Partial Monosomy 21q Due to De Novo t(15;21)(q26.3;q22.11): A Case Report with Clinical and Molecular Findings

Introduction

Chromosome 21 monosomy is a rare chromosomal disorder that may manifest as complete monosomy, mosaicism, or through translocations.^1,2 Partial deletion of the 21q region, contingent upon the size and location of the deleted segment, constitutes an exceedingly rare genetic condition characterized by a wide range of phenotypic presentations. Clinical features commonly associated with 21q deletion include growth retardation, intellectual disability, developmental delay, cerebral atrophy, neonatal seizures, microcephaly, clinodactyly, high or cleft palate, scoliosis, cardiac anomalies, and distinctive facial features such as epicanthal folds, a broad or depressed nasal bridge, and downward-slanting palpebral fissures.³ In numerous instances, individuals exhibiting a partial deletion of chromosome 21q also present with concomitant chromosomal abnormalities, such as translocations, deletions, or duplications involving other chromosomes.^1,4 Notably, deletions that impact the 21q22 region exert a more pronounced effect on the phenotype. Furthermore, it is essential to acknowledge that complete monosomy of chromosome 21 is incompatible with viability.⁵

Most research and case studies concerning partial deletions of chromosome 21q have primarily concentrated on the genetic and phenotypic manifestations of this chromosomal alteration. Developmental delays and intellectual disabilities are recognized as significant risk factors for the onset of psychiatric disorders.^6,7 Nevertheless, there exists a paucity of literature addressing the association between partial 21q deletions and psychiatric conditions. These conditions may encompass major depressive disorder, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder (ADHD), schizophrenia,⁸ psychotic episodes,⁹ and autism spectrum disorder (ASD).^10,11 In certain cases, behavioral issues such as hyperactivity, inattentiveness, oppositional behavior, and aggression have been documented even in the absence of a formal psychiatric diagnosis.^3,12 The majority of existing research has focused on deletions within a specific 31.2 Mb region (21q11.2-q22.11), which encompasses approximately 50 genes.^3,7,9,10

There is a scarcity of literature regarding the chromosome 15q26-qter deletion syndrome, commonly referred to as Drayer’s syndrome. This particular syndrome is marked by intrauterine growth restriction, varying levels of intellectual disability, postnatal growth failure, developmental delay, diaphragmatic hernia, and distinctive facial features,¹² but loss of 673 Kb of 15q26.3q26.3 is benign as per ACMG classification.¹³

A de novo event resulting in a pure deletion, an imbalanced translocation, or the formation of a ring chromosome 15 can contribute to the development of 15q26 monosomy. To date, 58 cases of pure deletion have been documented in the scientific literature. This chromosomal rearrangement impacts multiple sub-bands, encompassing numerous candidate genes associated with commonly observed symptoms such as pre- and postnatal growth retardation, developmental delay, and microcephaly. Furthermore, specific genes within this region are correlated with particular features, including congenital heart disease (CHD), skeletal abnormalities, diaphragmatic hernia,¹⁴ renal anomalies, and seizures. The variability in clinical presentations is influenced by differences in the locations of the breakpoints and the size of the deleted fragment.⁵

Patients with a deletion in the 15q26 region necessitate a comprehensive care protocol that incorporates an evaluation of their endocrine function, with particular attention given to the potential need for growth hormone therapy. Regular assessments in cardiology, orthopedics, and psychomotor functioning are imperative to support their overall health and well-being.Several structural rearrangements of chromosome 21, including deletions, duplications, and ring formations, have been reported with variable phenotypes such as growth retardation, intellectual disability, and multiple congenital anomalies. Recent molecular studies have further characterized these abnormalities and their genotype–phenotype correlations.^3,15–17 For instance, a case of de novo ring chromosome 21 associated with seizures, growth retardation, and congenital anomalies has been described, illustrating the clinical diversity of 21q aberrations (Molecular characterisation of de novo ring chromosome 21 in a child with seizures, growth retardation, and multiple congenital anomalies, 2020). The primary objective of this study was to report a rare de novo non-Robertsonian translocation involving chromosomes 15 and 21, while also emphasizing the critical importance of cytogenetic analysis in all clinically diagnosed cases with unexplained developmental delay or suspected chromosomal abnormalities.

