Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
Department of Paediatrics, University of Melbourne, Melbourne, Australia.
Hum Mutat. 2020 Nov;41(11):1884-1891. doi: 10.1002/humu.24101. Epub 2020 Sep 9.
Rapid genomic diagnosis programs are transforming rare disease diagnosis in acute pediatrics. A ventilated newborn with cerebellar hypoplasia underwent rapid exome sequencing (75 h), identifying a novel homozygous ASNS splice-site variant (NM_133436.3:c.1476+1G>A) of uncertain significance. Rapid ASNS splicing studies using blood-derived messenger RNA from the family trio confirmed a consistent pattern of abnormal splicing induced by the variant (cryptic 5' splice-site or exon 12 skipping) with absence of normal ASNS splicing in the proband. Splicing studies reported within 10 days led to reclassification of c.1476+1G>A as pathogenic at age 27 days. Intensive care was redirected toward palliation. Cost analyses for the neonate and his undiagnosed, similarly affected deceased sibling, demonstrate that early diagnosis reduced hospitalization costs by AU$100,828. We highlight the diagnostic benefits of adjunct RNA testing to confirm the pathogenicity of splicing variants identified via rapid genomic testing pipelines for precision and preventative medicine.
快速基因组诊断方案正在改变急性儿科中的罕见病诊断。一名接受通气的小脑发育不全的新生儿进行了快速外显子组测序（75 小时），发现一种新的杂合 ASNS 剪接位点变异（NM_133436.3：c.1476+1G>A），其意义不明。使用来自家族三人的血液衍生信使 RNA 进行快速 ASNS 剪接研究，证实了该变体诱导的一致异常剪接模式（隐蔽 5'剪接位点或外显子 12 跳跃），而先证者中不存在正常的 ASNS 剪接。在 10 天内报告的剪接研究导致 c.1476+1G>A 在 27 天大时被重新归类为致病性。将重症监护的重点转向姑息治疗。对新生儿及其未确诊、同样受影响的已故兄弟姐妹的成本分析表明，早期诊断可将住院费用降低 100,828 澳元。我们强调了辅助 RNA 测试的诊断益处，以确认通过快速基因组测试管道识别的剪接变异的致病性，以实现精准和预防医学。
