A Novel Splice Variant (c.438T&gt;A) of <i>APC</i>, Suspected by Family History and Confirmed by RNA Sequencing

Lee, Heerah; Kim, Hyunki; Yang, Suk-Kyun; Hong, Yong Sang; Lee, Woochang; Lim, Seok‐Byung; Byeon, Jeong‐Sik; Chun, Sail; Min, Won‐Ki

doi:10.3343/alm.2021.41.1.123

Cited by 1 publication

(1 citation statement)

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“…Tumor suppressor genes are the most widely sequenced genes in the clinical environment and are appropriate targets for RNA sequence analysis because of their loss-of-function disease mechanisms and blood expression ( Landrith et al, 2020 ; Lee et al, 2021 ; Gu et al, 2022 ; Na et al, 2022 ). In addition, the widespread adoption of state-of-the-art in silico tools for aberrant splicing prediction, such as SpliceAI ( Jaganathan et al, 2019 ), has increased the need to confirm the consequences of pre-mRNA splicing.…”

Section: Introductionmentioning

confidence: 99%

Reclassification of variants of tumor suppressor genes based on Sanger RNA sequencing without NMD inhibition

Ha,

Jang,

Kim

et al. 2023

Front. Genet.

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Introduction: RNA sequence analysis can be effectively used to identify aberrant splicing, and tumor suppressor genes are adequate targets considering their loss-of-function mechanisms. Sanger sequencing is the simplest method for RNA sequence analysis; however, because of its insufficient sensitivity in cases with nonsense-mediated mRNA decay (NMD), the use of cultured specimens with NMD inhibition has been recommended, hindering its wide adoption.Method: The results of Sanger sequencing of peripheral blood RNA without NMD inhibition performed on potential splicing variants of tumor suppressor genes were retrospectively reviewed. For negative cases, in which no change was identified in the transcript, the possibility of false negativity caused by NMD was assessed through a review of the up-to-date literature.Results: Eleven potential splice variants of various tumor suppressor genes were reviewed. Six variants were classified as pathogenic or likely pathogenic based on the nullifying effect identified by Sanger RNA sequencing. Four variants remained as variants of uncertain significance because of identified in-frame changes or normal expression of both alleles. The result of one variant was suspected to be a false negative caused by NMD after reviewing a recent study that reported the same variant as causing a nullifying effect on the affected transcript.Conclusion: Although RNA changes found in the majority of cases were expected to undergo NMD by canonical rules, most cases (10/11) were interpretable by Sanger RNA sequencing without NMD inhibition due to incomplete NMD efficiency or allele-specific expression despite highly efficient NMD.

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