Rapid exome sequencing and adjunct RNA studies confirm the pathogenicity of a novel homozygous ASNS splicing variant in a critically ill neonate
| Autor: | Fathimath Faiz, Kenneth Tan, Ilias Goranitis, Amanda Springer, Crystle Lee, Emma I. Krzesinski, Andrew Fennell, David S. Francis, Zornitza Stark, Sandra T. Cooper, Matthew F. Hunter, Katherine Rose, Sebastian Lunke, Mark R. Davis, Lauren S. Akesson, John Christodoulou, Adam Bournazos |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Proband Critical Illness RNA Splicing Biology 03 medical and health sciences Exon Intensive care Exome Sequencing Genetics Humans Amino Acid Sequence Genetics (clinical) Exome sequencing 030304 developmental biology 0303 health sciences business.industry 030305 genetics & heredity Infant Newborn RNA Aspartate-Ammonia Ligase Exons Pedigree RNA splicing Female Human genome Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor RNA Splice Sites Personalized medicine business |
| Zdroj: | Human Mutation. 41:1884-1891 |
| ISSN: | 1098-1004 1059-7794 |
| DOI: | 10.1002/humu.24101 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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