Department of Clinical Sciences, Paediatrics, Lund University, Lund, Sweden.
Centre for Thrombosis and Haemostasis, Skåne University Hospital, Malmö, Sweden.
Haemophilia. 2020 Mar;26(2):314-324. doi: 10.1111/hae.13948. Epub 2020 Feb 26.
Genetic screening using high-throughput DNA sequencing has become a tool in diagnosing patients with suspected inherited bleeding disorders (IBD). However, its usefulness and diagnostic efficacy in children is unclear.
To evaluate the diagnostic efficacy of genetic screening for IBD in children and downstream further testing.
After informed consent, children (<18 years) with suspected IBD underwent genetic screening with 94 selected genes.
A total of 68 heterozygous class 3-5 variants were detected in 30 children, 2.3 variants per patient. Directed specific functional testing was performed after genetic screening in a subset of patients. Adhering to the ACMG guidelines, the results of functional testing together with family history and previous publications classified three variants as likely disease causing (class 4) and two variants as disease causing (class 5), all in children with thrombocytopenia. The overall diagnostic rate was 16.7% (5/30). Children with thrombocytopenia had a significantly higher rate of significant genetic findings, 5/9 (55.6%) vs. 0/21 (0%; P = .0009).
We conclude that performing genetic screening in children is an effective tool especially for children with inherited thrombocytopenia and has the possibility to diagnose platelet disorders adequately early in life. Children with bleeding diathesis, normal coagulation work-up and without thrombocytopenia are unlikely to be diagnosed by genetic screening. Ethical issues such as incidental findings, variants associated with cancer and the interpretation of the genetic results into clinical practice remain problematic.
使用高通量 DNA 测序进行基因筛查已成为诊断疑似遗传性出血性疾病（IBD）患者的一种手段。然而，其在儿童中的应用价值和诊断效果尚不清楚。
评估基因筛查在儿童遗传性 IBD 中的诊断效果及其下游进一步检测的效果。
在获得知情同意后，对疑似 IBD 的儿童（<18 岁）进行了 94 个选定基因的基因筛查。
共在 30 名儿童中检测到 68 种杂合 3-5 级变异，每名患者 2.3 种变异。在基因筛查后，对部分患者进行了定向特异性功能检测。根据 ACMG 指南，功能检测结果、家族史和先前的出版物将三种变异归类为可能的致病变异（4 级），两种变异归类为致病变异（5 级），均在伴有血小板减少的儿童中发现。总的诊断率为 16.7%（5/30）。伴有血小板减少的儿童有显著遗传发现的比例明显更高，5/9（55.6%）比 0/21（0%）（P=0.0009）。
我们得出的结论是，对儿童进行基因筛查是一种有效的手段，尤其是对遗传性血小板减少症的儿童，它有可能在生命早期充分诊断血小板疾病。有出血倾向、正常凝血检查且无血小板减少的儿童不太可能通过基因筛查来诊断。偶然发现、与癌症相关的变异以及将遗传结果解释为临床实践等伦理问题仍然存在问题。
