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Rapid exome sequencing and adjunct RNA studies confirm the pathogenicity of a novel homozygous ASNS splicing variant in a critically ill neonate
Author(s) -
Akesson Lauren S.,
Bournazos Adam,
Fennell Andrew,
Krzesinski Emma I.,
Tan Kenneth,
Springer Amanda,
Rose Katherine,
Goranitis Ilias,
Francis David,
Lee Crystle,
Faiz Fathimath,
Davis Mark R.,
Christodoulou John,
Lunke Sebastian,
Stark Zornitza,
Hunter Matthew F.,
Cooper Sandra T.
Publication year - 2020
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24101
Subject(s) - rna splicing , biology , exome sequencing , exon , genetics , exome , proband , splice site mutation , splice , alternative splicing , bioinformatics , rna , mutation , gene
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.