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

Abstract

Background Array-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. Methods This 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. Results Of 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. Conclusions This 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.

Reclassification of Variants Following Renal Genetics Testing: Uncommon Yet Impactful for Diagnosis and Management

“…The impact of variant reclassifications on individual and familial medical management, risk counseling, and screening has been supported by studies in cancer genetics, 24 cardio-genetics, 14 and neurogenetics. 37 This study fills a gap in knowledge regarding the impact of variant reclassification in renal genetics and underscores the importance of periodic follow-up with patients who have undergone renal genetics testing to ensure that any variant reclassification, if it occurs, is appropriately communicated to patients and their families. Furthermore, this study supports the need for renal genetics societies to educate clinicians in general nephrology practice about the potential for variant reclassification and the necessary skills for managing and counseling patients with such amended reports.…”

Genetic Alterations in a Large Population of Italian Patients Affected by Neurodevelopmental Disorders

“…The considerable percentage of familial cases associated with a high concordance rate in monozygotic twins sustains a genetic basis of these disorders [66]. On the other hand, the functional significance of CNVs affecting individual genes and/or genomic regions is still notably incomplete, making diagnostic processes and genetic counselling difficult [67]. Consequently, the discovery of significant genes that can be considered causative or associated with neurodevelopmental disorders represents a necessary step in the diagnostic procedure, for a better understanding the pathophysiology of NDDs [68,69].…”

Exome sequencing improves the molecular diagnostics of paediatric unexplained neurodevelopmental disorders

“…The current guidelines for the genetic evaluation of individuals with NDDs and MCAs still recommend the chromosomal microarray analysis (CMA) as the first-tier molecular diagnostic test which overcomes the traditional karyotyping using G-banding [ 2 , 3 ]. However, other diagnostic test as fragile X testing or metabolic tests may be conclusive in those cases with suggestive and prominent clinical symptoms [ 4 ].…”