Clinical Report

The informed consent form was signed by the proband or their parents. This form has received approval from the Ethics Committee of Ardabil University of Medical Sciences. The proband was a 36-year-old woman who was referred to our clinic for genetic testing due to a history of developmental delay, short stature, and distinct craniofacial features. At birth, she had a low birth weight, and developmental milestones were significantly delayed. Clinically, she exhibited intellectual disability, short stature, a thin cleft on the right side of the upper lip, thin upper and lower lips, a depressed nasal bridge, broad (blunt) nasal tip, and hyperplastic nasal alae, which had been surgically corrected. Other notable dysmorphic features included mildly slanted eyes, mild hypertelorism, down-slanting palpebral fissures, reduced zygomatic prominence, and multiple dental caries. Her head circumference at 37 years of age measured 55.5 cm, which was borderline microcephalic considering her short stature. There was no history of seizures or major congenital anomalies. Family history was negative for intellectual disability or birth defects (Figure 1).

Figure 1 Pedigree of the proband’s family. The filled symbol represents the affected individual. The proband (VI-1), indicated by an arrow, is the only affected individual, while both parents are unaffected, consistent with a de novo chromosomal abnormality.

Materials and Methods

The patient’s and her parents’ peripheral blood samples were cultured for the chromosome study, and their metaphases were analyzed according to the routine GTG-band technique with 400–500 bands resolution (30 cells).

We performed Fluorescence In-Situ Hybridization (FISH) on prepared buccal smear slides using locus-specific probes for 13q14.2/18q21.3/21q22.1–22.2 regions (Metasystems Probes GmbH, Germany) according to the manufacturer’s procedure, and prepared slide were incubated at 37 °C overnight (24 hours) in a hybridizer. Then, cells were counterstained with DAPI and chromosomal targets were evaluated under a fluorescence microscope (Zeiss) and the images were captured with MultiMedia Catalog FISH (MMC FISH) software.

Whole genome Oligo-Array comparative genomic hybridization (CGH) was carried out on the patient’s peripheral blood using the SurePrint G3 ISCA V2 8X60K whole genome Oligo-Array version 2 (Agilent Technologies Inc., CA) and was analyzed using Agilent Cytogenomic software v4.

Results

In the first stage, the patient’s karyotype displayed a female karyotype with numerical and structural chromosomal abnormalities in the long arm of chromosome 15 and the absence of one chromosome 21, which indicated the possibility of the existence of a translocation between the 15q and 21q. The anticipated karyotype was 45,XX,der(15)t(15;21)(q26.3;q22.11),-21 (seen in all 30 investigated cells) (Figure 2). On the other hand, the parent’s karyotypes were normal.

Figure 2 GTG-banded karyotype of the proband showing a female karyotype 45,XX,der(15)t(15;21)(q26.3;q22.11),-21. The arrow indicates the derivative chromosome 15 resulting from an unbalanced translocation between 15q26.3 and 21q22.11, leading to a partial monosomy of chromosome 21q.

Given the aforementioned finding, to confirm the presence of an unbalanced translocation rearrangement between chromosomes 15 and 21, we carried out two molecular cytogenetic tests: FISH and array CGH.

Comparative analysis by array CGH distinguished two partial terminal deletions on the long arms of chromosomes 15 and 21. The deletion of chromosome 15 is 673 Kb and is reported as arr[GRCh37] 15q26.3(101710679_102383473)x1. This region comprises 13 genes. On the other hand, chromosome 21 deletion is 17.32 Mb, the affected band is 21q11.2q22.11. Reported as arr[GRCh37] 21q11.2q22.11(15485008_32812809)x1. This region comprises 37 genes.

