Systematic analysis of copy number variants of uncertain significance partially overlapping with the haploinsufficient or triplosensitive genes in clinical testing

<b>Background:</b> Copy number variants of uncertain significance (VUS) has brought much distress for patients and great counselling challenges for clinicians. Of these, a special type of VUS (HT-VUS), harbouring one or both breakpoints within the established haploinsufficient or triplosensitive genes, were considered to be more likely to cause clinical effects compared with other types of VUS. <b>Methods:</b> We retrospectively evaluated the properties and clinical significance of those HT-VUS samples in clinical testing for chromosome microarray analysis (CMA). <b>Results:</b> A total of 7150 samples were selected for HT-VUS screening, and 75 (1.05%) subjects with 75 HT-VUS were found. The majority of these HT-VUS were heterozygous duplications and chromosome X had the most HT-VUS. The prevalence of HT-VUS was 0.90% (28/3116) for prenatal low-risk samples, 1.18% (26/2196) for prenatal high-risk samples, 1.37% (10/728) for postnatal samples and 0.99% (11/1110) for early pregnancy loss samples. However, the incidence of HT-VUS was not statistically different between different groups. <b>Conclusions:</b> HT-VUS (deletions or duplications) involving introns and HT-VUS (duplications) including terminal coding exons (either the first or last exons) might be clinically neutral. Our study will be helpful for both interpretation and genetic counselling in the future. This study assessed the clinical impact and features of a special type of copy number variants of uncertain significance (HT-VUS) in samples from CMA retrospectively. Out of 7150 samples screened, 75 (1.05%) subjects had HT-VUS. Most HT-VUS were heterozygous duplications and chromosome X had the highest frequency of HT-VUS. HT-VUS (deletions or duplications) involving introns and HT-VUS (duplications) including terminal coding exons might be clinically neutral. This study would be helpful for future interpretation and genetic counselling.