Partial trisomy of the long arm of chromosome 3 (=3q), first described in 1966 [1], is a well-defined clinical entity. The most frequent clinical manifestations include characteristic facial dysmorphism, such as microcephaly and low-set ears, malformations of the hands and feet, hirsutism, congenital heart defects, and growth and psychomotor retardation [2]. Cases with isolated duplication of 3q are rare; in most cases, 3q duplications are associated with a partial monosomy of another autosomal region, often resulting from an unbalanced parental translocation. Accordingly, approximately 70% of such cases are inherited from a balanced translocation [3]. To date, 32 cases of pure partial 3q duplications with different breakpoints along the long arm of chromosome 3 have been described in the literature [3,4,5,6,7]. Since the comprehensive review by Serra et al. [3] in 2023, no additional pure 3q duplication cases have been published. The present case therefore represents the first documented case of pure 3q duplication since that review, further contributing to the limited body of literature on this rare chromosomal abnormality.

Cases presenting with isolated 3q duplications are particularly valuable for delineating the phenotypic spectrum associated with this chromosomal imbalance. Here, we describe a 17-year-old female carrying a de novo duplication of the 3q26.33-q28 region (~10.9 Mb), identified by chromosomal microarray analysis (CMA) and subsequently confirmed by fluorescence in situ hybridization (FISH).

Conventional chromosome analysis revealed normal karyotypes in both parents (Figure 1). In contrast, karyotyping of the proband identified an abnormal chromosome 3, 46, XX, add(3)(q?), indicating the presence of additional chromosomal material of unknown origin on the long arm of chromosome 3 (Figure 2).

CMA revealed a female hybridization pattern showing a duplication on the long arm of chromosome 3, spanning genomic coordinates 179,659,847 bp to 190,604,567 bp (GRCh37), corresponding to the cytogenetic region 3q26.33-q28. This duplication was reported as arr[GRCh37] 3q26.33q28(179,659,847_190,604,567) × 3 (Figure 3).

FISH analysis confirmed the presence of the duplicated segment on the derivative chromosome 3. The derivative chromosome 3 was therefore characterized as ish dup(3)(q26.33q28)(RP11-510K16+, RP11-110C15+, RP11-95L3+, RP11-510K16+, RP11-110C15+, RP11-95L3+, D3S4560+), consistent with a tandem duplication of the 3q26.33-q28 region (Figure 4).

The duplicated region spans approximately 10.9 Mb and contains several genes involved in neurodevelopment, growth regulation, and morphogenesis. Figure 5 illustrates the duplicated genomic interval 3q26.33-q28, highlighting several OMIM morbid genes, including SOX2, IGF2BP2, and TP63, which may contribute to the patient’s neurodevelopmental impairment and dysmorphic features.

In summary, the patient carries a de novo partial trisomy 3q26.33q28, corresponding to genomic coordinates 3q26.33q28(179,659,847_190,604,567)(GRCh37).

The minimal critical genomic region associated with the characteristic phenotype of 3q duplication syndrome was initially proposed to be limited to subband 3q26.3. Subsequent studies refined this critical interval to 3q26.3-3q27, while more recent reports extended it to 3q26.3-3q29. The clinical expression of 3q duplication syndrome is highly variable and largely depends on the size and precise breakpoints of the duplicated segment.

Despite this phenotypic heterogeneity, several recurrent clinical features have been consistently reported, including facial dysmorphism, hirsutism, microcephaly, intellectual disability, growth retardation, genitourinary anomalies, hands and feet malformations, as well as renal and congenital heart defects [2,3,4,5,6,7].

When comparing our patient’s phenotype with previously reported cases of pure 3q duplications (Table 1, Figure 6), several overlapping clinical features were identified. The patient showed facial dysmorphism, including high arched eyebrows, a thin upper lip, and a flat occiput, as well as a short neck and generalized hirsutism. In addition, she exhibited severe neurodevelopmental involvement, characterized by global developmental delay, intellectual disability, and autistic features.

Notably, no congenital cardiac malformations were identified in our patient. Cardiac involvement in 3q duplication syndrome shows considerable variability, with congenital heart defects reported in approximately 46% (6/13) of cases included in an early literature review. Nearly one-third of affected individuals do not survive beyond the first year of life, with mortality largely attributed to severe cardiac malformations and recurrent infections [2].

