RNA Analysis Enables Resolution and Reclassification of Reportedly Benign Synonymous Variants.

IF 2.3 3区 医学 Q2 GENETICS & HEREDITY
Adina Fuchs, Inbar Kobal, Dov Popper, Shay Porat, Joshua I Rosenbloom, Mordechai Slae, Shira Yanovsky Dagan, Vardiella Meiner, Vered Molho-Pessach, Hagit Daum, Tamar Harel
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引用次数: 0

Abstract

Synonymous variants can significantly impact protein levels and function, particularly through alterations in RNA processing. Consequently, variant classification must consider the broader impact on RNA splicing. We present three cases where synonymous variants were detected through exome sequencing. The variants in LARS1 and POLE were located at the last nucleotide of the exon (i.e., splice donor site), while the COL2A1 variant was located three nucleotides downstream of the splice acceptor site. Two variants were previously classified in ClinVar as "likely benign." Segregation analysis confirmed segregation of the variants with the phenotype in available family members, and RNA studies revealed exon skipping in conserved regions of the protein, leading to reclassification of these variants as "likely pathogenic" and ultimately improving clinical management. These findings highlight the importance of incorporating RNA-based testing to directly evaluate splicing effects and demonstrate the critical role of RNA analysis in the accurate interpretation of variants and their implications for diagnosis and treatment.

RNA分析使报告良性同义变异的决议和重新分类。
同义变异可以显著影响蛋白质水平和功能,特别是通过改变RNA加工。因此,变异分类必须考虑对RNA剪接的广泛影响。我们提出了三个同义变体通过外显子组测序检测到的情况。LARS1和POLE的变体位于外显子的最后一个核苷酸(即剪接供体位点),而COL2A1的变体位于剪接受体位点下游三个核苷酸。ClinVar先前将两种变体归类为“可能良性的”。分离分析证实了在可用的家族成员中具有表型的变体的分离,RNA研究揭示了蛋白质保守区域的外显子跳变,导致这些变体被重新分类为“可能致病”,并最终改善临床管理。这些发现强调了结合基于RNA的测试来直接评估剪接效应的重要性,并证明了RNA分析在准确解释变异及其对诊断和治疗的影响中的关键作用。
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来源期刊
Clinical Genetics
Clinical Genetics 医学-遗传学
CiteScore
6.50
自引率
0.00%
发文量
175
审稿时长
3-8 weeks
期刊介绍: Clinical Genetics links research to the clinic, translating advances in our understanding of the molecular basis of genetic disease for the practising clinical geneticist. The journal publishes high quality research papers, short reports, reviews and mini-reviews that connect medical genetics research with clinical practice. Topics of particular interest are: • Linking genetic variations to disease • Genome rearrangements and disease • Epigenetics and disease • The translation of genotype to phenotype • Genetics of complex disease • Management/intervention of genetic diseases • Novel therapies for genetic diseases • Developmental biology, as it relates to clinical genetics • Social science research on the psychological and behavioural aspects of living with or being at risk of genetic disease
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