Clinical utility of periodic reinterpretation of CNVs of uncertain significance: an 8-year retrospective study

Genome Medicine

Research

Émeline Renard¹  Geneviève Lefort²  Mylène Dexheimer²  Aurélie Becker²  Céline Bonnet³  Jean Muller⁴  Jean-Marie Ravel⁵  Laëtitia Lambert⁶  Bruno Leheup⁶  Mathilde Renaud⁶  Thomas Remen⁷  Philippe Jonveaux⁸ 

[1]Department of pediatrics, Regional University Hospital of Nancy, Allée du Morvan, 54511, Vandoeuvre-Lès-Nancy, France

[2]Laboratoire de génétique médicale, CHRU Nancy, Nancy, France

[3]Laboratoire de génétique médicale, CHRU Nancy, Nancy, France

[4]Université de Lorraine, F-54000Nancy, Inserm, NGERE, France

[5]Laboratoires de Diagnostic Génétique, Institut de Génétique Médicale d’Alsace (IGMA), Hôpitaux Universitaires de Strasbourg, Strasbourg, France

[6]Laboratoire de Génétique Médicale, INSERM, UMRS_1112, Institut de Génétique Médicale d’Alsace (IGMA), Université de Strasbourg Faculté de Médecine de Strasbourg, 67000, Strasbourg, France

[7]Unité Fonctionnelle de Bioinformatique Médicale Appliquée au Diagnostic (UF7363), Hôpitaux Universitaires de Strasbourg, 67000, Strasbourg, France

[8]Service de génétique médicale, CHRU de Nancy, Nancy, France

[9]Laboratoire de génétique médicale, CHRU Nancy, Nancy, France

[10]Université de Lorraine, F-54000Nancy, Inserm, NGERE, France

[11]Service de génétique médicale, CHRU de Nancy, Nancy, France

[12]Université de Lorraine, F-54000Nancy, Inserm, NGERE, France

[13]UMDS, CHRU Nancy, Nancy, France

[14]Université de Lorraine, F-54000Nancy, Inserm, NGERE, France

关键词: Array-CGH;    Copy-number variation;    CNV;    VUS reinterpretation;    ACMG criteria;   

DOI  :  10.1186/s13073-023-01191-6

 received in 2022-11-22, accepted in 2023-05-15,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundArray-CGH is the first-tier genetic test both in pre- and postnatal developmental disorders worldwide. Variants of uncertain significance (VUS) represent around 10~15% of reported copy number variants (CNVs). Even though VUS reanalysis has become usual in practice, no long-term study regarding CNV reinterpretation has been reported.MethodsThis retrospective study examined 1641 CGH arrays performed over 8 years (2010–2017) to demonstrate the contribution of periodically re-analyzing CNVs of uncertain significance. CNVs were classified using AnnotSV on the one hand and manually curated on the other hand. The classification was based on the 2020 American College of Medical Genetics (ACMG) criteria.ResultsOf the 1641 array-CGH analyzed, 259 (15.7%) showed at least one CNV initially reported as of uncertain significance. After reinterpretation, 106 of the 259 patients (40.9%) changed categories, and 12 of 259 (4.6%) had a VUS reclassified to likely pathogenic or pathogenic. Six were predisposing factors for neurodevelopmental disorder/autism spectrum disorder (ASD). CNV type (gain or loss) does not seem to impact the reclassification rate, unlike the length of the CNV: 75% of CNVs downgraded to benign or likely benign are less than 500 kb in size.ConclusionsThis study’s high rate of reinterpretation suggests that CNV interpretation has rapidly evolved since 2010, thanks to the continuous enrichment of available databases. The reinterpreted CNV explained the phenotype for ten patients, leading to optimal genetic counseling. These findings suggest that CNVs should be reinterpreted at least every 2 years.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

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Fig. 1

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