The duplicated segment identified in our patient (3q26.33-q28; chr3:179,659,847-190,604,567, GRCh37) is more distal than the initially defined critical region (3q26.3-q27.3), yet the patient exhibits most of the characteristic features of the 3q duplication syndrome. This observation suggests that key dosage-sensitive genes contributing to the core phenotype extend beyond the originally defined critical region into the 3q27-q28 interval.

The duplicated region encompasses hundreds of protein-coding genes, of which 31 are listed in the OMIM Morbid Map (Figure 5). To assess the functional impact of increased gene dosage, we evaluated the probability of triplosensitivity (pTriplo) for each of these 31 genes using the dosage sensitivity map. Three genes exceeded the high-confidence triplosensitivity threshold of pTriplo ≥ 0.94: TP63 (pTriplo = 1.00), AP2M1 (pTriplo = 0.99), and EIF4G1 (pTriplo = 0.98). Several additional genes showed intermediate scores, including FXR1 (0.90), DVL3 (0.86), YEATS2 (0.86), IGF2BP2 (0.81), and SOX2 (0.80), suggesting a broader dosage-sensitive landscape within this region. Among these, SOX2 (3q26.33), highly expressed during embryonic and fetal brain development, plays a crucial role in maintaining neural progenitor cells and promoting neuronal differentiation [10]. The severe intellectual disability, epilepsy, and autistic features observed in our patient may therefore be partially explained by increased dosage of SOX2 and other neurodevelopmentally relevant genes within this interval. TP63 (3q28), which achieved the highest pTriplo score of 1.00, is critical for limb and ectodermal development and may contribute to the ectodermal anomalies reported in some cases of 3q duplication [11]. AP2M1 and EIF4G1, both with pTriplo scores exceeding 0.98, encode proteins involved in intracellular trafficking and translational regulation, respectively, and their triplosensitivity may further modulate the neurodevelopmental phenotype.

Our patient exhibited increased birth weight (4000 g at 38 weeks of gestation), in contrast to the growth retardation reported in approximately 61.5% of patients with pure 3q duplications [3,5,9]. The biological basis of this overgrowth phenotype remains incompletely understood. IGF2BP2 (3q27.2), a member of the insulin-like growth factor 2 mRNA-binding protein family involved in prenatal and postnatal growth regulation, has previously been proposed as a candidate gene. However, its intermediate triplosensitivity score (pTriplo = 0.81), below the high-confidence threshold of 0.94 defined by Collins et al. [12], argues against a straightforward dosage-sensitive mechanism. Furthermore, cases 25-30 from the ECARUCA database (3q27-qter), whose duplication encompasses IGF2BP2, also presented with prenatal growth retardation, further challenging the hypothesis of IGF2BP2 as the sole determinant of growth outcome. These observations suggest that the overgrowth phenotype observed in our patient reflects a complex interplay of multiple dosage-sensitive genes within the 3q26.33-q28 interval, potentially modulated by epigenetic factors or genes acting in trans.

A more informative approach to genotype-phenotype correlation emerges from comparing cases with near-identical duplication boundaries. The case reported by Pavone et al. [9], with a 3q26.32-q28 duplication, represents the closest genomic comparator to our patient (3q26.33-q28). Both cases share elevated birth weight, postnatal overgrowth, absence of congenital cardiac anomalies, generalized hirsutism, facial dysmorphism, and intellectual disability, a striking phenotypic convergence that supports a direct contribution of the 3q26.33-q28 interval to these features. Serra et al. [3], reporting a 3q27.1-q29 duplication, also described overgrowth, further supporting the association of the distal 3q27 region with growth excess in selected cases.

A more consistent genotype-phenotype correlation emerges for cardiac and genitourinary involvement. Neither our patient nor Pavone et al. presented with cardiac defects or genitourinary anomalies, whereas Serra et al. and cases 14-24 (ECARUCA, 3q25-qter), both extending beyond 3q28, exhibited cardiac defects and urogenital anomalies. This pattern suggests that genes responsible for cardiac and genitourinary involvement reside in the more distal 3q28-q29 interval, beyond our patient’s duplication boundaries. However, as cardiac findings were not reported for cases 25-30 (ECARUCA, 3q27-qter), larger cohorts with complete phenotypic characterization will be needed to confirm this correlation.