Based on the results of interphase FISH, 200 cells were evaluated. Hybridization of chromosome 21 with a DNA probe localized to 21q22.1–22.2 (corresponding to the loci D21565) revealed two signals (Figures 3 and 4). The presence of two signals in this region of the mutated chromosome showed that the deletion/unbalanced translocation is located downstream of the probe region, and we will need to do a new FISH test to confirm the array findings that a deletion/unbalanced translocation involves chr 21q11.2-q22.11. This apparent discrepancy between FISH and array CGH findings can be explained by the fact that the probe used in FISH (targeting 21q22.1–q22.2) lies outside the deleted region (21q11.2–q22.11), and thus the probe detects two intact copies in the non-deleted region. Consequently, the FISH result appears normal despite the presence of a proximal 21q deletion.

Figure 3 (A) Fluorescence in situ hybridization (FISH) analysis using triple-color probes targeting 13q14.2 (green), 18q21.3 (purple), and 21q22.1–22.2 (red). Two hybridization signals for each probe (2R, 2G, 2P) were observed in all 200 examined nuclei, indicating that the 21q22.1–22.2 region is intact. These findings suggest that the deletion or unbalanced translocation occurs proximal to this locus. The Overview of nuclei with scale bar (5 µm). (B) Enlarged view (zoom-in) of the in Figure 3A.

Figure 4 Bioinformatics analysis using (a) Array CGH profile of the proband showing a 17.32 Mb deletion at 21q11.2–q22.11 and a benign 673 MB deletion at 15q26.3. These findings confirm the presence of an unbalanced translocation involving chromosomes 15 and 21. (b) Franklin and (c) DECIPHER databases. Both analyses confirm a 17.32 Mb pathogenic deletion at 21q11.2–q22.11 and a benign 673 Kb deletion at 15q26.3, consistent with the array CGH findings.

Discussion

Partial monosomy 21 is a rare chromosomal disorder with an estimated prevalence of less than 1 in 1,000,000 individuals.¹⁴ Fewer than 50 patients with variable deletion breakpoints have been reported so far.¹⁵ The disorder exhibits a wide spectrum of clinical presentations ranging from mild developmental delay to severe or even lethal phenotypes.³ Such variability in the clinical outcome is primarily influenced by the size and location of the deleted chromosomal region, the genes involved, and additional modifying genetic or environmental factors.^3,16,17 Despite this heterogeneity, intellectual disability remains a consistent feature among most individuals with segmental monosomy 21.¹⁵ Growth retardation, craniofacial dysmorphism, and skeletal anomalies are also commonly reported.^3,18

In our case, the clinical manifestations — including intellectual disability, developmental delay, and craniofacial dysmorphic features — closely match those previously described in 21q deletion cases. The patient’s 17.32 Mb deletion at 21q11.2–q22.11 encompasses genes known to play crucial roles in neurodevelopment, confirming the pathogenicity of this region and its relevance to the observed phenotype.

The combination of cytogenetic and molecular analyses confirmed that this patient carries a novel unbalanced translocation involving chromosomes 15 and 21, resulting in partial monosomy 21q. In addition, a small 673 kb deletion at 15q26.3 was identified, which is classified as benign according to the American College of Medical Genetics and Genomics (ACMG).¹⁹ This finding indicates that the major clinical phenotype is primarily attributable to the 21q deletion, while the 15q loss does not contribute significantly to the patient’s symptoms.

