West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.
West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.
Eur J Med Genet. 2022 Sep;65(9):104571. doi: 10.1016/j.ejmg.2022.104571. Epub 2022 Jul 14.
Genetic disorders are a significant cause of paediatric morbidity and mortality. Rapid exome sequencing was introduced by the National Health Service (NHS) in England on 1 October 2019 for acutely unwell children with a likely monogenic disorder, or to inform current pregnancy management where there was a previously affected child or fetus. We present results of a 12-month patient cohort from one large clinical genetics centre in England.
Patients were identified through local genetics laboratory records. We included all cases which underwent rapid exome sequencing between 1 October 2020 and 30 September 2021. DNA was extracted, quality checked and exported to the Exeter Genomic laboratory where library preparation, exome sequencing of all known human genes, gene-agnostic bioinformatic analysis, variant interpretation, MDT discussions and reporting were performed.
Ninety-five probands were included. Trio analysis was performed in 90% (85), duo in 8% (8), singleton in 2% (2). The median turnaround time for preliminary reports was 11 days. The overall diagnostic yield was 40% (38 patients); 36% (34 patients) made solely on exome with a further 4% on concomitant exome and microarray analysis. Highest diagnostic rates were seen in patients with neuro-regression, skeletal dysplasia, neuromuscular and neurometabolic conditions. Where the diagnosis was made solely through exome sequencing, management was altered for the proband or family in 97% (33/34). For the proband, this was most commonly that the diagnosis was able to inform current management and prognosis (20 patients, 59%), as well as direct specialist referrals (10 patients, 29%). For families, the exome sequencing results provided accurate recurrence risk counselling in 88% (30/34) with cascade testing offered if indicated in some families.
In the majority of cases, the genetic diagnoses influenced acute and long-term management for critically ill children and their families. Paediatric and neonatal clinicians in the NHS now have direct access to exome sequencing for their patients. The rapid turnaround time was particularly helpful to alter the management in acute clinical settings and is a powerful tool for diagnosing monogenic conditions. This study is an example of a highly successful integration of a national rapid exome sequencing service with diagnostic rates comparable to previously reported literature.
遗传疾病是导致儿科发病率和死亡率的重要原因。英国国民保健制度（NHS）于 2019 年 10 月 1 日推出了快速外显子组测序，用于治疗患有可能为单基因疾病的急性不适儿童，或在先前有受影响儿童或胎儿的情况下为当前妊娠管理提供信息。我们报告了英国一个大型临床遗传学中心的 12 个月患者队列的结果。
通过当地遗传实验室记录确定患者。我们纳入了 2020 年 10 月 1 日至 2021 年 9 月 30 日期间进行快速外显子组测序的所有病例。提取 DNA，进行质量检查并输出到埃克塞特基因组学实验室，在那里进行文库制备、所有已知人类基因的外显子测序、无基因的生物信息学分析、变体解释、MDT 讨论和报告。
95 名先证者被纳入研究。90%（85 例）进行了三核苷酸分析，8%（8 例）进行了二核苷酸分析，2%（2 例）进行了单核苷酸分析。初步报告的中位周转时间为 11 天。总体诊断率为 40%（38 例）；36%（34 例）仅通过外显子组测序获得，另有 4%通过外显子组和微阵列分析获得。在神经发育迟缓、骨骼发育不良、神经肌肉和神经代谢疾病患者中，诊断率最高。仅通过外显子组测序获得的诊断，97%（33/34）改变了先证者或家族的治疗方案。对于先证者，这通常是因为诊断能够为当前的管理和预后提供信息（20 例，59%），以及直接进行专科转诊（10 例，29%）。对于家族，外显子组测序结果在 88%（30/34）的情况下提供了准确的复发风险咨询，如果需要，一些家族还提供了级联检测。
在大多数情况下，基因诊断影响了重症儿童及其家庭的急性和长期管理。英国国民保健制度的儿科和新生儿临床医生现在可以直接为他们的患者提供外显子组测序。快速的周转时间特别有助于改变急性临床环境中的治疗方案，是诊断单基因疾病的有力工具。本研究是一个成功整合全国快速外显子组测序服务的例子，其诊断率与以前报道的文献相当。
