Newborn Screening for SCID in a High-Risk Population

描述(申请人提供)：严重联合免疫缺陷(SCID)是一种罕见的，但威胁生命的遗传性疾病，婴儿出生时没有T或B细胞功能。他们在出生的头几个月就会出现严重的感染，除非他们接受免疫重建治疗，如来自健康人的造血干细胞移植(HSCT)，否则他们无法在婴儿时期存活下来。出生后不久，在发生感染之前被诊断为SCID的婴儿，存活的机会最大，医疗并发症也更少。然而，要在感染发作之前识别SCID，就需要对新生儿进行普遍筛查。Puck博士开发了一种检测T细胞淋巴细胞减少症的方法，其基础是对从干燥血斑中提取的DNA中的T细胞受体切除环(TRECs)进行量化。TRECs存在于新形成的T细胞中，但基本上不存在于SCID婴儿的血液中，在SCID婴儿中，T细胞成熟受到损害。计划进行一项试点临床试验，以确定基于人群的前瞻性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两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是一种出生时不太明显的严重疾病，早期诊断可以改善健康结局。2.由于在阿萨巴斯坎血统的个体中发现了Artemis基因突变，纳瓦霍婴儿的SCID发病率至少是普通人群的20倍。大约每2000名纳瓦霍新生儿中就有一名感染SCID，这增加了在有限规模的试验中发现SCID的可能性。3.在纳瓦霍保留地实施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.被诊断为SCID的纳瓦霍婴儿在加州大学旧金山分校儿童医院接受骨髓移植，这是治疗所有SCID，特别是Artemis SCID的世界权威Cowan博士的计划。考恩博士和胡博士追踪了纳瓦霍SCID患者的结果。5.TREC检测方法需要在以人群为基础的研究中进行验证，以确定敏感性和特异性。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手段。 与公共卫生相关：患有严重联合免疫缺陷(SCID)的婴儿无法抵抗感染。他们在出生的头几个月就会患上严重的疾病，除非他们的免疫系统能够恢复，否则他们无法存活。如果及早发现，SCID可以通过骨髓移植治疗。我们正在研究一种新生儿筛查测试，旨在在感染发生之前诊断SCID。我们将在纳瓦霍印第安人保留地的高危人群中进行一项试点测试计划，那里每2000名婴儿中就有一名出生时患有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.