ClinGen framework reveals recurrent CNV burden in diagnostic microarray series

A retrospective analysis of constitutional chromosomal microarray testing found that recurrent copy-number variants accounted for nearly one-quarter of all pathogenic or likely pathogenic non-aneuploid findings at a single Turkish medical genetics center. Investigators at Trakya University reviewed 1,661 postnatal probands tested from 2014 onward and 401 prenatal samples tested from 2016 onward, excluding aneuploid cases. Applying strict, interval-matched criteria based on the Clinical Genome Resource Dosage Sensitivity Map, they detected recurrent CNVs in 5.54% of postnatal probands and 4.24% of prenatal samples, but found that only 71.74% and 41.18%, respectively, of recurrent-CNV carriers had variants classified as pathogenic or likely pathogenic.

The study used array comparative genomic hybridization and SNP-array records generated with two platforms over the study period. All software calls were manually reviewed, and potential findings were retained when they were at least 100 kilobases, involved at least 20 consecutive probes, or overlapped a known disease-associated gene or recurrent region. The researchers then re-curated all records against a single April 28, 2026 ClinGen release and converted earlier GRCh37 coordinates to GRCh38. This approach was designed to avoid counting partial overlaps, terminal abnormalities, complex rearrangements or unusually sized events as canonical recurrent CNVs merely because they touched a recognized locus.

To assign a recurrent region, investigators required agreement between the array-defined breakpoints and the flanking low-copy repeat blocks, together with a size compatible with the canonical interval. Minor endpoint differences were accepted when they were consistent with the same established region, but a percentage-overlap threshold was not used. Classification was a separate step: deletions were evaluated against region-specific haploinsufficiency evidence and duplications against triplosensitivity evidence under the 2019 ACMG/ClinGen standards. This distinction was central to the results, because recurrence describes how a copy-number change arises, whereas pathogenicity depends on its exact region, dosage direction and supporting evidence.

Overall, a pathogenic or likely pathogenic copy-number finding was identified in 278 of 1,661 postnatal probands, or 16.74%, and in 28 of 401 prenatal samples, or 6.98%. The study identified 109 recurrent-CNV carriers, including one postnatal proband with two independent recurrent events. Among the 92 postnatal carriers, 66 had pathogenic or likely pathogenic recurrent CNVs, representing 23.74% of all postnatal pathogenic copy-number findings. Seven of 17 prenatal carriers had pathogenic recurrent CNVs, accounting for 25.00% of prenatal pathogenic findings. The remaining recurrent events were classified as variants of uncertain significance or benign rather than being treated as diagnostically equivalent to pathogenic events.

The regional distribution varied between the two clinical settings. Proximal 22q11.21 deletions, associated with DiGeorge or velocardiofacial syndrome, and proximal 16p11.2 CNVs were the most frequent postnatal findings. Other recurrent entities included Xp22.31, proximal 7q11.23, 17q12 and 15q11.2–q13.1. Deletions predominated after birth, accounting for 64 of 93 postnatal recurrent-CNV events, or 68.82%. By contrast, duplications accounted for 11 of 17 prenatal events, or 64.71%. The prenatal pathogenic fraction was correspondingly lower, underscoring that the dosage direction of a recurrent CNV cannot be inferred from the region label alone.

Test purpose strongly influenced the observed yield among postnatal probands. Pathogenic recurrent CNVs were found in six of 19 cases tested because a specific recurrent-CNV syndrome was suspected, a yield of 31.58%, although this small subgroup had a wide 95% confidence interval of 15.36% to 53.99%. Among 1,589 phenotype-driven diagnostic tests without prior suspicion of a particular recurrent syndrome, 58 carried a pathogenic recurrent CNV, giving a yield of 3.65%. The targeted group produced the higher proportion, but phenotype-driven testing contributed 58 of the 66 postnatal pathogenic recurrent-CNV carriers. Neurodevelopmental and neurological referrals were the largest postnatal referral category and accounted for 38 of those 66 carriers.

Most fetal samples were referred because of an ultrasound abnormality, which was the primary indication in 348 of 401 cases, or 86.78%. Within this subgroup, 12 fetuses carried a recurrent CNV and six carried a pathogenic recurrent CNV, corresponding to 3.45% and 1.72%, respectively. The investigators described several concordant examples, including a 22q11.2 deletion with conotruncal and nuchal findings, a distal 1q21.1 deletion with left-sided cardiac hypoplasia and a 17q12/HNF1B deletion associated with a renal phenotype. They also reported discordant findings, such as a proximal 16p11.2 deletion in a fetus with myelomeningocele and Chiari II malformation, emphasizing that a pathogenic classification does not by itself establish that a CNV explains an ultrasound phenotype.

Inheritance added another layer to interpretation. Among 46 recurrent-CNV carriers for whom parental information was available, only one transmitting parent had a documented clinical diagnosis; the remaining information came from referral records rather than systematic parental examination. All 11 prenatal transmitting parents were recorded as clinically unaffected. In the prenatal cohort, five of six de novo findings were pathogenic, compared with two of 11 inherited findings, while nine inherited events were variants of uncertain significance or benign. These numbers were small and descriptive, but they illustrate the difficulty of predicting fetal outcomes from recurrence and inheritance alone, particularly for low-penetrance duplications and other regions with variable expressivity.

The authors said the results support region- and dosage-specific reporting of recurrent CNVs, with ClinGen reference coordinates, copy-number direction, ACMG/ClinGen classification, inheritance and phenotype concordance considered separately. This would help distinguish adjacent but clinically different intervals, such as proximal and distal 16p11.2 or the several recurrent regions around 22q11.21. The analysis was limited by its retrospective single-center design, unequal cohort sizes and periods, referral-based ascertainment, small subgroups and wide confidence intervals. It also excluded non-recurrent pathogenic CNVs, used two array platforms with different resolutions and reporting thresholds, and lacked systematic follow-up of pregnancy and postnatal outcomes. Consequently, its frequencies describe a clinical microarray referral population rather than population prevalence, and the authors did not estimate penetrance from the cohort.

Subject of Research: ClinGen-based classification of recurrent copy-number variants in prenatal and postnatal chromosomal microarray testing

Article Title: Recurrent CNVs in constitutional CMA: a ClinGen-anchored single-center postnatal and prenatal experience

Article References: Satkın, N. B., Atlı, E., Yalcintepe, S., Çelik, K. M., & Gürkan, H. (2026). Recurrent CNVs in constitutional CMA: a ClinGen-anchored single-center postnatal and prenatal experience. Frontiers in Genetics, 17, Article 1960791. https://doi.org/10.3389/fgene.2026.1960791

Image Credits: AI Generated

DOI: 10.3389/fgene.2026.1960791

Keywords: recurrent copy-number variants, chromosomal microarray, ClinGen, ACMG classification, prenatal diagnosis, postnatal diagnosis, dosage sensitivity, non-allelic homologous recombination, cytogenomics, Recurrent, CNVs, constitutional