Potentially relevant variants of unknown significance in NGS-tested patients with suspected skeletal dysplasia

Abstract

ACMG recognizes five different categories of sequence variants identified by next generation sequencing (pathogenic, likely pathogenic, variants of unknown significance, likely benign and benign). Sometimes, potentially relevant gene variants could be categorized as variants of unknown significance according to the level of available evidences. Because of that, detailed assessment of the phenotype-genotype correlation by the clinical geneticist in each individual case is crucially important. The interpretation and classification of a variant may change over time. Variant reinterpretation is defined as the practice of reevaluating all the evidence available about the pathogenicity of a genetic variant and taking into account any new evidence that is made available since the previous interpretation. For the last seven years, we had 168 patients with clinically suspected locus heterogeneous skeletal dysplasia. Next generation sequencing (NGS) using clinical exome sequencing or whole exome sequencing was performed for all. All patients underwent detailed phenotype-genotype correlation investigation. Molecular diagnosis by determining the pathogenic or likely pathogenic causative gene variant(s) was established for 102 out of 168 patients (60.71%). Additionally, in 10 patients (5.95%) variant of unknown significance (VUS) with good phenotype-genotype correlation was identified. These VUS variants could be potentially, and possibly are, causal, although there are no reliable evidences of their pathogenicity at the moment. In one of the positive patients in our study, the variant was initially classified as VUS, but with new evidence it was reclassified as likely pathogenic. In the present study, a potentially relevant variant of unknown significance was detected in 5.95% of patients, which is a non-negligible proportion. For all these patients, we have organized clinical follow-up with periodic reinterpretation and reclassification of the detected variants.