Pure 3q duplications should be distinguished from complex chromosomal rearrangements involving additional chromosomal imbalances, such as concomitant deletions of 3p [13] or mosaic deletion-duplication syndromes [14]. These complex rearrangements give rise to composite phenotypes that preclude precise genotype-phenotype attribution. In contrast, the present case represents a pure de novo 3q26.33-q28 duplication, confirmed by integrated conventional cytogenetic and molecular analyses. This finding provides valuable insight into the specific phenotypic contribution of this genomic region and further strengthens genotype-phenotype correlations for pure 3q duplication syndrome.

The presence of an isolated copy number gain involving a single chromosomal arm, in the absence of additional structural rearrangements, strongly suggests an intrachromosomal mechanism. Such duplications most likely arise through non-allelic homologous recombination (NAHR) between low-copy repeats (LCRs) or through replication-based mechanisms, including fork stalling and template switching (FoSTeS) or microhomology-mediated break-induced replication (MMBIR) [15,16]. The absence of additional chromosomal imbalances, as demonstrated by high-resolution chromosomal microarray analysis and confirmed by FISH, supports the hypothesis of an isolated intrachromosomal event rather than an unbalanced translocation inherited from a parental balanced rearrangement. Additionally, the integrity of the terminal end of chromosome 3 was confirmed by FISH using the subtelomeric probe D3S4560, which showed a normal signal pattern on both chromosomes 3, further excluding the possibility of an undetected parental cryptic translocation involving the 3q terminal region.

Furthermore, the tandem configuration confirmed by FISH showing consecutive signals for each probe (RP11-510K16+, RP11-110C15+, RP11-95L3+) provides additional insight into the underlying mutational mechanism. Examination of the genomic architecture at both breakpoint coordinates using the UCSC Genome Browser Segmental Duplications track (genomicSuperDups, GRCh37/hg19) revealed no segmental duplications within a 100 kb window flanking the proximal breakpoint (chr3:179,659,847). At the distal breakpoint (chr3:190,604,567), interchromosomal segmental duplications sharing homology with sequences on chromosomes 2, 19, and 3 were identified; however, these do not constitute the classical flanking intrachromosomal LCR architecture required for NAHR-mediated tandem duplication. The absence of flanking intrachromosomal LCRs at both breakpoints, combined with the non-recurrent and patient-specific nature of this rearrangement, strongly favors replication-based mechanisms, specifically FoSTeS or MMBIR, as the most plausible mutational mechanism underlying this duplication. The normal parental ages (28 and 32 years) fall within the normal reproductive range, suggesting that the duplication most likely arose as a sporadic mutational event during gametogenesis rather than as an age-associated chromosomal instability.

This report represents the first documented case of pure 3q duplication since Serra et al.’s comprehensive 2023 review [3]. Our findings refine the critical genomic region for 3q duplication syndrome, demonstrating that the duplication of the 3q26.33-q28 region contributes significantly to the core phenotype.

The phenotypic profile observed in our patient, including severe neurodevelopmental impairment, increased birth weight, and the absence of cardiac malformations, suggests region-specific effects within chromosome 3q. These observations support the hypothesis that distinct subregions of 3q differentially modulate growth, cardiac development, and neurological features, thereby improving genotype-phenotype correlations in pure 3q duplication syndrome.

The tandem configuration and de novo origin of the duplication, confirmed through integrated cytogenetic approaches, support an intrachromosomal replication-based mechanism, most consistent with FoSTeS or MMBIR, given the absence of flanking intrachromosomal low-copy repeats at both breakpoints. This case underscores the importance of combining conventional cytogenetics, FISH, and chromosomal microarray analysis for the accurate diagnosis of rare chromosomal disorders.

These findings contribute to refined genetic counseling for affected families and enhance our understanding of dosage-sensitive genes within the 3q region. Future studies integrating transcriptomic and functional analyses may further clarify the individual contributions of specific genes to the complex phenotype associated with 3q duplication syndrome.