Clinical application of CNV-seq for diagnosing abnormal brain development in children

The current study evaluates the diagnostic utility of copy number variation sequencing (CNV-Seq) in elucidating the genetic etiology of abnormal brain development (ABD) in pediatric patients. We analyzed 130 children diagnosed with ABD at Gansu Maternity and Child-care Hospital between December 2018 and October 2023. Patients were categorized into non-syndromic (NS-ABD) and syndromic (S-ABD) groups, and CNV-Seq was performed to identify chromosomal aneuploidies and copy number variations (CNVs). Of the 130 cases, 42 (32.3%) exhibited genetic abnormalities, comprising 3 aneuploidies (2.3%; 2 trisomy 21, 1 trisomy 18) and 39 CNVs (30%). In the NS-ABD group (n = 15), abnormalities included 1 aneuploidy (6.7%), 4 pathogenic CNVs (pCNVs; 26.7%), and 10 variants of uncertain significance (VUS; 66.7%). The S-ABD group (n = 27) showed 2 aneuploidies (7.4%), 19 pCNVs (70.4%), and 6 VUS (22.2%). Chi-square analysis confirmed a significantly higher pCNV detection rate in the S-ABD group compared to the NS-ABD group (χ² = 40.03, P < 0.001). CNV-Seq demonstrates a high diagnostic yield for ABD, particularly in S-ABD patients, where the detection rate of pCNVs is significantly elevated. NS-ABD patients, with subtler clinical phenotypes and lower positive detection rates, are at risk of underdiagnosis in clinical practice. Increased attention to NS-ABD cases, alongside timely prenatal diagnosis and genetic counseling, is essential to improve clinical outcomes.