Newborn Screening for T-Cell Disorders: Spectrum and Outcomes

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，其中婴儿出生时看起来健康，但缺乏免疫力 由T和B淋巴细胞提供。受影响的婴儿无法抵抗感染。他们发展成严重的传染病，除非接受免疫重建治疗，如骨髓或造血细胞移植（HCT），或在某些情况下接受酶替代疗法或基因疗法，否则无法存活。至少有14个已知基因可以导致SCID，但至少有10%的病例尚未发现基因诊断。出生后不久，在感染发展之前诊断出SCID，为成功治疗提供了最好的机会。因此，开发了针对SCID的基于人群的新生儿筛查（NBS）。Puck博士帮助开创了T淋巴细胞减少症的筛查，该筛查基于对干血斑（DBS）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，但在缺乏T细胞的SCID婴儿的血液中基本上不存在。在威斯康星州和马萨诸塞州进行试点试验后，现在在加利福尼亚州进行了TREC NBS;还有几个州已经在执行或计划执行TREC NBS。具有低T细胞的非SCID病症，包括“渗漏”SCID、SCID变体、具有T淋巴细胞减少症的综合征和继发性T淋巴细胞减少症，也可通过TREC筛查检测到，并且还赋予感染和免疫失调的风险，从而受益于早期诊断。然而，关于TREC检测的SCID和T淋巴细胞减少性疾病的发病率和谱仍然存在问题。我们将在CA每年出生的> 500，000名婴儿中评估TREC筛查（5年内为2，500，000名），监测新生儿期低TREC和T淋巴细胞减少症婴儿的临床特征，人口统计学和相关合并症。我们将研究具有典型SCID（定义为非常低的TRECs，<300个自体T细胞/uL和<10%的正常T细胞功能）的婴儿以及具有不太严重的T细胞缺陷的婴儿的分子缺陷。我们将前瞻性随访NBS发现的非SCID T淋巴细胞减少症婴儿，并测量来自CA出生的免疫缺陷儿童的存档NBS样本中的新生儿TREC。通过将免疫分型、深度测序和基因组分析与体外研究相结合，我们将发现新的疾病基因，并更全面地定义人类T淋巴细胞减少症的疾病谱。这些研究将建立新生儿筛查SCID和相关T细胞疾病的临床实用性，同时促进我们对人类原发性免疫缺陷的理解。

DESCRIPTION (provided by applicant): Severe combined immunodeficiency (SCID) is a rare, but life-threatening inherited disorder in which infants appear healthy at birth, but lack immunity provided by T and B lymphocytes. Affected infants are unable to resist infections. They develop severe infectious diseases and do not survive unless they receive immune- reconstituting treatment, such as a bone marrow or hematopoietic cell transplant (HCT), or in some cases enzyme replacement therapy or gene therapy. At least 14 known genes can cause SCID, but in at least 10% of cases a gene diagnosis has not been found. Diagnosing SCID soon after birth, before infections develop, offers the best chance for successful treatment. Population based newborn screening (NBS) for SCID has therefore been developed. Dr. Puck helped to pioneer screening for T lymphopenia based on quantitating T cell receptor excision circles (TRECs) in DNA from dried blood spots (DBS). TRECs are present in newly formed T cells, but essentially absent in the blood of infants with SCID, who lack T cells. TREC NBS is now done in CA following pilot trials in WI and MA; several more states are already performing or are planning to perform TREC NBS. Non-SCID conditions with low T cells, including "leaky" SCID, SCID variants, syndromes with T lymphopenia, and secondary T lymphopenia, are also detected by TREC screening and also confer a risk of infection and immune dysregulation, thus benefitting from early diagnosis. However, questions remain about the incidence and spectrum of SCID and T lymphopenic disorders detected by the TREC test. We will evaluate TREC screening in >500,000 infants born per year in CA (2,500,000 in 5 years), monitoring clinical features, demographics, and associated co-morbidities of infants with low TRECs and T lymphopenia in the newborn period. We will investigate the molecular defects in infants with both typical SCID (defined by very low TRECs, <300 autologous T cells/uL and <10% of normal T cell function) as well as infants with less profound T cell defects. We will prospectively follow infants with non-SCID T lymphopenia found by NBS and also measure newborn TRECs in archived NBS samples from CA-born children with immunodeficiencies. By combining immunophenotyping, deep sequencing and genomic analysis with in vitro studies we will find new disease genes and more fully define the spectrum of human T lymphopenic diseases. These studies will establish the clinical utility of newborn screening for SCID and related T cell disorders while advancing our understanding of human primary immunodeficiencies.