Based on the ACMG classification, the 17.32 Mb deletion at 21q11.2–q22.11 is pathogenic and aligns with the typical partial deletion of this region. The phenotypic severity in our patient corresponds well with the model proposed by Lyle et al,¹⁸ who subdivided the long arm of chromosome 21 into three critical regions based on genotype–phenotype correlations. Deletions in region 1 (centromere to 31.2 Mb, including 21q22.11) are associated with severe developmental and neurological phenotypes; region 2 (31.2–36 Mb, 21q22.11–q22.12) leads to nonviable outcomes; and region 3 (36 Mb to qter, 21q22.12–qter) results in milder phenotypes.^3,18 Furthermore, Errichiello et al divided region 1 into two subregions, linking deletions in the first subregion (centromere to 21q21.1) with intellectual disability and those in the second (21q21.1–21q22.11) with neurobehavioral disorders such as obsessive-compulsive traits, social interaction deficits, and susceptibility to psychosis.²⁰ Our patient’s deletion overlaps with both subregions, explaining the observed cognitive and behavioral symptoms.

Genes located within this deleted interval are directly involved in neuronal development, synaptic connectivity, and structural brain organization. Among these, GRIK1 (21q21.3) encodes a glutamate receptor subunit essential for synaptic plasticity and has been linked to autism spectrum disorders, anxiety, and schizophrenia.²⁰ BTG3 (21q21.1) regulates neuronal differentiation and apoptosis, with deletions associated with language delay and neurodevelopmental disorders.²⁰ NCAM2 (21q21.1) encodes a neural cell adhesion molecule critical for axonal growth and synaptic stability; its loss has been implicated in autism and other neurobehavioral conditions.^10,21 Additionally, genes such as ADAMTS1 and JAM2 contribute to extracellular matrix remodeling and vascular integrity, potentially influencing brain and psychomotor development. Altogether, the deletion of these genes provides a plausible molecular explanation for the patient’s neurodevelopmental phenotype.

In addition to classical deletions, recent studies have identified various structural abnormalities involving chromosome 21, including ring chromosome 21 and unbalanced translocations, each associated with overlapping but distinct clinical manifestations. These findings emphasize the phenotypic diversity resulting from different breakpoints and the importance of high-resolution molecular characterization in each case.^22,23 Few comparable cases have been reported in the literature. Rethore et al described a similar proximal 21q deletion (18–20 Mb) with severe intellectual disability and craniofacial abnormalities.²⁴ Chettouh et al reported a 17.51 Mb deletion extending from 21q11.1 to 21q21, associated with mental retardation and dysmorphic features.²⁵ Similarly, Lyle et al documented a partial monosomy involving 21q21–qter with overlapping phenotypes.¹⁸ Compared with these cases, our patient exhibits a deletion of comparable size but at distinct breakpoints, representing a unique translocation event between 15q26.3 and 21q22.11.

To our knowledge, this is the first reported case from Iran involving a partial monosomy 21q due to an unbalanced translocation with chromosome 15q26.3. This report contributes new data to the limited global literature on proximal 21q deletions and strengthens the understanding of genotype–phenotype relationships in this region. Furthermore, it underscores the importance of integrated cytogenetic and molecular diagnostic approaches (karyotyping, FISH, and array CGH) in patients with unexplained developmental delay or intellectual disability, enabling accurate detection of complex chromosomal rearrangements and informed genetic counseling for affected families.

Conclusion

In conclusion, we report a rare case of partial monosomy 21q resulting from a de novo unbalanced translocation t(15;21)(q26.3;q22.11), accompanied by a benign 15q26.3 deletion. The patient’s clinical manifestations—intellectual disability, developmental delay, and distinctive craniofacial dysmorphism—are consistent with previously described 21q deletion phenotypes. This case supports the pathogenic significance of the 21q11.2–q22.11 region and the contribution of deleted genes such as GRIK1, BTG3, and NCAM2 to neurodevelopmental and behavioral outcomes.

Importantly, our findings emphasize the essential role of comprehensive cytogenetic and molecular analyses in diagnosing patients with suspected chromosomal abnormalities or unexplained intellectual disability/developmental delay, enabling accurate detection of complex rearrangements and more effective genetic counseling.