Aug 2026· OSMANGAZİ JOURNAL OF MEDICINE· 0 citations· 21 references
TL;DR
The findings highlight the importance of detailed phenotyping, breakpoint analysis, and segregation studies in interpreting CNVs, particularly VUS and rare intragenic disruptions.
Abstract
Chromosomal microarray analysis (CMA) is a first-tier diagnostic tool for children with neurodevelopmental disorders and congenital anomalies; however, interpretation of variants of uncertain significance (VUS) remains challenging. This study aimed to characterize the copy number variant (CNV) spectrum in pediatric patients with congenital anomalies and/or dysmorphic features, focusing on VUS interpretation through segregation analysis and detailed phenotype–genotype correlation. We retrospectively evaluated 28 pediatric patients with abnormal CMA results referred to two tertiary genetics clinics between 2021 and 2022. Indications included neurodevelopmental delay, intellectual disability, dysmorphism, and/or congenital anomalies. CNVs were classified according to 2020 ACMG/ClinGen standards. Parental segregation analysis was performed for 15 CNVs in 13 families, with particular attention to gene disruption caused by CNV breakpoints. The cohort included 16 males and 12 females, with a mean age of 5.28±4.39 years. Thirty-four CNVs were identified, including 14 deletions and 20 duplications; seven were pathogenic/likely pathogenic and 27 were VUS. Segregation analysis identified five de novo, six maternal, and four paternal variants. A 2q22.2 gain disrupting KYNU at intron 12 was identified in a patient with VACTERL-like features. Three patients had additional karyotypic abnormalities, highlighting the complementary role of CMA. A de novo 4p16.3 duplication disrupting both HTT and ADD1 was also identified. Our findings highlight the importance of detailed phenotyping, breakpoint analysis, and segregation studies in interpreting CNVs, particularly VUS and rare intragenic disruptions. Integrating genomic findings with clinical features and inheritance patterns may improve phenotype–genotype correlation and support the identification of candidate loci.
This study provides the first systematic, mutational-level characterization of a Cypriot Mendelian disease cohort, establishing a local baseline diagnostic yield and revealing a high proportion of novel variants that reflect the underrepresentation of Eastern Mediterranean populations in global databases.
A. Theodosiou, L. Kousoulidou, Ioannis Papaevripidou et al.· Genes· 0 citations
Background/Objectives: Chromosomal microarray analysis (CMA) is widely used in the genetic evaluation of autism spectrum disorder (ASD), yet its diagnostic contribution in clinically nonsyndromic ASD, particularly in Brazilian populations, remains insufficiently characterized. This study aimed to determine the diagnostic yield of CMA and characterize clinically relevant copy number variants (CNVs) in a cohort of individuals with clinically nonsyndromic ASD from southern Brazil. Methods: In this observational cohort study, 215 individuals with clinically diagnosed ASD underwent high-resolution CMA using the Agilent CGH + SNP Array 180K platform. Individuals with dysmorphic features, known or suspected genetic syndromes, major congenital malformations, epilepsy, or macrocephaly/microcephaly were excluded. CNVs were classified according to American College of Medical Genetics and Genomics guidelines, and the diagnostic yield was compared with that of national and international reference cohorts using Fisher’s exact test. Results: Pathogenic or likely pathogenic CNVs were identified in six individuals, corresponding to a diagnostic yield of 2.8% (95% CI, 1.3–6.1%). These included deletions at 2q11.1–q11.2, 2p16.3 (NRXN1), 15q11.2 (BP1–BP2), and 3q29, and duplications at 16p11.2 and 6p22.3–p22.2. Although the diagnostic yield was lower than that reported in phenotypically heterogeneous ASD cohorts, it did not differ significantly from yields observed in comparably selected nonsyndromic subgroups. Conclusions: CMA identified clinically relevant recurrent CNVs at neurodevelopmental loci even in a clinically nonsyndromic ASD cohort. The comparatively low diagnostic yield highlights the substantial influence of clinical and phenotypic selection on the diagnostic contribution of CMA.
Willian de Souza Santos, B. C. de Figueiredo, R. G. Mello et al.· Diagnostics· 0 citations
Ongoing need for chromosome microarray analysis (CMA) characterization prompted the description of all 16,138 copy number variants (CNVs) found in 3832 patients studied from 2009 to 2024, 92% of them with developmental disabilities and/or autism. Detailed reporting shows the overlap of variants qualified as benign (15,083 CNVs, sizes 0.1 Kb–3 Mb) or of uncertain significance (216 CNVs, sizes 11 Kb–20 Mb) with pathogenic CNVs (836, 11 Kb–31 Mb), which are emphasized in most studies. Further distinguishing pathogenic CNVs were 88 recurring microdeletion/duplications and 86 in single patients, with all of the former and 66 of the latter having previous syndrome associations. Diagnoses were provided in 749 (20% of) patients, increasing to 21% among the 2470 patients (2015–2024) with their karyotypes recorded. Diagnoses included 61 known chromosomal syndromes, with CMA confirming or clarifying the abnormal karyotype in 187 (7.6%) or 55 (2.2%). The 90 microdeletions averaged 6439 kb in length (with chromosomes 6, 8, 17, and 22 accounting for most cases), while the 90 microduplications averaged 6895 kb (with chromosomes 8, 14, 17, 22, and X accounting for most cases). Together, these represent an average imbalance of 798,000 nucleotides per patient (0.75% of their genome). Continued reporting that match detailed CNV findings with patient profiles, especially symptom spectra, is needed to optimize CMA potential for presymptomatic diagnosis and therapy.
