trial in a population with a high incidence of SCID is the most efficient means to measure test validity. PUBLIC HEALTH RELEVANCE: Babies with severe combined immunodeficiency (SCID) are unable to fight infections. They become severely ill in their first months of life and do not survive unless their immune systems can be restored. SCID can be treated by bone marrow transplant if recognized early. We are working on a newborn screening test designed to diagnose SCID before infections occur. We will conduct a pilot testing program in a high-risk population on the Navajo Indian Reservation, where 1 in 2,000 infants is born with SCID.