Scientific Basis for a Newborn Screening for Cystinosis and Spinal Muscular Atrophy
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 300,000
- 试验地点
- 8
- 主要终点
- Number of participants with heterozygous mutations
研究概览
简要总结
Newborn screening in Germany is a voluntary program. Cystinosis and spinal muscular atrophy (SMA) are rare autosomal recessive diseases. They are inherited in an autosomal recessive manner, i.e. both parents carry a defective gene. Neither disease can be detected early by the methods established in routine newborn screening. However, common genetic mutations are known for both diseases.
The aim of the study presented here is to provide the scientific basis for molecular genetic newborn screening for cystinosis and SMA. In particular, to investigate whether inclusion of these diseases in general newborn screening should be recommended.
The participating screening laboratories for this project are Labor Becker & Kollegen, Munich, Germany and Screening Laboratory Hannover, Germany. Hospitals that send their dry blood spot cards for routine newborn screening to these laboratories will receive an offer to participate in the pilot project. Participation is free of charge.
Parents who wish to participate in this pilot project will receive an information sheet explaining the screening process and objectives. A parent and the treating physician sign the information sheet as documentation of informed consent. Their signature and informed consent are required for the pilot.
Routine NBS according to German pediatric guidelines involves the collection of dried blood spot cards 36-72 hours after birth. Molecular genetic screening in the pilot project will be performed with the same dried blood spot card used for routine newborn screening.
In cystinosis, genetic testing for the 3 most common mutations in Germany will be performed. In SMA, a homozygous deletion of exon 7 in the SMN gene is detected by a PCR test. The molecular genetic test is performed on the same day as routine newborn screening.Normal findings are not reported to parents. However, they can contact the laboratories to inquire about them.
Parents of newborns with two mutations in the cystinosis gene or with a homozygous deletion of exon 7 in the SMN gene are immediately informed of the disease by a physician. Further diagnostics to confirm the disease will be organized close to home.
The study started on Jan. 15, 2018, and recruitment was completed on Sept. 30, 2022.
详细描述
Population-based newborn screening (NBS) is an important public health program that has vastly improved the course of several diseases through early detection. The selection of screened disorders generally follows the 10 principles outlined by Wilson and Jungner. In Germany, NBS has been a voluntary National Health Service program since 1969 which currently covers 17 disorders. Current NBS methods, which employ tandem mass-spectrometric analysis of newborn dried blood spots, cannot detect many potentially treatable genetic conditions. At the same time, molecular-based NBS is increasingly feasible because DNA can be extracted from a dried blood spot, next generation sequencing has become economical, and molecular diagnostics have greater reliability and increased validity as genetic databases become more refined and comprehensive. Nephropathic cystinosis and spinal muscular atrophy (SMA) are eligible for molecular-based NBS because effective therapies are available.
This study will provide a scientific basis for newborn screening for cystinosis and SMA and investigate whether inclusion of these diseases in general newborn screening should be recommended. By observing identified infants compared to symptomatically diagnosed patients outside the pilot project, we will determine whether and to what extent early diagnosis and initiation of therapy leads to a more favorable prognosis.
Cystinosis: Cystinosis is a rare autosomal recessive systemic disease with high morbidity and mortality caused by pathogenic variants in the CTNS gene that encodes the lysosomal cystine transporter cystinosin, leading to accumulation of cystine within the lysosome. Life-long cystine-depleting therapy with oral cysteamine, the only specific therapy for cystinosis, along with the availability of renal replacement therapy in childhood, has dramatically improved patient outcomes. There is robust evidence that early initiation and sustained therapy with cysteamine are both essential for delaying progression to chronic kidney disease (CKD) and end-organ damage.
Currently, the diagnosis of cystinosis is based on the presence of elevated cystine levels in white blood cells. This method is unsuitable for NBS.
Spinal Muscular Atrophy (SMA): Spinal muscular atrophy has a prevalence of approximately 1:10,000 live births in Germany. It is inherited in an autosomal recessive manner. Newborns with spinal muscular atrophy are without clinical symptoms after birth.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Screening
- 盲法
- None
入排标准
- 年龄范围
- 36 Hours 至 72 Hours（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Newborns whose dry bloodspot card was sent to screening labs involved in the project
- •Consent of guardians
排除标准
- •no consent of guardians
结局指标
主要结局
Number of participants with heterozygous mutations
时间窗: up to 4 weeks
Newborns identified with heterozygous CTNS mutations of 57-kb CTNS and heterozygous c.18_21delGACT p.T7Ffs\*7 mutations and heterozygous c.926_927insG, p.S310Qfs \* 55 mutations
time interval until start of treatment for both diseases
时间窗: up to 4 weeks
For both diseases the time interval will be evaluated from the time of identification in screening to the introduction of therapy.
Number of participants with confirmed diagnosis of Cystinosis
时间窗: up to 60 months
Newborns identified with 57-kb CTNS mutation homozygous, compound heterozygous , with c.18_21delGACT p.T7Ffs\*7 homozygous or compound heterozygous or c.926_927insG, p.S310Qfs \* 55 homozygous or compound heterozygous and elevated white blood cell cystine level.
Number of participants with confirmed diagnosis of SMA
时间窗: up to 48 months
Newborns identified with homozygous deletion of exon 7 in the SMN1-gene
次要结局
未报告次要终点