Santosh Chaval, Sahil S. Tonk, Golder N. Wilson et al.· Current Issues in Molecular...· 0 citations
Increased CNV burden, in both number and cumulative genomic size, co-occurred more frequently in individuals with severe phenotypes, including ASD with intellectual disability, epilepsy, and broader NDDs, reflecting a real-world clinical setting rather than a prospectively recruited research cohort.
M. R. Di Iorio, Ilaria La Monica, Antonio Imperatore et al.· International Journal of Mol...· 0 citations
This study aimed to investigate the relationship between fetal congenital heart disease (CHD) phenotypes and genetic abnormalities and to evaluate the use of stepwise genetic testing [karyotyping, chromosomal microarray analysis (CMA), and whole-exome sequencing (WES)] for prenatal diagnosis and outcome prediction.
This retrospective study included 1,354 CHD fetuses undergoing karyotyping and CMA; cases with negative results underwent WES. CHD was classified by type, complexity, and extracardiac anomalies. Phenotype-outcome associations were analyzed.
Among 1,354 fetuses, karyotyping and CMA detected pathogenic abnormalities in 11.5% (156/1.354); WES identified 16 pathogenic/likely pathogenic (P/LP) (12.2%) and 2 variant of uncertain significance (VOUS) (1.5%) variants among the 131 cases negative on karyotyping and CMA. The highest detection rates occurred in conotruncal anomalies (25.0%) and atrioventricular septal defects (45.5%). Rates were higher in non-isolated versus isolated CHD (p < 0.001) and complex versus simple CHD (p < 0.05). Pathogenic abnormalities were associated with lower live birth rates (p < 0.001), largely attributed to pregnancy termination.
Fetal CHD is strongly associated with genetic abnormalities, which can be effectively detected via stepwise testing (karyotyping, CMA, and WES) and are linked to adverse outcomes. Ultrasound findings suggest that genetic risk varies by CHD type, complexity, and extracardiac anomalies. Integrating detailed phenotypes may inform more precise prenatal genetic risk stratification, though prospective validation is needed to establish clinical utility.
Qing-Cheng Chen, Longzhuang Peng, Youchun Cai et al.· Frontiers in Medicine· 0 citations
ABSTRACT Background Prenatal alcohol exposure (PAE) can result in fetal alcohol spectrum disorder (FASD), a permanent, heterogeneous condition characterized by severe neurodevelopmental impairments with or without microcephaly, characteristic facial dysmorphology, and congenital anomalies. Clinical and pre‐clinical studies suggest that genetic factors, in the mother or fetus, influence the phenotypic outcomes following PAE. The objectives of this study were to evaluate the prevalence and types of DNA copy number variants (CNVs) in children (0–18 years) diagnosed with FASD and to identify genes known to be associated with neurodevelopmental disorders. Methods Chromosomal microarray (CMA) was performed in children diagnosed with FASD in the NSW CICADA FASD Service—a state‐wide multidisciplinary diagnostic clinic in Australia. We performed a retrospective chart review of 175 patients diagnosed with FASD between 2015 and 2022 to obtain data on medical and family history, phenotype, and genotype. All CMA results were reviewed by a clinical geneticist. Results A rare CNV was identified in 38 of 157 (24.2%) patients who had CMA testing and 40 unique CNVs were identified. In four patients, a neurodevelopmental susceptibility syndrome was identified including Xq28 microduplication syndrome, 16p12.2 microdeletion syndrome, 17q11.2 microduplication syndrome, and an atypical variant of 22q11.2 deletion syndrome. Two children had incidental pathogenic variants. In 32 of 38 (84.2%) cases with a rare CNV, 34 variants of unknown significance (VOUS) were identified, of which 13 encoded a total of 14 genes associated with common neurodevelopmental disorders. Three variants of uncertain significance (VOUS) encoded different subunits of the voltage‐dependent calcium channel complex protein (CACNB2, CACNA1A, CACNA2D3). Conclusion These novel results suggest that approximately one in four children diagnosed with FASD may harbor a rare CNV, of which 85.0% are currently of uncertain clinical significance. Genetic testing can support the FASD diagnostic process and may reveal additional diagnoses or sources of genetic vulnerability to FASD.
Suzy Byrnes, F. Collins, E. Elliott· Alcohol, clinical & experime...· 0 citations
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