Title |
Rapid exome sequencing and adjunct RNA studies confirm the pathogenicity of a novel homozygous ASNS splicing variant in a critically ill neonate
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Published in |
Human Mutation, September 2020
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DOI | 10.1002/humu.24101 |
Pubmed ID | |
Authors |
Lauren S. Akesson, Adam Bournazos, Andrew Fennell, Emma I. Krzesinski, Kenneth Tan, Amanda Springer, Katherine Rose, Ilias Goranitis, David Francis, Crystle Lee, Fathimath Faiz, Mark R. Davis, John Christodoulou, Sebastian Lunke, Zornitza Stark, Matthew F. Hunter, Sandra T. Cooper |
Abstract |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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Australia | 8 | 80% |
United States | 1 | 10% |
Unknown | 1 | 10% |
Demographic breakdown
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Scientists | 6 | 60% |
Members of the public | 4 | 40% |
Mendeley readers
Geographical breakdown
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Unknown | 16 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Researcher | 3 | 19% |
Student > Ph. D. Student | 2 | 13% |
Librarian | 1 | 6% |
Unspecified | 1 | 6% |
Student > Doctoral Student | 1 | 6% |
Other | 0 | 0% |
Unknown | 8 | 50% |
Readers by discipline | Count | As % |
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Unspecified | 1 | 6% |
Economics, Econometrics and Finance | 1 | 6% |
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Medicine and Dentistry | 1 | 6% |
Other | 0 | 0% |
Unknown | 9 | 56% |